leptin has been researched along with Body-Weight* in 3640 studies
280 review(s) available for leptin and Body-Weight
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Effect of Liposuction on Body Weight and Serum Concentrations of Leptin, Lipids, Glucose, and Insulin: A Meta-Analysis.
Abdominal obesity has been associated with an increased risk of insulin resistance, metabolic syndrome, and diabetes. Central fat removal procedures such as liposuction, lipectomy, and abdominoplasty are among the most common surgical procedures. The impact of the latter on the former is controversial and understudied. The authors aimed to explore the effect of subcutaneous fat elimination procedures on insulin resistance measures and adipokine levels.. Relevant studies regarding the effects of surgical subcutaneous fat removal on glucose, insulin, adipokines, and lipid metabolism, as well as blood pressure, were identified by searching PubMed and Ovid-Cochrane without limits in date, type of publication, or language. After the selection process, 24 studies were obtained. The results of the articles were summarized using descriptive statistics. For the final analysis, a randomized effects model was used to evaluate heterogeneity; averages and meta-analytic differences were expressed with a confidence interval of 95%.. All studies reported a reduction in weight (-2.64 kg; 95% CI, -4.32 to -0.96; P = 0.002; I 2 = 36%; P of I 2 < 0.001) and body mass index after liposuction. A significant improvement in triglycerides (-10.06 mg/dL; 95% CI, -14.03 to -6.09; P < 0.001; I 2 = 48%; P of I 2 = 0.05), serum glucose concentration (-4.25 mg/dL; 95% CI, -5.93 to -2.56; P < 0.001; I 2 = 68%; P of I 2 < 0.001), serum insulin concentration (-2.86 μIU/mL; 95% CI, -3.75 to -1.97; P < 0.001; I 2 = 59%; P of I 2 = 0.003), and serum leptin concentration (-7.70 ng/mL; 95% CI, -11.49 to -3.92; P = 0.0001; I 2 = 96%; P of I 2 < 0.001) was consistently observed.. In addition to weight loss, there is a significant decrease in leptin, triglyceride, glucose, and insulin serum concentrations after liposuction, a fact that should be considered in future discussions. Topics: Blood Glucose; Body Mass Index; Body Weight; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Lipectomy; Lipids; Obesity | 2023 |
The dual hypothesis of homeostatic body weight regulation, including gravity-dependent and leptin-dependent actions.
Body weight is tightly regulated when outside the normal range. It has been proposed that there are individual-specific lower and upper intervention points for when the homeostatic regulation of body weight is initiated. The nature of the homeostatic mechanisms regulating body weight at the lower and upper ends of the body weight spectrum might differ. Previous studies demonstrate that leptin is the main regulator of body weight at the lower end of the body weight spectrum. We have proposed that land-living animals use gravity to regulate their body weight. We named this homeostatic system the Topics: Animals; Body Weight; Energy Metabolism; Homeostasis; Leptin; Mice; Obesity | 2023 |
Acupuncture at Sifeng (EX-UE 10) for pediatric anorexia: A systematic review and meta-analysis.
The purpose of this study was to assess the efficacy and safety of acupuncture at Sifeng for pediatric anorexia.. The randomized controlled trials (RCTs) of acupuncture at Sifeng for pediatric anorexia from their beginning to October 2022 were looked up in the seven databases. The Cochrane risk of bias evaluation tool was applied to the risk of bias analysis of the included studies. A meta-analysis of the total efficiency, score of food intake reduction, time to normalize food intake, body weight, leptin levels, and blood zinc levels was performed using Review Manager 5.3 software. The GRADE criteria were applied to assess the evidence's quality.. A total of 24 RCTs were included, involving 2202 children. The allocation of concealment, blinding, and selective reporting has a high or unclear risk of bias. All experiments compared acupuncture at Sifeng with traditional Chinese medicine or Western medicine. The results showed that, compared with medicine, acupuncture at Sifeng could significantly improve the total efficiency (OR=6.44, 95%CI [4.78,8.66]), lower the score of food intake reduction (MD=-0.69, 95%CI [-1.00, -0.39]), decrease leptin levels (MD=-5.19, 95%CI [-8.09, -2.29]) and time to normal food intake (MD=-2.22, 95%CI [-2.42, -2.01]), increase blood zinc (MD=0.79, 95%CI [0.21, 1.37]) and body weight (MD=1.28, 95%CI [0.85, 1.72]). Seven studies found that the treatment was safe both during and after. Based on the GRADE criteria, the quality of the evidence for the majority of indicators was extremely poor.. The low certainty of evidence suggested that acupuncture at Sifeng was effective and safe in the therapy of pediatric anorexia. Future high-quality clinical studies are needed to provide more reliable evidence of the effectiveness and safety of the therapy. Topics: Acupuncture Therapy; Anorexia; Body Weight; Child; Humans; Leptin; Zinc | 2023 |
Monogenic Obesity Syndromes Provide Insights Into the Hypothalamic Regulation of Appetite and Associated Behaviors.
Neuronal circuits within the hypothalamus play a critical role in the homeostatic regulation of body weight. By disrupting the development or function of these circuits, human monogenic disorders cause hyperphagia (increased food intake), neuroendocrine abnormalities, impaired sympathetic nervous system activation, and obesity. Some genetic disorders also cause maladaptive behaviors such as anxiety, autism, emotional lability, and aggression, highlighting the role of the specific molecules expressed by these hypothalamic neurons in the regulation of innate behaviors that are essential to survival. These findings inform understanding of a wide range of clinical disorders and highlight the challenges associated with targeting these hypothalamic pathways for weight loss therapy. Topics: Appetite; Body Weight; Humans; Hypothalamus; Leptin; Obesity; Syndrome | 2022 |
Leptin, the brain and energy homeostasis: From an apparently simple to a highly complex neuronal system.
Leptin, produced and secreted by white adipose tissue in tight relationship with adipose mass, informs the brain about the status of the energy stores serving as the main peripheral signal for energy balance regulation through interaction with a multitude of highly interconnected neuronal populations. Most obese patients display resistance to the anorectic effect of the hormone. The present review unravels the multiple levels of complexity that trigger hypothalamic response to leptin with the objective of highlighting those critical hubs that, mainly in the hypothalamic arcuate nucleus, may undergo obesity-induced alterations and create an obstacle to leptin action. Several mechanisms underlying leptin resistance have been proposed, possibly representing useful targets to empower leptin effects. Among these, a special focus is herein dedicated to detail how leptin gains access into the brain and how neuronal plasticity may interfere with leptin function. Topics: Body Weight; Brain; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Leptin | 2022 |
Tissue-Specific Effects of Leptin on Glucose and Lipid Metabolism.
The discovery of leptin was intrinsically associated with its ability to regulate body weight. However, the effects of leptin are more far-reaching and include profound glucose-lowering and anti-lipogenic effects, independent of leptin's regulation of body weight. Regulation of glucose metabolism by leptin is mediated both centrally and via peripheral tissues and is influenced by the activation status of insulin signaling pathways. Ectopic fat accumulation is diminished by both central and peripheral leptin, an effect that is beneficial in obesity-associated disorders. The magnitude of leptin action depends upon the tissue, sex, and context being examined. Peripheral tissues that are of particular relevance include the endocrine pancreas, liver, skeletal muscle, adipose tissues, immune cells, and the cardiovascular system. As a result of its potent metabolic activity, leptin is used to control hyperglycemia in patients with lipodystrophy and is being explored as an adjunct to insulin in patients with type 1 diabetes. To fully understand the role of leptin in physiology and to maximize its therapeutic potential, the mechanisms of leptin action in these tissues needs to be further explored. Topics: Animals; Body Weight; Glucose; Humans; Insulin; Leptin; Lipid Metabolism; Organ Specificity | 2021 |
Prenatal stress and later metabolic consequences: Systematic review and meta-analysis in rodents.
Numerous rodent studies have evaluated the effects of maternal stress (MS) on later in life susceptibility to Metabolic Syndrome (MetS) intermediate phenotypes with varying results. The aim of this study was to quantitatively synthesize the available data on the effects of MS on offspring obesity, estimated indirectly by body mass (BM), body fat (BF) and plasma leptin; systolic blood pressure (SBP); plasma glucose (and insulin) and blood lipid concentrations.. Literature was screened and summary estimates of the effect of MS outcomes were calculated by using random-effects models. Data on the effects of exogenous corticosteroid administration (or inhibition of 11β-HSD2) during pregnancy in rodents was analysed separately to characterize the direct phenotypic effects of prenatal corticosteroid excess (PCE).. We conducted 14 separate meta-analyses and synthesized relevant data on outcomes scarcely reported in literature. Both MS and PCE were associated with low birth weight without rapid catch-up growth resulting in decreased body mass later in life. Our analysis also revealed significant and contradictory effects on offspring adiposity. Little evidence was found for effects on glucose metabolism and blood lipids. We identified increased SBP in offspring exposed to PCE; however, there is not enough data to draw any conclusion about effects of MS on SBP.. Neonatal weight proved to be decreased in offspring prenatally exposed to stress or corticosteroids, but laboratory rodents in the absence of a challenging environment did not show catch-up growth. The available evidence is inconclusive regarding the effect on adiposity revealing clear methodological and knowledge gaps. This meta-analysis also confirmed a significant positive association between PCE and SBP. Nevertheless, additional studies should address the association with MS. Topics: Adipose Tissue; Adiposity; Animals; Birth Weight; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Female; Insulin; Leptin; Lipids; Metabolic Syndrome; Mice; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Risk Factors; Rodentia; Stress, Psychological; Triglycerides | 2020 |
Sleep Apnea, Obesity, and Disturbed Glucose Homeostasis: Epidemiologic Evidence, Biologic Insights, and Therapeutic Strategies.
Obstructive sleep apnea (OSA), obesity, and disturbed glucose homeostasis are usually considered distinct clinical condition, although they are tightly related to each other. The aim of our manuscript is to provide an overview of the current evidence on OSA, obesity, and disturbed glucose homeostasis providing epidemiologic evidence, biological insights, and therapeutic strategies.. The mechanisms hypothesized to be involved in this complex interplay are the following: (1) "direct weight-dependent" mechanisms, according to which fat excess compromises respiratory mechanics, and (2) "indirect weight-dependent" mechanisms such as hyperglycemia, insulin resistance and secondary hyperinsulinemia, leptin resistance and other hormonal dysregulations frequently found in subjects with obesity, type 2 diabetes, and/or sleep disorders. Moreover, the treatment of each of these clinical conditions, through weight loss induced by diet or bariatric surgery, the use of anti-obesity or antidiabetic drugs, and continuous positive airway pressure (CPAP), seems to positively influence the others. These recent data suggest not only that there are multiple connections among these diseases but also that treating one of them may result in an improvement of the others. Topics: Bariatric Surgery; Body Weight; Continuous Positive Airway Pressure; Diabetes Mellitus, Type 2; Diet; Glucose; Homeostasis; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Obesity; Risk Factors; Sleep Apnea, Obstructive; Weight Loss | 2020 |
Temporal Leptin to Determine Cardiovascular and Metabolic Fate throughout the Life.
Leptin links peripheral adiposity and the central nervous system (CNS) to regulate cardiometabolic physiology. Within the CNS, leptin receptor-expressing cells are a counterpart to circulating leptin, and leptin receptor-mediated neural networks modulate the output of neuroendocrine and sympathetic nervous activity to balance cardiometabolic homeostasis. Therefore, disrupted CNS leptin signaling is directly implicated in the development of metabolic diseases, such as hypertension, obesity, and type 2 diabetes. Independently, maternal leptin also plays a central role in the development and growth of the infant during gestation. Accumulating evidence points to the dynamic maternal leptin environment as a predictor of cardiometabolic fate in their offspring as it is directly associated with infant metabolic parameters at birth. In postnatal life, the degree of serum leptin is representative of the level of body adiposity/weight, a driving factor for cardiometabolic alterations, and therefore, the levels of blood leptin through the CNS mechanism, in a large part, are a strong determinant for future cardiometabolic fate. The current review focuses on highlighting and discussing recent updates for temporal dissection of leptin-associated programing of future cardiometabolic fate throughout the entire life. Topics: Adiposity; Body Weight; Cardiometabolic Risk Factors; Cardiovascular System; Central Nervous System; Female; Humans; Leptin; Longevity; Male; Maternal Nutritional Physiological Phenomena; Pregnancy; Receptors, Leptin; Signal Transduction; Temporal Lobe | 2020 |
Programming of Cardiovascular Dysfunction by Postnatal Overfeeding in Rodents.
Nutritional environment in the perinatal period has a great influence on health and diseases in adulthood. In rodents, litter size reduction reproduces the effects of postnatal overnutrition in infants and reveals that postnatal overfeeding (PNOF) not only permanently increases body weight but also affects the cardiovascular function in the short- and long-term. In addition to increased adiposity, the metabolic status of PNOF rodents is altered, with increased plasma insulin and leptin levels, associated with resistance to these hormones, changed profiles and levels of circulating lipids. PNOF animals present elevated arterial blood pressure with altered vascular responsiveness to vasoactive substances. The hearts of overfed rodents exhibit hypertrophy and elevated collagen content. PNOF also induces a disturbance of cardiac mitochondrial respiration and produces an imbalance between oxidants and antioxidants. A modification of the expression of crucial genes and epigenetic alterations is reported in hearts of PNOF animals. In vivo, a decreased ventricular contractile function is observed during adulthood in PNOF hearts. All these alterations ultimately lead to an increased sensitivity to cardiac pathologic challenges such as ischemia-reperfusion injury. Nevertheless, caloric restriction and physical exercise were shown to improve PNOF-induced cardiac dysfunction and metabolic abnormalities, drawing a path to the potential therapeutic correction of early nutritional programming. Topics: Adiposity; Animals; Body Weight; Female; Heart; Insulin; Leptin; Litter Size; Male; Obesity; Overnutrition; Pregnancy; Rats, Sprague-Dawley; Rats, Wistar | 2020 |
Foraging theory and the propensity to be obese: an alternative to thrift.
The evolutionary origin of obesity is classically believed to be genetic or developmentally induced thrift, as an adaptation to ancestral feast and famine conditions. However, recently the thrift family of hypotheses have attracted serious criticism necessitating alternative thinking. Optimization of foraging behaviour is an important aspect of behavioural evolution. For a species evolved for optimizing nutritional benefits against predation or other foraging risks, reduction in foraging risk below a threshold dramatically increases the steady-state body weight. In modern life where feeding is detached from foraging, the behavioural regulation mechanisms are likely to fail resulting into escalation of adiposity. At a proximate level the signalling pathways for foraging optimization involve fear induced signal molecules in the brain including Cocaine and Amphetamine Regulated Transcript (CART) interacting with adiposity signals such as leptin. While leptin promotes the expression of the fear peptides, the fear peptides promote anorectic action of leptin. This interaction promotes foraging drive and risk tolerance when the stored energy is low and suppresses hunger and foraging drive when the perceived risk is high. The ecological model of foraging optimization and the molecular model of interaction of these peptides converge in the outcome that the steady state adiposity is an inverse square root function of foraging risk. The foraging optimization model is independent of thrift or insurance hypotheses, but not mutually exclusive. We review existing evidence and suggest testable predictions of the model. Understanding obesity simultaneously at proximate and ultimate levels is likely to suggest effective means to curb the obesity epidemic. Topics: Anthropology, Physical; Anxiety; Appetitive Behavior; Biological Evolution; Body Weight; Fear; Humans; Leptin; Metabolism; Models, Biological; Obesity | 2019 |
GEOFFREY HARRIS PRIZE LECTURE 2018: Novel pathways regulating neuroendocrine function, energy homeostasis and metabolism in humans.
The discovery of leptin, an adipocyte-secreted hormone, set the stage for unraveling the mechanisms dictating energy homeostasis, revealing adipose tissue as an endocrine system that regulates appetite and body weight. Fluctuating leptin levels provide molecular signals to the brain regarding available energy reserves modulating energy homeostasis and neuroendocrine response in states of leptin deficiency and to a lesser extent in hyperleptinemic states. While leptin replacement therapy fails to provide substantial benefit in common obesity, it is an effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy. Current evidence suggests that regulation of eating behavior in humans is not limited to homeostatic mechanisms and that the reward, attention, memory and emotion systems are involved, participating in a complex central nervous system network. It is critical to study these systems for the treatment of typical obesity. Although progress has been made, further studies are required to unravel the physiology, pathophysiology and neurobehavioral mechanisms underlying potential treatments for weight-related problems in humans. Topics: Adipose Tissue; Body Weight; Brain; Energy Metabolism; Homeostasis; Humans; Leptin; Neurosecretory Systems; Obesity | 2019 |
Leptin resensitisation: a reversion of leptin-resistant states.
Leptin resistance refers to states in which leptin fails to promote its anticipated effects, frequently coexisting with hyperleptinaemia. Leptin resistance is closely associated with obesity and also observed in physiological situations such as pregnancy and in seasonal animals. Leptin resensitisation refers to the reversion of leptin-resistant states and is associated with improvement in endocrine and metabolic disturbances commonly observed in obesity and a sustained decrease of plasma leptin levels, possibly below a critical threshold level. In obesity, leptin resensitisation can be achieved with treatments that reduce body adiposity and leptinaemia, or with some pharmacological compounds, while physiological leptin resistance reverts spontaneously. The restoration of leptin sensitivity could be a useful strategy to treat obesity, maintain weight loss and/or reduce the recidivism rate for weight regain after dieting. This review provides an update and discussion about reversion of leptin-resistant states and modulation of the molecular mechanisms involved in each situation. Topics: Adiposity; Animals; Blood Pressure; Body Weight; Diet; Eating; Energy Intake; Female; Fertility; Humans; Hyperglycemia; Leptin; Male; Mice; Obesity; Phosphorylation; Photoperiod; Pregnancy; Pregnancy, Animal; Signal Transduction; Thermogenesis; Weight Loss | 2019 |
Leptin, An Adipokine With Central Importance in the Global Obesity Problem.
Leptin has central importance in the global obesity and cardiovascular disease problem. Leptin is principally secreted by adipocytes and acts in the hypothalamus to suppress appetite and food intake, increase energy expenditure, and regulate body weight. Based on clinical translation of specific and networked actions, leptin affects the cardiovascular system and may be a marker and driver of cardiometabolic risk factors with interventions that are actionable by cardiologists. Leptin subnetwork analysis demonstrates a statistically significant role for ethnoculturally and socioeconomically appropriate lifestyle intervention in cardiovascular disease. Emergent mechanistic components and potential diagnostic or therapeutic targets include hexokinase 3, urocortins, clusterin, sialic acid-binding immunoglobulin-like lectin 6, C-reactive protein, platelet glycoprotein VI, albumin, pentraxin 3, ghrelin, obestatin prepropeptide, leptin receptor, neuropeptide Y, and corticotropin-releasing factor receptor 1. Emergent associated symptoms include weight change, eating disorders, vascular necrosis, chronic fatigue, and chest pain. Leptin-targeted therapies are reported for lipodystrophy and leptin deficiency, but they are investigational for leptin resistance, obesity, and other chronic diseases. Topics: Adipokines; Biomarkers; Body Weight; Energy Metabolism; Global Health; Humans; Leptin; Morbidity; Obesity | 2018 |
Leptin and the maintenance of elevated body weight.
Obesity represents the single most important risk factor for early disability and death in developed societies, and the incidence of obesity remains at staggering levels. CNS systems that modulate energy intake and expenditure in response to changes in body energy stores serve to maintain constant body adiposity; the adipocyte-derived hormone leptin and its receptor (LEPR) represent crucial regulators of these systems. As in the case of insulin resistance, a variety of mechanisms (including feedback inhibition, inflammation, gliosis and endoplasmic reticulum stress) have been proposed to interfere with leptin action and impede the systems that control body energy homeostasis to promote or maintain obesity, although the relative importance and contribution of each of these remain unclear. However, LEPR signalling may be increased (rather than impaired) in common obesity, suggesting that any obesity-associated defects in leptin action must result from lesions somewhere other than the initial LEPR signal. It is also possible that increased LEPR signalling could mediate some of the obesity-associated changes in hypothalamic function. Topics: Animals; Body Weight; Energy Metabolism; Homeostasis; Humans; Leptin; Obesity; Receptors, Leptin; Signal Transduction | 2018 |
Breastfeeding, Breast Milk Composition, and Growth Outcomes.
Breastfed infants have a growth pattern that is different from formula-fed infants, which is regarded as the optimal growth pattern. Breastfed infants increase more in weight, length, and BMI during the first 2-3 months of life and then have a slower growth velocity up to 12 months. They also have a higher accumulation of fat during early infancy. Breastfed infants have lower levels of circulating IGF-I and insulin, which could be part of the explanation of their growth pattern. Many studies and meta-analyses have examined the association between breastfeeding and later obesity. Most find a moderate reduction in the risk of later obesity, but it has been argued that this could be biased due to residual confounding and reverse causation. From studies in low- and middle-income countries randomizing women to breastfeeding promotion, there was only little effect on early growth. Recent studies have found associations between breast milk composition (total fat, protein, human milk oligosaccharides, adiponectin, leptin, and insulin) and growth. However, the studies are few, and the results are inconsistent. More studies, including studies of maternal factors influencing breast milk composition, are needed to better understand how breastfeeding influences current and later growth and thereby short- and long-term health. Topics: Adiponectin; Body Composition; Body Height; Body Mass Index; Body Weight; Breast Feeding; Child; Child, Preschool; Fats; Female; Humans; Infant; Infant Formula; Infant Nutritional Physiological Phenomena; Infant, Newborn; Insulin; Insulin-Like Growth Factor I; Leptin; Milk Proteins; Milk, Human; Obesity; Oligosaccharides; Poverty; Somatomedins; Weight Gain | 2018 |
Pharmacological Effects and Regulatory Mechanisms of Tobacco Smoking Effects on Food Intake and Weight Control.
Beyond promoting smoking initiation and preventing smokers from quitting, nicotine can reduce food intake and body weight and thus is viewed as desirable by some smokers, especially many women. During the last several decades, the molecular mechanisms underlying the inverse correlation between smoking and body weight have been investigated extensively in both animals and humans. Nicotine's weight effects appear to result especially from the drug's stimulation of α3β4 nicotine acetylcholine receptors (nAChRs), which are located on pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC), leading to activation of the melanocortin circuit, which is associated with body weight. Further, α7- and α4β2-containing nAChRs have been implicated in weight control by nicotine. This review summarizes current understanding of the regulatory effects of nicotine on food intake and body weight according to the findings from pharmacological, molecular genetic, electrophysiological, and feeding studies on these appetite-regulating molecules, such as α3β4, α7, and α4β2 nAChRs; neuropeptide Y (NPY); POMC; melanocortin 4 receptor (MC4R); agouti-related peptide (AgRP); leptin, ghrelin, and protein YY (PYY). Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Humans; Leptin; Neuropeptide Y; Nicotine; Receptors, Nicotinic; Tobacco Smoking | 2018 |
Leptin as a breast milk component for the prevention of obesity.
Leptin ingested as a component of breast milk is increasingly recognized to play a role in the postnatal programming of a healthy phenotype in adulthood. Besides its primary function in controlling body weight, leptin may be an essential nutrient required during lactation to ensure that the system controlling fat accumulation and body composition is well organized from the early stages of development. This review delves into the following topics: (1) the imprinted protective function of adequate leptin intake during lactation in future metabolic health; (2) the consequences of a lack of leptin intake or of alterations in leptin levels; and (3) the mechanisms described for the effects of leptin on postnatal programming. Furthermore, it highlights the importance of breastfeeding and the need to establish optimal or reference intake values for leptin during lactation to design patterns of personalized nutrition from early childhood. Topics: Adipose Tissue; Adult; Body Composition; Body Weight; Breast Feeding; Child; Diet; Eating; Female; Humans; Lactation; Leptin; Milk, Human; Obesity | 2018 |
The Association between High Fat Diet around Gestation and Metabolic Syndrome-related Phenotypes in Rats: A Systematic Review and Meta-Analysis.
Numerous rodent studies have evaluated the effects of a maternal high-fat diet (HFD) on later in life susceptibility to Metabolic Syndrome (MetS) with varying results. Our aim was to quantitatively synthesize the available data on effects of maternal HFD around gestation on offspring's body mass, body fat, plasma leptin, glucose, insulin, lipids and systolic blood pressure (SBP). Literature was screened and summary estimates of the effect of maternal HFD on outcomes were calculated by using fixed- or random-effects models. 362 effect sizes from 68 studies together with relevant moderators were collected. We found that maternal HFD is statistically associated with higher body fat, body weight, leptin, glucose, insulin and triglycerides levels, together with increased SBP in offspring later in life. Our analysis also revealed non-significant overall effect on offspring's HDL-cholesterol. A main source of variation among studies emerged from rat strain and lard-based diet type. Strain and sex -specific effects on particular data subsets were detected. Recommendations are suggested for future research in the field of developmental programming of the MetS. Despite significant heterogeneity, our meta-analysis confirms that maternal HFD had long-term metabolic effects in offspring. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Female; Insulin; Leptin; Male; Metabolic Syndrome; Phenotype; Pregnancy; Publication Bias; Rats, Sprague-Dawley; Rats, Wistar; Triglycerides | 2017 |
Neuroendocrinology of Adipose Tissue and Gut-Brain Axis.
Food intake and energy expenditure are closely regulated by several mechanisms which involve peripheral organs and nervous system, in order to maintain energy homeostasis.Short-term and long-term signals express the size and composition of ingested nutrients and the amount of body fat, respectively. Ingested nutrients trigger mechanical forces and gastrointestinal peptide secretion which provide signals to the brain through neuronal and endocrine pathways. Pancreatic hormones also play a role in energy balance exerting a short-acting control regulating the start, end, and composition of a meal. In addition, insulin and leptin derived from adipose tissue are involved in long-acting adiposity signals and regulate body weigh as well as the amount of energy stored as fat over time.This chapter focuses on the gastrointestinal-, pancreatic-, and adipose tissue-derived signals which are integrated in selective orexigenic and anorexigenic brain areas that, in turn, regulate food intake, energy expenditure, and peripheral metabolism. Topics: Adipose Tissue; Adiposity; Appetite Regulation; Body Weight; Brain; Eating; Energy Intake; Energy Metabolism; Gastrointestinal Hormones; Gastrointestinal Tract; Humans; Insulin; Insulin-Secreting Cells; Leptin; Obesity; Pancreas; Pancreatic Hormones | 2017 |
Effect of Sibutramine on Plasma C-Reactive Protein, Leptin and Adipon ectin Concentrations: A Systematic Review and Meta-Analysis of Randomized Contr olled Trials.
Sibutramine is an anti-obesity medication whose effects on weight loss have been widely explored. Moreover, limited number of studies also evidenced its correlates on adipokines and proinflammatory markers; however, their results have not been conclusive. Hence, a systematic review and meta-analysis of available evidence was conducted in order to calculate the effect size of sibutramine therapy on C-reactive protein (CRP), leptin and adiponectin concentrations. Seven randomized clinical trials with a total of 601 subjects met the eligibility criteria. Random effect meta-analysis evidenced a significant decrease in plasma levels of CRP and leptin (weighted mean difference [WMD] -15.58%, 95% confidence interval [95%CI]: -28.84, -2.33, p=0.021 and WMD -9.25, 95%CI: -15.73, -2.78, p=0.005, respectively) and increase of adiponectin (WMD 9.86%, 95%CI: 1.76, 17.96, p=0.017) following sibutramine therapy. Subgroup analysis showed a greater CRP-lowering effect of sibutramine with doses <15 mg/day (WMD -17.26%, 95%CI: -31.02, -3.5, p=0.014) compared with doses .15 mg/day (WMD 6.01%, 95%CI: -43.38, 55.40, p=0.811). In meta-regression analysis, changes in CRP were found to be independent of baseline or percentage change in body mass index. These results suggest a significant improvement of plasma CRP, leptin and adiponectin levels following treatment with sibutramine. Possible impacts and relevance of these alterations on cardiovascular risk profile remain to be clarified, especially in post-hoc analyses of sibutramine outcome trials among people without pre-existing cardiovascular disease. Topics: Adiponectin; Anti-Obesity Agents; Body Mass Index; Body Weight; C-Reactive Protein; Cyclobutanes; Humans; Leptin; Randomized Controlled Trials as Topic | 2017 |
Putative Effects of Obesity on Linear Growth and Puberty
.
Childhood obesity is a major public health problem that has grown to epidemic proportions throughout the world. Obesity is influenced by genetic and environmental factors. The nutritional status plays an important role in growth and body weight regulation. Excess adiposity during childhood can affect the process of growth and puberty. Obese children are frequently tall for their age, with accelerated epiphyseal growth plate maturation despite low growth hormone levels. Several regulatory hormones may affect the process of linear growth in the constellation of obesity, as high levels of insulin and leptin are observed in obese children. Leptin can act as a skeletal growth factor, with a direct effect on skeletal growth centers. The finding that overweight children, especially girls, tend to mature earlier than lean children has led to the hypothesis that the degree of body fatness may trigger the neuroendocrine events that lead to the onset of puberty. Leptin receptors have been identified in the hypothalamus, as well as in gonadotrope cells, ovarian follicular cells, and Leydig cells. The increased leptin and androgen levels seen in obese children may be implicated in their earlier onset of puberty and accelerated pubertal growth. This review is focused on the interaction between childhood obesity and growth and pubertal processes. . Topics: Adiposity; Adolescent; Adolescent Development; Androgens; Body Height; Body Weight; Child; Child Development; Humans; Leptin; Obesity; Puberty | 2017 |
Improvement of plasma adiponectin, leptin and C-reactive protein concentrations by orlistat: a systematic review and meta-analysis.
To conduct a systematic review and meta-analysis of relevant randomized clinical trials (RCTs) to ascertain the effect size of orlistat in modulating plasma levels of adipokines, ghrelin and C-reactive protein (CRP).. Medline, SCOPUS, Web of Science and Google Scholar databases were searched. A random-effects model and the generic inverse variance method were used for quantitative data synthesis. Heterogeneity was quantitatively assessed using I(2) index. Sensitivity analyses were conducted using the one-study remove approach. Random-effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the impact of duration of treatment, percentage change in body mass index (BMI) and baseline BMI values as potential confounders of the estimated effect size.. Meta-analysis suggested a significant increase in plasma levels of adiponectin [weighted mean difference (WMD): 19.18%, 95% confidence interval (CI): 5.80, 32.57, p = 0.005] and significant reductions in plasma levels of leptin (WMD: -13.24%, 95% CI: -20.69, -5.78, p = 0.001) and CRP (WMD: -11.52%, 95% CI: -16.55, -6.49, p < 0.001) following treatment with orlistat. In meta-regression, changes in plasma concentrations of adiponectin, leptin and CRP were associated with duration of treatment, but not with either change in BMI or baseline BMI values.. Orlistat is effective in increasing plasma concentrations of adiponectin and decreasing those of leptin and CRP. Topics: Adiponectin; Anti-Obesity Agents; Body Weight; C-Reactive Protein; Ghrelin; Humans; Lactones; Leptin; Metabolic Syndrome; Orlistat; Randomized Controlled Trials as Topic | 2016 |
New therapeutic approaches for the treatment of obesity.
This review discusses current and future pharmacological approaches to the treatment of obesity, with a focus on the biological control of energy balance. Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Bile Acids and Salts; Body Weight; Diabetes Mellitus, Type 2; Drug Discovery; Energy Metabolism; Feeding Behavior; Homeostasis; Humans; Hypothalamus; Inflammation; Leptin; Obesity; Oxidative Phosphorylation; Pediatric Obesity | 2016 |
Making sense of the sensory regulation of hunger neurons.
AgRP and POMC neurons are two key cell types that regulate feeding in response to hormones and nutrients. Recently, it was discovered that these neurons are also rapidly modulated by the mere sight and smell of food. This rapid sensory regulation "resets" the activity of AgRP and POMC neurons before a single bite of food has been consumed. This surprising and counterintuitive discovery challenges longstanding assumptions about the function and regulation of these cells. Here we review these recent findings and discuss their implications for our understanding of feeding behavior. We propose several alternative hypotheses for how these new observations might be integrated into a revised model of the feeding circuit, and also highlight some of the key questions that remain to be answered. Topics: Agouti-Related Protein; Animals; Anticipation, Psychological; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Energy Metabolism; Feedback, Physiological; Gene Expression Regulation; Ghrelin; Homeostasis; Humans; Hunger; Hypothalamus; Leptin; Neurons; Pro-Opiomelanocortin; Satiation | 2016 |
Renaissance of leptin for obesity therapy.
Diet-induced obesity and its metabolic comorbidities constitute an overwhelming health crisis and there is an urgent need for safe and effective pharmacological interventions. Being largely shelved for decades, scientists are now revisiting the anti-obesity virtues of leptin. Whereas it remains evident that leptin as a stand-alone therapy is not an effective approach, the potential for employing sensitising pharmacology to unleash the weight-lowering properties of leptin has injected new hope into the field. Fascinatingly, these leptin-sensitising agents seem to act via distinct metabolic pathways and may thus, in parallel with their clinical development, serve as important research tools to progress our understanding of the molecular, physiological and behavioural pathways underlying energy homeostasis and obesity pathophysiology. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3 , and by Gerald Shulman and colleagues, DOI: 10.1007/s00125-016-3909-4 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ). Topics: Animals; Body Weight; Energy Metabolism; Homeostasis; Humans; Leptin; Obesity; Signal Transduction | 2016 |
Leptin Dysfunction and Alzheimer's Disease: Evidence from Cellular, Animal, and Human Studies.
There is accumulating evidence from epidemiological studies that changes in body weight are associated with Alzheimer's disease (AD) from mid-life obesity increasing the risk of developing AD to weight loss occurring at the earliest stages of AD. Therefore, factors that regulate body weight are likely to influence the development and progression of AD. The adipocyte-derived hormone leptin has emerged as a major regulator of body weight mainly by activating hypothalamic neural circuits. Leptin also has several pleotropic effects including regulating cognitive function and having neuroprotective effects, suggesting a potential link between leptin and AD. Here, we will examine the relationship between leptin and AD by reviewing the recent evidence from cellular and animal models to human studies. We present a model where leptin has a bidirectional role in AD. Not only can alterations in leptin levels and function worsen cognitive decline and progression of AD pathology, but AD pathology, in of itself, can disrupt leptin signaling, which together would lead to a downward spiral of progressive neurodegeneration and worsening body weight and systemic metabolic deficits. Collectively, these studies serve as a framework to highlight the importance of understanding the molecular mechanisms underlying the body weight and systemic metabolic deficits in AD, which has the potential to open new avenues that may ultimately lead to novel therapeutic targets and diagnostic tools. Topics: Alzheimer Disease; Animals; Body Weight; Disease Models, Animal; Humans; Leptin; Neuroprotective Agents; Translational Research, Biomedical | 2016 |
Does omega-3 fatty acids supplementation affect circulating leptin levels? A systematic review and meta-analysis on randomized controlled clinical trials.
Omega-3 fatty acids have attracted researchers for their effect on circulatory hormone-like peptides affecting weight control.. Our objective was to conduct a systematic review and meta-analysis on randomized controlled trials (RCTs) assessed the effects of omega-3 supplementation on serum leptin concentration and to find the possible sources of heterogeneity in their results.. We searched PubMed/Medline, Google Scholar, Ovid, SCOPUS and ISI web of science up to April 2014. RCTs conducted among human adults, examined the effect of omega-3 fatty acid supplements on serum leptin concentrations as an outcome variable were included. The mean difference and standard deviation (SD) of changes in serum leptin levels were used as effect size for the meta-analysis. Summary mean estimates with their corresponding SDs were derived using random effects model.. Totally 14 RCTs were eligible to be included in the systematic review, and the meta-analysis was performed on 13 articles. Our analysis showed that omega-3 supplementation significantly reduces leptin levels (mean difference (MD) = -1·71 ng/ml 95% confidence interval (CI): -3·17 to -0·24, P = 0·022). Subgroup analysis based on BMI status showed that the omega-3 supplementation reduces leptin when used for nonobese subjects (MD = -3·60 ng/ml; 95% CI -6·23 to -0·90; P = 0·011); however, this was not true for obese participants (MD = -0·86 ng/ml; 95% CI: -2·63 to -0·90; P = 0·296). Subgroup analysis based on omega-3 source also showed that omega-3 from marine sources may significantly reduce leptin levels (MD = -1·73 ng/ml; 95% CI -3·25 to -0·2; P = 0·026), but plant sources do not significantly affect serum leptin levels (MD = -1·48 ng/ml; 95% CI -6·78 to 3·23; P = 0·585). Our results were highly sensitive to one study.. Omega-3 supplementation might moderately decrease circulatory leptin levels only among nonobese adults. RCTs with longer follow-up period, using higher doses for obese adults and exploring the effect in different genders, are needed to replicate our results. Topics: Adult; Aged; Body Weight; Dietary Supplements; Fatty Acids, Omega-3; Female; Humans; Leptin; Male; Middle Aged; Randomized Controlled Trials as Topic | 2015 |
Leptin treatment: facts and expectations.
Leptin has key roles in the regulation of energy balance, body weight, metabolism, and endocrine function. Leptin levels are undetectable or very low in patients with lipodystrophy, hypothalamic amenorrhea, and congenital leptin deficiency (CLD) due to mutations in the leptin gene. For these patients, leptin replacement therapy with metreleptin (a recombinant leptin analog) has improved or normalized most of their phenotypes, including normalization of endocrine axes, decrease in insulin resistance, and improvement of lipid profile and hepatic steatosis. Remarkable weight loss has been observed in patients with CLD. Due to its effects, leptin therapy has also been evaluated in conditions where leptin levels are normal or high, such as common obesity, diabetes (types 1 and 2), and Rabson-Mendenhall syndrome. A better understanding of the physiological roles of leptin may lead to the development of leptin-based therapies for other prevalent disorders such as obesity-associated nonalcoholic fatty liver disease, depression and dementia. Topics: Animals; Body Weight; Energy Metabolism; Hormone Replacement Therapy; Humans; Leptin | 2015 |
Leptin resistance and diet-induced obesity: central and peripheral actions of leptin.
Obesity is a chronic disease that represents one of the most serious global health burdens associated to an excess of body fat resulting from an imbalance between energy intake and expenditure, which is regulated by environmental and genetic interactions. The adipose-derived hormone leptin acts via a specific receptor in the brain to regulate energy balance and body weight, although this protein can also elicit a myriad of actions in peripheral tissues. Obese individuals, rather than be leptin deficient, have in most cases, high levels of circulating leptin. The failure of these high levels to control body weight suggests the presence of a resistance process to the hormone that could be partly responsible of disturbances on body weight regulation. Furthermore, leptin resistance can impair physiological peripheral functions of leptin such as lipid and carbohydrate metabolism and nutrient intestinal utilization. The present document summarizes those findings regarding leptin resistance development and the role of this hormone in the development and maintenance of an obese state. Thus, we focused on the effect of the impaired leptin action on adipose tissue, liver, skeletal muscle and intestinal function and the accompanying relationships with diet-induced obesity. The involvement of some inflammatory mediators implicated in the development of obesity and their roles in leptin resistance development are also discussed. Topics: Animals; Body Weight; Central Nervous System; Diet; Humans; Leptin; Obesity; Peripheral Nervous System | 2015 |
Effect of overweight/obesity on response to periodontal treatment: systematic review and a meta-analysis.
The objective of this study was to investigate whether the response to periodontal treatment differs among obese, overweight or normal-weight patients.. Both randomized and non-randomized studies were identified from searches up to July 2013. Risk of bias was assessed with the Downs-Black checklist, the Cochrane tool and the GRADE framework. Quantitative synthesis was conducted with random-effects meta-analyses in subgroups for systemically healthy and diabetic patients.. A total of 15 studies including 867 patients were included. No significant difference was found for any clinical periodontal parameter between overweight/obese and normal-weight patients. Periodontal treatment in systemically healthy overweight/obese patients was associated with higher decrease in TNFα levels (1 study) and higher decrease in HbA1c levels (1 study) compared to systemically healthy normal-weight patients. Contrary to diabetic normal-weight patients, periodontal treatment in diabetic overweight/obese patients was associated with an increase in adiponectin levels (2 studies) and a decrease in leptin levels (2 studies). However, the quality of existing evidence is low due to inconsistency, imprecision and lack of studies.. Whereas no difference was found in clinical periodontal parameters, significant differences in inflammatory or metabolic parameters were found between overweight/obese and normal-weight patients, but existing evidence is weak. Topics: Adiponectin; Body Weight; Diabetes Complications; Glycated Hemoglobin; Humans; Leptin; Obesity; Overweight; Periodontal Diseases; Tumor Necrosis Factor-alpha | 2015 |
Leptin signaling as a therapeutic target of obesity.
Leptin is a hormone with a key role in food intake and body weight homeostasis. Congenital leptin deficiency (CLD) is a rare disease that causes hyperphagia and early severe obesity. However, common obesity conditions are associated with hyperleptinemia and leptin resistance.. The main signaling pathways activated by leptin as well as the mechanisms underlying the regulatory actions of leptin on food intake and on lipid and glucose metabolism are reviewed. The potential mechanisms involving leptin resistance and the main regulatory hormonal and nutritional factors controlling leptin production/functions are also analyzed. The pathophysiology of leptin in human obesity, and especially the trials analyzing effects of leptin replacement therapy in patients with CLD or in subjects with common obesity and in post-obese weight-reduced subjects are also summarized.. The use of drugs or specific bioactive food components with anti-inflammatory properties to reduce the inflammatory state associated with obesity, especially at the hypothalamus, may help to overcome leptin resistance. Research should also be focused on investigating dietary strategies, food supplements or drugs capable of avoiding or reversing the leptin fall during weight management, in order to promote sustained body weight lowering and weight loss maintenance. Topics: Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Body Weight; Humans; Hypothalamus; Inflammation; Leptin; Molecular Targeted Therapy; Obesity; Signal Transduction | 2015 |
A systematic review and meta-analysis of randomized controlled trials of the impact of sleep duration on adiposity and components of energy balance.
Recent epidemiological and ecological trends in humans indicate a possible causal relationship between sleep duration and energy balance. We aimed to find experimental evidence that has tested this relationship between sleep duration and measures of body composition, food intake or biomarkers related to food intake. We conducted a systematic literature review using six databases throughout 7 August 2014. We sought reports of randomized controlled trials where sleep duration was manipulated and measured outcomes were body weight or other body composition metrics, food intake, and/or biomarkers related to eating. We found 18 unique studies meeting all criteria: eight studies with an outcome of body weight (4 - increased sleep, 4 - reduced sleep); four studies on food intake; four studies of sleep restriction on total energy expenditure and three of respiratory quotient; and four studies on leptin and/or ghrelin. Few controlled experimental studies have addressed the question of the effect of sleep on body weight/composition and eating. The available experimental literature suggests that sleep restriction increases food intake and total energy expenditure with inconsistent effects on integrated energy balance as operationalized by weight change. Future controlled trials that examine the impact of increased sleep on body weight/energy balance factors are warranted. Topics: Adiposity; Body Composition; Body Weight; Energy Intake; Energy Metabolism; Female; Humans; Leptin; Male; Obesity; Randomized Controlled Trials as Topic; Sleep; Sleep Deprivation; Weight Gain | 2015 |
[The diversity of leptin].
The role of leptin in regulation of energy homeostasis is well established, yet both the diagnostic as well as the therapeutic relevance of leptin in diet-induced obesity remains unresolved. Nevertheless, in the last few years, the substantial impact of leptin substitution in selected forms of monogenic obesity has advanced our knowledge about the neuroendocrine network of body weight regulation. Moreover, leptin seems to play a crucial role in intestinal nutrient reabsorption, regulation of blood pressure, fertility, inflammation and autoimmune diseases. A better understanding of these processes could possibly provide novel diagnostic and therapeutic options in the future. Topics: Autoimmune Diseases; Blood Pressure; Body Composition; Body Weight; Energy Metabolism; Fertility; Homeostasis; Humans; Inflammation; Intestinal Absorption; Leptin; Obesity | 2015 |
Direct and indirect effects of leptin on adipocyte metabolism.
Leptin is hypothesized to function as a negative feedback signal in the regulation of energy balance. It is produced primarily by adipose tissue and circulating concentrations correlate with the size of body fat stores. Administration of exogenous leptin to normal weight, leptin responsive animals inhibits food intake and reduces the size of body fat stores whereas mice that are deficient in either leptin or functional leptin receptors are hyperphagic and obese, consistent with a role for leptin in the control of body weight. This review discusses the effect of leptin on adipocyte metabolism. Because adipocytes express leptin receptors there is the potential for leptin to influence adipocyte metabolism directly. Adipocytes also are insulin responsive and receive sympathetic innervation, therefore leptin can also modify adipocyte metabolism indirectly. Studies published to date suggest that direct activation of adipocyte leptin receptors has little effect on cell metabolism in vivo, but that leptin modifies adipocyte sensitivity to insulin to inhibit lipid accumulation. In vivo administration of leptin leads to a suppression of lipogenesis, an increase in triglyceride hydrolysis and an increase in fatty acid and glucose oxidation. Activation of central leptin receptors also contributes to the development of a catabolic state in adipocytes, but this may vary between different fat depots. Leptin reduces the size of white fat depots by inhibiting cell proliferation both through induction of inhibitory circulating factors and by contributing to sympathetic tone which suppresses adipocyte proliferation. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. Topics: Adipocytes; Adipose Tissue; Animals; Body Fat Distribution; Body Weight; Eating; Energy Metabolism; Humans; Leptin; Mice | 2014 |
Adaptations of leptin, ghrelin or insulin during weight loss as predictors of weight regain: a review of current literature.
Numerous laboratory studies involving both animal and human models indicate that weight loss induces changes in leptin, ghrelin and insulin sensitivity, which work to promote weight regain. It is unclear, however, whether these biological changes serve as a biomarker for predicting weight regain in free-living humans in which biological, behavioral and environmental factors are likely at play. We identified 12 studies published between January 1995 and December 2011 that reported changes in leptin, ghrelin or insulin during intentional weight loss with a follow-up period to assess regain. Two of the nine studies examining leptin suggested that larger decreases were associated with greater regain, three studies found the opposite (smaller decreases were associated with greater regain), whereas four studies found no significant relationship; none of the studies supported the hypothesis that increases in ghrelin during weight loss were associated with regain. One study suggested that improvements in insulin resistance were associated with weight gain, but five subsequent studies reported no association. Changes in leptin, ghrelin or insulin sensitivity, taken alone, are not sufficient to predict weight regain following weight loss in free-living humans. In future studies, it is important to include a combination of physiological, behavioral and environmental variables in order to identify subgroups at greatest risk of weight regain. Topics: Biomarkers; Body Mass Index; Body Weight; Diet, Reducing; Exercise; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Predictive Value of Tests; Weight Gain; Weight Loss | 2014 |
Leptin and the OB-receptor as anti-obesity target: recent in silico advances in the comprehension of the protein-protein interaction and rational drug design of anti- obesity lead compounds.
The OB-receptor or leptin receptor (LR) is crucial for energy homeostasis and regulation of food uptake. Leptin is a 16 kDa hormone that is mainly secreted by fat cells into the bloodstream. Under normal circumstances, circulating leptin levels are proportionate to the fat body mass. Sensing of elevated leptin levels by the hypothalamic neuro-circuitry activates a negative feedback loop resulting in reduced food intake and increased energy expenditure. Decreased leptin concentrations lead to opposite effects. Therefore, rational design of leptin agonists/antagonists could be an appealing challenge in the battle against obesity. The Leptin/LR interactions have been studied in several works by means of different molecular modelling approaches, spreading from homology modelling to manual docking. No small molecules have ever been proposed as agonists of the Ob receptor but researchers' efforts focused only on leptin-related synthetic peptides as receptor antagonists and on peptidomimetics. In this review we try to track a timeline of obtained in silico information to clarify the mechanism of interaction between leptin and its receptor, together to summarize the more recent efforts to propose new drugs usable in anti-obesity therapy. Final considerations could be useful starting points for the rational drug design of new lead compounds. Topics: Anti-Obesity Agents; Body Weight; Drug Design; Humans; Infant, Newborn; Leptin; Models, Molecular; Obesity; Protein Binding; Receptors, Leptin; Risk Factors; Signal Transduction | 2014 |
Obesity-induced dysfunctions in female reproduction: lessons from birds and mammals.
Follicle wall rupture and ovum release, i.e., ovulation, has been described as a controlled inflammatory event. The process involves tissue remodeling achieved through leukocyte-mediated proteolysis. In birds, ovulation is the first step in the energy-intensive process of egg formation, yet hens that consume energy in excess of productive requirements experience impaired egg-laying ability. Broiler chickens, selected for rapid lean muscle gain, and coincidentally hyperphagia, develop adult obesity when given free access to feed. Obese broiler hens experience elevated circulating concentrations of insulin and leptin, changes in lipid and lipoprotein metabolism similar to those of human metabolic syndrome, as well as increased systemic inflammation. Overall, the manifestations in poultry are similar to those of women with polycystic ovary syndrome. It was shown recently that, in hens, as in mammals, changes in lipid synthesis and metabolism cause granulosa cell apoptosis and altered immune function and hormone production, further compromising ovarian function. To date, there is insufficient information on the means used by the ovary to direct leukocyte function toward successful ovulation. More information is needed regarding the control of proteolytic actions by leukocytes with regards to the roles of specific enzymes in both ovulation and atresia. The broiler hen has provided unique insight into the interrelations of energy intake, obesity, leukocyte function, and reproduction. Additional work with this model can serve the dual purposes of improving avian reproduction and providing novel insights into polycystic ovary syndrome in women. Topics: Animals; Body Weight; Chickens; Disease Models, Animal; Energy Intake; Female; Humans; Insulin; Leptin; Mammals; Obesity; Ovary; Oviposition; Polycystic Ovary Syndrome; Reproduction | 2014 |
Bacteria, viruses, and hypothalamic inflammation: potential new players in obesity.
Being overweight and obese has become an increasingly serious clinical and socioeconomic problem worldwide. The rapidly rising prevalence of obesity has prompted studies on modifiable, causative factors and novel treatment options for this disorder. Recent evidence indicates that excessive weight gain that leads to being overweight and obese may result from alterations in gut microflora. Studies in humans and animals demonstrated that the composition of gut microbiota may differ in lean and obese subjects, suggesting that these differences result in the increased efficiency of caloric extraction from food, enhanced lipogenesis, and impaired central and peripheral regulation of energy balance. Other studies revealed an excessive increase in body weight in a significant percentage of people infected with human adenoviruses SMAM-1 and Ad-36. Dysregulation of adipocyte function by viruses appears to be the most likely cause of excessive fat accumulation in these individuals. Studies on the pathomechanisms related to the pathogenesis of obesity indicated that a high-fat diet triggers the inflammatory response in the hypothalamus, an event that promotes weight gain and further defends elevated body weight through the initiation of central leptin and insulin resistance and impairment of regenerative capacity of hypothalamic neurons. Exposure to a high-calorie diet appears to predispose individuals to obesity not only because of excessive caloric intake but also because of the induction of microbiota- and central inflammatory response-dependent changes that lead to a dysregulation of energy balance. Topics: Animals; Bacterial Infections; Body Weight; Energy Intake; Energy Metabolism; Gastrointestinal Tract; Humans; Hypothalamus; Inflammation; Insulin Resistance; Leptin; Obesity; Virus Diseases | 2014 |
The role of hypothalamic estrogen receptors in metabolic regulation.
Estrogens regulate key features of metabolism, including food intake, body weight, energy expenditure, insulin sensitivity, leptin sensitivity, and body fat distribution. There are two 'classical' estrogen receptors (ERs): estrogen receptor alpha (ERS1) and estrogen receptor beta (ERS2). Human and murine data indicate ERS1 contributes to metabolic regulation more so than ESR2. For example, there are human inactivating mutations of ERS1 which recapitulate aspects of the metabolic syndrome in both men and women. Much of our understanding of the metabolic roles of ERS1 was initially uncovered in estrogen receptor α-null mice (ERS1(-/-)); these mice display aspects of the metabolic syndrome, including increased body weight, increased visceral fat deposition and dysregulated glucose intolerance. Recent data further implicate ERS1 in specific tissues and neuronal populations as being critical for regulating food intake, energy expenditure, body fat distribution and adipose tissue function. This review will focus predominantly on the role of hypothalamic ERs and their critical role in regulating all aspects of energy homeostasis and metabolism. Topics: Animals; Body Weight; Energy Metabolism; Estrogens; Humans; Hypothalamus; Leptin; Receptors, Estrogen | 2014 |
20 years of leptin: role of leptin in energy homeostasis in humans.
The hyperphagia, low sympathetic nervous system tone, and decreased circulating concentrations of bioactive thyroid hormones that are common to states of congenital leptin deficiency and hypoleptinemia following and during weight loss suggest that the major physiological function of leptin is to signal states of negative energy balance and decreased energy stores. In weight-reduced humans, these phenotypes together with pronounced hypometabolism and increased parasympathetic nervous system tone create the optimal circumstance for weight regain. Based on the weight loss induced by leptin administration in states of leptin deficiency (obese) and observed similarity of phenotypes in states of congenital and dietary-induced states of hypoleptinemia (reduced obese), it has been suggested that exogenous leptin could potentially be useful in initiating, promoting, and sustaining weight reduction. However, the responses of human beings to exogenous leptin administration are dependent not only on extant energy stores but also on energy balance. Leptin administration to humans at usual weight has little, if any, effect on body weight while leptin administration during weight loss mitigates hunger, especially if given in supraphysiological doses during severe caloric restriction. Leptin repletion is most effective following weight loss by dietary restriction. In this state of weight stability but reduced energy stores, leptin at least partially reverses many of the metabolic, autonomic, neuroendocrine, and behavioral adaptations that favor weight regain. The major physiological function of leptin is to signal states of negative energy balance and decreased energy stores. Leptin, and pharmacotherapies affecting leptin signaling pathways, is likely to be most useful in sustaining weight loss. Topics: Body Weight; Energy Metabolism; Homeostasis; Humans; Leptin; Models, Biological; Obesity; Signal Transduction | 2014 |
Genetic strategies to understand physiological pathways regulating body weight.
Body weight is a highly heritable trait across species. In humans, genetic variation plays a major role in determining the inter-individual differences in susceptibility or resistance to environmental factors which influence energy intake and expenditure. In this review, I discuss how genetic studies have contributed to our understanding of the central pathways that govern energy homeostasis. The study of individuals harboring highly penetrant genetic variants that disrupt the leptin-melanocortin pathway has informed our understanding of the physiological pathways involved in mammalian energy homeostasis. Topics: Animals; Body Weight; Energy Metabolism; Genetic Variation; Genome-Wide Association Study; Humans; Leptin; Metabolic Networks and Pathways; Obesity; Receptor, Melanocortin, Type 4; Signal Transduction | 2014 |
Mechanisms in endocrinology: the crosstalk between thyroid gland and adipose tissue: signal integration in health and disease.
Obesity and thyroid diseases are common disorders in the general population and they frequently occur in single individuals. Alongside a chance association, a direct relationship between 'thyroid and obesity' has been hypothesized. Thyroid hormone is an important determinant of energy expenditure and contributes to appetite regulation, while hormones and cytokines from the adipose tissue act on the CNS to inform on the quantity of energy stores. A continuous interaction between the thyroid hormone and regulatory mechanisms localized in adipose tissue and brain is important for human body weight control and maintenance of optimal energy balance. Whether obesity has a pathogenic role in thyroid disease remains largely a matter of investigation. This review highlights the complexity in the identification of thyroid hormone deficiency in obese patients. Regardless of the importance of treating subclinical and overt hypothyroidism, at present there is no evidence to recommend pharmacological correction of the isolated hyperthyrotropinemia often encountered in obese patients. While thyroid hormones are not indicated as anti-obesity drugs, preclinical studies suggest that thyromimetic drugs, by targeting selected receptors, might be useful in the treatment of obesity and dyslipidemia. Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Autoimmunity; Body Weight; Energy Intake; Energy Metabolism; Feedback, Physiological; Feeding Behavior; Humans; Hypothyroidism; Leptin; North America; Obesity; Randomized Controlled Trials as Topic; Thyroid Gland; Thyroid Hormones; Thyroid Neoplasms; Thyroiditis, Autoimmune; Thyrotropin | 2014 |
A missing link in body weight homeostasis: the catabolic signal of the overfed state.
Mammals regulate fat mass so that increases or reductions in adipose tissue mass activate responses that favor return to one's previous weight. A reduction in fat mass activates a system that increases food intake and reduces energy expenditure; conversely, overfeeding and rapid adipose tissue expansion reduces food intake and increases energy expenditure. With the identification of leptin nearly two decades ago, the central circuit that defends against reductions in body fat was revealed. However, the systems that defend against rapid expansion of fat mass remain largely unknown. Here we review the physiology of the overfed state and evidence for a distinct regulatory system, which unlike the leptin-mediated system, we propose primarily measures a functional aspect of adipose tissue and not total mass per se. Topics: Adipose Tissue; Animals; Body Weight; Eating; Energy Metabolism; Humans; Leptin; Receptors, Leptin; Signal Transduction | 2014 |
Adaptive thermogenesis with weight loss in humans.
Adaptive thermogenesis (AT) with weight loss refers to underfeeding-associated fall in resting and non-resting energy expenditure (REE, non-REE); this is independent of body weight and body composition. In humans, the existence of AT was inconsistently shown and its clinical significance has been questioned.. Discrepant findings are mainly due to different definitions of AT, the use of various and nonstandardized study protocols, and the limits of accuracy of methods to assess energy expenditure. With controlled underfeeding, AT takes more than 2 wk to develop. AT accounts to an average of 0.5 MJ (or 120 kcal) with a considerable between subject variance.. Low-sympathetic nervous system activity, 3,5,3'-tri-iodothyronine (T3) and leptin are likely to add to AT; however, the kinetic changes of their plasma levels with underfeeding differ from the time course of AT and controlled intervention studies substituting and titrating these hormones are rare in humans. AT in response to underfeeding is independent of thermogenesis in response to either diet or cold. Although fat-free mass (FFM) and, thus, liver, and skeletal muscle are considered as major sites of AT, cold-induced nonshivering thermogenesis relates to the metabolism of brown adipose tissue (BAT). In humans, diet-induced thermogenesis is related to postprandial substrate metabolism of FFM with a questionable role of BAT. Obviously, the REE component of AT differs from and its non-REE component with respect to organ contribution as well as mechanisms. Thus, AT cannot be considered as unique.. AT should be characterized based on individual components of daily energy expenditure, detailed body composition analyses, and mathematical modeling. The biological basis of AT as well as the influences of age, sex, obesity, stress, and inflammation remain to be established in humans. Topics: Adipose Tissue, Brown; Body Composition; Body Weight; Diet; Energy Intake; Energy Metabolism; Humans; Leptin; Rest; Sympathetic Nervous System; Thermogenesis; Weight Loss | 2013 |
Treatment options for children with monogenic forms of obesity.
Mutations in genes involved in energy balance regulation within the central nervous system lead to monogenic forms of obesities. Individuals with these mutations are characterized by early-onset obesity and in some cases by endocrine abnormalities. Carriers of leptin gene mutations are able to normalize their body weight after daily subcutaneous leptin administration. Pharmacotherapy targeting the specific-gene deficiencies has not clinically been tested in other monogenic obesities. Mutations in the melanocortin 4 receptor gene (MC4R) represent the most common monogenic cause of human obesity. Several treatment options have been investigated in subjects with MC4R mutations. Few studies showed that an intensive life-style intervention induces similar weight reduction in MC4R mutation carriers in comparison to MC4R mutation noncarriers. However, long-term body weight maintenance is hardly ever achieved in MC4R mutation carriers. Sibutramine, serotonin and noradrenalin reuptake inhibitor, in MC4R mutation carriers induced weight reduction and improved cardiometabolic health risks. This result was also found in our homozygous MC4R mutation carrier. In vitro studies of melanocortin agonists efficiently activate mutated MC4R with impaired endogenous agonist functional response and thus, further research in the development of drugs for MC4R mutations is needed. An administration of intranasal adrenocorticotropic hormone was not shown to be effective in subjects with pro-opiomelanocortin gene mutations. Bariatric surgery has also been performed in few of MC4R mutation carriers. After gastric banding, lower body weight reduction and worse improvement of metabolic complications was found in MC4R mutation carriers versus noncarriers. However, preliminary results suggest that diversionary operations as gastric bypass represent a suitable method also for MC4R mutation carriers. In conclusion, the management of monogenic obesities still remains a challenge. Topics: Bariatric Surgery; Body Mass Index; Body Weight; Child; Cyclobutanes; Energy Metabolism; Heterozygote; Homozygote; Humans; Leptin; Mutation; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Weight Loss | 2013 |
Obesity and growth during childhood and puberty.
Growth during childhood and adolescence occurs at different rates and is influenced by the interaction between genetic and environmental factors. Nutritional status plays an important role in regulating growth, and excess body weight early in life can influence growth patterns. Childhood obesity is a growing and alarming problem, associated with several short-term and long-term metabolic and cardiovascular complications. In addition, there is evidence suggesting that excess adiposity during childhood influences growth patterns and pubertal development. Several studies have shown that during prepubertal years obese children have higher height velocity and accelerated bone age compared to lean subjects. However, this prepubertal advantage in growth tends to gradually decrease during puberty, when obese children show a reduced growth spurt compared with lean subjects. Growth hormone (GH) secretion in obese children is reduced, therefore suggesting that increased growth is GH independent. Factors which have been implicated in the accelerated growth in obese children include increased leptin and insulin levels, adrenal androgens, insulin-like growth factor (IGF)-1, IGF-binding protein-1 and GH-binding proteins. Excess body weight during childhood can also influence pubertal development, through an effect on timing of pubertal onset and levels of pubertal hormonal levels. There is clear evidence indicating that obesity leads to early appearance of pubertal signs in girls. In addition, obese girls are also at increased risk of hyperandrogenism. In boys, excess adiposity has been associated with advanced puberty in some studies, whereas others have reported a delay in pubertal onset. The existing evidence on the association between childhood and adolescence obesity underlines a further reason for fighting the epidemics of childhood obesity; that is preventing abnormal growth and pubertal patterns. Topics: Adiposity; Adolescent; Body Height; Body Weight; Child; Child Development; Child, Preschool; Female; Humans; Hyperandrogenism; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Leptin; Male; Nutritional Status; Pediatric Obesity; Puberty; Risk Factors | 2013 |
Emerging combinatorial hormone therapies for the treatment of obesity and T2DM.
Peptide hormones and proteins control body weight and glucose homeostasis by engaging peripheral and central metabolic signalling pathways responsible for the maintenance of body weight and euglycaemia. The development of obesity, often in association with type 2 diabetes mellitus (T2DM), reflects a dysregulation of metabolic, anorectic and orexigenic pathways in multiple organs. Notably, therapeutic attempts to normalize body weight and glycaemia with single agents alone have generally been disappointing. The success of bariatric surgery, together with emerging data from preclinical studies, illustrates the rationale and feasibility of using two or more agonists, or single co-agonists, for the treatment of obesity and T2DM. Here, we review advances in the science of co-agonist therapy, and highlight promising areas and challenges in co-agonist development. We describe mechanisms of action for combinations of glucagon-like peptide 1, glucagon, gastric inhibitory polypeptide, gastrin, islet amyloid polypeptide and leptin, which enhance weight loss whilst preserving glucoregulatory efficacy in experimental models of obesity and T2DM. Although substantial progress has been achieved in preclinical studies, the putative success and safety of co-agonist therapy for the treatment of patients with obesity and T2DM remains uncertain and requires extensive additional clinical validation. Topics: Animals; Blood Glucose; Body Weight; Central Nervous System; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Leptin; Obesity | 2013 |
Leptin signaling and leptin resistance.
Leptin is secreted into the bloodstream by adipocytes and is required for the maintenance of energy homeostasis and body weight. Leptin deficiency or genetic defects in the components of the leptin signaling pathways cause obesity. Leptin controls energy balance and body weight mainly through leptin receptor b (LEPRb)-expressing neurons in the brain, particularly in the hypothalamus. These LEPRb-expressing neurons function as the first-order neurons that project to the second-order neurons located within and outside the hypothalamus, forming a neural network that controls the energy homeostasis and body weight. Multiple factors, including inflammation and endoplasmic reticulum (ER) stress, contribute to leptin resistance. Leptin resistance is the key risk factor for obesity. This review is focused on recent advance about leptin action, leptin signaling, and leptin resistance. Topics: Animals; Body Weight; Energy Metabolism; Homeostasis; Humans; Leptin; Mice; Neurons; Obesity; Risk Factors; Signal Transduction | 2013 |
Roles for central leptin receptors in the control of meal size.
The adiposity hormone leptin has been implicated in the regulation of behavioral and metabolic controls of body weight. Leptin receptors are found in multiple peripheral and central tissues, particularly within hypothalamic and brainstem neuronal populations. Central leptinergic signaling acts as an indirect control to modulate the feeding inhibitory potency of the direct controls of meal size. Mouse models of neuronal leptin loss and gain of function have helped to identify and characterize how central leptin contributes to the central control of food intake. Topics: Adiposity; Animals; Body Weight; Eating; Feeding Behavior; Humans; Hypothalamus; Leptin; Meals; Models, Animal; Obesity; Portion Size; Receptors, Leptin; Signal Transduction | 2013 |
Role of oxytocin in energy metabolism.
The basic mechanisms that lead obesity are not fully understood; however, several peptides undoubtedly play a role in regulating body weight. Obesity, a highly complex metabolic disorder, involves central mechanisms that control food intake and energy expenditure. Previous studies have shown that central or peripheral oxytocin administration induces anorexia. Recently, in an apparent discrepancy, rodents that were deficient in oxytocin or the oxytocin receptor were shown to develop late-onset obesity without changing their total food intake, which indicates the physiological importance of oxytocin to body metabolism. Oxytocin is synthesized not only within magnocellular and parvocellular neurons but also in several organs, including the ovary, uterus, placenta, testis, thymus, kidney, heart, blood vessels, and skin. The presence of oxytocin receptors in neurons, the myometrium and myoepithelial cells is well recognized; however, this receptor has also been identified in other tissues, including the pancreas and adipose tissue. The oxytocin receptor is a typical class I G protein-coupled receptor that is primarily linked to phospholipase C-β via Gq proteins but can also be coupled to other G proteins, leading to different functional effects. In this review, we summarize the present knowledge of the effects of oxytocin on controlling energy metabolism, focusing primarily on the role of oxytocin on appetite regulation, thermoregulation, and metabolic homeostasis. Topics: Adipose Tissue; Appetite Regulation; Body Temperature Regulation; Body Weight; Eating; Energy Metabolism; Homeostasis; Humans; Leptin; Neurons; Obesity; Oxytocin; Phospholipase C beta; Receptors, Oxytocin | 2013 |
[Monogenic obesity in human].
Obesity is a heterogeneous pathologic condition that is driven by interactions between multiple genetic and environmental factors. The discovery of leptin has provided the useful clue to the molecular dissection of central pathways involved in the regulation of food intake and body weight. Monogenic obesity in human has been documented. Several obesity causing genes within the leptin-POMC-melanocortin axis have been identified: Leptin, leptin receptor, proopiomelanocortin (POMC), prohormone convertase 1 (PC1), and melanocortin receptor-4 (MC4-R) genes. The patients who have a mutation of such genes developed early onset of obesity and distinct metabolic abnormalities. Also, several gene mutations have been identified in some syndromes presenting hereditary symptomatic obesity. Topics: Body Weight; Humans; Leptin; Mutation; Obesity; Receptor, Melanocortin, Type 4; Receptors, Leptin | 2013 |
The role of nesfatin-1 in the regulation of food intake and body weight: recent developments and future endeavors.
Nesfatin-1 was discovered in 2006 and introduced as a potential novel anorexigenic modulator of food intake and body weight. The past years have witnessed increasing evidence establishing nesfatin-1 as a potent physiological inhibitor of food intake and body weight and unravelled nesfatin-1's interaction with other brain transmitters to exert its food consumption inhibitory effect. As observed for other anorexigenic brain neuropeptides, nesfatin-1 is also likely to exert additional, if not pleiotropic, actions in the brain and periphery. Recent studies established the prominent expression of the nesfatin-1 precursor, nucleobindin2 (NUCB2), in the stomach and pancreas, where nesfatin-1 influences endocrine secretion. This review will highlight the current experimental state-of-knowledge on the effects of NUCB2/nesfatin-1 on food intake, body weight and glucose homeostasis. Potential implications in human obesity will be discussed in relation to the evidence of changes in circulating levels of NUCB2/nesfatin-1 in disease states, the occurrence of genetic NUCB2 polymorphisms and--in contrast to several other hormones--the independence of leptin signalling known to be blunted under conditions of chronically increased body weight. Topics: Animals; Appetite Regulation; Body Weight; Calcium-Binding Proteins; DNA-Binding Proteins; Forecasting; Humans; Leptin; Nerve Tissue Proteins; Nucleobindins; Obesity; Signal Transduction | 2013 |
[Food intake regulation - 1st part].
The review article summarizes a very complex process of appetite regulation: the part focused on homeostatic regulation of food intake. The aim of homeostatic regulation is to achieve energy balance, stabile weight and optimal nutrient intake, in contrast to hedonic regulation of food intake, in which emotional and motivational factors are involved. Homeostatic regulation could be divided into shortterm and longterm regulation and comprises mainly gastrointestinal peptides, fat tissue hormones and central mechanisms localized in hypothalamus. It is a resultant of the action of orexigenic factors (increasing appetite and food intake) and anorexigenic factors (decreasing appetite and thus food intake), respectively. The anorexigenic factors include gastrointestinal peptides (e.g. cholecystokinin, glucagonlike peptide 1, bombesin, peptide YY and others), hormone of fat tissue leptin and centrally acting melanocortin system. On the contrary, orexigenic factors comprise of gastric ghrelin and centrally acting system of neuropeptide Y/ Agoutirelated peptide. Understanding the principles of the regulation of food intake is essential for comprehension of pathogenesis of eating disorders and obesity, whose prevalence has been recently increasing, and it provides potential targets for pharmacological interventions. Topics: Adipose Tissue; Appetite Regulation; Body Weight; Eating; Energy Metabolism; Gastrointestinal Hormones; Homeostasis; Humans; Hypothalamus; Leptin; Neuropeptide Y; Obesity | 2013 |
Control of body weight versus tumorigenesis by concerted action of leptin and estrogen.
Improper body weight control is most critical to the development of morbid obesity, which is often associated with alternation in leptin (Ob) signaling in the central nervous system. Leptin acts to control fat mass through the regulation of both food intake and energy expenditure. In addition to the primary action in metabolic signaling, leptin has also been found to play a role in reproduction and even in breast tumorigenesis in obese patients. Interestingly, estrogen, a sex hormone, has also been recognized as another crucial factor for energy balance and breast tumorigenesis in obese subjects. Obesity in postmenopausal women has been associated with higher risk of breast cancer. There are substantial data in the literature on the connection of estrogen and leptin pathways in development of obesity and breast cancer. In this review, we discuss the cross-talk of leptin and estrogen signaling pathways in body weight control and breast cancer development. Topics: Animals; Body Weight; Breast Neoplasms; Carcinogenesis; Estrogens; Female; Humans; Leptin; Obesity | 2013 |
Is leptin the parabiotic "satiety" factor? Past and present interpretations.
In 1959 Hervey hypothesized that a circulating feedback signal informed the hypothalamus of the size of fat stores and initiated appropriate corrections to energy balance. The hypothesis resulted from a parabiosis study in which one animal became obese following lesioning of the ventromedial hypothalamus. The partner of the lesioned rat was hypophagic and lost a large amount of body fat. Similar results came from parabiosis studies with obese Zucker rats and rats that overate due to stimulation of the lateral hypothalamus. In studies in which one parabiont was made obese by overfeeding the non-overfed partners lost substantial amounts of fat with a minimal reduction in food intake and no loss of lean tissue. The loss of fat was due to inhibition of adipose lipogenesis and other metabolic adjustments typical of food restriction. Parabiosis with genetically obese mice implied that ob/ob mice did not produce the feedback signal and subsequently the mutant ob protein, leptin, was identified. This paper provides a review and interpretation of parabiosis work that preceded the discovery of leptin, an evaluation of leptin in relation to its function as the circulating feedback signal and evidence for additional circulating factors involved in the control of adipose tissue mass. Topics: Adipose Tissue; Animals; Body Weight; Eating; Energy Metabolism; History, 20th Century; History, 21st Century; Humans; Hypothalamus; Leptin; Mice; Mice, Obese; Nutritional Sciences; Obesity; Parabiosis; Rats; Rats, Zucker; Satiation | 2013 |
Ghrelin and leptin pathophysiology in chronic kidney disease.
Ghrelin is an orexigenic hormone with additional effects on the regulation of inflammation and the cardiovascular system. It may play an important role in the pathogenesis of cachexia/protein-energy wasting (PEW), inflammation and cardiovascular complications in chronic kidney disease (CKD). There are three circulating gene products of ghrelin, namely, acyl ghrelin, des-acyl ghrelin and obestatin, each with individual distinct functions. Perturbations of these circulating ghrelin proteins impact the overall milieu of CKD. Leptin is an anorexigenic hormone which is secreted from the adipocytes and interacts with ghrelin and other appetite-regulating hormones. Leptin also plays a role in regulating inflammation and the cardiovascular system. Indeed, ghrelin and leptin may play yin-and-yang roles in CKD pathophysiology. Clinical trials involving the use of the mimetics or antagonists of these hormones are limited to short-term phase I/II studies. Further understanding of their interactions in CKD pathophysiology is needed for potential large-scale clinical trials, which may impact the quality of life and survival of patients with CKD. Topics: Animals; Appetite Regulation; Body Weight; Cardiovascular Diseases; Disease Progression; Ghrelin; Humans; Inflammation; Kidney; Leptin; Malnutrition; Prognosis; Renal Insufficiency, Chronic; Signal Transduction | 2013 |
Molecular mechanisms of central leptin resistance in obesity.
The rapidly increasing prevalence of obesity confers a huge health burden globally. The hypothalamus plays a central role in the regulation of energy homeostasis by integrating multiple metabolic signals from peripheral organs and modulating feeding behavior and energy metabolism. Leptin, a key appetite-regulating hormone derived from the white adipose tissue, primarily acts on hypothalamic neurons to activate catabolic pathway and inhibit anabolic pathway, which can result in anorexia and weight reduction. Despite striking obesity resulting from leptin deficiency, treatment with this hormone in human obesity has been unsuccessful due to leptin resistance. In this review, we describe recent researches extending our understanding of obesity-associated hypothalamic leptin resistance. Topics: Animals; Body Weight; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Leptin; Obesity | 2013 |
Role of the hypothalamus in the neuroendocrine regulation of body weight and composition during energy deficit.
Energy deficit in lean or obese animals or humans stimulates appetite, reduces energy expenditure and possibly also decreases physical activity, thereby contributing to weight regain. Often overlooked in weight loss trials for obesity, however, is the effect of energy restriction on neuroendocrine status. Negative energy balance in lean animals and humans consistently inhibits activity of the hypothalamo-pituitary-thyroid, -gonadotropic and -somatotropic axes (or reduces circulating insulin-like growth factor-1 levels), while concomitantly activating the hypothalamo-pituitary-adrenal axis, with emerging evidence of similar changes in overweight and obese people during lifestyle interventions for weight loss. These neuroendocrine changes, which animal studies show may result in part from hypothalamic actions of orexigenic (e.g. neuropeptide Y, agouti-related peptide) and anorexigenic peptides (e.g. alpha-melanocyte-stimulating hormone, and cocaine and amphetamine-related transcript), can adversely affect body composition by promoting the accumulation of adipose tissue (particularly central adiposity) and stimulating the loss of lean body mass and bone. As such, current efforts to maximize loss of excess body fat in obese people may inadvertently be promoting long-term complications such as central obesity and associated health risks, as well as sarcopenia and osteoporosis. Future weight loss trials would benefit from assessment of the effects on body composition and key hormonal regulators of body composition using sensitive techniques. Topics: Adipose Tissue; Animals; Appetite; Body Composition; Body Weight; Disease Models, Animal; Energy Intake; Energy Metabolism; Fasting; Humans; Hypothalamus; Leptin; Neuropeptides | 2012 |
Metabolic dysfunction in Alzheimer's disease and related neurodegenerative disorders.
Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies. Topics: Adiponectin; Alzheimer Disease; Body Weight; Brain-Derived Neurotrophic Factor; Ghrelin; Glucagon-Like Peptide 1; Glucose; Humans; Leptin; Metabolic Diseases; Neurodegenerative Diseases | 2012 |
Adiposity and cognitive decline: underlying mechanisms.
Level of adiposity is linked to manifest dementia and Alzheimer's disease in epidemiological studies. Overweight and obesity in mid- and late-life may increase risk for dementia, whereas decline in body weight or body mass index and underweight in years preceding and at the time of a dementia diagnosis may also relate to dementia. The role of adiposity during the period of cognitive decline is, as yet, not understood; however, some hypotheses relating adipose tissue to brain can be drawn. This review focuses on potential, varied mechanisms whereby adipose tissue may influence or interact with the brain and/or dementia risk during the dynamic period of life characterized by both body weight and cognitive decline. These mechanisms relate to: a) adipose tissue location and cell types, b) body composition, c) endocrine adipose, and d) the interplay among adipose, brain structure and function, and genes. This review will illustrate that adipose tissue is a quintessential, multifunctional tissue of the human body. Topics: Adiponectin; Adipose Tissue; Adiposity; Body Composition; Body Mass Index; Body Weight; Brain; Cognition Disorders; Cytokines; Dementia; Glucagon-Like Peptide 1; Humans; Leptin | 2012 |
At the crossroad of T cells, adipose tissue, and diabetes.
The study of how different intracellular metabolic signaling pathways impact the control of self-immune tolerance and how metabolic dysregulation in overweight, obesity, and diabetes is able to alter self-immune tolerance are topics of intensive investigation. Recent evidence suggests that metabolic and autoimmune diseases, both characterized by chronic inflammation and an altered self-immune tolerance, are more common in affluent countries. The reasons for such phenomena are still not completely understood, but the 'metabolic pressure' induced by nutritional overload, typical of more developed countries, seems to play a role. In this context, the discovery of the adipose tissue-derived hormone leptin has shed fundamental insights on how these processes might occur. We believe that there is a strong relationship among leptin, metabolic state, and immunological self-tolerance. We hypothesize that the leptin-induced metabolic pressure sets the basis for an exaggerated immuno-inflammatory response to altered self or non-self, leading to chronic inflammation, metabolic dysregulation, and autoimmunity in subjects with risk factors (i.e. genetic predisposition, environment, sex, infectious agents, etc). Capitalizing on our joint effort and trans-disciplinary expertise in metabolism, self-tolerance, and autoimmune diseases, this review highlights key questions on the basic mechanisms governing immune tolerance in the context of metabolic and autoimmune disease susceptibility. Topics: Adipose Tissue; Animals; Autoimmune Diseases; Body Weight; Diabetes Mellitus; Energy Metabolism; Humans; Immune Tolerance; Inflammation; Leptin; Self Tolerance; Signal Transduction; T-Lymphocytes | 2012 |
Nesfatin-1: a novel inhibitory regulator of food intake and body weight.
The protein nucleobindin 2 (NUCB2) or NEFA (DNA binding/EF-hand/acidic amino acid rich region) was identified over a decade ago and implicated in intracellular processes. New developments came with the report that post-translational processing of hypothalamic NUCB2 may result in nesfatin-1, nesfatin-2 and nesfatin-3 and convergent studies showing that nesfatin-1 and full length NUCB2 injected in the brain potently inhibit the dark phase food intake in rodents including leptin receptor deficient Zucker rats. Nesfatin-1 also reduces body weight gain, suggesting a role as a new anorexigenic factor and modulator of energy balance. In light of the obesity epidemic and its associated diseases, underlying new mechanisms regulating food intake may be promising targets in the drug treatment of obese patients particularly as the vast majority of them display reduced leptin sensitivity or leptin resistance while nesfatin-1's mechanism of action is leptin independent. Although much progress on the localization of NUCB2/nesfatin-1 in the brain and periphery as well as on the understanding of nesfatin-1's anorexic effect have been achieved during the past three years, several important mechanisms have yet to be unraveled such as the identification of the nesfatin-1 receptor and the regulation of NUCB2 processing and nesfatin-1 release. Topics: Animals; Appetite Regulation; Body Weight; Calcium-Binding Proteins; Disease Models, Animal; DNA-Binding Proteins; Eating; Energy Intake; Humans; Hypothalamus; Leptin; Nerve Tissue Proteins; Nucleobindins; Obesity; Peptide Hormones; Rats; Satiety Response; Signal Transduction | 2011 |
Genetic, molecular and physiological insights into human obesity.
Obesity and its associated co-morbidities represent one of the biggest public health challenges facing the western world today. Although environmental factors have driven the recent rise in the prevalence of obesity, the heritability of body weight is high and there is evidence that genetic variation plays a major role in determining the susceptibility to weight gain.. Genetic approaches can be used to investigate the mechanisms underlying the regulation of weight and the development of obesity.. The discovery that leptin, a hormone that is secreted by adipocytes, could regulate weight through effects on food intake and energy expenditure represented a major breakthrough in our understanding of the molecular components of the systems involved in energy homeostasis.. I discuss how the identification of humans with mutations in the genes encoding leptin and its downstream targets has provided insights into the role of leptin responsive pathways in the regulation of body weight, neuroendocrine axes and immunity. Topics: Animals; Appetite; Body Weight; Energy Metabolism; Female; Genetic Variation; Humans; Leptin; Male; Obesity; Rats; Risk Factors; Weight Gain | 2011 |
Leptin and beyond: an odyssey to the central control of body weight.
The 2010 Lasker Award for basic medical research was shared by Douglas Coleman and Jeffery Friedman for their discovery of leptin, a breakthrough that revealed insight into the genetic basis of obesity. This mini-review aims to review landmark studies on the physiologic system of body weight control. The basic research on the leptin system has broad implications for the genetic control of body weight, thus contributing to solve the global obesity crisis. Topics: Animals; Awards and Prizes; Body Weight; Endocrine System; Homeostasis; Humans; Hypothalamus; Leptin; Neural Pathways; Obesity | 2011 |
Genetic approaches to understanding human obesity.
Obesity and its associated comorbidities represent one of the biggest public health challenges facing the world today. The heritability of body weight is high, and genetic variation plays a major role in determining the interindividual differences in susceptibility or resistance to the obesogenic environment. Here we discuss how genetic studies in humans have contributed to our understanding of the central pathways that govern energy homeostasis. We discuss how the arrival of technological advances such as next-generation sequencing will result in a major acceleration in the pace of gene discovery. The study of patients harboring these genetic variants has informed our understanding of the molecular and physiological pathways involved in energy homeostasis. We anticipate that future studies will provide the framework for the development of a more rational targeted approach to the prevention and treatment of genetically susceptible individuals. Topics: Adaptation, Physiological; Animals; Body Weight; Dietary Fats; Energy Metabolism; Environment; Gene Dosage; Genetic Association Studies; Genome-Wide Association Study; Genomic Imprinting; Humans; Leptin; Melanocortins; Mice; Mice, Mutant Strains; Obesity; Receptor, Melanocortin, Type 4; Receptors, Leptin; Syndrome | 2011 |
Sixteen years and counting: an update on leptin in energy balance.
Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound effects on behavior, metabolic rate, endocrine axes, and glucose fluxes. Leptin deficiency in mice and humans causes morbid obesity, diabetes, and various neuroendocrine anomalies, and replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure. Here, we provide an update on the most current understanding of leptin-sensitive neural pathways in terms of both anatomical organization and physiological roles. Topics: Adaptation, Physiological; Adipose Tissue, White; Animals; Body Weight; Brain; Disease Models, Animal; Energy Metabolism; Feeding Behavior; Glucose; Humans; Hypothalamus; Leptin; Mice; Mice, Obese; Models, Biological; Overnutrition; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Leptin; Starvation; Sympathetic Nervous System | 2011 |
Obesity, leptin, and Alzheimer's disease.
Obesity has various deleterious effects on health largely associated with metabolic abnormalities including abnormal glucose and lipid homeostasis that are associated with vascular injury and known cardiac, renal, and cerebrovascular complications. Advanced age is also associated with increased adiposity, decreased lean mass, and increased risk for obesity-related diseases. Although many of these obesity- and age-related disease processes have long been subsumed to be secondary to metabolic or vascular dysfunction, increasing evidence indicates that obesity also modulates nonvascular diseases such as Alzheimer's disease (AD) dementia. The link between peripheral obesity and neurodegeneration will be explored, using adipokines and AD as a template. After an introduction to the neuropathology of AD, the relationship between body weight, obesity, and dementia will be reviewed. Then, population-based and experimental studies that address whether leptin modulates brain health and mitigates AD pathways will be explored. These studies will serve as a framework for understanding the role of adipokines in brain health. Topics: Aging; Alzheimer Disease; Animals; Biomarkers; Body Weight; Brain; Disease Models, Animal; Female; Humans; Leptin; Male; Mice; Models, Neurological; Obesity; Receptors, Leptin; Risk Factors; Signal Transduction | 2011 |
Obesity and thyroid function.
A moderate elevation of thyrotropin (TSH) concentrations, which is associated with triiodothyronine (T3) values in or slightly above the upper normal range, is frequently found in obese humans. These alterations seem rather a consequence than a cause of obesity since weight loss leads to a normalization of elevated thyroid hormone levels. Elevated thyroid hormone concentrations increase the resting energy expenditure (REE). The underlying pathways are not fully understood. As a consequence of the increased REE, the availability of accumulated energy for conversion into fat is diminished. In conclusion, the alterations of thyroid hormones in obesity suggest an adaptation process. Since rapid weight loss is associated with a decrease of TSH and T3, the resulting decrease in REE may contribute towards the difficulties maintaining weight loss. Leptin seems to be a promising link between obesity and alterations of thyroid hormones since leptin concentrations influence TSH release. Topics: Adipokines; Animals; Anorexia Nervosa; Body Weight; Energy Metabolism; Humans; Leptin; Obesity; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Triiodothyronine | 2010 |
Leptin and the control of body weight: a review of its diverse central targets, signaling mechanisms, and role in the pathogenesis of obesity.
Topics: Animals; Blood-Brain Barrier; Body Weight; Brain; Feeding Behavior; Humans; Leptin; Neuronal Plasticity; Obesity; Receptors, Leptin; Reward; Satiety Response; Signal Transduction; Synaptic Transmission | 2010 |
Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators.
Body weight is tightly controlled in a species-specific range from insects to vertebrates and organisms have developed a complex regulatory network in order to avoid either excessive weight gain or chronic weight loss. Energy homeostasis, a term comprising all processes that aim to maintain stability of the metabolic state, requires a constant communication of the different organs involved; i.e. adipose tissue, skeletal muscle, liver, pancreas and the central nervous system (CNS). A tight hormonal network ensures rapid communication to control initiation and cessation of eating, nutrient processing and partitioning of the available energy within different organs and metabolic pathways. Moreover, recent experiments indicate that many of these homeostatic signals modulate the neural circuitry of food reward and motivation. Disturbances in each individual system can affect the maintenance and regulation of the others, making the analysis of energy homeostasis and its dysregulation highly complex. Though this cross-talk has been intensively studied for many years now, we are far from a complete understanding of how energy balance is maintained and multiple key questions remain unanswered. This review summarizes some of the latest developments in the field and focuses on the effects of leptin, insulin, and nutrient-related signals in the central regulation of feeding behavior. The integrated view, how these signals interact and the definition of functional neurocircuits in control of energy homeostasis, will ultimately help to develop new therapeutic interventions within the current obesity epidemic. Topics: Animals; Body Weight; Brain; Diabetes Mellitus; Eating; Energy Metabolism; Glucose; Homeostasis; Humans; Hypothalamus; Insulin; Leptin; Neurosecretory Systems; Nutritional Physiological Phenomena; Obesity; Signal Transduction | 2010 |
Role of the arcuate nucleus of the hypothalamus in regulation of body weight during energy deficit.
Acute or long-term energy deficit in lean or obese rodents or humans stimulates food intake or appetite and reduces metabolic rate or energy expenditure. These changes contribute to weight regain in post-obese animals and humans. Some studies show that the reduction in metabolic rate with energy deficit in overweight people is transient. Energy restriction has been shown in some but not all studies to reduce physical activity, and this may represent an additional energy-conserving adaptation. Energy restriction up-regulates expression of the orexigenic neuropeptide Y, agouti related peptide and opioids and down-regulates that of the anorexigenic alpha-melanocyte stimulating hormone or its precursor pro-opioomelanocortin and the co-expressed cocaine and amphetamine-regulated transcript in the arcuate nucleus of the hypothalamus. Recapitulating these hypothalamic changes in sated animals mimics the effects of energy deficit, namely increased food intake, reduced physical activity and reduced metabolic rate, suggesting that these energy-conserving adaptations are at least partially mediated by the hypothalamus. Topics: Agouti-Related Protein; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Energy Metabolism; Fasting; Humans; Leptin; Motor Activity; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Oxygen Consumption; Pro-Opiomelanocortin; Signal Transduction; Weight Loss | 2010 |
Central effects of estradiol in the regulation of food intake, body weight, and adiposity.
In recent years, obesity and its associated health disorders and costs have increased. Accumulation of adipose tissue, or fat, in the intra-abdominal adipose depot is associated with an increased risk of developing cardiovascular problems, type-2 diabetes mellitus, certain cancers, and other disorders like the metabolic syndrome. Males and females differ in terms of how and where their body fat is stored, in their hormonal secretions, and in their neural responses to signals regulating weight and body fat distribution. Men and post-menopausal women accumulate more fat in their intra-abdominal depots than pre-menopausal women, resulting in a greater risk of developing complications associated with obesity. The goal of this review is to discuss the current literature on sexual dimorphisms in body weight regulation, adipose tissue accrual and deposition. Topics: Adiposity; Animals; Body Fat Distribution; Body Weight; Cholecystokinin; Eating; Estradiol; Female; Ghrelin; Humans; Hypothalamic Hormones; Insulin; Leptin; Male; Melanins; Mice; Neuropeptide Y; Pituitary Hormones; Rats; Receptors, Estrogen; Serotonin; Sex Characteristics | 2010 |
Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins.
Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors. Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Humans; Hypertension; Kidney; Leptin; Melanocortins; Mice; Models, Biological; Neurons; Obesity; Pro-Opiomelanocortin; Rats; Receptor, Melanocortin, Type 4; Sympathetic Nervous System | 2010 |
Perinatal environment and its influences on metabolic programming of offspring.
The intrauterine environment supports the development and health of offspring. Perturbations to this environment can have detrimental effects on the fetus that have persistent pathological consequences through adolescence and adulthood. The developmental origins of the health and disease concept, also known as the "Barker Hypothesis", has been put forth to describe the increased incidence of chronic disease such as cardiovascular disease and diabetes in humans and animals exposed to a less than ideal intrauterine environment. Maternal infection, poor or excess nutrition, and stressful events can negatively influence the development of different cell types, tissues and organ systems ultimately predisposing the organism to pathological conditions. Although there are a variety of conditions associated to exposure to altered intrauterine environments, the focus of this review will be on the consequences of stress and high fat diet during the pre- and perinatal periods and associated outcomes related to obesity and other metabolic conditions. We further discuss possible neuroendocrine and epigenetic mechanisms responsible for the metabolic programming of offspring. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009. Topics: Animals; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Susceptibility; Energy Metabolism; Environment; Epigenesis, Genetic; Female; Glucocorticoids; Humans; Insulin; Leptin; Male; Pregnancy; Prenatal Exposure Delayed Effects; Sex Factors | 2010 |
Insights into amylin-leptin synergy.
Although the adipokine leptin is regarded as the prototypical long-term signal of energy balance, obese individuals are largely nonresponsive to exogenous leptin administration. Restoration of leptin responsiveness in obesity has been elusive despite a detailed understanding of the molecular mechanisms of leptin signaling. Recent translational research findings point to a potential therapeutic approach that incorporates amylin (a beta-cell hormone) and leptin agonism, with amylin restoring or enhancing leptin sensitivity. Here we hypothesize various physiological, neurobiological and molecular mechanisms that could mediate the interaction of these two neurohormonal signals and discuss several methodological challenges. Understanding how amylin agonism improves leptin function could point to general therapeutic strategies for combating leptin resistance and associated obesity. Topics: Animals; Body Weight; Drug Synergism; Humans; Hypothalamus; Islet Amyloid Polypeptide; Leptin; Obesity; Rhombencephalon | 2010 |
Metabolic impact of sex hormones on obesity.
Obesity and its associated health disorders and costs are increasing. Men and post-menopausal women have greater risk of developing complications of obesity than younger women. Within the brain, the hypothalamus is an important regulator of energy homeostasis. Two of its sub-areas, the ventrolateral portion of the ventral medial nucleus (VL VMN) and the arcuate (ARC) respond to hormones and other signals to control energy intake and expenditure. When large lesions are made in the hypothalamus which includes both the VL VMN and the ARC, animals eat more, have reduced energy expenditure, and become obese. The ARC and the VL VMN, in addition to other regions in the hypothalamus, have been demonstrated to contain estrogen receptors. There are two estrogen receptors, estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). We and others have previously demonstrated that activation of ERalpha by estrogens reduces food intake and increases body weight. This review focuses on the relative contribution of activation of ERalpha by estrogens in the ARC and the VL VMN in the regulation of food intake and body weight. Additionally, estrogen receptors have been found in many peripheral tissues including adipose tissue. Estrogens are thought to have direct effects on adipose tissue and estrogens may provide anti-inflammatory properties both in the periphery and the in the central nervous system (CNS) which may protect women from diseases associated with inflammation. Understanding the mechanisms by which estrogens regulate body weight and inflammation will assist in determining potential therapeutic agents for menopausal women to decrease the propensity of diseases associated with obesity. Topics: Body Weight; Eating; Energy Metabolism; Estrogens; Female; Humans; Hypothalamus; Leptin; Male; Obesity; Receptors, Estrogen | 2010 |
Neuroendocrine control of energy homeostasis: update on new insights.
Recent upsurge in research has uncovered distinct circuitries that regulate appetite, energy expenditure and fat accrual under the supervision of hormonal feedback signalling of adipocyte leptin and gastric ghrelin in the hypothalamic integration of energy homeostasis. A host of messenger molecules of diverse chemical composition and origin mediate the crosstalk between the three circuitries. Leptin is now recognized as the mandatory afferent signal in maintenance of weight homeostasis. Leptin insufficiency in the hypothalamus due to diminished transport of leptin across the blood-brain barrier (BBB) imposed by environmental causes, such as consumption of energy-enriched diets and diminished energy expenditure, orchestrates unregulated fat accrual and the attendant disease cluster of metabolic syndrome. Bioavailability of leptin selectively in the hypothalamic targets with the aid of gene therapy successfully averted the environmentally induced metabolic afflictions and normalized lifespan. Thus, sustenance of optimal sufficiency in leptin signalling solely in the hypothalamus is a novel strategy to combat the worldwide epidemic of obesity and metabolic syndrome. Topics: Animals; Appetite; Body Weight; Energy Metabolism; Ghrelin; Homeostasis; Humans; Hypothalamus; Leptin; Metabolic Syndrome; Neurosecretory Systems; Obesity; Signal Transduction | 2010 |
Thermoregulation, energy balance, regulatory peptides: recent developments.
Energy balance of the body is determined mainly by the function of various hypothalamic and brainstem nuclei, according to a complex interaction between the regulation of body temperature (actual metabolic rate vs. heat loss) and regulation of body weight (metabolic rate vs. food intake). The direct effect of central anabolic neuropeptides (neuropeptide Y, orexins, melanin concentrating hormone, etc.) is to enhance food intake and suppress metabolic rate with a tendency to cause hypothermia, while central catabolic neuropeptides (melanocortins, corticotropin releasing factor, cocaine-amphetamine regulated peptide, etc.) suppress food intake and enhance energy expenditure with a tendency to induce hyperthermia. Many other neuropeptides are neither clearly anabolic, nor clearly catabolic, but still influence these complex hypothalamic/brainstem functions. Some peripheral peptides (e.g. leptin, insulin, ghrelin) acting at either peripheral or cerebral sites also contribute to the regulation of energy balance. The prevailing thermoregulatory status, the substances or neural signals representing actual feeding vs. established nutritional states, and the aging process may modify the expression and/or activity of peripheral and central peptides and peptide receptors. Topics: Adiponectin; Aging; Animals; Body Temperature Regulation; Body Weight; Cholecystokinin; Eating; Energy Metabolism; Female; Ghrelin; Humans; Hypothalamic Hormones; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Male; Melanins; Melanocortins; Neuropeptides; Orexins; Peptides; Pituitary Hormones; Signal Transduction | 2010 |
Nonhomeostatic control of human appetite and physical activity in regulation of energy balance.
Ghrelin and leptin, putative controllers of human appetite, have no effect on human meal-to-meal appetite but respond to variations in energy availability. Nonhomeostatic characteristics of appetite and spontaneous activity stem from inhibition by leptin and ghrelin of brain reward circuit that is responsive to energy deficit, but refractory in obesity, and from the operation of a meal-timing circadian clock. Topics: Animals; Appetite; Body Weight; Circadian Rhythm; Energy Intake; Energy Metabolism; Female; Ghrelin; Homeostasis; Humans; Leptin; Mice; Motor Activity; Obesity; Rats; Reward | 2010 |
Hypothalamic regulation of bone.
On initial inspection, bone remodeling, the process whereby the skeleton adapts through time, appears to be relatively simple. Two cell types, the bone-forming osteoblasts and the bone-resorbing osteoclasts, interact to keep bone mass relatively stable throughout adult life. However, the complexity of the regulatory influences on these cells is continuing to expand our understanding of the intricacy of skeletal physiology and also the interactions between other organ systems and bone. One such example of the broadening of understanding in this field has occurred in the last decade with study of the central, neural regulation of bone mass. Initial studies of an adipose-derived hormone, leptin, helped define a direct, sympathetic pathway involving efferent neural signals from the hypothalamus to receptors on the osteoblast. Since the leptin-mediated pathway has been continuously modified to reveal a complex system involving neuromedin U, cocaine- and amphetamine-related transcript and serotonin interacting within the hypothalamus and brainstem to regulate both bone formation and resorption in cancellous bone, a number of other systems have also been identified. Neuropeptide Y, acting through hypothalamic Y2 receptors, is capable of skeleton-wide modulation of osteoblast activity, with important coordination between body weight and bone mass. Cannabinoids, acting through central cannabinoid receptor 1 and bone cell cannabinoid receptor 2 receptors, modulate osteoclast activity, thereby identifying pathways active on both aspects of the bone remodeling process. This review explores the key central pathways to bone and explores the complexity of the interactions being revealed by this emergent field of research. Topics: Animals; Body Weight; Bone and Bones; Humans; Hypothalamus; Leptin; Osteogenesis; Serotonin | 2010 |
Leptin, ghrelin, and endocannabinoids: potential therapeutic targets in anorexia nervosa.
Anorexia nervosa (AN) has the highest mortality rate between psychiatric disorders, and evidence for managing it is still very limited. So far, pharmacological treatment has focused on a narrow range of drugs and only a few controlled studies have been performed. Furthermore, the studies have been of short duration and included a limited number of subjects, often heterogenic with regard to stage and acute nutritive status. Thus, novel approaches are urgently needed. Body weight homeostasis is tightly regulated throughout life. With the discovery of orexigenic and anorectic signals, an array of new molecular targets to control eating behavior has emerged. This review focuses on recent advances in three important signal systems: leptin, ghrelin, and endocannabinoids toward the identification of potential therapeutical breakthroughs in AN. Our review of the current literature shows that leptin may have therapeutic potentials in promoting restoration of menstrual cycles in weight restored patients, reducing motor restlessness in severely hyperactive patients, and preventing osteoporosis in chronic patients. Ghrelin and endocannabinoids exert orexigenic effects which may facilitate nutritional restoration. Leptin and endocannabinoids may exert antidepressive and anxiolytic effects. Finally, monitoring serum concentration of leptin may be useful in order to prevent refeeding syndrome. Topics: Animals; Anorexia Nervosa; Anxiety; Body Weight; Cannabinoid Receptor Modulators; Depression; Endocannabinoids; Ghrelin; Humans; Leptin; Menstrual Cycle | 2009 |
Leptin-mediated neuroendocrine alterations in anorexia nervosa: somatic and behavioral implications.
Hypoleptinemia is a key endocrinological feature of anorexia nervosa (AN). Several symptoms in acute AN are related to the low circulating leptin levels including amenorrhea and semi-starvation-induced hyperactivity. The drop in leptin levels results from the loss of fat mass; once leptin levels fall below specific thresholds the hypothalamic-pituitary-gonadal and -thyroid axes are down-regulated; in contrast, the hypothalamic-pituitary-adrenal axis is up-regulated. Hypoleptinemia is the major signal underlying both somatic and behavioral adaptations to starvation. Because the mechanisms involved in this adaptation are similar in rodents and humans, rodent models can be used to investigate the relevant central pathways which underly the respective starvation-induced symptoms. During therapeutically induced weight gain, leptin levels can intermittently increase above normal concentrations. This hyperleptinemia could predispose to renewed weight loss. Topics: Adolescent; Amenorrhea; Anorexia Nervosa; Body Weight; Female; Humans; Leptin; Motor Activity; Neurosecretory Systems; Osteoporosis; Starvation; Weight Loss | 2009 |
Leptin at 14 y of age: an ongoing story.
The cloning of the ob gene and its gene product leptin has led to the elucidation of a robust physiologic system that maintains constancy of fat stores. Leptin is a peptide hormone secreted by adipose tissue and regulates adipose tissue mass and energy balance. Recessive mutations in the leptin gene are associated with massive obesity in mice and in some humans, which establishes a genetic basis for obesity. Leptin circulates in blood and acts on the brain to regulate food intake and energy expenditure. When fat mass decreases, plasma leptin concentrations decrease, which stimulates appetite and suppresses energy expenditure until fat mass is restored. When fat mass increases, leptin concentrations increase, which suppresses appetite until weight is lost. This system maintains homeostatic control of adipose tissue mass. Topics: Adipose Tissue; Animals; Body Weight; Cloning, Molecular; Humans; Leptin | 2009 |
The role of leptin-melanocortin system and human weight regulation: lessons from experiments of nature.
Common obesity is a multi-factorial trait, contributed by the "obesogenic" environment of caloric abundance and increasing automation, sedentary lifestyle and an underlying genetic susceptibility. There have been major advances in the past decade in our understanding of the human weight regulation mechanism and pathogenesis of obesity, abetted by discoveries of genetic defects which lead to human obesity.. Reports of genetic mutations causing obesity in humans and murine models were reviewed.. Humans with genetic defects resulting in leptin deficiency, leptin receptor deficiency, proopiomelanocortin deficiency (POMC), and melanocortin 4 receptor (MC4R) deficiency developed severe obesity as the dominant phenotypic feature, though these are rare autosomal recessive conditions, except MC4R deficiency which is inherited in an autosomal co-dominant fashion. Common and rare variants of the POMC and melanocortin 3 receptor genes may be predisposing factors in the development of common obesity. Recent reports of human obesity associated with thyrosine kinase B (TrkB) defect and brain derived neurotrophic factor (BDNF) disruption, coupled with other murine studies, supported the role of BDNF/TrkB as effectors downstream of the melanocortin receptors.. Despite exciting discoveries of single gene mutations resulting in human obesity, most cases of obesity are likely the result of subtle interactions of several related genetic variants with environmental factors which favour the net deposition of calories as fat, culminating in the obese phenotype. The mechanisms of action of these genes in the development of obesity are now being examined, with the aim of eventually discovering a therapeutic intervention for obesity. Topics: Animals; Body Weight; Disease Models, Animal; Humans; Leptin; Melanocortins; Mice; Mutation; Obesity | 2009 |
Synergy of nature and nurture in the development of childhood obesity.
Epidemiological studies suggest that maternal undernutrition, obesity and diabetes during gestation and lactation can all produce obesity in human offspring. Animal models provide a means of assessing the independent consequences of altering the pre- vs postnatal environments on a variety of metabolic, physiological and neuroendocrine functions, which lead to the development of offspring obesity, diabetes, hypertension and hyperlipidemia. During the gestational period, maternal malnutrition, obesity, type 1 and type 2 diabetes, and psychological and pharmacological stressors can all promote offspring obesity. Normal postnatal nutrition can sometimes reduce the adverse effect of some of these prenatal factors, but may also exacerbate the development of obesity and diabetes in offspring of dams that are malnourished during gestation. The genetic background of the individual is also an important determinant of outcome when the perinatal environment is perturbed. Individuals with an obesity-prone genotype are more likely to be adversely affected by factors such as maternal obesity and high-fat diets. Many perinatal manipulations are associated with reorganization of the central neural pathways which regulate food intake, energy expenditure and storage in ways that enhance the development of obesity and diabetes in offspring. Both leptin and insulin have strong neurotrophic properties so that an excess or an absence of either of them during the perinatal period may underlie some of these adverse developmental changes. As perinatal manipulations can permanently and adversely alter the systems that regulate energy homeostasis, it behooves us to gain a better understanding of the factors during this period that promote the development of offspring obesity as a means of stemming the tide of the emerging worldwide obesity epidemic. Topics: Animals; Body Weight; Child; Disease Models, Animal; Energy Metabolism; Exercise; Female; Humans; Infant, Newborn; Insulin; Lactation; Leptin; Maternal Nutritional Physiological Phenomena; Mice; Mice, Inbred Strains; Obesity; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Weaning | 2009 |
Minireview: Molecular targets for obesity therapy in the brain.
Energy balance (intake and expenditure) is under the control of complex and redundant neural pathways that regulate feeding behavior and energy metabolism in response to availability of nutrients in the circulation or in fat stores. A number of hormones are secreted from peripheral organs and act in the hypothalamus to influence appetite and energy expenditure. This review will summarize recent progress in the identification of the neural pathways that respond to peripheral signals of energy availability such as leptin and macronutrients. Although the impact of environmental factors on obesity is underscored by the modern obesity epidemic, new insights into the pathophysiology of weight control provide new targets for therapeutic intervention for obesity. Topics: Animals; Body Weight; Brain; Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity | 2009 |
[Pleiotropic effects of leptin].
Leptin, also called the satiation hormone plays a key role in regulating body weight, energy intake, and expenditure. Leptin interacts with its receptors, mainly located in the hypothalamus. Moreover, there has been an increasing evidence that leptin exerts pleiotropic effects. Multiple peripheral effects of leptin have been recently described including synthesis of the various hormones, e.g., sexual hormones, thyroid hormones, and growth hormone, as well as regulation of blood pressure, reproduction, osteogenesis, hematopoesis, angiogenesis. Leptin also plays a regulatory function in immunity.and in the process of tumorigenesis. Despite intensive investigations since leptin discovery in 1994 we have much to learn about the leptin mechanism of actions and effects. Topics: Animals; Body Weight; Cell Transformation, Neoplastic; Energy Metabolism; Hematopoiesis; Hormones; Humans; Leptin; Neoplasms; Neovascularization, Physiologic; Receptors, Leptin | 2009 |
Sex-dependent alterations in response to maternal deprivation in rats.
We review here our latest results regarding short- and long-term effects of a neonatal maternal deprivation (MD) stress [24h at postnatal day (PND) 9] on diverse psychoneuroimmunoendocrine parameters, pointing out the existence of numerous sexual dimorphisms. Behavioral changes observed in MD animals might be at least in part attributable to neurodevelopmental effects of MD-induced elevated corticosterone levels. Our findings of short-term effects of MD on hippocampal and cerebellar neurons and glial cells appear to support this hypothesis. However, it is important to note that these cellular effects were more marked in males than in females. Moreover, in analyzing the effects of this neonatal stress on the endocannabinoid system (hippocampal endocannabinoid levels and CB1 receptors) we have also found that males were more affected by MD. Since all these sexual dimorphisms were found at an early neonatal age (PND 13), they are attributable to organizational effects of gonadal steroids. We discuss the potential implications of the elevated corticosterone and decreased leptin levels shown by MD animals in their diverse functional alterations, including the above mentioned neural effects as well as the intriguing persistent deficit in their immunological system. We also emphasize the necessity of analyzing the important influence of sex as regards the specific consequences of early life stress. Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Brain; Cannabinoid Receptor Modulators; Chemotaxis; Corticosterone; Disease Models, Animal; Humans; Leptin; Lymphocyte Activation; Maternal Deprivation; Mental Disorders; Receptors, Cannabinoid; Sex Characteristics; Stress, Psychological | 2009 |
Influence of Helicobacter pylori on gastric regulation of food intake.
To evaluate the influence of Helicobacter pylori infection on the gastric regulation of food intake and body weight.. H. pylori infection leads to a decrease of circulating ghrelin through a reduction of ghrelin-producing cells in the gastric mucosa and increases the amount of gastric leptin with no effect on circulating leptin levels. Eradication of H. pylori reverses the abnormal regulation of gastric hormone secretion. This finding is suggested to favor weight gain after H. pylori eradication and points to the potential effect of H. pylori in the pathophysiology of obesity.. H. pylori has an influence on the release of gastric hormones and therefore plays a role in the regulation of body weight, hunger and satiety. Topics: Appetite; Body Weight; Eating; Gastric Mucosa; Gastritis; Ghrelin; Helicobacter Infections; Helicobacter pylori; Homeostasis; Humans; Leptin | 2009 |
Functional body composition: insights into the regulation of energy metabolism and some clinical applications.
The application of advanced methods and techniques and their continuous development enable detailed body composition analyses (BCAs) and modeling of body composition at different levels (e.g., at atomic, molecular, organ-tissue and whole body level). Functional body composition integrates body components into regulatory systems (e.g., on energy balance). Regulation of body weight is closely linked to the mass and function of individual body components. Fat mass is part of the energy intake regulatory feedback system. In addition, fat-free mass (FFM) and fat mass are both determinants of resting energy expenditure (REE). Up to 80% of the variance in energy intake and energy expenditure is explained by body composition. A deviation from normal associations between body components and function suggests a metabolic disequilibrium (e.g., in the REE-FFM relationship or in the plasma leptin-fat mass association) that may occur in response to weight changes and diseases. The concept of functional body composition adds to a more sophisticated view on nutritional status and diseases, as well as to a characterization of biomedical traits that will provide functional evidence relating genetic variants. Topics: Adipose Tissue; Basal Metabolism; Body Composition; Body Weight; Energy Intake; Humans; Leptin | 2009 |
Central leptin gene therapy ameliorates diabetes type 1 and 2 through two independent hypothalamic relays; a benefit beyond weight and appetite regulation.
Although its role in energy homeostasis is firmly established, the evidence accumulated over a decade linking the adipocyte leptin-hypothalamus axis in the pathogenesis of diabetes mellitus has received little attention in the contemporary thinking. In this context various lines of evidence are collated here to show that (1) under the direction of leptin two independent relays emanating from the hypothalamus restrain insulin secretion from the pancreas and mobilize peripheral organs--liver, skeletal muscle and brown adipose tissue--to upregulate glucose disposal, and (2), leptin insufficiency in the hypothalamus produced by either leptinopenia or restriction of leptin transport across the blood brain barrier due to hyperleptinemia of obesity and aging, initiate antecedent pathophysiological sequalae of diabetes type 1 and 2. Further, we document here the efficacy of leptin replenishment in vivo, especially by supplying it to the hypothalamus with the aid of gene therapy, in preventing the antecedent pathophysiological sequalae--hyperinsulinemia, insulin resistance and hyperglycemia--in various animal models and clinical paradigms of diabetes type 1 and 2 with or without attendant obesity. Overall, the new insights on the long-lasting antidiabetic potential of two independent hypothalamic relays engendered by central leptin gene therapy and the preclinical safety indicators in rodents warrant further validation in subhuman primates and humans. Topics: Animals; Appetite Regulation; Body Weight; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose; Humans; Hypothalamus; Insulin; Leptin; Obesity; Signal Transduction | 2009 |
Recent advances in understanding leptin signaling and leptin resistance.
The brain controls energy homeostasis and body weight by integrating various metabolic signals. Leptin, an adipose-derived hormone, conveys critical information about peripheral energy storage and availability to the brain. Leptin decreases body weight by both suppressing appetite and promoting energy expenditure. Leptin directly targets hypothalamic neurons, including AgRP and POMC neurons. These leptin-responsive neurons widely connect to other neurons in the brain, forming a sophisticated neurocircuitry that controls energy intake and expenditure. The anorexigenic actions of leptin are mediated by LEPRb, the long form of the leptin receptor, in the hypothalamus. LEPRb activates both JAK2-dependent and -independent pathways, including the STAT3, PI 3-kinase, MAPK, AMPK, and mTOR pathways. These pathways act coordinately to form a network that fully mediates leptin response. LEPRb signaling is regulated by both positive (e.g., SH2B1) and negative (e.g., SOCS3 and PTP1B) regulators and by endoplasmic reticulum stress. Leptin resistance, a primary risk factor for obesity, likely results from impairment in leptin transport, LEPRb signaling, and/or the neurocircuitry of energy balance. Topics: Animals; Body Weight; Brain; Humans; Leptin; Obesity; Receptors, Leptin; Signal Transduction | 2009 |
Adipokines: emerging therapeutic targets.
Adipose tissue can affect human physiology through its secreted products, collectively termed adipokines, which mediate complex crosstalk between organs. Adipokines have been linked to a wide range of pathologies in many tissues; however, the pathophysiological significance of these cytokines remains poorly understood, and more research is needed in this area. Adipokines may have both beneficial and potentially harmful effects; for example, leptin reduces body weight, but also impairs immune responses. A cautious approach is therefore warranted when considering the pharmacological manipulation of adipokines to treat diseases, and novel approaches may be required to target specific organs or actions to reduce the potential for adverse effects. Topics: Adipokines; Adipose Tissue; Animals; Body Weight; Drug Delivery Systems; Humans; Leptin | 2009 |
Melanocortin-4 receptor mutations in obesity.
The current alarming spread of obesity in many parts of the world is caused by a sudden environmental shift characterized by replacement of a frugal diet with low cost, energy dense food, and little requests for physical activity during work and leisure time. Yet, not all people exposed to an obesogenic environment become obese, and individual differences in the propensity to gain weight as well as the occurrence of different obese phenotypes within the same environment indicate that the genetic heritage in this regard is significant and heterogeneous. The central melanocortin circuit has received much attention during the past decade, since mutations of genes expressing some key molecules in neurons of this system were discovered, which may cause monogenic forms of obesity in animals and humans. Within the arcuate nucleus of the hypothalamus the prohormone proopiomelanocortin is posttranslationally cleaved to produce the alpha-melanocyte stimulating hormone, a peptide with anorexigenic effects upon activation of the melanocortin-4 receptor (MC4R) expressed on the surface of target neurons. Studies regarding the frequency of MC4R mutations associated with human obesity have provided variable results (up to 6% of obese subjects). Various findings suggest an oligogenic and codominant mode of inheritance for MC4R deficiency, with modulation of expressivity and penetrance of the phenotype. The yield of MC4R testing in clinical diagnosis and treatment of obesity is at present undefined since the relatively low prevalence of MC4R pathogenic variants in the general population, along with the high number of sequence variants, has so far compromised the devising of systematic controlled intervention studies. Hopefully, in the future, MC4R testing will have practical implications for the development of new mechanism-based therapy of obesity as well as for the design of specific and more effective protocols, based on lifestyle intervention and current pharmacological or surgical approaches, for management of obesity in MC4R-mutated individuals. Topics: Agouti-Related Protein; alpha-MSH; beta-MSH; Body Weight; Central Nervous System; Humans; Leptin; Mutation; Obesity; Receptor, Melanocortin, Type 4 | 2009 |
[Leptin-melanocortin system, body weight regulation and obesity].
Obesity is a multifactorial disease that is rarely associated to single gene defects. However, due to their direct cause-effect relationships, those genetic defects that cause some forms of monogenic obesity are relevant in the study of mechanisms that contribute to increased energy intake and body fat accumulation. Most of the genes that have been shown to cause monogenic obesity are related to the leptin-melanocortin system. The functionality of this system has been elucidated through natural mutations (Agouti, ob and db) in mice and knock-out models. Mutations related to human monogenic obesity have been described in leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1 or melanocortin receptor 4 genes. Therapy with human recombinant leptin in patients with genetic deficiency of the hormone is an effective medical treatment of obesity, although only applicable to very few families. The use of leptin-melanocortin agonists, drugs to avoid leptin resistance or combinations of treatments with leptin and other satiating peptides are currently being investigated for multifacotiral human obesity. Topics: Animals; Body Weight; Humans; Leptin; Melanocortins; Mice; Mutation; Obesity | 2009 |
The regulation of seasonal changes in food intake and body weight.
Seasonal rhythms of body weight, reflecting altered food intake, energy storage and expenditure, are a common feature of mammals inhabiting temperate and arctic latitudes. They have evolved so that predictable annual changes in the external environment can be anticipated and animals can adjust their physiology and behaviour in preparation for the changing demands of the seasons. These long-term changes in energy balance are not simply effected by the brain centres and peptidergic pathways known to underlie short-term homeostatic regulation. Screens of altered gene expression in Siberian hamsters comparing the anabolic summer state in long photoperiods and the catabolic 'winter' state in short photoperiods have identified differential gene expression in the hypothalamus. The majority of gene expression changes are confined to two restricted areas: the dorsomedial posterior arcuate nucleus, and the ventral ependymal layer of the third ventricle. Functions encoded by these 'seasonal' genes include thyroid hormone metabolism, retinoic acid and histaminergic signalling, and VGF and secretogranin production. The changes in thyroid hormone availability that are brought about by differential activity of deiodinase enzymes are of particular importance because experimental manipulation of central thyroid levels can prevent seasonal cyclicity. Given the importance of thyroid hormone in the initial development of the brain, we hypothesise that thyroid hormone-dependent plasticity of hypothalamic connections and neurogenesis underlie seasonal cycles of food intake and body weight. Topics: Animals; Body Weight; Circadian Rhythm; Cricetinae; Eating; Energy Metabolism; Homeostasis; Hypothalamus; Leptin; Neuronal Plasticity; Photoperiod; Seasons; Thyroid Hormones | 2008 |
Role of hypothalamic AMP-kinase in food intake regulation.
Adenosine monophosphate-activated protein kinase (AMPK) functions as a cellular fuel gauge that regulates metabolic pathways in nutrient metabolism. Recent studies have strongly implicated that AMPK in the hypothalamus regulates energy metabolism by integrating inputs from multiple hormones, peptides, neurotransmitters, and nutrients. Leptin is an adipocyte hormone that regulates food intake and energy expenditure in peripheral tissues. Leptin inhibits AMPK activity in the arcuate and paraventricular hypothalamus, and its inhibition is necessary for the anorexic effect of leptin. Alteration of hypothalamic AMPK activity is sufficient to change food intake and body weight. Furthermore, fasting/refeeding, glucose, and melanocortin receptor alter AMPK activity in the hypothalamus. Adiponectin has also been shown to increase food intake by activating AMPK in the arcuate hypothalamus. Recent data have shown that acetyl-coenzyme A carboxylase/malonyl-coenzyme A/carnitine palmitoyltransferase-1/fatty acid oxidation and mammalian target of rapamycin signalings are putative downstream pathways for food intake regulation in response to hypothalamic AMPK. Thus, these results suggest that food intake and nutrient metabolism are coordinately regulated by the common signaling pathway of AMPK in the hypothalamus. Topics: Adenylate Kinase; Animals; Body Weight; Eating; Energy Metabolism; Feeding Behavior; Hormones; Hypothalamus; Leptin; Mice; Signal Transduction | 2008 |
Hypothalamic neuronal histamine regulates body weight through the modulation of diurnal feeding rhythm.
Hypothalamic neuronal histamine and its H(1) receptor (H(1)-R), a leptin signaling pathway in the brain, regulate body weight and adiposity by affecting food intake and energy expenditure. Glucagon-like peptide-1 and/or corticotrophin-releasing hormone mediate leptin signaling to neuronal histamine. Leptin-induced suppression of food intake and upregulation of uncoupling protein-1 expression in brown adipose tissue were partially attenuated in histamine H(1)-R knockout (H(1)KO) mice. H(1)KO mice developed maturity-onset obesity. Hyperphagia and decreased energy expenditure assessed by the expression of uncoupling protein-1 mRNA were observed in older (48-wk-old) obese H(1)KO mice but not in younger (12-wk-old) non-obese H(1)KO mice. However, the diurnal feeding rhythm was impaired even in younger non-obese animals. Specifically, disruption of the feeding rhythm developed before the onset of obesity in H(1)KO mice. Correction of these abnormal feeding rhythms with scheduled feeding improved the obesity and associated metabolic disorders in the H(1)KO mice. These findings suggest that histamine H(1)-R is crucial for regulating the feeding rhythm and in mediating the effects of leptin. Early disruption of H(1)-R-mediated functions in H(1)KO mice may lead to hyperphagia and decreased energy expenditure, which may contribute to the development of obesity in these animals. Topics: Animals; Appetite Regulation; Behavior, Animal; Body Weight; Circadian Rhythm; Eating; Energy Metabolism; Feeding Behavior; Histamine; Hypothalamus; Leptin; Mice; Obesity | 2008 |
Diet-induced inflammation of the hypothalamus in obesity.
Dysfunction of specific hypothalamic neurons is regarded as an important mechanism predisposing to the development of obesity. Recent studies have revealed that the consumption of fat-rich foods can activate an inflammatory response in the hypothalamus, which disturbs the anorexigenic and thermogenic signals generated by the hormones leptin and insulin, leading in turn to anomalous body mass control. Depending on diet composition, cytokines are expressed in the hypothalamus, contributing to the activation of intracellular inflammatory signal transduction. At least 4 distinct signaling pathways have been identified and the molecular mechanisms leading to the impairment of the leptin and insulin actions have been determined. Here, we present the mechanisms involved in diet-induced resistance to leptin and insulin action in the hypothalamus and discuss some of the potential applications of this knowledge in the therapeutics of obesity. Topics: Animals; Body Weight; Cytokines; Dietary Fats; Encephalitis; Humans; Hypothalamus; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Obesity; Signal Transduction | 2008 |
Neuropeptide Y and alpha-melanocyte-stimulating hormone: interaction in obesity and possible role in the development of hypertension.
Obesity and hypertension frequently coexist and both represent important risk factors for cardiovascular disease. The mechanisms implicated in the regulation of food intake have not been completely elucidated. Recent data suggests that peripheral and central neuropeptides play an important role in the maintenance of energy balance. More specifically, leptin, neuropeptide Y (NPY) and alpha-melanocyte-stimulating hormone (a-MSH) appear to be implicated in the pathogenesis of obesity and also contribute to the development of hypertension in obesity.. Analysis of the pertinent bibliography published in PubMed database.. Leptin is produced in the adipose tissue directly correlated with fat tissue mass. Leptin acts on two distinct neural populations in the hypothalamus: the first expresses the orexigenic peptides NPY and agouti-related protein (AgRP), the second pro-opiomelanocortin (POMC). The activation of POMC neurons increases the production of the anorexigenic hormone a-MSH and inhibits the release of NPY and AgRP. In addition, the hypothalamus integrates the neuroendocrine systems with the autonomic nervous system and controls the activity of the latter. Stimulation of hypothalamic nuclei elicits sympathetic responses including blood pressure elevation. Both NPY and a-MSH appears to be implicated in the hypothalamic regulation of sympathetic nervous system (SNS) activity.. Alterations in leptin, NPY and a-MSH are frequently observed in obesity and might stimulate SNS activity, contributing to the development of hypertension in obese patients. These neuropeptides might provide a pathophysiologic link between excess weight and hypertension. However, more research is needed before the pharmacologic manipulation of these complex neuroendocrine systems can be applied in the treatment of obesity and hypertension. Topics: alpha-MSH; Appetite Regulation; Body Weight; Humans; Hypertension; Leptin; Neuropeptide Y; Obesity; Sympathetic Nervous System | 2008 |
Hormone-based therapies in the regulation of fuel metabolism and body weight.
The integrated central actions of hormones secreted from pancreatic islets, the gut and adipocytes regulate both energy homeostasis and body weight. Dysregulation in these neurohormonal pathways probably contributes to pathogenesis of obesity and type 2 diabetes.. To examine hormone-based therapies targeting these interrelated pathways as potential treatments for obesity and diabetes.. Preclinical and clinical data on therapies based on hormones secreted from the pancreas (glucagon, insulin, amylin and pancreatic polypeptide), gut (glucagon-like peptide-1, glucose dependent insulinotropic polypeptide, cholecystokinin and peptide YY) and adipose tissue (leptin and adiponectin) as potential treatments for diabetes and obesity are reviewed.. In diabetes, hormone-based treatments have translated into new clinical platforms including insulin analogs, the GLP-1-like peptide receptor agonist exenatide and amylinomimetic pramlintide, which due to their complex interplay and the progressive nature of diabetes, can be utilized in different settings. Various peptide hormones and agonists/antagonists are currently under investigation as new approaches to treatment of obesity and diabetes. Topics: Adipocytes; Adiponectin; Adipose Tissue; Amyloid; Animals; Body Weight; Diabetes Mellitus, Type 2; Energy Metabolism; Glucagon-Like Peptide 1; Homeostasis; Hormones; Humans; Intestinal Mucosa; Islet Amyloid Polypeptide; Leptin; Mice; Obesity; Pancreas | 2008 |
Molecular physiology of weight regulation in mice and humans.
Evolutionary considerations relating to efficiency in reproduction, and survival in hostile environments, suggest that body energy stores are sensed and actively regulated, with stronger physiological and behavioral responses to loss than gain of stored energy. Many physiological studies support this inference, and suggest that a critical axis runs between body fat and the hypothalamus. The molecular cloning of leptin and its receptor-projects based explicitly on the search for elements in this axis-confirmed the existence of this axis and provided important tools with which to understand its molecular physiology. Demonstration of the importance of this soma-brain reciprocal connection in body weight regulation in humans has been pursued using both classical genetic approaches and studies of physiological responses to experimental weight perturbation. This paper reviews the history of the rationale and methodology of the cloning of leptin (Lep) and the leptin receptor (Lepr), and describes some of the clinical investigation characterizing this axis. Topics: Adipose Tissue; Animals; Body Weight; Brain; Energy Metabolism; Homeostasis; Humans; Leptin; Mice; Receptors, Leptin | 2008 |
Leptin as a nutritional signal regulating appetite and reproductive processes in seasonally-breeding ruminants.
Photoperiod and nutrition both exert major influences on reproduction. Thus, it seems axiomatic that seasonal rhythms in ovulation are influenced by nutrition. In this context, leptin is one of the most important hormonal signals involved in the control of energy homeostasis, feeding behavior and reproductive function in mammals. However, the number of published investigations establishing a functional interaction between leptin and photoperiodism in seasonal breeders is limited. In common with most seasonally-breeding mammals, sheep exhibit robust circannual cycles in body weight and reproduction, which are driven mainly by changes in day-length. Recently, attention has focused on the role of leptin in this process, particularly in its roles as a major peripheral signal controlling appetite, melatonin and prolactin secretion. The purpose herein is to review current concepts in the overall biology of leptin, to summarize its influence on the hypothalamic-pituitary axis, and to highlight recent developments in our understanding of its interaction with season in regulating appetite, body weight and reproduction in seasonally-breeding mammals. The latter observations may be important in delineating states of leptin resistance and obesity in humans. Topics: Animals; Appetite Regulation; Body Weight; Female; Humans; Hypothalamo-Hypophyseal System; Leptin; Male; Photoperiod; Pituitary-Adrenal System; Reproduction; Seasons; Sheep; Signal Transduction | 2008 |
The role of syndecans in the regulation of body weight and synaptic plasticity.
Body weight is tightly regulated by a feedback mechanism involving peripheral adiposity signals and multiple central nervous system neurotransmitter pathways. Despite the tight regulation of body weight there is an increase in the prevalence of obesity and overweight in Western society. Obesity and overweight are conditions of excess body weight stored as fat. Syndecan-3, a member of the syndecan family of type I transmembrane heparan sulfate proteoglycans is a novel a regulator of feeding behavior and body weight. Syndecans are extracellular matrix molecules (ECMs) that modulate cell adhesion, cell-cell interactions and ligand-receptor interactions. The finding that syndecan-3 can regulate body weight is novel and provides a unique link between the extracellular matrix and body weight regulatory mechanisms. Uniquely, hormones such as leptin previously thought only to regulate body weight by modulating neuropeptide levels, have now been demonstrated to regulate neuronal plasticity in the hypothalamus. ECMs and syndecans have long been recognized as regulators of plasticity. Therefore, this review will focus on highlighting the role of syndecans and in particular syndecan-3 in neuronal development and synaptic organization and how these processes may integrate body weight regulation. As part of this review, we will highlight how syndecan-3 can mediate the activity of adiposity signals, such as leptin, and facilitate changes in neuronal plasticity. Topics: Animals; Body Weight; Brain; Feedback, Physiological; Gene Expression Regulation, Developmental; Humans; Leptin; Mice; Mice, Knockout; Neural Pathways; Neuronal Plasticity; Obesity; Polymorphism, Genetic; Rats; Synaptic Transmission; Syndecans | 2008 |
Leptin and the sympathetic connection of fat to bone.
Loss of body weight is associated with bone loss, and body weight gain is associated with increased bone formation. The molecular mechanisms linking body weight, body composition, and bone density are now better understood. Lean mass is likely to have a significant, local effect on bone modeling and remodeling through mechanotransduction pathways. In contrast to the local regulation of bone formation and resorption by muscle-derived stimuli, peripheral body fat appears to influence bone mass via secretion of systemic, endocrine factors that link body weight to bone density even in non-weight bearing regions (e.g., the forearm). The cytokine-like hormone leptin, which is secreted by fat cells, is an important candidate molecule linking changes in body composition with bone formation and bone resorption. Increases in body fat increase leptin levels and stimulate periosteal bone formation through its direct anabolic effects on osteoblasts, and through central (CNS) effects including the stimulation of the GH-IGF-1 axis and suppression of neuropeptide Y, a powerful inhibitor of bone formation. Stimulation of beta2-adrenergic receptors through central (hypothalamic) leptin receptors does, however, increase remodeling of trabecular bone, resulting in a lower cancellous bone volume that may be better adapted to a concomitantly larger cortical bone compartment. These findings suggest that body weight and body fat can regulate bone mass and structure through molecular pathways that are independent of load-bearing. Furthermore, pharmacological manipulation of the signaling pathways activated by leptin may have significant potential for the treatment and prevention of bone loss. Topics: Adipogenesis; Animals; Body Weight; Bone Density; Bone Development; Humans; Leptin; Mice; Obesity; Polymorphism, Genetic; Receptors, Leptin; Receptors, Neuropeptide Y | 2008 |
The development of tolerance to drugs that suppress food intake.
Appetite suppressants have been available as weight-reducing aids for over 50 years. The first discovered was amphetamine, which was potent, but possessed undesirable side effects (it is a stimulant and elevates blood pressure). Subsequently, a variety of appetite drugs was developed, all structurally related to amphetamine, but mostly lacking unwanted side effects. Until recently, fenfluramine (FEN) was the most widely used; presently, sibutramine is the most commonly used appetite suppressant. While these appetite suppressants are effective at reducing hunger and food intake when given as a single dose or for short periods of time, their effectiveness diminishes when administered chronically. The biological mechanisms underlying this tolerance have not been carefully studied, but many possibilities have been identified, including the down-regulation in brain of neurotransmitter receptors that might mediate the action of these drugs and adaptive responses of the appetite control circuitry in brain. To date, however, few studies have examined these possibilities in any detail. This article focuses on the question of why appetite suppressants lose efficacy, when given chronically, because this issue is important to the development of the next generation of appetite suppressants. Chronic efficacy should be an issue studied relatively early in the drug development process. This issue is of particular relevance, since obesity treatment is now recognized as a long-term, not a short-term, process. If appetite suppressants are to become a more important tool in obesity treatment, agents that do not lose efficacy when administered for extended periods of time must be identified. Topics: Animals; Appetite Depressants; Body Weight; Cyclobutanes; Drug Tolerance; Eating; Fenfluramine; Humans; Leptin; Obesity; Rats; Time Factors; Weight Loss | 2008 |
From feeding one to feeding many: hormone-induced changes in bodyweight homeostasis during pregnancy.
Pregnancy is associated with hyperphagia, increased fat mass, hyperleptinaemia and hyperprolactinaemia. The neuroendocrine control of bodyweight involves appetite-regulating centres in the hypothalamus, containing both orexigenic and anorexigenic neurons that express leptin receptors (LepR). In the rat, central leptin resistance develops during mid pregnancy, well after hyperphagia becomes apparent, to negate the appetite suppressing effects of leptin. We have investigated the hypothalamic response to leptin during pregnancy and examined the role of pregnancy hormones in inducing these changes. We have shown that there are multiple levels of leptin resistance during pregnancy. Despite elevated serum leptin, neuropeptide Y and agouti related peptide mRNA in the arcuate nucleus are not suppressed and may even be increased during pregnancy. LepR mRNA and leptin-induced pSTAT3 expression, however, are relatively normal in the arcuate nucleus. In contrast, both LepR and leptin-induced pSTAT3 are reduced in the ventromedial hypothalamic nucleus. Injecting alpha-melanocyte-stimulating hormone (alpha-MSH) into the brain, to bypass the first-order leptin-responsive neurons in the arcuate nucleus, also fails to suppress food intake during pregnancy, suggesting that pregnancy is also a melanocortin-resistant state. Using a pseudopregnant rat model, we have demonstrated that in addition to the changes in maternal ovarian steroid secretion, placental lactogen production is essential for the induction of leptin resistance in pregnancy. Thus, hormonal changes associated with pregnancy induce adaptive changes in the maternal hypothalamus, stimulating food intake and then allowing elevated food intake to be maintained in the face of elevated leptin levels, resulting in fat deposition to provide energy stores in preparation for the high metabolic demands of late pregnancy and lactation. Topics: Animals; Body Weight; Eating; Energy Metabolism; Female; Homeostasis; Leptin; Pregnancy; Pregnancy, Animal; Pseudopregnancy; Rats | 2008 |
Leptin and ghrelin levels in patients with schizophrenia during different antipsychotics treatment: a review.
Energy homeostasis is achieved by the integration of peripheral metabolic signals by the neural circuits involving specific hypothalamic nuclei and brain stem regions. These neural circuits mediate many of the effects of the adipocyte-derived hormone leptin and gut-derived hormone ghrelin. The former is strongly anorexigenic while the latter is the only orexigenic agent active when administered by a peripheral route. Abnormal regulation of these 2 antagonistic regulatory peptides in patients with schizophrenia could play a role in the impairment in the regulation of food intake and energy balance. This bibliographical analysis aims to compare 27 prospective and cross-sectional studies published on circulating leptin and ghrelin levels during acute and chronic administration of antipsychotics treatment, especially atypical ones. Fasting morning leptin levels of schizophrenic patients increase rapidly in the first 2 weeks after atypical antipsychotic (AAP) treatment (mostly olanzapine and clozapine) and remain somehow elevated after that period up to several months. On the contrary, conventional antipsychotics (such as haloperidol) do not interfere with leptin levels. In contrast to leptin, fasting morning ghrelin levels decrease during the first few weeks after the beginning of AAPs treatment while they increase in the longer run. Surprisingly, body weight gain and correlations between the variation of these 2 peptides and adiposity and metabolism-related parameters such as the body mass index and abdominal perimeter were not systematically considered. Finally, an objective evaluation of feeding behavior during antipsychotic treatment remains to be determined. Topics: Adult; Antipsychotic Agents; Appetite; Body Weight; Cross-Sectional Studies; Eating; Energy Metabolism; Female; Ghrelin; Homeostasis; Humans; Leptin; Male; Middle Aged; Prospective Studies; Schizophrenia; Young Adult | 2008 |
Impact of atypical antipsychotic therapy on leptin, ghrelin, and adiponectin.
Many adverse effects of atypical antipsychotic treatment are associated with antagonism of monoamine receptors; however, data indicate that important metabolic effects, such as hypertriglyceridemia and impairment in glucose/insulin homeostasis, may not be related to these mechanisms, leading investigators to explore alternative hypotheses. Promising candidates include a possible impact of antipsychotics on peptide hormonal regulators of metabolic control such as leptin, ghrelin, and adiponectin. The purpose of this review is to summarize recent data on changes in these hormones during atypical antipsychotic treatment.. A Medline search was performed for papers published from January 1999 to January 2007 using key words antipsychotic, atypical antipsychotic, and individual atypical antipsychotic drug names cross-referenced with leptin, ghrelin, and adiponectin.. The bulk of the published work focused on changes in body weight and serum leptin, with far less data on ghrelin, and adiponectin, and nonweight metabolic changes. Leptin changes were directly related to a medication's weight gain liability, with no added antipsychotic effects on leptin signaling. Conflicting results emerged for the other markers, but all three long-term studies on ghrelin showed increased levels in patients on atypical antipsychotics with weight gain liabilities.. Leptin increases during antipsychotic treatment are a result of weight gain rather than a direct impact of atypical antipsychotics on leptin physiology. Preliminary long-term data show increased ghrelin levels, but this finding must be replicated. The association with antipsychotic effects on glucose and lipid metabolism and these hormones remains virtually unstudied. Future research should indicate whether ghrelin and other peptide hormones may be useful predictors of weight gain or metabolic changes in patients on antipsychotics. Topics: Adiponectin; Adult; Animals; Antipsychotic Agents; Body Mass Index; Body Weight; Cross-Sectional Studies; Female; Ghrelin; Humans; In Vitro Techniques; Leptin; Male; Metabolic Syndrome; Obesity; Pharmacogenetics; Prospective Studies; Rats; Schizophrenia | 2008 |
Monogenic human obesity.
We and others have identified several single gene defects that disrupt the molecules in the leptinmelanocortin pathway causing severe obesity in humans. In this review, we consider these human monogenic obesity syndromes and discuss how far the characterisation of these patients has informed our understanding of the physiological role of leptin and the melanocortins in the regulation of human body weight and neuroendocrine function. Topics: Body Weight; Child; Child, Preschool; Humans; Leptin; Mutation; Obesity; Phenotype; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptor, trkB; Receptors, Leptin; Recombinant Proteins | 2008 |
Hypothalamic malonyl-coenzyme A and the control of energy balance.
An intermediate in the fatty acid biosynthetic pathway, malonyl-coenzyme A (CoA), has emerged as a major regulator of energy homeostasis not only in peripheral metabolic tissues but also in regions of the central nervous system that control satiety and energy expenditure. Fluctuations in hypothalamic malonyl-CoA lead to changes in food intake and peripheral energy expenditure in a manner consistent with an anorexigenic signaling intermediate. Hypothalamic malonyl-CoA is regulated by nutritional and endocrine cues including glucose and leptin, respectively. That malonyl-CoA is an essential component in the energy homeostatic signaling system of the hypothalamus is supported by convergence of physiological, pharmacological, and genetic evidence. This review will focus on evidence implicating malonyl-CoA as a central player in the control of body weight and adiposity as well as clues to the molecular mechanism by which carbon flux through the fatty acid biosynthetic pathway is linked to the neural control of energy balance. Topics: Adiposity; Animals; Body Weight; Carboxy-Lyases; Central Nervous System; Eating; Energy Metabolism; Fatty Acid Synthases; Fatty Acids; Glucose; Homeostasis; Humans; Hypothalamus; Leptin; Malonyl Coenzyme A; Mice; Models, Biological; Muscle, Skeletal; Oxidation-Reduction; Signal Transduction | 2008 |
[Effect of obesity on bone metabolism].
Obesity regulates bone metabolism not only by increasing weight loading but by modulating cytokines or hormones which are known to affect bone remodeling. As a result, it has been generally believed that obesity leads to an increase in bone mass. However, recent observations revealed that excessive fat mass may not protect against osteoporotic fractures. Topics: Adipocytes; Body Weight; Bone and Bones; Bone Remodeling; Cell Differentiation; Diet, Reducing; Fractures, Bone; Humans; Leptin; Obesity; Osteoblasts; Osteoporosis; Risk | 2008 |
Central nervous system regulation of energy metabolism: ghrelin versus leptin.
In this brief review, we introduce some major themes in the regulation of energy, lipid, and glucose metabolism by the central nervous system (CNS). Rather than comprehensively discussing the field, we instead will discuss some of the key findings made regarding the interaction of the hormones ghrelin and leptin with the CNS. Topics: Aged; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Central Nervous System; Diabetes Mellitus; Energy Metabolism; Ghrelin; Glucose; Homeostasis; Humans; Hypothalamus; Leptin; Obesity | 2008 |
Role of islet-, gut-, and adipocyte-derived hormones in the central control of food intake and body weight: implications for an integrated neurohormonal approach to obesity pharmacotherapy.
Contrary to its historical epithet as a lifestyle disorder, obesity is now widely recognized as having a neurobiological basis. This progress is due to our knowledge not only about energy homoeostatic pathways within the central nervous system (CNS), but also about the role of peripheral peptide hormones acting upon the CNS. These hormones include long-term adiposity signals, such as leptin, that inform the CNS primarily of changes in the body's overall fat and energy reserves, and short-term signals such as amylin, peptide YY (PYY) and ghrelin, that primarily reflect changes in the immediate nutritive state (energy intake). The limited weight loss effects achieved with current monotherapy approaches to obesity have been attributed, at least in part, to the redundancies and potent counter-regulatory responses within the neurohormonal feedback loop governing energy balance. Recently, we reported that combinations of amylin, leptin and PYY(3-36) resulted in additive and/or synergistic interactions and caused marked weight loss in the diet-induced obese rat model, which to date has reasonably predicted the clinical effects of several hormones in obese humans. If confirmed in ongoing translational clinical research studies, these findings may provide a physiological rationale for a novel, integrated neurohormonal approach to pharmacotherapy for obesity. Topics: Adipocytes; Adipokines; Body Weight; Brain; Energy Intake; Energy Metabolism; Feedback; Gastrointestinal Hormones; Homeostasis; Humans; Intestines; Islets of Langerhans; Leptin; Models, Biological; Pancreatic Hormones; Signal Transduction | 2008 |
The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review.
Leptin and ghrelin are two hormones that have been recognized to have a major influence on energy balance. Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation. As a growing number of people suffer from obesity, understanding the mechanisms by which various hormones and neurotransmitters have influence on energy balance has been a subject of intensive research. In obese subjects the circulating level of the anorexigenic hormone leptin is increased, whereas surprisingly, the level of the orexigenic hormone ghrelin is decreased. It is now established that obese patients are leptin-resistant. However, the manner in which both the leptin and ghrelin systems contribute to the development or maintenance of obesity is as yet not clear. The purpose of this review is to provide background information on the leptin and ghrelin hormones, their role in food intake and body weight in humans, and their mechanism of action. Possible abnormalities in the leptin and ghrelin systems that may contribute to the development of obesity will be mentioned. In addition, the potentials of leptin and ghrelin as drug targets will be discussed. Finally, the influence of the diet on leptin and ghrelin secretion and functioning will be described. Topics: Body Weight; Energy Intake; Energy Metabolism; Ghrelin; Humans; Leptin; Obesity; Peptide Hormones | 2007 |
[An increase in body weight after eradication of Helicobacter pylori].
Topics: Animals; Body Mass Index; Body Weight; Female; Gastritis; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Humans; Leptin; Male; Mice; Obesity; Pepsinogens; Rats | 2007 |
New targets for obesity pharmacotherapy.
An understanding of the mechanisms that regulate energy homeostasis is essential for understanding novel obesity therapies. The status of energy reserves is communicated to the brain by adiposity and satiety signals. These signals modify either anabolic or catabolic pathways and, consequently, alter food intake in line with signaled energy requirements. New antiobesity therapies are in development that target anabolic or catabolic regulatory networks to reduce food intake and/or increase energy expenditure to promote weight loss. Topics: Adiposity; Animals; Anti-Obesity Agents; Body Weight; Cannabinoid Receptor Modulators; Cholecystokinin; Energy Metabolism; Glucagon-Like Peptide 1; Humans; Leptin; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptor, Cannabinoid, CB1; Serotonin; Serotonin Receptor Agonists; Thyroid Hormones | 2007 |
Leptin and insulin homeostasis in epilepsy: relation to weight adverse conditions.
During managing patients with epilepsy, there is a great risk of weight changes, particularly weight gain with some antiepileptic medications. Weight gain is not only a cosmetic problem that leads to non-compliance to medications but also increases the risk for atherosclerosis and its related complications. The mechanisms underlying weight gain in epilepsy are multiple and controversial and have been attributed to the effect of epilepsy and more commonly the effect of antiepileptic medications on the central and peripheral mechanisms regulating weight homeostasis including the two main homeostatic hormones, leptin, a protein product of obesity gene secreted by adipocytes and insulin, a protein product of pancreatic beta-cells. Increased blood levels of leptin and insulin due to leptin and insulin resistance is observed in patients with epilepsy. Leptin forms an important link between weight gain, insulin resistance, epilepsy and atherosclerosis. The knowledge of the novel roles of leptin in patients with epilepsy will help identification of early markers for the related adverse weight changes, thus allowing proper characterization of suitable antiepileptic medication as initial step during management and follow up of patients. Topics: Animals; Anticonvulsants; Body Weight; Epilepsy; Homeostasis; Humans; Insulin; Leptin; Valproic Acid | 2007 |
[Obesity and hypothyroidism: myth or reality?].
While obesity has been historically considered a criteria to establish the diagnosis of hypothyroidism, the association between them is seldom encountered in patients. Nowadays the main metabolic criteria is the gain of weight in the presence of other symptoms of hypothyroidism. The large differences between the thermogenesis of hypothyroid and hyperthyroid patients underline the complex relationship of thyroid hormones and metabolic pathways. The treatment of a subclinical hypothyroidism has almost no influence on the body weight, whereas in more severe dysfunctions a weight loss is expected, usually less than 10% of body weight. Thereafter severe obesity may not be secondary to a thyroid failure. Topics: Body Mass Index; Body Weight; Humans; Hypothyroidism; Leptin; Obesity; Thyrotropin; Thyroxine | 2007 |
The leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics.
The recent rapid increase in the prevalence of obesity across the world is undoubtedly due to changes in diet and lifestyle. However, it is also indisputable that different people react differently to this change in environment and this variation in response is likely to be genetically determined. While for the majority of people this effect is presumed to be polygenic in origin, there is now strong evidence for a small number of genes having a large effect in some families with severe obesity. Studies of these families, coupled with parallel studies in murine models, have provided novel insights into the molecules involved in the regulation of appetite, energy expenditure and nutrient partitioning. We review here the lessons we have learnt from mouse models of obesity, both naturally occurring and artificially generated through targeted gene deletions, and more importantly from human monogenic syndromes of obesity. These have illuminated the critical role in which the central leptin melanocortin pathway plays in the control of mammalian food intake and body weight. Topics: Animals; Appetite Regulation; Body Weight; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Melanocortins; Mice; Obesity | 2007 |
Influence of ghrelin on food intake and energy homeostasis.
The purpose of this review is to provide updated information on the role of ghrelin in food intake and energy homeostasis, and on its mechanism of action. Moreover, the potential of ghrelin as a target for drugs to treat cachexia and obesity will be discussed.. Whereas the effects of ghrelin in the regulation of appetite, food intake and energy homeostasis have been fairly well documented, the pathways responsible for the effects of ghrelin are now increasingly being understood. As a consequence, clinical applications of ghrelin are now being developed.. Ghrelin is an endogenous orexigenic peptide recently discovered in the stomach. Ghrelin is involved in short-term regulation of food intake since its plasma levels increase before meals and decrease strongly postprandially. Ghrelin is also involved in long-term body-weight regulation by inducing adiposity. Ghrelin might be useful for cachexia and obesity treatment. Topics: Anorexia; Appetite; Body Weight; Energy Intake; Energy Metabolism; Ghrelin; Humans; Leptin; Obesity | 2007 |
[The regulation of body mass and its relation to the development of obesity].
Body mass--strictly speaking: the adipose tissue mass--is regulated in a feed-back system by the hypothalamus and brainstem, where adiposity signals (leptin, insulin, amylin) and intestinal peptides (ghrelin, PYY, PP, GLP-1, OXM, CCK) and the vagal nerve provide afferent information to the central controller on the size of white adipose tissue and the actual nutritional state, respectively. Two distinct groups of neurons in the arcuate nucleus accept and process the afferent information provided by leptin produced by white adipocytes in proportion to their mass. Leptin binding to the leptin-receptors on the surface of these neurons initiates intracellular signal transduction and activation of target genes, resulting in the synthesis and release of neuropeptides (POMC, CART) with anorectic effects. Secondary centers in the brain are also activated, and finally integrated effector mechanisms are generated in order to regulate the balance between energy intake and expenditure. The regulation of body weight is carried out by the central nervous system in a complex and redundant way, characterized by interconnections and overlaps with other neuroendocrine functions, such as growth, thyroid and adrenal function, memory, addictive and reward mechanisms. Targeting one or another component of this complicated system with drugs might result in interference with other systems and functions, so the occurrence of adverse events is probable. The worldwide epidemic of obesity--resulting mostly from the abundance of energy-dense foods and sedentary lifestyle coupled with a regulatory system unable to cope with this environment--has resulted in a continuous increase of research activities in both academic and industrial centers to develop new drugs and treatment strategies beyond lifestyle changes (diet, physical activity and behavioral therapy) to fight obesity more effectively. Topics: Adipose Tissue, White; Amyloid; Animals; Anti-Obesity Agents; Appetite; Appetite Regulation; Body Composition; Body Mass Index; Body Weight; Brain; Brain Stem; Eating; Energy Intake; Energy Metabolism; Gastrointestinal Hormones; Ghrelin; Global Health; Humans; Hypothalamus; Insulin; Islet Amyloid Polypeptide; Leptin; Nerve Tissue Proteins; Neurosecretory Systems; Obesity; Peptide Hormones; Pro-Opiomelanocortin; Satiety Response; Signal Transduction | 2007 |
Pharmacotherapy for obesity.
Obesity is a chronic metabolic disorder that affects one third of American adults. Modest weight losses of just 5% to 10% of body weight, which are achievable with lifestyle modification and pharmacotherapy, can lead to remarkable improvements in many obesity-associated co-morbidities, including dyslipidemia, hypertension, and type 2 diabetes. In this review, the indications for pharmacotherapy and the goals of treatment are discussed, and current and future pharmacologic approaches to the treatment of obesity are examined. Current pharmacologic therapies for obesity are limited, but recent advances in our understanding of the complex and overlapping endocrine pathways that regulate body weight have led to new opportunities for antiobesity drug development. Important drug targets that are highlighted in this review include adipocyte-derived hormones, hypothalamic neuropeptides, and gastrointestinal hormones. Topics: Amyloid; Anti-Obesity Agents; Appetite Depressants; Body Weight; Chronic Disease; Comorbidity; Cyclobutanes; Exenatide; Gastrointestinal Hormones; Humans; Islet Amyloid Polypeptide; Lactones; Leptin; Metformin; Obesity; Orlistat; Peptides; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Venoms | 2007 |
Obesity and asthma: cause for concern.
Epidemiological data indicate that obesity is a risk factor for incident asthma, and that obesity is also associated with increased asthma severity. Importantly, obesity antedates asthma. The observations that weight loss improves asthma and that obese mice have innate airway hyperresponsiveness and increased responses to asthma triggers also support a relationship between obesity and asthma. The basis for this relationship is unknown, but might be the result of common etiologies, comorbidities, effects of obesity on lung volume or adipokines. Understanding the mechanistic basis for the relationship between obesity and asthma could lead to new therapeutic strategies for treatment of this susceptible population. Topics: Adiponectin; Adipose Tissue; Animals; Asthma; Body Weight; Comorbidity; Humans; Leptin; Mice; Mice, Obese; Obesity; Respiratory Function Tests; Risk Factors; Tumor Necrosis Factor-alpha | 2006 |
Mechanisms of the anorexia of aging in the Brown Norway rat.
Aging is associated with a loss of the ability to maintain homeostasis in response to physiologic and environmental disturbances. Age-related dysregulation of food intake and energy balance appears to be the result of impaired responsiveness of hypothalamic integrative circuitry to metabolic cues, which can lead to lack of appropriate food intake (the anorexia of aging) and thus to inappropriate weight loss in response to acute or chronic illness or other stressors. Using the Brown Norway (BN) male rat model, we have shown that old animals fail to appropriately increase food intake after the metabolic challenge of a 72 h fast, resulting in the failure to re-gain lost body weight upon refeeding. Leptin levels increase with adiposity and age, and remain elevated above levels of young animals even after a 72 h fast, suggesting that hyperleptinemia may be influencing the energy balance dysregulation. It is unclear whether this age-related response is due to a failure of the network of hypothalamic neurons to appropriately integrate hormonal and neural inputs, or due to a failure of the neurons to produce the appropriate neuropeptides. We hypothesize that sequential, age-related alterations in the expression patterns of neuropeptides that maintain melanocortinergic tone, and in the hormone mediators that inform the system of the state of energy balance, result in a diminished ability to maintain energy homeostasis with increasing age. We have undertaken a number of interventional approaches to test this hypothesis, including manipulations of the hormones ghrelin, insulin and testosterone, and direct application of neuropeptides to the central nervous system in these animals. Topics: Aging; Animals; Anorexia; Appetite Regulation; Body Weight; Eating; Energy Intake; Ghrelin; Homeostasis; Hypothalamus; Insulin; Leptin; Models, Anatomic; Nutritional Status; Peptide Hormones; Rats; Testosterone | 2006 |
The effects of high fat diets on the blood-brain barrier transport of leptin: failure or adaptation?
Leptin is a pluripotent regulatory protein secreted by fat and exerts many effects through the CNS. Interpretation of the characteristics by which it crosses the blood-brain barrier (BBB) supports the view that leptin most potently signals the brain at serum levels well below those associated with the current definition of ideal body weight. This fits with the perspective that low serum levels of leptin are a signal to brain that a sufficient store of calories are available for the organism to expend energy for efforts unrelated to acquisition of calories. This would explain why low serum levels of leptin are permissive in many of the non-feeding actions of leptin, such as enhancing CNS-mediated immune function, memory, bone growth, reproduction, breathing, and neurogenesis. Triglycerides inhibit the transport of leptin across the BBB and so could be key in the onset of the peripheral leptin resistance, which is a hallmark of obesity. These results explain the paradox of why obesity should induce resistance to an anorectic: hypertriglyceridemia also occurs with starvation and we postulate that triglyceride-induced resistance to leptin transport across the BBB initially evolved to limit the signal of an anorectic to the brain during starvation. Topics: Adaptation, Physiological; Animals; Appetite Regulation; Blood-Brain Barrier; Body Weight; Dietary Fats; Feeding Behavior; Humans; Leptin | 2006 |
The role of leptin in leptin resistance and obesity.
Although the presence of hyperleptinemia with leptin resistance and obesity has long been recognized, a causal role of elevated leptin in these biological states remains unclear. This article summarizes some recent work from our laboratory supporting the concept that leptin, in and of itself, promotes leptin resistance and such resistance compounds the metabolic impact of diet-induced obesity. Results from multiple studies demonstrate that (1) chronically elevated central leptin decreases hypothalamic leptin receptor expression and protein levels and impairs leptin signaling; (2) leptin resistance and obesity are associated with reduced leptin receptors and diminished maximal leptin signaling capacity; and (3) leptin resistance confers increased susceptibility to diet-induced obesity. In essence, the augmented leptin accompanying obesity contributes to leptin resistance, and this leptin resistance promotes further obesity, leading to a vicious cycle of escalating metabolic devastation. Topics: Age Factors; Animals; Body Weight; Dietary Fats; Energy Metabolism; Humans; Hypothalamus; Leptin; Mice; Mice, Transgenic; Obesity; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction | 2006 |
Leptin: a promising therapeutic target with pleiotropic action besides body weight regulation.
Leptin seems to regulate various physiological mechanisms besides body weight. Leptin plays a role in vascular biology and pathology as well as renal function. In addition, leptin has been implicated in the regulation of fertility and reproduction. The effect of pharmaceutical agents on circulating plasma leptin levels has been assessed. Among the drugs investigated are glitazones, statins, fibrates, serotonin reuptake inhibitors and cannabinoid-1 receptor antagonists. Since these agents are used to treat pathological conditions there is a potential role for leptin in these states. The degree of involvement of leptin in several pathophysiological states needs to be defined to aid in the development of potentially useful therapeutic agents. Topics: Animals; Body Weight; Humans; Leptin; Receptors, Cell Surface; Receptors, Leptin | 2006 |
Investigational therapies in the treatment of obesity.
Obesity is a major public health concern and environmental factors are involved in its development. The hypothalamus is a primary site for the integration of signals for the regulation of energy homeostasis. Dysregulation of these pathways can lead to weight loss or gain. Some drugs in development can have favourable effects on body weight, acting on some of these pathways and leading to responses resulting in weight loss. Strategies for the management of weight reduction include exercise, diet, behavioural therapy, drug therapy and surgery. Investigational antiobesity medications can modulate energy homeostasis by stimulating catabolic or inhibiting anabolic pathways. Investigational drugs stimulating catabolic pathways consist of leptin, agonists of melanocortin receptor-4, 5-HT and dopamine; bupropion, growth hormone fragments, cholecystokinin subtype 1 receptor agonist, peptide YY3-36, oxyntomodulin, ciliary neurotrophic factor analogue, beta3-adrenergic receptor agonists, adiponectin derivatives and glucagon-like peptide-1. On the other hand, investigational drugs inhibiting anabolic pathways consist of the ghrelin receptor, neuropeptide Y receptor and melanin-concentrating hormone-1 antagonists; somatostatin analogues, peroxisome proliferator-activated receptor-gamma and -beta/delta antagonists, gastric emptying retardation agents, pancreatic lipase inhibitors, topiramate and cannabinoid-1 receptor antagonists. These differing approaches are reviewed and commented on in this article. Topics: Animals; Anti-Obesity Agents; Body Weight; Drugs, Investigational; Energy Metabolism; Humans; Hypothalamus; Leptin; Obesity; Peroxisome Proliferator-Activated Receptors; Randomized Controlled Trials as Topic; Receptor, Melanocortin, Type 4; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2C; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Receptors, Neuropeptide Y; Recombinant Proteins; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists | 2006 |
Monogenic human obesity syndromes.
Over the past decade we have witnessed a major increase in the scale of scientific activity devoted to the study of energy balance and obesity. This explosion of interest has, to a large extent, been driven by the identification of genes responsible for murine obesity syndromes, and the novel physiological pathways revealed by those genetic discoveries. Others and we have also recently identified several single gene defects causing severe human obesity. Many of these defects have been in molecules identical or similar to those identified as a cause of obesity in rodents. I will review the human monogenic obesity syndromes that have been characterised to date and discuss how far such observations support the physiological role of these molecules in the regulation of human body weight and neuroendocrine function. Topics: Body Weight; Endocrine System; Humans; Leptin; Metabolic Diseases; Obesity; Pro-Opiomelanocortin | 2006 |
What can we learn from seasonal animals about the regulation of energy balance?
Weight loss in humans requires, except during an illness, some form of imposed restriction on food intake or increase in energy expenditure. This necessitates overcoming powerful peripheral and central signals that serve to protect against negative energy balance. The identification of the systems and pathways involved has come from mouse models with genetic and targeted mutations, e.g., ob/ob and MC4 R(-/-) as well as rat models of obesity. Study of seasonal animals has shown that they undergo annual cycles of body fattening and adipose tissue loss as important adaptations to environmental change, yet these changes appear to involve mechanisms distinct from those known already. One animal model, the Siberian hamster, exhibits marked, but reversible, weight loss in response to shortening day length. The body weight is driven by a decrease in food intake with the magnitude of the loss of body weight being directly related to the length of time of exposure to short photoperiod. The most important facet of this response is that the point of energy balance is continuously re-adjusted during the transition in body weight reflecting an apparent 'sliding set point'. Studies have focused on identifying the neural basis of this mechanism. Initial studies of known genes (e.g., NPY, POMC, and AgRP) both through the measurement of gene expression in the arcuate nucleus as well as following intracerebroventricular (i.c.v.) injection indicated that the systems involved are not those involved in restoring energy balance following energy deficits. Instead, a novel mechanism of regulation is implied. Recent studies have begun to explore the neural basis of the seasonal body weight response. A discrete and novel region of the posterior arcuate nucleus, the dorsal medial posterior arcuate nucleus (dmpARC) has been identified, where a battery of gene expression changes for signalling molecules (vgf and histamine H3 receptor) and transcription factors (RXRgamma and RAR) occur in association with seasonal changes in body weight. This work provides the basis of a potentially novel mechanism of energy balance regulation. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Energy Metabolism; Gene Expression Regulation; Leptin; Photoperiod; Seasons | 2006 |
Regulation of body weight by leptin, with special reference to hypoxia-induced regulation.
Since first cloned and reported by Zhang et al in 1994 (Nature 372:425), the obese gene and its product-leptin has been studied profoundly. Our knowledge in body weight regulation and the role played by leptin has increased substantially. Leptin serves as an adiposity signal to inform the brain of the adipose tissue mass in a negative feedback loop regulating food intake and energy expenditure. Many articles have reported weight loss at high altitude, but the explanation has been limited to loss of appetite. New ideas were highlighted after studies by Grosfeld et al and Ambrosini et al on the obese gene under hypoxia condition. Cells with hypoxia treatment upregulated obese gene transcription and suggested that enhancement of leptin secretion in vivo under hypoxia environment may be one of the potential therapeutic methods for obesity treatment. Topics: Body Weight; Humans; Hypoxia; Leptin | 2006 |
[Congenital leptin deficiency].
Topics: Amino Acid Sequence; Animals; Appetite; Body Weight; Carbohydrate Metabolism; Endocrine System; Energy Metabolism; Humans; Immune System; Leptin; Lipid Metabolism; Molecular Sequence Data; Obesity | 2006 |
Emerging therapeutic strategies for obesity.
The rising tide of obesity is one of the most pressing health issues of our time, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Fortunately, a recent burgeoning of mechanistic insights into the neuroendocrine regulation of body weight provides an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceuticals. In this review, we articulate a set of conceptual principles that we feel could help prioritize among these molecules in the development of obesity therapeutics, based on an understanding of energy homeostasis. We focus primarily on central targets, highlighting selected strategies to stimulate endogenous catabolic signals or inhibit anabolic signals. Examples of the former approach include methods to enhance central leptin signaling through intranasal leptin delivery, use of superpotent leptin-receptor agonists, and mechanisms to increase leptin sensitivity by manipulating SOCS-3, PTP-1B, ciliary neurotrophic factor, or simply by first losing weight with traditional interventions. Techniques to augment signaling by neurochemical mediators of leptin action that lie downstream of at least some levels of obesity-associated leptin resistance include activation of melanocortin receptors or 5-HT2C and 5-HT1B receptors. We also describe strategies to inhibit anabolic molecules, such as neuropeptide Y, melanin-concentrating hormone, ghrelin, and endocannabinoids. Modulation of gastrointestinal satiation and hunger signals is discussed as well. As scientists continue to provide fundamental insights into the mechanisms governing body weight, the future looks bright for development of new and better antiobesity medications to be used with diet and exercise to facilitate substantial weight loss. Topics: Anti-Obesity Agents; Body Weight; Cannabinoid Receptor Antagonists; Eating; Gastrointestinal Hormones; Humans; Leptin; Metabolism; Neuropeptides; Neurosecretory Systems; Obesity | 2006 |
Genetics of obesity in humans.
Considerable attention has focused on deciphering the hypothalamic pathways that mediate the behavioral and metabolic effects of leptin. We and others have identified several single gene defects that disrupt the molecules in the leptin-melanocortin pathway causing severe obesity in humans. In this review, we consider these human monogenic obesity syndromes and discuss how far the characterization of these patients has informed our understanding of the physiological role of leptin and the melanocortins in the regulation of human body weight and neuroendocrine function. Topics: Body Weight; Humans; Leptin; Melanocortins; Mutation; Neurosecretory Systems; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptor, trkB; Signal Transduction | 2006 |
Leptin and hypertension in obesity.
Leptin, a peptide discovered more than 10 years ago, decreases food intake and increases sympathetic nerve activity to both thermogenic and non-thermogenic tissue. Leptin was initially believed to be an anti-obesity hormone, owing to its metabolic effects. However, obese individuals, for unknown reasons, become resistant to the satiety and weight-reducing effect of the hormone, but preserve leptin-mediated sympathetic activation to non-thermogenic tissue such as kidney, heart, and adrenal glands. Leptin has been shown to influence nitric oxide production and natriuresis, and along with chronic sympathetic activation, especially to the kidney, it may lead to sodium retention, systemic vasoconstriction, and blood pressure elevation. Consequently, leptin is currently considered to play an important role in the development of hypertension in obesity. Topics: Abdominal Fat; Animals; Antihypertensive Agents; Appetite Regulation; Blood Pressure; Body Weight; Energy Metabolism; Humans; Hypertension; Kidney; Leptin; Nitric Oxide; Obesity; Renin-Angiotensin System; Sympathetic Nervous System; Time Factors | 2006 |
Body weight is regulated by the brain: a link between feeding and emotion.
Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence. Topics: alpha-MSH; Animals; Antipsychotic Agents; Appetite Regulation; Body Weight; Diabetes Mellitus; Emotions; Energy Metabolism; Feeding and Eating Disorders; Homeostasis; Humans; Leptin; Neuropeptide Y; Obesity; RNA, Messenger | 2005 |
The regulation of energy balance by the central nervous system.
Topics: Body Weight; Central Nervous System; Energy Metabolism; Ghrelin; Glucocorticoids; Humans; Hypothalamus; Insulin; Leptin; Neuropeptide Y; Obesity; Peptide Hormones; Pro-Opiomelanocortin; Signal Transduction | 2005 |
Central regulation of energy balance: inputs, outputs and leptin resistance.
The regulation of energy balance is complex and, in man, imprecise. Nevertheless, in many individuals intake and expenditure are balanced with <1% error with little or no conscious effect. Essential components of such a regulatory system are signals, leptin and insulin, that reflect the size of lipid stores. Leptin receptors signal via phosphatidylinositol 3-kinase (as do insulin receptors) and via the transcription factor signal transducer and activator of transcription-3 to activate various types of neurone. Obese rodents, and possibly man, are resistant to leptin; in some cases because of genetic or perinatal programming (primary resistance), but commonly in response to high leptin levels (secondary resistance). Secondary leptin resistance may be a result of reduced transport of leptin to the brain or down-regulation of leptin signalling. Signals that reflect lipid stores form the tonic homeostatic regulatory system. They interact with episodic homeostatic signals carried by neurones, hormones and metabolites to regulate meal size and frequency. They also interact with signals related to the palatability of food, biorhythms and learning. Many neurotransmitters and hormones mediate responses to more than one input (e.g. gastric and adipocyte leptin), but are nevertheless most involved with particular inputs (e.g. leptin with adipocyte fat stores). Feeding can be divided into appetitive (preparation for feeding) and consummatory phases, which can both be further subdivided. Different sets of neurotransmitters and hormones are involved at each stage. In the long term it may be possible to customise obesity therapies according to those inputs and outputs that are most disturbed and most amenable to intervention in individual subjects. Topics: Adipose Tissue; Appetite Regulation; Body Weight; Energy Intake; Energy Metabolism; Humans; Leptin; Signal Transduction | 2005 |
Brain somatic cross-talk: ghrelin, leptin and ultimate challengers of obesity.
Energy balance is largely regulated by the central nervous system (CNS), which senses metabolic status from a wide range of humoral and neural signals, and controls energy intake. Accumulating evidence supports the model that stimulation of leptin- and ghrelin-responsive pathways, including the central melanocortin system, in the hypothalamus, contributes to the maintenance of body weight. Ghrelin is the brain-gut peptide with growth hormone-releasing and appetite-inducing activities. It is mainly secreted from the stomach and acts as an afferent signal to the hypothalamus and hindbrain. Leptin, the adipocyte hormone, is believed to tonically act as an afferent signal from adipose tissue to the brain, in particular hypothalamus, as a part of negative feedback loop regulating the size of energy stores and energy balance. Dysregulation of these pathways is a marker of changes in energy balance. Ghrelin is negatively correlated with weight and obese subjects have lower ghrelin levels than lean subjects, consistent with a compensatory rather than causal role for ghrelin in obesity. On the contrary, circulating leptin levels correlate in proportion to adiposity being high in obesity suggesting that human obesity is associated with insensitivity to leptin. The leptin resistance in diet-induced obesity emphasizes that environmental factors can modulate leptin sensitivity. It is speculated that through hypothalamic/pituitary axis ghrelin and leptin operate as a metabolic switch. Ghrelin actually transfers information from the stomach to the hypothalamus in cooperation with leptin and provides calories that growth hormone (GH) needs for growth and repair. Pharmacological manipulations of circulating hormone levels may work well in "cheating" the brain regarding information from the periphery. It might also be necessary to combine two or three agents to fight obesity. A combination of drugs that decrease preprandial appetite (ghrelin antagonist) and increase post-prandial satiety (gut hormone fragment peptide YY 3-36) might have a chance of achieving sustained weight loss. The administration of exogenous satiety hormone peptide YY 3-36 (PYY) may prevent the action of appetite-stimulating hypothalamic circuits on the anorexigenic melanocortin pathways. Topics: Adipose Tissue; Animals; Appetite; Body Weight; Brain; Energy Metabolism; Ghrelin; Humans; Hypothalamus; Leptin; Obesity; Peptide Fragments; Peptide Hormones; Peptide YY; Pituitary Gland; Satiation; Signal Transduction | 2005 |
Dietary influences on peripheral hormones regulating energy intake: potential applications for weight management.
The significant burden of overweight and obesity on our society necessitates the development of lifestyle strategies that facilitate successful long-term body weight management. Recently, the discovery of novel cellular modulators of the brain-gut axis have generated much interest in possible therapeutic manipulation of these and other hormones that regulate energy intake. These modulators include the enterohormones ghrelin, peptide YY 3-36, and cholecystokinin, and the adipocyte-derived hormone leptin. There is some evidence that dietary macronutrient composition can influence concentrations of these hormones, which could impact sensations of hunger, satiety, and ultimately energy intake. The purpose of this review is to provide background information on these four peripheral hormones involved in energy intake regulation, to discuss what is currently known about their mechanism of action, and to present research findings related to the effect of macronutrient composition on concentrations and efficacy of these hormones. Potential applications of this information are also discussed. Topics: Body Weight; Brain; Cholecystokinin; Eating; Energy Intake; Energy Metabolism; Feeding Behavior; Gene Expression Regulation; Ghrelin; Humans; Leptin; Peptide Fragments; Peptide Hormones; Peptide YY | 2005 |
[Recent development in research and management of cancer anorexia-cachexia syndrome].
Cachexia is among the most debilitating and life-threatening aspects of cancer, and is more common in children and elderly patients. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. This could be done by persistent inhibition of feeding-stimulatory circuitry including neuropeptide Y. Cachexia should be suspected in patients with cancer if an involuntary weight loss of greater than five percent of premorbid weight occurs within a 3-6-month period. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome has led to, and continues to lead to, effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide-all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. The outcomes of drug studies in cancer cachexia should focus on the symptomatic and quality-of-life advantages rather than simply on nutritional end points, since the survival of cachexia cancer patients may be limited to weeks or months due to the incurable nature of the underlying malignancy. Communication among physicians and other health care professionals provides the patient with a multidisciplinary approach to care. The patient record will be an excellent resource to document a plan of care and patient responses to treatment. Psychological distress and psychiatric disorders are common among cancer patients. These problems are also as common among the family members of people with cancer. The use of psychological and behavioral interventions in cancer is incr Topics: Animals; Anorexia; Appetite; Body Weight; Cachexia; Energy Intake; Energy Metabolism; Humans; Leptin; Neoplasms; Quality of Life; Research | 2005 |
Role of postmenopausal hormone replacement therapy on body fat gain and leptin levels.
During menopause women tend to gain body fat. The increase in adiposity seems to be a consequence of the decline in endogenous estrogens and the reduced energy expenditure. The role of post-menopausal hormone replacement therapy (pHT) in modulating visceral obesity is controversial. Some studies have shown that pHT has no effect on body weight while in other studies pHT increased body weight. Leptin is an adipocyte-derived hormone and its levels reflect the amount of adipose tissue. Obesity is associated with elevated serum leptin levels. The effect of pHT on leptin levels is also controversial. In some studies pHT increased leptin levels while other studies have not confirmed this increasing effect. The major problem encountered during administration of hormone therapy seems to be the timing of pHT initiation which is a strong confounder on the effect of pHT on leptin levels in postmenopausal women. Topics: Adipose Tissue; Body Composition; Body Constitution; Body Weight; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Humans; Leptin; Middle Aged; Obesity; Postmenopause | 2005 |
Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis.
The past decade has greatly increased our understanding and appreciation of the ability of the central nervous system (CNS) to regulate food intake and body weight. This was spearheaded by the discovery of key molecules regulating body weight homeostasis. It is now also apparent that the CNS, especially the hypothalamus, plays a primary role in directly regulating glucose homeostasis, independently of effects on body weight. These discoveries are important given the increasing incidences of obesity and type II diabetes in Western societies. In this article, we will highlight recent data from genetically modified mice. These data and other models have helped to dissect the CNS pathways regulating body weight and glucose homeostasis. Finally, although these studies have been illustrative, they also underscore our relative lack of knowledge and highlight the need for more definitive approaches to unravel the functional significance of these pathways. Topics: Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Eating; Homeostasis; Hypoglycemic Agents; Hypothalamus; Immunohistochemistry; Leptin; Mice; Neurons; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin | 2005 |
[Peptides regulating food intake and body weight].
Regulation of food intake and body weight depends on direct and feedback signals from adipose tissue, alimentary canal and pancreas to the hypothalamus nuclei, where hunger and satiety centers are. During the last decade a few signaling molecules of peptide origin were discovered, which play an important role in the regulation of energy intake and energy expenditure as well as in obesity. So, adipocytes synthesize and express leptin, the product of Ob gene, a regulator of long-term food intake, in amounts proportional to the fat amount, while alimentary canal hormones are regulators of short-term food intake (from meal to meal). Some peptides decrease food intake as they promote satiety (anorexigenic signals), other peptides, contrary, increase food intake as they induce appetite (orexigenic signals). Disturbed equilibrium between the anorexigenic and orexigenic factors manifests as food intake disorders, increase in body weight and obesity or decrease in body weight, i.e. cachexia. Topics: Adipocytes; Adiponectin; Appetite Regulation; Body Weight; Cachexia; Eating; Energy Metabolism; Humans; Hypothalamus; Leptin; Neuropeptides; Obesity; Peptide Hormones; Peptides | 2005 |
[Mechanisms of the body weight gain induced by novel antipsychotic drugs and concomitant lipid abnormalities].
The authors presents the state of knowledge on the prevalence and proposed mechanisms leading to weight gain during treatment with atypical antipsychotics. A short review on the therapeutic approaches is also supplied. Topics: Antipsychotic Agents; Body Weight; Clozapine; Dibenzothiazepines; Humans; Hyperlipidemias; Leptin; Piperazines; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Thiazoles; Weight Gain | 2005 |
Obesity wars: molecular progress confronts an expanding epidemic.
The worldwide prevalence of obesity is increasing at an alarming rate, with major adverse consequences for human health. This "obesity epidemic" is paralleled by a rapid and substantive increase in our understanding of molecular pathways and physiologic systems underlying the regulation of energy balance. While efforts to address the environmental factors that are responsible for the recent "epidemic" must continue, new molecular and physiologic insights into this system offer exciting possibilities for future development of successful therapies. Topics: Animals; Body Weight; Brain; Digestive System; Disease Outbreaks; Energy Metabolism; Humans; Hypothalamic Hormones; Leptin; Melanins; Models, Biological; Obesity; Pituitary Hormones; Receptors, Cell Surface; Receptors, Leptin | 2004 |
Effect of conjugated linoleic acid on body composition and plasma lipids in humans: an overview of the literature.
Studies in mice have indicated that feeding diets containing 0.5-1% conjugated linoleic acid (CLA) considerably reduces body fat. These findings have attracted much interest because of the potential use of CLA as a tool to promote weight loss in humans. Several CLA studies in humans have now been published, and the objective of the present review was to give an overview of these experiments. Most of the studies were done in free-living subjects and were not strictly controlled for nutrient and energy intakes. None of the studies found a significant reduction in body weight, and only 2 studies showed a significant but relatively small body fat-lowering effect. Some studies suggested that CLA may have a tendency to increase lean body mass. Furthermore, there are indications from animal studies that CLA may have effects on plasma lipids. However, only one study in humans showed a significant HDL-cholesterol-lowering effect of CLA; in all the other studies, there were no significant effects on plasma total, LDL-, and HDL-cholesterol concentrations or on plasma triacylglycerol concentrations. Thus, the results of the studies in humans indicate that the effect of CLA on body fat is considerably less than that anticipated from mice studies and that CLA has no major effect on plasma lipids. Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Weight; Energy Metabolism; Humans; Insulin; Leptin; Linoleic Acid; Lipids; Meta-Analysis as Topic | 2004 |
Minireview: A hypothalamic role in energy balance with special emphasis on leptin.
The hypothalamus is a major site for integration of central and peripheral signals that regulate energy homeostasis. Within the hypothalamus, neurons residing in the ARC (arcuate nucleus)-PVN (paraventricular)-PF/LH (perifornical/lateral hypothalamus) axis communicate among each other and are subjected to the influence of several peripheral factors, including leptin and insulin. Proper signaling in the hypothalamus by leptin, a long-sought peripheral factor that relays the status of fat stores, is critical to normal regulation of food intake and body weight. Leptin action in the hypothalamus is mediated by a large number of orexigenic and anorectic peptide-producing neurons of the ARC-PVN-PF/LH axis. Not only the classical JAK2 (Janus kinase 2)-STAT3 (signal transducer and activator of transcription 3) pathway, but also the phosphatidylinositol-3 kinase-phosphodiesterase 3B-cAMP pathway mediates hypothalamic leptin receptor signaling. It appears that hypothalamic leptin resistance, possibly due to defective nutritional regulation of leptin receptor expression and/or reduced STAT3 signaling in the hypothalamus, contributes to the development of obesity associated with high-fat feeding and aging. Interestingly, hypothalamic neurons may develop leptin resistance despite an intact JAK2-STAT3 signaling path. The role of suppressor of cytokine signaling 3 and other negative regulators of leptin signaling in central leptin resistance needs to be established, an important area of future investigation. Further understanding of the neural circuitry and leptin signaling in the hypothalamus is critical not only for the advancement of our knowledge on the hypothalamic role in energy balance but also for future development of drugs for the attenuation or treatment of obesity and related disorders in humans. Topics: Animals; Body Weight; Eating; Energy Metabolism; Homeostasis; Hypothalamus; Leptin; Neuropeptides | 2004 |
[Bone mass regulation by leptin: a hypothalamic control of bone formation].
Bone mass is maintained constant between puberty and menopause by the balance between osteoblasts and osteoclasts activity. The existence of a hormonal control of osteoblast activity has been speculated for years by analogy to osteoclast biology. Through the search for such humoral signal(s) regulating bone formation, leptin has been identified as a powerful inhibitor of bone formation. Furthermore, by means of intracerebroventricular infusion of leptin, it has been shown that the effect of this adipocyte-derived hormone on bone is mediated via a brain relay, like all its other functions. Subsequent studies have led to the identification of hypothalamic neurons involved in leptin's antiosteogenic function. In addition, it has been shown that those neurons or neuronal pathways are distinct from neurons responsible for the regulation of energy metabolism. Finally, the peripheral mediator of leptin's antiosteogenic function has been identified as being the sympathetic nervous system. Catecholamine-deficient mice have a high bone mass and sympathomimetics administered to mice decreased bone formation and bone mass. Conversely, beta-blockers increased bone formation and bone mass and blunt the bone loss induced by ovariectomy. Topics: Adipocytes; Adrenergic beta-Antagonists; Animals; Body Weight; Bone Development; Energy Metabolism; Homeostasis; Humans; Immunity, Innate; Leptin; Mice; Mice, Obese; Neurons; Obesity; Organ Size; Osteoblasts; Osteoporosis, Postmenopausal; Receptors, Adrenergic, beta; Receptors, Leptin; Sympathetic Nervous System; Ventromedial Hypothalamic Nucleus | 2004 |
[Role of leptin during childhood growth and development].
Leptin, the peptide hormone product of the ob gene, regulates food intake and energy expenditure at the hypothalamic level. Leptin is a trigger for puberty onset in rodents, as a metabolism signals to link reproductive function to the nutritional status, and has a similar effect in childhood growth and development. Topics: Body Weight; Child; Child Development; Humans; Hypothalamus; Leptin; Puberty; Reproduction; Sex Factors | 2004 |
Modern science versus the stigma of obesity.
Topics: Animals; Body Weight; Brain; Eating; Energy Metabolism; Humans; Leptin; Obesity | 2004 |
Leptin functioning in eating disorders.
Leptin is an adipocyte-derived hormone, which is involved predominantly in the long-term regulation of body weight and energy balance by acting as a hunger suppressant signal to the brain. Leptin is also involved in the modulation of reproduction, immune function, physical activity, and some endogenous endocrine axes. Since anorexia nervosa (AN) and bulimia nervosa (BN) are characterized by abnormal eating behaviors, dysregulation of endogenous endocrine axes, alterations of reproductive and immune functions, and increased physical activity, extensive research has been carried out in the last decade in order to ascertain a role of this hormone in the pathophysiology of these syndromes. In this article, we review the available data on leptin physiology in patients with eating disorders. These data support the idea that leptin is not directly involved in the etiology of AN or BN. However, malnutrition-induced alterations in its physiology may contribute to the genesis and/or the maintenance of some clinical manifestations of AN and BN and may have an impact on the prognosis of AN. Topics: Adipose Tissue; Animals; Anorexia Nervosa; Body Weight; Brain; Bulimia; Energy Metabolism; Humans; Hunger; Leptin | 2004 |
Adiposity signals, genetic and body weight regulation in humans.
Numerous signals convey information about body fat status from the periphery to the brain areas that control energy homeostasis so that, throughout life, body weight remains nearly stable. These signals mainly originate, either from the adipose tissue, like leptin and to a lesser extent interleukin 6, or from the pancreas, like insulin and amylin. These factors circulate in proportion to body fat mass and they are referred to as "adiposity signals". It is well established, at least for leptin and insulin, that they enter the brain from the plasma where they induce/repress a network of important neuropeptide regulators of energy intake and expenditure. Beside these endocrine signals, a growing amount of literature show data relative to adipocyte-derived molecules, most of them belonging to the cytokine family, like IL6, TNFalpha, IL8, IL10 whose secretion also correlates with body fat mass and that may locally regulate fat mass expansion. Others, like adiponectin, are negatively correlated with body fat mass. These "adiposity molecules" have already been involved in insulin resistance associated with obesity and inflammatory process. They may participate to a complex inter organ dialogue. In this review, we will synthesize data relative to the role played by insulin, leptin and amylin, either alone or through a cross talk, in "energy level sensing" at the brain level. Furthermore, we will develop how "adiposity molecules" through their paracrin and/or autocrin action may contribute to maintain fat mass expansion, therefore representing new adiposity molecules per se. Lastly, since any distortion in the metabolic circuitry of energy homeostasis is susceptible to lead to a pathological status like obesity, the impact of known genetic polymorphisms in genes encoding the adiposity signals will be discussed. Topics: Adipose Tissue; Animals; Body Weight; Cytokines; Homeostasis; Humans; Inflammation; Insulin; Leptin; Obesity; Signal Transduction | 2004 |
Overlapping and interactive pathways regulating appetite and craving.
Multidisciplinary research in recent years has delineated the hypothalamic hardcore wiring that encodes appetitive drive. The appetite regulating network (ARN) consisting of distinct orexigenic and anorexigenic circuitries operates in the arcuate nucleus-paraventricular nucleus axis of the hypothalamus to propagate and relay the appetitive drive, and is subject to modulation by excitatory and inhibitory messages from the lateral hypothalamus and ventromedial nucleus, respectively. Reciprocal afferent humoral signals, comprised of anorexigenic leptin from white adipose tissue and orexigenic ghrelin from stomach, to the ARN integrate the moment-to-moment regulation of energy homeostasis. Various loci in the ARN and afferent hormonal feedback circuitry in the rodent brain are important for food craving elicited by drugs of abuse. This convergence of neurochemical and hormonal signaling has now paved the way to address the fundamental question of whether cellular and molecular events that underlie the appetitive drive in response to diminished energy stores in the body are akin to drug craving during withdrawal in humans. Topics: Adipose Tissue; Appetite Regulation; Body Weight; Cannabinoid Receptor Modulators; Energy Intake; gamma-Aminobutyric Acid; Ghrelin; Humans; Hypothalamus; Intracellular Signaling Peptides and Proteins; Leptin; Narcotics; Neuropeptides; Nicotine; Orexins; Peptide Hormones; Signal Transduction; Stomach; Ventromedial Hypothalamic Nucleus | 2004 |
Leptin and the control of metabolism: role for stearoyl-CoA desaturase-1 (SCD-1).
The incidence of obesity has increased sharply in recent years, making it one of the most urgent public health concerns worldwide. The hormone leptin is the central mediator in a negative feedback loop regulating energy homeostasis. Leptin administration leads to reduced food intake, increased energy expenditure, and weight loss. Leptin also mediates unique metabolic effects, specifically depleting lipid from liver and other peripheral tissues. While elucidation of leptin's role has permitted a more detailed view of the biology underlying energy homeostasis, most obese individuals are leptin resistant. A more complete understanding of the molecular components of the leptin pathway is necessary to develop effective treatment for obesity and the Metabolic Syndrome. We review here studies on the identification of one such component, stearoyl-CoA desaturase-1 (SCD-1), as a gene specifically repressed by leptin and discuss the role of this process in mediating the metabolic effects of leptin. Data indicate that pharmacologic manipulation of SCD-1 may be of benefit in the treatment of obesity, diabetes, hepatic steatosis, and other components of the Metabolic Syndrome. Topics: Animals; Body Weight; Fatty Liver; Humans; Leptin; Liver; Metabolic Syndrome; Obesity; Stearoyl-CoA Desaturase | 2004 |
Appetite regulation and seasonality: implications for obesity.
High circulating concentrations of leptin in obesity are associated with an apparent loss of its characteristic anorexic action within the hypothalamic region of the brain. Central insensitivity to leptin may therefore contribute to the aetiology of this disease, and an increased understanding of the underlying mechanisms will identify potential means of prevention and/or therapeutic targets. Seasonal animals such as sheep and Siberian hamsters (Phodopus sungorus) exhibit annual photoperiod-driven cycles of appetite and body weight. Increased food intake and weight gain in long days (summer) are associated with high circulating leptin, and decreased intake and weight loss in short days (winter) with low leptin. Critically, these cycles are associated with reversible changes in sensitivity to leptin. High sensitivity is seen in short days and relative insensitivity in long days, demonstrated both in sheep given leptin centrally via intracerebroventricular cannulas and in hamsters given leptin peripherally. In addition, primary hypothalamic appetite-regulating targets for leptin (i.e. neuropeptide Y, melanocortin and cocaine- and amphetamine-regulated transcript pathways) respond differently in these species to changes in circulating leptin and nutritional status induced by photoperiod as opposed to such changes induced by food restriction. Studies of seasonal animals will help to resolve causes of altered sensitivity to leptin and whether these changes reflect altered transport into the brain and/or altered signalling at the receptor or post-receptor level. Increased knowledge of the mechanism(s) and time-course for development and reversal of reduced central leptin sensitivity will provide new insights into the development and control of obesity. Topics: Animals; Appetite Regulation; Body Weight; Energy Metabolism; Humans; Leptin; Melatonin; Obesity; Photoperiod; Seasons | 2004 |
Leptin and energy expenditure.
A fundamental advance in our understanding of endocrine control of energy balance and body weight came with the discovery of the adipocyte-derived hormone leptin. The leptin pathway appeared to be the long-sought peripheral signal pathway from the adipose tissue to the brain involved in the regulation of feeding and energy balance.. Initially, leptin was considered to function as the long-sought antiobesity hormone. According to this hypothesis, rising concentrations of leptin with increasing adiposity would generate a signal to reduce food intake and increase energy expenditure in order to limit further weight gain. However, widespread resistance to the proposed antiobesity action of leptin is observed in humans, which might reflect the fact that the inability to store energy efficiently at times of abundance is evolutionarily disadvantageous. According to this alternative view, falling leptin concentrations observed during fasting act as a peripheral signal of starvation, which serves to conserve energy in the face of limited reserves. However, leptin administration failed to blunt the changes in energy expenditure during severe energy restrictions in several clinical studies. In addition, leptin therapy in several different human low-leptin states failed to affect energy expenditure in recent studies.. Increasing evidence from human studies suggests that leptin predominantly influences the human energy balance through appetite but appears not to be involved in regulating energy expenditure. None of the expected factors such as resting metabolic rate, total diurnal energy expenditure or dietary induced thermogenesis was related to blood leptin concentrations. Topics: Adipose Tissue; Appetite; Body Weight; Energy Metabolism; Humans; Leptin | 2004 |
[Body weight regulation through the central nervous system. The development of a pathogenetically based adiposity therapy].
The last decade witnessed a dramatic increase in knowledge concerning regulation of body weight and obesity. According to recent concepts constancy of body weight is a side product of regulatory events which ensure constant glucose fluxes to the brain. Within these control systems glucocorticoids and melanocortins play a fundamental role at several sites. The melanocortin neurons in the arcuate nucleus of the hypothalamus are important mediators of the feedback effects of leptin and insulin. Glucocorticoid and mineralocorticoid receptors in hippocampal neurons are crucial, as they define the balance between glucose allocation processes and food intake. Thereby, the hippocampal structures determine the setpoint for body weight regulation. A modulation of these brain structures by intranasal administration of melanocortin and inhisulin has been shown to reduce body weight and body fat mass in humans. So the manipulation of weight-regulating centers in the brain opens a novel approach to a pathogenetically based treatment of obesity. Topics: Administration, Intranasal; alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Cannabinoids; Disease Models, Animal; Energy Intake; Feedback; Glucocorticoids; Glucose; Hippocampus; Humans; Hypothalamus; Insulin; Leptin; Obesity; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Weight Loss | 2004 |
Gut peptides and other regulators in obesity.
Obesity has reached epidemic levels in industrialized countries and is increasing worldwide. This trend has serious public health consequences, since obesity increases the risk of diabetes, hypertension, heart disease, sleep apnea, cancer, arthritis, cholelithiasis, fatty liver disease, and other complications. Obesity is the result of an imbalance between energy intake and expenditure; hence, an understanding of how gastrointestinal function is integrated with the hormonal regulation of energy balance is pertinent to the pathophysiology of obesity. Nutrients, peptides, and neural afferents from the gut influence the size and frequency of meals and satiety. The long-term regulation of energy stores is mediated primarily through the actions of adiposity hormones, such as leptin and insulin, in the hypothalamus and other neuronal circuits in the brain. Efforts are underway to determine how these peripheral and central pathways may be targeted for treatment of obesity and related diseases. Topics: Animals; Appetite; Body Weight; Cholecystokinin; Energy Metabolism; Gastrointestinal Hormones; Ghrelin; Humans; Insulin; Leptin; Obesity; Peptide Hormones; Peptide YY; Peptides; Satiety Response; Stomach | 2004 |
The conjugated linoleic acid (CLA) isomer, t10c12-CLA, is inversely associated with changes in body weight and serum leptin in subjects with type 2 diabetes mellitus.
Isomers of conjugated linoleic acid (CLA) are found in beef, lamb and dairy products. Diets containing CLA reduce adipose mass in various depots of experimental animals. In addition, CLA delays the onset of diabetes in the ZDF rat model for obesity-linked type 2 diabetes mellitus. We hypothesize that there would be an inverse association of CLA with body weight and serum leptin in subjects with type 2 diabetes mellitus. In this double-blind study, subjects with type 2 diabetes mellitus were randomized into one of two groups receiving either a supplement containing mixed CLA isomers (CLA-mix; 8.0 g daily, 76% pure CLA; n = 12) or a supplement containing safflower oil (placebo; 8.0 g daily safflower oil, n = 9) for 8 wk. The isomers of CLA in the CLA-mix supplement were primarily c9t11-CLA ( approximately 37%) and t10c12-CLA ( approximately 39%) in free fatty acid form. Plasma levels of CLA were inversely associated with body weight (P < 0.05) and serum leptin levels (P < 0.05). When levels of plasma t10c12-CLA isomer were correlated with changes in body weight or serum leptin, t10c12-CLA, but not c9t11-CLA, was inversely associated with body weights (P < 0.05) and serum leptin (P < 0.02). These findings strongly suggest that the t10c12-CLA isomer may be the bioactive isomer of CLA to influence the body weight changes observed in subjects with type 2 diabetes. Future studies are needed to determine a causal relationship, if any, of t10c12-CLA or c9t11-CLA to modulate body weight and composition in subjects with type 2 diabetes. Furthermore, determining the ability of CLA isomers to influence glucose and lipid metabolism as well as markers of insulin sensitivity is imperative to understanding the role of CLA to aid in the management of type 2 diabetes and other related conditions of insulin resistance. Topics: Adult; Animals; Body Weight; Diabetes Mellitus, Type 2; Humans; Leptin; Linoleic Acid; Obesity; Randomized Controlled Trials as Topic | 2003 |
Critical review of acylation-stimulating protein physiology in humans and rodents.
In the last few years, there has been increasing interest in the physiological role of acylation-stimulating protein (ASP). Recent studies in rats and mice, in particular in C3 (-/-) mice that are ASP deficient, have advanced our understanding of the role of ASP. Of note, the background strain of the mice influences the phenotype of delayed postprandial triglyceride clearance in ASP-deficient mice. Administration of ASP in all types of lean and obese mice studied to date, however, enhances postprandial triglyceride clearance. On the other hand, regardless of the background strain, ASP-deficient mice demonstrate reduced body weight, reduced leptin and reduced adipose tissue mass, suggesting that ASP deficiency results in protection against development of obesity. In humans, a number of studies have examined the relationship between ASP, obesity, diabetes and dyslipidemia as well as the influence of diet, exercise and pharmacological therapy. While many of these studies have small subject numbers, interesting observations may help us to better understand the parameters that may influence ASP production and ASP action. The aim of the present review is to provide a comprehensive overview of the recent literature on ASP, with particular emphasis on those studies carried out in rodents and humans. Topics: Adipose Tissue; Animals; Blood Proteins; Body Weight; Cardiovascular Diseases; Complement C3; Complement C3a; Complement Factor B; Complement Factor D; Diabetes Mellitus; Humans; Hyperlipidemias; Insulin Resistance; Leptin; Mice; Mice, Knockout; Models, Animal; Obesity; Postprandial Period; Rats; Serine Endopeptidases; Triglycerides | 2003 |
Leptin--a critical body weight signal and a "master" hormone?
Leptin, initially identified as a hormone produced by white fat that acted as a satiety signal, has since been found to be synthesized in various tissues and to subserve diverse functions, including regulation of blood glucose concentrations and blood vessel growth, and signaling to the reproductive and immune systems. Recent research suggests that leptin, acting through the sympathetic nervous system, may also regulate bone density. Trayhurn discusses this research in the context of the established bidirectional interaction between leptin and the sympathetic nervous system, and the need to elucidate a unifying theme with which to make sense of leptin's myriad, seemingly quite disparate, functions. Topics: Adipose Tissue; Animals; Body Weight; Brain; Feedback, Physiological; Hormones; Humans; Leptin; Models, Biological; Signal Transduction; Sympathetic Nervous System | 2003 |
[Current therapy strategies for nonalcoholic fatty liver disease].
Topics: Antioxidants; Body Weight; Fatty Liver; Humans; Insulin Resistance; Leptin; Lipids; Liver | 2003 |
[Molecular mechanisms and clinical implications for the regulatory feedback loop of feeding and body adiposity].
Topics: Adipose Tissue; Animals; Appetite Regulation; Body Mass Index; Body Weight; Energy Metabolism; Feedback, Physiological; Humans; Leptin; Mice; Mice, Knockout; Obesity | 2003 |
Photoperiodic programming of body weight through the neuroendocrine hypothalamus.
The photoperiodic mammal undergoes quite remarkable changes in physiology as part of its natural adaptations to seasonal fluctuations in the environment. Changes in energy balance and body weight are among these adaptations. In some seasonal mammals, such as the Siberian hamster (Phodopus sungorus), these changes in body weight have been explored in detail, and there is evidence for tightly controlled systems of energy balance that are coordinated by photoperiod acting via the temporal pattern of melatonin secretion from the pineal gland. The pathways and systems involved appear to be quite distinct from the hypothalamic pathways identified to regulate energy balance in studies of both mice and rats thus far. Instead it appears that in the Siberian hamster a tightly regulated system under the control of photoperiod is able to reset the tone of the systems involved in energy balance regulation. Understanding how photoperiod and melatonin act within the hypothalamus to regulate energy balance offers potentially fundamental and important new insights into the control of energy balance. This review describes the current state of our knowledge. Topics: Animals; Body Weight; Cricetinae; Eating; Energy Metabolism; Humans; Hypothalamus; Leptin; Mammals; Melatonin; Photoperiod | 2003 |
Common endocrine control of body weight, reproduction, and bone mass.
Bone mass is maintained constant between puberty and menopause by the balance between osteoblast and osteoclast activity. The existence of a hormonal control of osteoblast activity has been speculated for years by analogy to osteoclast biology. Through the search for such humoral signal(s) regulating bone formation, leptin has been identified as a strong inhibitor of bone formation. Furthermore, intracerebroventricular infusion of leptin has shown that the effect of this adipocyte-derived hormone on bone is mediated via a brain relay. Subsequent studies have led to the identification of hypothalamic groups of neurons involved in leptin's antiosteogenic function. In addition, those neurons or neuronal pathways are distinct from neurons responsible for the regulation of energy metabolism. Finally, the peripheral mediator of leptin's antiosteogenic function has been identified as the sympathetic nervous system. Sympathomimetics administered to mice decreased bone formation and bone mass. Conversely, beta-blockers increased bone formation and bone mass and blunted the bone loss induced by ovariectomy. Topics: Body Weight; Bone Density; Endocrine System; Humans; Leptin; Reproduction; Sympathetic Nervous System | 2003 |
Ghrelin-leptin tango in body-weight regulation.
Topics: Animals; Body Weight; Ghrelin; Humans; Leptin; Peptide Hormones | 2003 |
Molecular and genetic mechanisms of obesity: implications for future management.
Obesity has become a worldwide public health problem affecting millions of people. A disruption of the balance between energy intake and energy expenditure is believed to be the major cause of obesity. Substantial progress has been made in deciphering the pathogenesis of energy homeostasis over the past few years. The fact that obesity is under strong genetic control has been well established. Human monogenic obesity is rare in large populations, the most common form of obesity is considered to be a polygenic disorder arising from the interaction of multiple genetic and environmental factors. Here, we attempt to briefly review the most recent understanding of molecular mechanisms involved in energy homeostasis and adipogenesis. We discuss the advantages and disadvantages of various approaches commonly used in search for susceptibility genes for obesity. The main results from these genetic studies are summarized, with comments made on the most striking or representative findings. Finally, the implications of the recent advances in the understanding of molecular genetic mechanisms of body weight regulation on prevention and therapeutic intervention of obesity will be discussed. Topics: Adipose Tissue; Animals; Body Mass Index; Body Weight; Disease Models, Animal; Genetic Markers; Homeostasis; Humans; Leptin; Mice; Obesity; Peptides; Phenotype; Temperature | 2003 |
Cachexia and obesity: two sides of one coin?
Leptin, a member of the interleukin-6 superfamily of proteins, modifies the gene expression and synthetic pathway of both orexigenic (appetite-stimulating) and anorexigenic (appetite-suppressing) molecules in the hypothalamus, thereby controlling adipocyte energy stores. Lack of leptin secretion or the inability of leptin to interact with these molecules via leptin receptors, prevent leptin's effects and lead to obesity. It is not well known, however, how these feeding-regulatory molecules are affected in cachexia associated with cancer and other critical conditions in which cytokines such as interleukin-1 and interleukin-6 may have a key role.. Decreased leptin and increased leptin-like signaling by cytokines in the hypothalamus are the hallmark of obesity and cachexia, respectively. Increased orexigenic and impaired anorexigenic signaling produces hyperphagia and obesity, while the reverse applies to anorexia-cachexia in which adaptive feeding response to starvation is lacking or insufficient.. Imbalanced operation of orexigenic and anorexigenic circuits perturbs the homeostatic loop of body weight regulation leading to either obesity or cachexia. Modifiers of the central effects on appetite and energy metabolism could restore the balance and be effective for treating both conditions. In cachexia this may especially be true when combined with agents that target muscle and protein breakdown. Topics: Anorexia; Body Weight; Cachexia; Energy Metabolism; Homeostasis; Humans; Leptin; Obesity | 2003 |
Leptin-induced adipose apoptosis: Implications for body weight regulation.
Great strides have been made in understanding the genetics of body weight regulation, in part due to the study of rodent models of obesity that are characterized by mutations affecting leptin or its receptors. Leptin, produced in adipose tissue, acts both centrally and peripherally to orchestrate complex metabolic and behavioral changes that increase loss of adipose tissue, including suppressing food intake and increasing thermogenesis. In addition, recent evidence indicates that leptin acts centrally to trigger an apoptotic process resulting in adipocyte deletion. Loss of adipocytes by apoptosis may provide an explanation for the unexpected delay in return to initial energy status following leptin treatments. This review summarizes the major aspects of leptin-induced adipose tissue apoptosis, including some of the newest findings about possible mechanisms of action. Topics: Adipocytes; Adipose Tissue; Animals; Apoptosis; Body Weight; Humans; Leptin; Obesity; Signal Transduction; Thermogenesis | 2003 |
[Appetite regulation by ghrelin - a novel neuro-endocrine gastric peptide hormone in the gut-brain-axis].
Ghrelin a novel peptide consisting of 28 amino acids was first identified in the stomach in 1999. It is mainly produced in endocrine cells of the human gastric mucosa, but it was also found in several other tissues e. g. in the pituitary, the hypothalamus and the pancreas. The functional receptor belongs to the family of the 7-transmembrane G-protein receptors and is predominantly detected in the pituitary and at lower levels in hypothalamic nuclei, the stomach, heart, lungs, kidneys, gut, the adipose and many other tissues. According to the widespread distribution of the peptide and its receptor, ghrelin has multiple biological effects: it stimulates the release of growth hormone in the pituitary and induces a rise in the serum concentration of ACTH, cortisol, catecholamines and prolactin. Ghrelin causes an increase of food intake and body weight by stimulating the production of neuropeptide Y (NPY) and agouti-related protein (AGP) in the nucleus arcuatus. It further leads to elevated concentrations of plasma glucose. A physiological antagonism between ghrelin and GLP-1 in the hypothalamic regulation of appetite is being discussed. The basic serum level of ghrelin depends on the state of nutrition and is negatively correlated with the body-mass-index. It shows a certain pattern of variation before and after food intake with a preprandial increase and a postprandial decrease. Ghrelin modulates gastric acid secretion and the gastrointestinal motility via vagal cholinergic pathways. The discovery of ghrelin definitely contributes to the understanding of the growth-hormone secretion and of the regulation of appetite and food intake. Topics: Adrenocorticotropic Hormone; Animals; Appetite Regulation; Blood Glucose; Body Mass Index; Body Weight; Catecholamines; Eating; Gastrointestinal Motility; Ghrelin; Growth Hormone; Homeostasis; Humans; Hydrocortisone; Hypothalamus; Leptin; Neuropeptide Y; Nutritional Status; Peptide Hormones; Prolactin; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Stomach; Tissue Distribution; Weight Gain | 2003 |
Galanin-like peptide functions more like leptin than like galanin.
Topics: Animals; Body Weight; Energy Intake; Galanin; Galanin-Like Peptide; Humans; Leptin | 2003 |
Nutritional status in the neuroendocrine control of growth hormone secretion: the model of anorexia nervosa.
Growth hormone (GH) plays a key role not only in the promotion of linear growth but also in the regulation of intermediary metabolism, body composition, and energy expenditure. On the whole, the hormone appears to direct fuel metabolism towards the preferential oxidation of lipids instead of glucose and proteins, and to convey the energy derived from metabolic processes towards the synthesis of proteins. On the other hand, body energy stores and circulating energetic substrates take an important part in the regulation of somatotropin release. Finally, central and peripheral peptides participating in the control of food intake and energy expenditure (neuropeptide Y, leptin, and ghrelin) are also involved in the regulation of GH secretion. Altogether, nutritional status has to be regarded as a major determinant in the regulation of the somatotropin-somatomedin axis in animals and humans. In these latter, overweight is associated with marked impairment of spontaneous and stimulated GH release, while acute dietary restriction and chronic undernutrition induce an amplification of spontaneous secretion together with a clear-cut decrease in insulin-like growth factor I (IGF-I) plasma levels. Thus, over- and undernutrition represent two conditions connoted by GH hypersensitivity and GH resistance, respectively. Anorexia nervosa (AN) is a psychiatric disorder characterized by peculiar changes of the GH-IGF-I axis. In these patients, low circulating IGF-I levels are associated with enhanced GH production rate, highly disordered mode of somatotropin release, and variability of GH responsiveness to different pharmacological challenges. These abnormalities are likely due not only to the lack of negative IGF-I feedback, but also to a primary hypothalamic alteration with increased frequency of growth hormone releasing hormone discharges and decreased somatostatinergic tone. Given the reversal of the above alterations following weight recovery, these abnormalities can be seen as secondary, and possibly adaptive, to nutritional deprivation. The model of AN may provide important insights into the pathophysiology of GH secretion, in particular as regards the mechanisms whereby nutritional status effects its regulation. Topics: Animals; Anorexia Nervosa; Body Composition; Body Weight; Cytokines; Eating; Energy Metabolism; Ghrelin; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Nutritional Status; Peptide Hormones; Pituitary Gland | 2003 |
Follicle growth, corpus luteum function and their effects on embryo development in postpartum dairy cows.
Absent or irregular ovarian cycles in lactating dairy cows are caused by failure to ovulate the dominant follicle at the appropriate time. The follicle then either regresses or develops into a cyst. This process can be triggered by a variety of metabolic and disease factors that act at the hypothalamus and pituitary gland to inhibit pulsatile LH secretion and the LH surge, and at the ovary to reduce follicular growth and oestradiol production. Cows of poor energy status have low circulating concentrations of insulin-like growth factor I (IGF-I). Predisposing factors include calving difficulties, inappropriate diet, reduced intake of dry matter and a high rate of body condition score loss. Various stressors predispose the follicle to cyst development by inhibiting the LH surge and ovulation; these include common infections, such as mastitis. Even when ovulation does occur, poor follicular development may result in production of an inadequate corpus luteum. The timing of the increase in progesterone in the early luteal phase (days 4-5) appears to be a key determinant of fertility, probably because it alters the secretory activity of the reproductive tract, thus influencing embryonic growth and interferon-tau production. A period of negative energy balance after calving can reduce fertility even though metabolic parameters have apparently improved at the time of service. Topics: Animals; Body Weight; Cattle; Cattle Diseases; Corpus Luteum; Embryonic and Fetal Development; Estradiol; Female; Gonadotropins, Pituitary; Insulin; Insulin-Like Growth Factor I; Lactation; Leptin; Maternal Nutritional Physiological Phenomena; Ovarian Cysts; Ovarian Follicle; Ovulation; Pregnancy; Pregnancy Complications, Infectious; Progesterone | 2003 |
A critical interaction: leptin and ghrelin.
Continuing research has increased our understanding of regulatory factors involving appetite, food intake, and energy metabolism. There appears to be a complex interaction among insulin, leptin, and ghrelin. A new study explored these interactions and indicates that leptin may regulate ghrelin levels and affect body weight changes. Topics: Animals; Body Weight; Energy Intake; Energy Metabolism; Ghrelin; Humans; Insulin; Leptin; Mice; Neuropeptide Y; Obesity; Peptide Hormones; Rats | 2003 |
Genetic aspects of human obesity: a review.
Topics: alpha-MSH; Body Weight; Genetic Predisposition to Disease; Humans; Leptin; Obesity; Pakistan | 2003 |
[Leptin and psychiatric disorders].
As early as the beginning of the 20th century, changes in appetite and weight were recognized as important symptoms of severe psychiatric disorders. Particularly in the last decade, understanding of the regulation of appetite and weight has made major progress. In this context, the discovery of the adipose tissue hormone leptin, which signals the size of the peripheral fat stores to the CNS, was crucial. In addition, leptin is also involved in a number of CNS networks regulating behavior and thus of great importance for the pathophysiology of psychiatric disorders. Apart from sexual behavior, those networks include motor activity, sleep, and cognition. Moreover, leptin seems to be involved in the development and maturation of the brain. The present paper summarizes current studies which suggest that, in psychiatric disorders, leptin could be of importance not only for disease-associated or drug-related changes in appetite and weight but also for alterations in behavior and cognition. Topics: Alcoholism; Animals; Appetite; Body Weight; Brain; Cognition; Humans; Leptin; Mental Disorders; Motor Activity; Schizophrenia; Sexual Behavior; Sleep | 2002 |
Weight in the balance.
The adage 'we are what we eat' is taking on a new meaning in our well-fed and increasingly sedentary culture, as many of us convert much of our excess food into body fat; in the USA, 60% of the population is now considered to be overweight. Obesity brings with it an increased risk of developing type II diabetes, hypertension and heart disease, so the mechanisms that control food intake and body weight are of considerable importance for public health and clinical medicine. The mass of body fat is now known to be regulated by several hormones and neuropeptides. Two of these, the circulating peptide hormones leptin and ghrelin have actions that include reciprocal effects on appetite-regulating neurons in the hypothalamus. This article reviews data discussed at a recent meeting(1), where an overview of recent developments in research into leptin and ghrelin was presented. Topics covered are the roles of leptin and ghrelin in the regulation of food intake and energy production; the integration of food intake with other energy-regulated processes, such as growth, sexual maturation and reproduction, sleep and the immune response; and pathological conditions, ranging from diabetes to psychiatric disorders.1 This report summarizes conclusions of the meeting 'Brain Somatic Cross-Talk and the Central Metabolism' held in Paris on January 28, 2002. Topics: Body Weight; Disease; Eating; Energy Metabolism; Ghrelin; Humans; Immunity; Leptin; Obesity; Peptide Hormones; Peptides; Reproduction | 2002 |
The role of leptin in the control of body weight.
Physiologic responses to high and low leptin concentrations are strikingly asymmetrical. High concentrations often produce minimal effects, whereas low concentrations provoke strong counterregulatory responses. A model and rationale for the physiology is presented. Topics: Animals; Body Weight; Energy Metabolism; Female; Humans; Leptin; Male; Mice; Obesity | 2002 |
The function of leptin in nutrition, weight, and physiology.
Recent advances indicate that a robust physiologic system acts to maintain relative constancy of weight in mammals. A key component of this system is leptin. Leptin is an adipocyte hormone that functions as the afferent signal in a negative feedback loop regulating body weight. In addition, leptin functions as a key link between nutrition and the function of most, if not all other physiologic systems. When at their set point, individuals produce a given amount of leptin and in turn maintain a state of energy balance. Weight gain results in an increased plasma leptin level, which elicits a biologic response characterized in part by a state of negative energy balance. Weight loss among both lean and obese subjects results in decreased plasma levels of leptin, which lead to a state of positive energy balance and a number of other physiologic responses. In humans, both the intrinsic sensitivity to leptin and its rate of production vary and both appear to contribute to differences in weight. Further studies of leptin, its receptor, and the molecular components of this system are likely to have a major impact on our understanding of obesity and the interplay between nutrition and physiology. Topics: Animals; Body Weight; Humans; Leptin; Male; Mice; Nutritional Physiological Phenomena; Obesity | 2002 |
Neuropeptides, food intake and body weight regulation: a hypothalamic focus.
Energy homeostasis is controlled by a complex neuroendocrine system consisting of peripheral signals like leptin and central signals, in particular, neuropeptides. Several neuropeptides with anorexigenic (POMC, CART, and CRH) as well as orexigenic (NPY, AgRP, and MCH) actions are involved in this complex (partly redundant) controlling system. Starvation as well as overfeeding lead to changes in expression levels of these neuropeptides, which act downstream of leptin, resulting in a physiological response. In this review the role of several anorexigenic and orexigenic (hypothalamic) neuropeptides on food intake and body weight regulation is summarized. Topics: Body Weight; Eating; Homeostasis; Hypothalamus; Insulin; Leptin; Neurons; Neuropeptides | 2002 |
[Food intake: who controls what?].
Since the discovery of leptin and the characterization of the mechanisms leading to obesity in several animal models, considerable advance has been gained in the field of energy homeostasis. The hypothalamus plays a pivotal role in the short and long term regulatory loops that control food intake and body weight. Multiple peripheral signals, including leptin and insulin, convey information on the nutritional and metabolic status to the central nervous system. In the hypothalamus, these signals modulate several neuropeptides and intricate neuronal pathways that trigger appropriate responses of food intake and also of the autonomous nervous system and of the pituitary functions. Peripheral signals and hypothalamic neuropeptides, characterized in the last decade may represent potential targets for new pharmacological treatments of obesity. However, because of the complexity of weight regulation, such approaches may appear troublesome. Topics: Afferent Pathways; Animals; Body Weight; Eating; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Insulin; Leptin; Neurons; Neuropeptides; Obesity; Signal Transduction | 2002 |
Past, present and future strategies to study the genetics of body weight regulation.
Genetic advances have made remarkable progress towards our understanding of body weight regulation. Much of our current knowledge has come from the cloning and characterisation of the genes responsible for obesity syndromes in the mouse, and the identification of homologous mutations causing rare forms of obesity in humans. Gene targeting experiments in mice have been instrumental in confirming the importance of many genes in the aetiology of obesity, and the existence of a fundamental physiological pathway that controls energy balance is becoming clear. The genetic determinants that underlie common forms of human obesity are largely polygenic, with most genes producing small effects. Thus, elucidating the many genetic determinants of obesity is a current challenge for modern geneticists. Despite the inherent difficulties, progress has been made through linkage/association studies and a genetic map of quantitative trait loci for human obesity is beginning to emerge. Obesity research is now very much in a transition period. Not so long ago, access to high throughput screening, as well as microarray and proteomic techniques, was prohibitively expensive and available only to the few. In recent years, these technologies have become more accessible to the larger scientific community and, in this paper, we will discuss how such technological advances are likely to drive the next wave of progress in obesity research. For example, large-scale mutagenesis screens in rodents coupled with high throughput screening are likely to emerge as important technologies for identifying genes previously unexpected to be involved in body weight regulation. Furthermore, applications of microarray and proteomic techniques will further refine our understanding of currently known peptides as well as identify novel pathways and molecules which are involved in energy homeostasis. Topics: Agouti Signaling Protein; Agouti-Related Protein; alpha-MSH; Animals; Body Weight; Cloning, Molecular; Disease Models, Animal; Genomics; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 1; Proteins; Proteomics; Receptors, Cell Surface; Receptors, Leptin; Receptors, Melanocortin | 2002 |
Leptin and renal disease.
Leptin is a small peptide hormone that is mainly, but not exclusively, produced in adipose tissue. The circulating leptin concentration therefore directly reflects the amount of body fat. Leptin was identified through positional cloning of the obese (ob) gene, which is mutated in the massively obese ob/ob mouse, and it has a pivotal role in regulating food intake and energy expenditure. It binds to the so-called long receptor (Ob-Rb) in the hypothalamus and regulates food intake through the release of other neurotransmitters. Moreover, leptin exerts several other important metabolic effects on peripheral tissue, including modification of insulin action, induction of angiogenesis, and modulation of the immune system. As a small peptide, leptin is cleared principally by the kidney. Not surprisingly, serum leptin concentrations are increased in patients with chronic renal failure and those undergoing maintenance dialysis. Whether the hyperleptinemia of chronic renal failure contributes to some uremic manifestations, such as anorexia and weight loss, requires additional investigation. The kidney expresses abundant concentrations of the truncated isoform of the leptin receptor Ob-Ra, but only a small amount of the full-length receptor Ob-Rb. We recently discovered that leptin has direct effects on renal pathophysiological characteristics. Both cultured glomerular endothelial cells and mesangial cells obtained from the diabetic db/db mouse possess the Ob-Ra receptor, but whether biological effects of leptin are transduced through this receptor remains unknown. In glomerular endothelial cells, leptin stimulates cellular proliferation, transforming growth factor-beta1 (TGF-beta1) synthesis, and type IV collagen production. Conversely, in mesangial cells, leptin upregulates synthesis of the TGF-beta type II receptor, but not TGF-beta1, and stimulates glucose transport and type I collagen production through signal transduction pathways involving phosphatidylinositol-3-kinase. These data suggest that leptin triggers a paracrine interaction in which glomerular endothelial cells secrete TGF-beta, to which sensitized mesangial cells may respond. Both cell types increase their expression of extracellular matrix in response to leptin. Infusion of leptin into normal rats for 3 weeks fosters the development of focal glomerulosclerosis and proteinuria. Additional previously described direct and indirect effects of leptin on the kidney include natriuresis, increased sympathe Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Humans; Kidney Diseases; Leptin; Obesity | 2002 |
Obesity-related hypertension: role of the sympathetic nervous system, insulin, and leptin.
Heightened sympathetic nervous system activity, hyperinsulinemia, insulin resistance, and hyperleptinemia contribute to obesity-related hypertension. However, the precise mechanism and sequence of events in this pathophysiologic event have not been clarified. This review concentrates on studies helping to clarify the mechanisms of blood pressure elevation associated with weight change, concentrating on the temporal changes in neuroendocrine factors that are known to control energy metabolism and blood pressure. A better understanding of the pathophysiologic mechanisms of obesity-related hypertension may help in prevention, treatment, and slowing of the cardiovascular complications of obesity. Topics: Blood Pressure; Body Weight; Exercise; Feeding Behavior; Humans; Hypertension; Insulin; Japan; Leptin; Neurotransmitter Agents; Obesity; Risk Factors; Sweden; Sympathetic Nervous System | 2002 |
Regulation of body weight.
Topics: Animals; Body Weight; Carrier Proteins; Cholecystokinin; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Orexins; Pro-Opiomelanocortin; Reproduction | 2002 |
[A new problem after Helicobacter pylori eradication 'obesity'].
Topics: Animals; Body Mass Index; Body Weight; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Leptin; Obesity; RNA, Messenger | 2002 |
Aspects of the neuroendocrine regulation of body weight homeostasis.
Topics: Animals; Body Weight; Carrier Proteins; Homeostasis; Humans; Leptin; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Neurosecretory Systems; Serotonin Plasma Membrane Transport Proteins; Thyroid Hormones | 2002 |
[Central control of bone formation].
Topics: Animals; Body Weight; Humans; Leptin; Neurosecretory Systems; Obesity; Osteogenesis; Reproduction | 2002 |
Thyroid hormones in the pathogenesis and treatment of obesity.
Thyroid hormones (TH) are potent modulators of adaptive thermogenesis and can potentially contribute to development of obesity. The decrease of T(3) in association with reduction of calorie intake is centrally regulated via decreases in leptin and melanocortin concentrations and peripherally via a decrease in deiodinase activity, all aimed at protein and energy sparing. The use of TH in the treatment of obesity is hardly justified except in cases of elevated thyrotropin (TSH) with low/normal T(3) and T(4) and/or a low T(3) or T'(3)/T(4) or a high TSH/T(3) ratio. TH treatment with small doses of T(3) can also be exceptionally applied in obese patients resistant to dietary therapy who are taking beta-adrenergic blockers or with obesity developed after cessation of cigarette smoking and with hyperlipidemia and a concomitant high thryrotropin/T(3) ratio. Supplementation with Se(2+) and Zn(2+) may be tried along with more severe calorie restriction to prevent decline of T(3). Topics: Animals; Body Weight; Eating; Humans; Hyperthyroidism; Hypothyroidism; Leptin; Models, Biological; Obesity; Thyroid Hormones | 2002 |
Leptin and the treatment of obesity: its current status.
Leptin, the protein product of the ob gene, is primarily an adipocyte-secreted hormone, whose functional significance is rapidly expanding. Although early research efforts were focused on defining leptin's role in reversing obesity in rodents, there is now substantial evidence indicating that its influence extends to several hypothalamic-pituitary-endocrine axes, including gonadal, adrenal, thyroid, growth hormone, and pancreatic islets. A role for leptin in hematopoiesis, angiogenesis, immune function, osteogenesis, and wound healing has also been documented. The results of recent clinical trials with recombinant human leptin indicated that its effectiveness in restoring energy balance and correcting obesity-related endocrinopathies in genetically obese rodent models extended only partially to the management of human obesity. New efforts in drug development have focused on leptin-related synthetic peptide agonists as potential anti-obesity pharmacophores. Topics: Animals; Body Weight; Clinical Trials as Topic; Humans; Leptin; Obesity; Recombinant Proteins | 2002 |
Role of leptin in glucose metabolism in type 2 diabetes.
Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Glucose; Humans; Leptin; Obesity; Pregnancy | 2002 |
Metabolic lessons from genetically lean mice.
Different types of lean mice have been produced by genetic manipulation. Leanness can result from deficiency of stored energy or a lack of adipocytes to store the lipid. Mice lacking functional adipocytes are usually insulin resistant and have fatty livers, and elevated circulating triglyceride levels. Insulin resistance may result from the lack of adipocyte hormones (such as leptin) and increased metabolite (such as triglyceride) levels in nonadipose tissue. Mice with depleted adipocyte triglyceride levels typically are insulin sensitive and have normal or low liver and circulating triglycerides. Mechanisms to produce depleted adipocytes include increased energy expenditure by peripheral tissues, peripheral mechanisms to decrease food intake, and altered central regulation of these processes. Topics: Adipocytes; Animals; Body Weight; Energy Metabolism; Fatty Liver; Insulin; Insulin Resistance; Leptin; Mice; Thinness; Triglycerides | 2002 |
Leptin signaling, adiposity, and energy balance.
A chronic minor imbalance between energy intake and energy expenditure may lead to obesity. Both lean and obese subjects eventually reach energy balance and their body weight regulation implies that the adipose tissue mass is "sensed", leading to appropriate responses of energy intake and energy expenditure. The cloning of the ob gene and the identification of its encoded protein, leptin, have provided a system signaling the amount of adipose energy stores to the brain. Leptin, a hormone secreted by fat cells, acts in rodents via hypothalamic receptors to inhibit feeding and increase thermogenesis. A feedback regulatory loop with three distinct steps has been identified: (1) a sensor (leptin production by adipose cells) monitors the size of the adipose tissue mass; (2) hypothalamic centers receive and integrate the intensity of the leptin signal through leptin receptors (LRb); (3) effector systems, including the sympathetic nervous system, control the two main determinants of energy balance-energy intake and energy expenditure. While this feedback regulatory loop is well established in rodents, there are many unsolved questions about its applicability to body weight regulation in humans. The rate of leptin production is related to adiposity, but a large portion of the interindividual variability in plasma leptin concentration is independent of body fatness. Gender is an important factor determining plasma leptin, with women having markedly higher leptin concentrations than men for any given degree of fat mass. The ob mRNA expression is also upregulated by glucocorticoids, whereas stimulation of the sympathetic nervous system results in its inhibition. Furthermore, leptin is not a satiety factor in humans because changes in food intake do not induce short-term increases in plasma leptin levels. After its binding to LRb in the hypothalamus, leptin stimulates a specific signaling cascade that results in the inhibition of several orexigenic neuropeptides, while stimulating several anorexigenic peptides. The orexigenic neuropeptides that are downregulated by leptin are NPY (neuropeptide Y), MCH (melanin-concentrating hormone), orexins, and AGRP (agouti-related peptide). The anorexigenic neuropeptides that are upregulated by leptin are alpha-MSH (alpha-melanocyte-stimulating hormone), which acts on MC4R (melanocortin-4 receptor); CART (cocaine and amphetamine-regulated transcript); and CRH (corticotropin-releasing-hormone). Obese humans have high plasma leptin Topics: Adipose Tissue; Body Weight; Energy Metabolism; Female; Humans; Hypothalamus; Leptin; Male; Signal Transduction | 2002 |
Effects of neuropeptides and leptin on nutrient partitioning: dysregulations in obesity.
Body weight homeostasis is maintained via a series of complex interactions that occur between the brain (particularly the hypothalamus) and the periphery, notably via the hormone leptin, which is synthesized in and secreted from adipose tissue. Under normal conditions, a dynamic equilibrium exists between anabolic neuropeptides (orexigenic peptides), which favor food intake, decrease energy expenditure, and facilitate fat storage, and catabolic ones (anorexigenic peptides), which decrease food intake, increase energy expenditure, and facilitate the loss of fat stores. Secreted leptin, although it may have some direct peripheral effects, exerts its action principally within the brain. Following its transport through the blood-brain barrier, leptin reaches the hypothalamic area, where it binds to its long receptor isoform. After a specific signaling cascade, leptin inhibits many of the orexigenic neuropeptides while favoring many of the anorexigenic ones. Thus, leptin decreases food intake and body weight, and it increases fat oxidation and energy expenditure, ultimately favoring leanness. Lack of leptin secretion, the inability of leptin to reach the brain, or the inability of leptin to interact with hypothalamic leptin receptors, prevent leptin's effects and lead to obesity. Topics: alpha-MSH; Body Weight; Corticotropin-Releasing Hormone; Eating; Energy Metabolism; Homeostasis; Humans; Hypothalamic Hormones; Leptin; Melanins; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Obesity; Opioid Peptides; Pituitary Hormones | 2001 |
Leptin controls bone formation through a hypothalamic relay.
Menopause favors osteoporosis and obesity protects from it. In an attempt to decipher the molecular bases of these two well-known clinical observations, we hypothesized that they meant that bone remodeling, body weight, and reproduction are controlled by identical endocrine pathways. We used mouse genetics as a tool to translate these clinical observations into a molecular hypothesis. The ob/ob and db/db mice were valuable models, since two of the three functions thought to be co-regulated are affected in these mice: they are obese and hypogonadic. Surprisingly, given their hypogonadism, both mouse mutant strains have a high bone mass phenotype. Subsequent analysis of the mechanism leading to this high bone mass revealed that it was due to an increase of bone formation. All data collected indicate that, in vivo, leptin does not act directly on osteoblasts but rather through a central pathway following binding to its specific receptors located on hypothalamic nuclei. This result revealed that bone remodeling, like most other homeostatic functions, is under hypothalamic control. The nature of the signal downstream of the hypothalamus is unknown but current experiments are attempting to identify it. Topics: Animals; Body Weight; Bone and Bones; Bone Development; Bone Remodeling; Humans; Hypogonadism; Leptin; Mice; Mice, Transgenic; Obesity; Phenotype; Signal Transduction | 2001 |
[New findings on the role of leptins in regulation of the reproductive system in humans].
The reproductive activity is closely related to the nutritional status of the organism. A new hormone--leptin has been discovered a few years ago, which informs the brain about fat supplies in the body. Leptin participates in the regulation of the reproductive system at both, peripheral and central, levels. There are discussions about leptin as a possible trigger of puberty. The prepubertal leptin levels are low in both sexes; they increase with the onset of puberty. It has been suggested that leptin resistance might exist in the childhood, allowing the onset of the puberty only at the moment, when the adipose stores are adequate for the strongly demanding period of the adolescence. The role of leptin in pathogenesis of polycystic ovary syndrome (PCOS) is studied. The significance of leptin during pregnancy and after birth remains still unclear. Topics: Body Weight; Female; Humans; Leptin; Male; Polycystic Ovary Syndrome; Puberty; Reproduction | 2001 |
Molecular regulation of eating behavior: new insights and prospects for therapeutic strategies.
Obesity is highly prevalent in industralized countries and is increasing worldwide. It is also a major risk factor for type 2 diabetes, hypertension, coronary artery disease and certain cancers. An understanding of the regulation of eating behavior is pertinent to obesity, as the latter results from an imbalance between food consumption and energy expenditure. Leptin and other hormones regulate feeding and energy balance by modulating the expression of neuropeptides in the brain. Major efforts are underway to determine whether the peripheral and central pathways involved in the regulation of feeding behavior and energy balance could be targeted for the treatment of obesity. Topics: Animals; Body Weight; Cytokines; Digestive System Physiological Phenomena; Eating; Feeding Behavior; Humans; Leptin; Models, Biological; Neurotransmitter Agents; Obesity; Peptides; Perception; Rats | 2001 |
[Changes of leptin levels in menopause].
One of the main advances in the field of metabolic control of body weight and obesity treatment was the identification of the OB protein or leptin, that plays an important role in controlling body weight, signalling to the CNS the amount of body fat. Indeed, leptin levels are positively correlated to indices of body fat, namely total fat mass, percent body fat and body mass index (BMI). This protein may be also the signal that indicates the nutritional status to the reproductive axis. Whether this signal is exerted directly on the gonads or through the neuroendocrine axis is still to be determined. A sexual dimorphism between male and female in serum leptin levels has been observed, with the latter showing higher serum leptin levels. This evidence has led to the hypothesis that estrogens might have a stimulatory role in leptin secretion. To evaluate this hypothesis, several authors have determined serum leptin levels in postmenopausal women that have estrogen levels comparable to those present in men. The results of these studies are contradictory and the aim of this article has been the revision of data present in the literature regarding serum leptin levels in menopause and to correlate them to body composition changes taking place during menopause. Topics: Adult; Age Factors; Animals; Body Composition; Body Weight; Clinical Trials as Topic; Estrogen Replacement Therapy; Estrogens; Female; Humans; Leptin; Male; Menopause; Middle Aged; Ovariectomy; Postmenopause; Rats; Reproduction; Sex Factors | 2001 |
Regulation of appetite: role of leptin in signalling systems for drive and satiety.
The healthy regulation of appetite involves a balance between excitatory (drive) and inhibitory (satiety) processes. For many years research has concentrated on the identification of signalling systems that mediate satiety to the relative exclusion of drive-inducing biological events. However, the so-called long-term regulation of body weight has recently been given substance by the identification of a chemical signal believed to link the brain with adipose tissue stores.. This signal, leptin, is in position to modulate the expression of a drive to eat. Studies on the relationship between leptin and perceived hunger, and on the eating behaviour of leptin-deficient individuals, are consistent with the intervention of leptin in a drive system. The contrast between the roles of leptin and serotonin in appetite regulation reflects the difference between drive-signalling and satiety signalling processes.. It is proposed that leptin modulates the drive signals arising from the metabolic demand for energy but also shows some properties of a post-prandial satiety signal. Topics: Animals; Appetite; Body Weight; Humans; Leptin; Models, Biological; Obesity; Satiation | 2001 |
Human leptin regulation and promise in pharmacotherapy.
In rodents leptin inhibits food intake, stimulates energy expenditure, reverses obesity, ameliorates insulin resistance, and accelerates sexual maturation. These potent and diverse effects have stimulated interest in exploring a role for leptin in the treatment of human metabolic disorders. However, the significance of leptin in human (patho)physiology is still being investigated. The present review summarizes current knowledge of leptin regulation, provides a critical assessment of initial experience with leptin therapy, and discusses potential targets for recombinant leptin therapy in humans. The results of numerous studies indicate that leptin is indeed a regulated human hormone: The physiological factors that influence leptin secretion include gender, adiposity, physical exercise, feeding, and caloric restriction. Several hormones, including insulin, glucocorticoids, estradiol, growth hormone, testosterone, somatostatin, and insulin-like growth factor-I also modulate leptin secretion. The results of initial trials of leptin therapy in humans have become available. Treatment with recombinant human leptin (0.028 mg/kg) induced a progressive weight loss (without evidence of tachyphylaxis) in a morbidly obese patient with congenital leptin deficiency. The weight loss averaged 1-2 kg/month, was associated with preservation of lean muscle mass, and was almost exclusively accounted for by depletion of body fat. Administration ofrecombinant leptin (0.01-0.3 mg/kg) also resultedin a dose-dependentweight loss among lean and obese humans with presumably normal leptin genotype. Thus leptin may have a therapeutic role in humans, but its physiological functions and regulation first need to be fully unravelled. Topics: Animals; Body Weight; Forecasting; Gene Expression Regulation; Glucose Tolerance Test; Hormones; Humans; Leptin; Sex Characteristics | 2001 |
Neuropeptides and the control of energy homeostasis.
Topics: Adipose Tissue; Amyloid; Animals; Body Weight; Drug Tolerance; Energy Intake; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Insulin; Islet Amyloid Polypeptide; Leptin; Neuropeptides; Obesity | 2001 |
Brain histamine and feeding behavior.
Food intake is regulated by many endogenous substances, such as peptides and neurotransmitters in the central nervous system. Based on the clinical observation that some antidepressants and antipsychotics with antihistaminic activity stimulate food intake and increase body weight, histamine has been thought to be an anorectic agent. Several lines of evidence suggest that histamine decreases food intake via H(1)-receptors (H1R) at least in the ventromedial hypothalamus or the paraventricular nucleus. Recently, mutant mice lacking H1R were generated and the interaction between the histaminergic system and leptin-induced suppression of food intake was evidenced by using these mice. In regulating food intake, histamine is indicated to functionally associate with neuropeptide Y, peptide YY, and bombesin. However, the question remained as to why the circadian variation in the level of histamine is inversely correlated to the pattern of feeding. Topics: Animals; Appetite; Body Weight; Brain Mapping; Feeding Behavior; Histamine; Humans; Leptin; Mice; Mice, Knockout; Paraventricular Hypothalamic Nucleus; Rats; Receptors, Histamine H1; Ventromedial Hypothalamic Nucleus | 2001 |
The role of leptin in human physiology and pathophysiology.
This review focuses on current knowledge of leptin biology and the role of leptin in various physiological and pathophysiological states. Leptin is involved in the regulation of body weight. Serum leptin can probably be considered as one of the best biological markers reflecting total body fat in both animals and humans. Obesity in man is accompanied by increased circulating leptin concentrations. Gender differences clearly exist. Leptin is not only correlated to a series of endocrine parameters such as insulin, glucocorticoids, thyroid hormones, testosterone, but it also seems to be involved in mediating some endocrine mechanisms (onset of puberty, insulin secretion) and diseases (obesity, polycystic ovary syndrome). It has also been suggested that leptin can act as a growth factor in the fetus and the neonate. Topics: Adipose Tissue; Animals; Anorexia Nervosa; Body Weight; Carrier Proteins; Female; Humans; Infant, Newborn; Leptin; Male; Obesity; Polycystic Ovary Syndrome; Puberty; Receptors, Cell Surface; Receptors, Leptin; Sex Characteristics; Thyroid Gland | 2001 |
Brain pathways controlling food intake and body weight.
Evidence has existed for more than 50 years in support of the hypothesis that body energy stored in the form of fat is homeostatically regulated. Implicit in this concept is the existence of a biological system that operates dynamically over time to match cumulative energy intake to energy expenditure. For example, to compensate for weight loss induced by energy restriction, animals must enter a period of positive energy balance (i.e., energy intake greater than energy expenditure) that is sustained for as long as it takes to correct the deficit in body fat stores. Having reached this point, the animal must return to a state of neutral energy balance if stable fat mass is to be maintained. The identification of neuronal circuits in the hypothalamus that, when activated, exert potent, unidirectional effects on energy balance provides a cornerstone of support for this model. The additional finding that these central effector pathways are regulated by humoral signals generated in proportion to body fat stores, including the hormones insulin and leptin, helps to round out the picture of how energy homeostasis is achieved. The goal of this overview is to highlight the evidence that specific subsets of hypothalamic neurons containing specific signaling molecules participate in this dynamic regulatory process, and to put these observations in the larger context of a biological system that controls body adiposity. Topics: Body Weight; Brain; Eating; Energy Intake; Energy Metabolism; Feeding Behavior; Humans; Insulin; Leptin; Neurons; Obesity; Weight Loss | 2001 |
Genetics of pathways regulating body weight in the development of obesity in humans.
Although rapid globalization of the Westernized way of life is responsible for the large rise in the number of obesity cases (about 1 billion individuals are now overweight or frankly obese), obesity is a typical common multifactorial disease in that environmental and genetic factors interact, resulting in a disease state. There is strong evidence for a genetic component to human obesity: e.g., the familial clustering (the relative risk among siblings being 3-7) and the high concordance of body composition in monozygotic twins. However, the role of genetic factors in many human obesities (referred to as "common obesity" in this review) is complex, being determined by interaction of several genes (polygenic), each of which may have relatively small effects (i.e., they are "susceptibility" genes and work in combination with each other as well as with environmental factors such as nutrients, physical activity, and smoking). Topics: Adipocytes; Body Weight; Chromosome Mapping; Diseases in Twins; Family Health; Genetic Linkage; Humans; Hypothalamus; Leptin; Models, Biological; Obesity; Polymorphism, Genetic | 2001 |
Leptin and the control of obesity.
Leptin is an adipocyte-derived hormone that is essential for normal body weight regulation. Its main physiological role may be to coordinate the metabolic, endocrine and behavioural responses to starvation. Recent work has identified many factors that regulate leptin production and secretion, including nutrients, hormones and the sympathetic nervous system. Some characteristics of leptin-responsive hypothalamic neurones have now been defined. Other roles for leptin in gut and immune regulation and in foetal development have been proposed. Leptin itself seems ineffective in treating most human obesity, but alternative means of activating appetite-regulatory pathways downstream of leptin are targets for future pharmacological approaches to aid weight loss. Topics: Animals; Body Weight; Carrier Proteins; Humans; Leptin; Obesity; Receptors, Cell Surface; Receptors, Leptin; Sympathetic Nervous System | 2001 |
Recent insights into body weight control: from physiology to pathology.
Over the past several years, new modulators of feeding and body weight have been discovered, and our knowledge of the mechanisms and neurohumoral interactions between anorexigenic and orexigenic compounds has increased dramatically. This review aims to summarize the present knowledge of the role of leptin and several hypothalamic neuropeptides, such as neuropeptide Y (NPY), corticotropin-releasing hormone (CRH) and melanocortins, in the regulation of appetite and body weight. It also presents the progress made in the design of interactions between leptin and hypothalamic peptides in the regulation of feeding. The role of these compounds in the pathogenesis of obesity in animals and humans, and their potential usefulness in the treatment of this disorder, are discussed. Topics: Animals; Appetite; Body Weight; Corticotropin-Releasing Hormone; Drug Interactions; Humans; Leptin; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity | 2001 |
The prothrombotic effects of leptin possible implications for the risk of cardiovascular disease in obesity.
Human obesity is associated with leptin resistance, elevated leptin levels in the circulation, and increased risk of arterial and venous thrombotic disease. Our studies suggest that elevated leptin levels may directly promote arterial thrombosis in vivo. We found that leptin-deficient ob/ob mice had prolonged times to thrombosis after arterial injury with ferric chloride and that exogenously administered leptin corrected their phenotype in a dose-dependent manner. These effects appear to result from a direct, receptor-mediated effect of leptin on platelets, because leptin stimulated the aggregation of murine (wild-type and ob/ob) and human platelets, but it had no effect on platelets from leptin receptor-deficient db/db mice. Moreover, db/db mice had an attenuated thrombotic response to ferric chloride injury (indistinguishable from that of the ob/ob mice), which was unaffected by exogenous leptin. Our results raise the possibility that elevated plasma levels of leptin may contribute to the risk of atherothrombotic complications in human obesity. Topics: Animals; Body Weight; Cardiovascular Diseases; Homeostasis; Humans; Leptin; Mice; Mice, Obese; Obesity; Platelet Aggregation; Risk Assessment; Thrombosis | 2001 |
Pro-opiomelanocortin and weight regulation: from mice to men.
Significant progress in our understanding of the mechanisms of weight homeostasis has been made by studying the many genetic mouse models of obesity. Positional cloning in the obese mouse led to the discovery of leptin as a feedback messenger indicating the adequacy of peripheral energy stores. This was the first in a series of important advances in this field. Shortly after this discovery, two research laboratories presented evidence for the role of hypothalamic pro-opiomelanocortinergic (POMC) neurons as important mediators in the regulation of feeding behavior, insulin levels and, ultimately, body weight. One of these mouse obesity models, the lethal yellow mouse, constitutively overexpresses the agouti protein, an endogenous antagonist of both the melanocortin 1 (MC1) and melanocortin 4 (MC4) receptors. A second mouse obesity model was created by knocking out the MC4 receptor. Investigations using both the autosomal dominant lethal yellow mouse and MC4 receptor knockout mouse have provided clear evidence for the role of hypothalamic POMC neurons and the MC4 receptor in the regulation of weight homeostasis in the rodent. Furthermore, the recent discovery of agouti-related protein (AGRP), an agouti-like peptide naturally found in the hypothalamus, provides further evidence for the importance of POMC neurons in the regulation of weight. Although the significance of central POMC and AGRP in the rodent is apparent, the role of POMC neurons in the regulation of weight and feeding behavior in humans is only now being appreciated. Topics: Agouti Signaling Protein; Agouti-Related Protein; Animals; Body Weight; Genetic Predisposition to Disease; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Melanocyte-Stimulating Hormones; Mice; Mice, Mutant Strains; Obesity; Pro-Opiomelanocortin; Proteins; Signal Transduction | 2001 |
How the brain regulates food intake and body weight: the role of leptin.
The brain plays a key role in the regulation of energy homeostasis, balancing food intake and energy expenditure to maintain adipose tissue mass. A widely accepted model proposes that energy homeostasis is modulated by hormones that circulate in the blood in proportion to adipose tissue mass. A major candidate 'adiposity signal' to the brain is the adipocyte hormone, leptin; this inhibits neuropeptide circuits that promote anabolic metabolism, and stimulates those that promote catabolic metabolism. It is hypothesized that leptin-responsive circuits in the hypothalamus project to caudal brainstem neuronal groups that integrate satiety signals converging on the brain from the stomach and intestine following ingestion of food. Leptin signaling to the brainstem via hypothalamic pathways potentially increases the brain's motor and autonomic responses to satiety signals, leading to smaller individual meals, reduced cumulative food intake, and a lower body weight. This mechanism explains how leptin deficiency or defects in the brain's processing of leptin signaling can result in a sustained increase in food intake and obesity. Topics: Adipose Tissue; Animals; Anorexia; Body Weight; Brain; Eating; Humans; Leptin; Signal Transduction | 2001 |
Regulation and the ponderostat.
Control theory is concerned mainly with the treatment of signals. This article takes into account that living beings not only treat information, but they are open systems traversed by flows of energy and mass. A block diagram of the regulation process is proposed, taking into account this fundamental difference between engineered and living systems. This new diagram is used to describe the stability of body weight. The ponderostat is hypothesized to work as a regulation of blood glucocorticoids with a hypothalamic set-point related to CRH concentration. Topics: Body Weight; Corticotropin-Releasing Hormone; Feedback; Homeostasis; Humans; Leptin; Mathematics; Obesity | 2001 |
Insulin as an adiposity signal.
Insulin is now well established as an adiposity signal that acts in the brain to influence energy homeostasis. It is secreted in direct proportion to adiposity; it enters the brain from the blood, and it interacts with neurons in the ventral hypothalamus. Experimental manipulation of brain insulin causes predictable changes of food intake and body weight. Because insulin shares many properties with other adiposity signals, especially leptin, in this regard, it is important to recognize the similarities and differences in the signal each conveys to the brain in order to design effective therapeutic approaches to treat pathologies of eating and body weight. Topics: Adipose Tissue; Body Weight; Brain; Eating; Energy Metabolism; Homeostasis; Humans; Insulin; Leptin; Signal Transduction | 2001 |
Leptin action in the brain: view from the chair.
Topics: Appetite; Body Weight; Brain; Humans; Leptin; Neuropeptides; Obesity | 2001 |
Neuroendocrine mechanisms regulating food intake and body weight.
In the field of obesity research, two separate lines of study have emerged which explore the mechanism by which food intake is regulated: short-term control of food intake, and the central regulation of energy balance. The former studies the satiety response during consumption of meals, whereby satiety signalling originating in the gut is transduced into a neural signal that modulates satiety pathways in the brainstem. This review describes a neuroanatomically based model in which leptin and insulin signalling in the hypothalamus governs long-term regulation of energy balance via mechanisms that are integrated with satiety hormone signalling in the brainstem. The functional outcome of this integration is a cumulative meal-to-meal regulation of food intake, that over relatively long intervals serves to maintain stable adipose stores. Our model provides a context within which continued investigation of neuroendocrine mechanisms that control food intake and body weight can be explored, and has potential application to our current understanding of clinical obesity and its treatment. Topics: Body Weight; Brain; Brain Stem; Eating; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Insulin; Leptin; Neurosecretory Systems; Satiation; Signal Transduction | 2000 |
Biological determinants of spontaneous physical activity.
A decline in daily physical activity levels is clearly a major factor contributing to the current obesity epidemic affecting both developed and developing countries in the world. This escalating problem is associated with increased morbidity and mortality and reduced psychosocial health. Thus, increasing physical activity has become the strategy of choice in public health strategies to prevent obesity. Efforts to improve levels of physical activity in the population rely upon an accurate understanding of the determinants of physical activity. Most research has focused on environmental and social influences, while the potential for physical activity to be controlled by intrinsic biological processes has been largely overlooked. This review presents some of the compelling and diverse evidence that has emerged recently showing that physical activity energy expenditure is a critical factor in both the successful regulation of energy balance in normal individuals, as well as the abnormal regulation of energy balance that characterizes obesity. Although the metabolic and genetic factors involved in these regulatory processes remain mostly unidentified, some novel discoveries have been made in this area recently and these are described within this review. Topics: Animals; Body Weight; Energy Metabolism; Exercise; Humans; Leptin; Obesity; Physical Exertion | 2000 |
Transgenic approach to the study of body weight regulation.
Energy homeostasis is accomplished through a highly integrated and redundant neurohumoral system. Recently, novel molecular mediators and regulatory pathways for feeding and body weight regulation have been identified in the brain and the periphery. Because of the multitude and complexity of disturbances in energy intake, expenditure, and partitioning that are associated with obesity, it has been difficult to determine which abnormalities are causative versus less important phenomena that are consequences of the altered neuroendocrine and metabolic milieu. Transgenic technology has provided new opportunities to modify the complex body weight-regulating system and to assess the relative importance of the individual components. Observations of mutant mice have shed new light on the understanding of energy homeostasis equation. Once created, transgenic animal models may be useful in assessing the efficacy or determining the mode of action of potential new therapeutic agents. However, the interpretation of targeted mutation is sometimes not straightforward in unraveling the physiology because of the redundancy and compensation of the regulatory machinery, as well as the inherent problems of manipulation of the gene. Modifying the synthesis of a particular gene at all sites and developmental stages may be a relatively crude way of investigating its functions. Advanced gene-targeting strategies aimed at specific alterations (on and off) of a gene product at desired tissues and times could lead to a better understanding of the system. Topics: Animals; Animals, Genetically Modified; Body Weight; Disease Models, Animal; Humans; Hypothalamus; Leptin; Mice; Mice, Transgenic; Obesity | 2000 |
[Regulation of body weight by leptin].
Topics: Adipose Tissue; Animals; Body Weight; Carrier Proteins; Energy Metabolism; Humans; Leptin; Mutation; Obesity; Receptors, Cell Surface; Receptors, Leptin; Ventral Thalamic Nuclei | 2000 |
Food intake and the regulation of body weight.
This chapter reviews the recent literature on hormonal and neural signals critical to the regulation of individual meals and body fat. Rather than eating in response to acute energy deficits, animals eat when environmental conditions (social and learned factors, food availability, opportunity, etc.) are optimal. Hence, eating patterns are idiosyncratic. Energy homeostasis, the long-term matching of food intake to energy expenditure, is accomplished via controls over the size of meals. Individuals who have not eaten sufficient food to maintain their normal weight have lower levels of adiposity signals (leptin and insulin) in the blood and brain, and one consequence is that meal-generated signals (such as CCK) are less efficacious at reducing meal size. The converse is true if individuals are above their normal weight, when they tend to eat smaller meals. The final section reviews how these signals are received and integrated by the CNS, as well as the neural circuits and transmitters involved. Topics: Animals; Body Weight; Eating; Homeostasis; Humans; Hypothalamus; Insulin; Leptin; Nerve Net; Neuropeptides; Obesity | 2000 |
Leptin: an essential regulator of lipid metabolism.
This paper reviews the general mechanisms by which leptin acts as a regulator of lipid reserves through changes in food intake, energy expenditure and fuel selection, with an emphasis on its direct effects on cellular lipid metabolism. Briefly, when leptin levels increase, food consumption decreases via modulation of hypothalamic neuropeptides. As well, normal decreases in energy expenditures (e.g. with diurnal cycles or reduced caloric intake) do not occur. This is probably caused by an increase in mitochondrial proton leak mediated by leptin via increases in sympathetic nervous system stimulation and thyroid hormone release. The decrease in caloric input coupled with relatively higher energy expenditure, therefore, leads to negative energy balance. Leptin also changes the fuel source from which ATP is generated. Fuel preference switches from carbohydrate (glucose) to lipid (fatty acids). This effect arises through stimulation of triacylglycerol catabolism by leptin. In vitro studies show that leptin is a potent stimulator of lipolysis and fatty acid oxidation in adipocytes and other cell types. Consequently, leptin is also a regulator of cellular triacylglycerol content. Hormonal regulation of leptin, as well as its role in fasting and seasonal weight gain and energy expenditure are also briefly discussed. Topics: Adipocytes; Animals; Appetite; Body Weight; Energy Metabolism; Fasting; Humans; Insulin; Leptin; Lipid Metabolism; Lipolysis; Seasons | 2000 |
The changing lifestyle in the world. Body weight and what else?
Body weight and the prevalence of obesity are rising so rapidly in many countries that the World Health Organization has recognized that there is a "global epidemic of obesity." The prevalence of type 2 diabetes is rising in parallel. In view of its associated cardiovascular complications, we are facing a severe public health problem. Both obesity and type 2 diabetes have a combined genetic and environmental background, but the epidemic must be due to major changes in the environment. By definition, obesity is a result of a positive energy balance, which usually amounts to a tiny proportion of the total energy turnover. Energy intake, energy expenditure, and energy accumulation (as fat) may all be primarily disturbed. There is a great, and still insufficiently understood, variation in prevalence of obesity and in the rate of change of the prevalence. The prevailing contention is that the epidemic is due to the changes in the society--the so-called modernization--leading to overnutrition and a sedentary life. These factors are likely contributors, but it has been difficult to provide consistent evidence for their effects. In Denmark, a steep rise has taken place in the prevalence of obesity among schoolboys and young men in two phases linked to the birth cohorts of the 1940s and of the mid-1960s and later. This rise suggests that environmental influences operating early in life are involved. In conclusion, a global obesity epidemic is developing, but the causes of the epidemic are not yet clear and more research is needed to establish the grounds for prevention. Topics: Adipose Tissue; Body Weight; Denmark; Diet; Energy Metabolism; Exercise; Humans; Leptin; Life Style; Lipid Metabolism; Obesity | 2000 |
Leptin: a multifunctional hormone.
Leptin is the protein product encoded by the obese (ob) gene. It is a circulating hormone produced primarily by the adipose tissue. ob/ob mice with mutations of the gene encoding leptin become morbidly obese, infertile, hyperphagic, hypothermic, and diabetic. Since the cloning of leptin in 1994, our knowledge in body weight regulation and the role played by leptin has increased substantially. We now know that leptin signals through its receptor, OB-R, which is a member of the cytokine receptor superfamily. Leptin serves as an adiposity signal to inform the brain the adipose tissue mass in a negative feedback loop regulating food intake and energy expenditure. Leptin also plays important roles in angiogenesis, immune function, fertility, and bone formation. Humans with mutations in the gene encoding leptin are also morbidly obese and respond to leptin treatment, demonstrating that enhancing or inhibiting leptin's activities in vivo may have potential therapeutic benefits. Topics: Animals; Appetite; Body Weight; Carrier Proteins; DNA-Binding Proteins; Hormones; Humans; Hypothalamus; Janus Kinase 1; Leptin; Mice; Protein-Tyrosine Kinases; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; STAT1 Transcription Factor; Trans-Activators | 2000 |
Regulation of metabolism and body fat mass by leptin.
The relative stability of body weight over the long term and under a variety of environmental conditions that alter short-term energy intake and expenditure provides strong evidence for the regulation of body energy content. The lipostatic theory of energy balance regulation proposed 40 years ago that circulating factors, generated in proportion to body fat stores, acted as signals to the brain, eliciting changes in energy intake and expenditure. The discovery of leptin and its receptors has now provided a molecular basis for this theory. Leptin functions as much more than an adipocyte-derived signal of lipid stores, however. Although suppression of food intake is an important centrally mediated effect of leptin, considerable evidence indicates that leptin also functions both directly and indirectly, via the brain, to orchestrate complex metabolic changes in a number of organs and tissues, altering nutrient flux to favor energy expenditure over energy storage. Topics: Adipocytes; Animals; Body Weight; Carbohydrates; Central Nervous System; Energy Metabolism; Humans; Leptin; Lipids; Neuropeptides; Neurosecretory Systems; Nutritional Status | 2000 |
[Leptin and stress protein (heat shock protein 72: HSP72) in patients with obstructive sleep apnea-hypopnea syndrome].
Leptin is a circulating hormone that is expressed abundantly and specifically in adipose tissue. Leptin induces a complex response involving control of body weight, energy expenditure and fat distribution. It is difficult for patients with obstructive sleep apnea-hypopnea syndrome to reduce and maintain their weights. Therefore, it is important to understand the circadian rhythms and regulation of serum leptin levels in order to control the body weight of obstructive sleep apnea-hypopnea syndrome (OSAHS) patients. Heat shock protein(HSP) 72 is generally known to be a stress-inducible isoform that is barely detectable under unstressed conditions but which is rapidly synthesized during or after stress. Recent data suggest that OSAHS may have significant effects on the serum leptin levels and HSP72 levels in peripheral blood mononuclear cells(PBMC) of patients with OSAHS. Topics: Adipose Tissue; Body Weight; Circadian Rhythm; Heat-Shock Proteins; HSP72 Heat-Shock Proteins; Humans; Leptin; Sleep Apnea, Obstructive; Stress, Physiological | 2000 |
The acquisition of obesity: insights from cellular and genetic research.
The acquisition of increased adipose tissue mass in man occurs during prolonged periods of positive energy balance. Normally, energy homeostasis in children and adults is regulated strictly and the energy stores are kept within the defined age-dependent physiological range. Susceptibility to definitive increases in the level of energy balance during times of reduced energy consumption or increased energy intake, leading to changes in body composition and/or changes in relative body weight, seems to be genetically determined. Although at present much information on the regulation of energy homeostasis and related unfavourable factors exists from animal studies, knowledge of the regulation of energy balance in human subjects is still insufficient. Some evidence on relevant factors involved in the regulation of energy balance in man has been obtained from epidemiological data, as well as from studies of patients with rare monogenetic forms of obesity. In the present article a special focus will be put on the regulation of body energy stores at the level of the adipose tissue, with emphasis on the regulation of human adipocyte differentiation. In addition to the currently intensive scientific interest in the central regulation of energy homeostasis in man, there is sufficient evidence to support the idea that the acquisition of an increased adipose tissue mass is also dependent on the susceptibility of pre-adipocytes to proliferate, to differentiate or to enter into apoptosis. Topics: Adipocytes; Adipose Tissue; Body Weight; Energy Metabolism; Homeostasis; Humans; Leptin; Obesity | 2000 |
Body fat mass, leptin and puberty.
Leptin, the ob gene product, provides a molecular basis for the lipostatic theory of the regulation of energy balance. Leptin circulates as a monomeric 16 kDa protein in rodent and human plasma and is also bound to leptin binding proteins that may form large high molecular weight complexes. Initial models of leptin action included leptin-deficient ob/ob mice and leptin-insensitive db/db mice. Peripheral or central administration of leptin reduced body weight, adiposity, and food intake in ob/ob mice but not in db/db mice. In ob/ob mice leptin treatment restored fertility. Leptin interacts with many messenger molecules in the brain. For example, leptin suppresses neuropeptide Y (NPY) expression in the arcuate nucleus. Increased NPY activity has an inhibitory effect on the gonadotropin axis and represents a direct mechanism for inhibiting sexual maturation and reproductive function in conditions of food restriction and/or energy expenditure. By modulating the hypothalamo-pituitary-gonadal axis both directly and indirectly, leptin may thus serve as the signal from fat to the brain about the adequacy of fat stores for pubertal development and reproduction. Normal leptin secretion is necessary for normal reproductive function to proceed and leptin may be a signal allowing for the point of initiation of and progression toward puberty. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Central Nervous System; Female; Hormones; Humans; Hypothalamo-Hypophyseal System; Leptin; Male; Pregnancy; Puberty | 2000 |
CNS-periphery relationships and body weight homeostasis: influence of the glucocorticoid status.
The obesity-like effects produced by the chronic intracerebroventricular (i.c.v.) neuropeptide Y (NPY) infusion in normal rats require the presence of glucocorticoids, as none of them occurs when NPY is similarly infused in adrenalectomized rats. NPY effects are present again when i.c.v. NPY is infused together with i.c.v. dexamethasone in adrenalectomized animals. The inhibitory effect of leptin on food intake and body weight observed when the hormone is i.c.v. administered to normal rats is markedly enhanced and longer lasting when the same dose of leptin is i.c.v. administered to adrenalectomized rats. Glucocorticoid administration to adrenalectomized rats dose-dependently reduces, then abolishes, this potent effect of leptin. Thus, glucocorticoids limit leptin-induced effects. The chronic i.c.v. infusion of glucocorticoids (dexamethasone) to normal rats produces an obesity syndrome with its several abnormalities. This appears to be due to glucocorticoid-elicited increases in hypothalamic NPY levels together with decreases in those of CRH. Thus, the status of the hypothalamo-pituitary-adrenal axis and related glucocorticoid output is a relevant facet of body weight homeostasis. It may be a deleterious environmental factor responsible for the development of obesity, insulin as well as leptin resistance, and type 2 diabetes. Topics: Animals; Body Weight; Central Nervous System; Glucocorticoids; Homeostasis; Insulin Resistance; Leptin; Neuropeptide Y; Obesity; Peripheral Nervous System; Rats | 2000 |
Physiopathology of prolactin secretion in obesity.
In many species prolactin is of biological importance and has a major role in determining the deposition and mobilization of fat. In human physiology, outside pregnancy, prolactin secretion is altered by increasing body weight in both children and adults. Prolactin in this circumstance appears to be marker of hypothalamic-pituitary function: the prolactin response to insulin-hypoglycaemia, thyrotrophin releasing hormone stimulation and other stimulatory factors may be diminished. In addition, obesity alters the 24h spontaneous release of prolactin with a generalised dampening of release. A number of explanations have been given as possible causes for these alterations, but it seems likely that they reflect obesity per se and are associated with hyperinsulinaemia. Weight reduction, with accompanying decrease in plasma insulin levels, leads to a normalization of prolactin responses in most, but not all, circumstances. To date, no molecular basis has been identified which links prolactin with increasing body fatness, weight and appetite: new data suggests a possible link in obese men between fasting plasma prolactin and leptin concentrations. Topics: Adrenal Glands; Body Weight; Humans; Hypothalamus; Leptin; Obesity; Pituitary Gland; Prolactin; Thyrotropin-Releasing Hormone | 2000 |
Role of adipose tissue in body-weight regulation: mechanisms regulating leptin production and energy balance.
Adipose tissue performs complex metabolic and endocrine functions. Among the endocrine products produced by adipose tissue are tumour necrosis factor alpha, interleukin 6, acylation-stimulating protein and leptin. The present review will focus primarily on mechanisms regulating leptin production and leptin action, and the implications of this regulation in the control of energy balance. Leptin acts in the central nervous system where it interacts with a number of hypothalamic neuropeptide systems to regulate feeding behaviour and energy expenditure. The presence of extreme obesity in animals and human subjects with mutations of the leptin gene or the leptin receptor demonstrates that normal leptin production and action are critical for maintaining energy balance. Insulin is the major regulator of leptin production by adipose tissue. Insulin infusions increase circulating leptin concentrations in human subjects. Plasma leptin levels are markedly decreased in insulin-deficient diabetic rodents, and the low leptin levels contribute to diabetic hyperphagia. Based on in vitro studies, the effect of insulin to stimulate leptin production appears to involve increased glucose metabolism. Blockade of glucose transport or glycolysis inhibits leptin expression and secretion in isolated adipocytes. Evidence suggests that anaerobic metabolism of glucose to lactate does not stimulate leptin production. Alterations in insulin-mediated glucose metabolism in adipose tissue are likely to mediate the effects of energy restriction to decrease, and refeeding to increase, circulating leptin levels. Changes in glucose metabolism may also explain the observation that high-fat meals lower 24h circulating leptin levels relative to high-carbohydrate meals in human subjects, suggesting a mechanism that may contribute to the effects that high-fat diets have in promoting increased energy intake, weight gain and obesity. The decreased circulating leptin observed during energy restriction is related to increased sensations of hunger in human subjects. Thus, decreases in leptin during energy-restricted weight-loss regimens may contribute to the strong propensity for weight regain. A better understanding of the precise mechanisms regulating leptin production and leptin action may lead to new approaches for managing obesity. Topics: Adipose Tissue; Animals; Body Weight; Circadian Rhythm; Energy Metabolism; Humans; Insulin; Leptin; Obesity; Time Factors | 2000 |
Human leptin: from an adipocyte hormone to an endocrine mediator.
Leptin is a mainly adipocyte-secreted protein that was discovered 5 years ago. Most of the research following this discovery focused on the role of leptin in body weight regulation, aiming to illuminate the pathophysiology of human obesity. However, more and more data are emerging that leptin is not only important in the regulation of food intake and energy balance, but that it also has a function as a metabolic and neuroendocrine hormone. It is now clear that it is especially involved in glucose metabolism, as well as in normal sexual maturation and reproduction. Besides this, interactions with the hypothalamic-pituitary-adrenal, thyroid and GH axes and even with haematopoiesis and the immune system have also been described. It has been shown that leptin secretion by the adipocyte is partly regulated by other hormones, such as insulin, cortisol, and sex steroids, mainly testosterone. Also, other hormones like thyroid hormone and GH are possibly involved in leptin synthesis. Leptin itself exerts effects on different endocrine axes, mainly on the hypothalamic-pituitary-gonadal axis and on insulin metabolism, but also on the hypothalamic-pituitary-adrenal, thyroid and GH axes. Leptin may thus be considered a new endocrine mediator, besides its obvious role in body weight regulation. Topics: Adipocytes; Animals; Body Weight; Endocrine Glands; Female; Hormones; Humans; Insulin; Insulin Secretion; Leptin; Male; Pregnancy; Reproduction; Sex Characteristics | 2000 |
Synergistic interaction between CCK and leptin to regulate food intake.
Leptin administered (either intracerebroventricularly, icv, or intraperitoneally, ip) acts in synergy with CCK to suppress food intake and body weight in lean mice or rats. The potentiating effect induced by the co-injection of ip CCK and leptin to inhibit food consumption in mice is mediated by the CCK-A receptor and capsaicin sensitive afferents. In vitro, studies in rats showed that a subset of gastric vagal afferent fibers responded to leptin injected directly into the gastric artery only after a prior intra-arterial CCK injection. Moreover, the tonic activity of gastric-related neurons in the nucleus tractus solitarius (NTS) increased when leptin was delivered into the gastric chamber of an in vitro stomach-brainstem preparation. CCK co-injected with leptin potentiated Fos expression selectively in the area postrema, NTS and paraventricular nucleus of the hypothalamus (PVN), which points to the PVN as part of the afferent and efferent limbs of the circuitry involved in the synergistic interaction between leptin and CCK. The dampening of CCK or leptin inhibitory action on ingestive behavior when either factor is not present or their receptors are non functional supports the notion that such leptin-CCK interaction may have a physiological relevance. These observations provide a mean through which leptin and CCK integrate short- and mid-term meal-related input signals into long-term control of energy balance. Topics: Animals; Body Weight; Cholecystokinin; Drug Synergism; Eating; Humans; Leptin; Mice; Rats | 2000 |
Adiposity signals and the control of energy homeostasis.
Recent technologic innovations have enabled probing the workings of individual cells and even molecules. As a result, our knowledge of the biological controls over eating and the regulation of body adiposity is increasing at a rapid pace. We review the evidence that food intake is controlled by separate but interacting groups of molecular signals. One group, termed satiety signals, are proportional to what is being consumed and help to determine meal size. Cholecystokinin is the best known of these, and its premeal administration causes a dose-dependent reduction of meal size. In and of itself, however, cholecystokinin (and other satiety signals) has little impact on body-fat stores. The second group, termed adiposity signals, circulate in proportion to body adiposity and enter the brain, where they interact with satiety signals in the brainstem and hypothalamus. Insulin and leptin are the best known of these adiposity signals, and the administration of either into the brain causes a dose-dependent reduction of both food intake and body weight. Within the brain, parallel but opposing pathways originating in the hypothalamic arcuate nuclei integrate adiposity signals with satiety signals. Those with a net anabolic effect increase food intake and reduce energy expenditure and are represented (among many such signals) by neuropeptide Y; those with a net catabolic effect decrease food intake and energy expenditure and are represented by brain melanocortins. This complex regulatory mechanism allows individuals to adapt their feeding schedule to idiosyncratic environmental constraints, eating whenever it is desirable or possible. Body-weight regulation occurs as adiposity signals alter the efficacy of meal-generated satiety signals. Topics: Adipose Tissue; Amyloid; Animals; Body Weight; Brain; Eating; Energy Metabolism; Homeostasis; Humans; Insulin; Islet Amyloid Polypeptide; Leptin; Obesity; Signal Transduction | 2000 |
Gonadal steroids and energy homeostasis in the leptin era.
Gonadal steroids influence food intake and body weight. Although the specific mechanisms underlying these effects are not clear, a consideration of their effects in the context of current models of energy homeostasis may ultimately lead to the identification of these mechanisms. When compared with leptin, the prototypical humoral signal of energy balance, sex steroids share many common properties related to food intake and body weight. Specifically, gonadal steroids circulate in proportion to fat mass and current energy balance, and administration of these compounds influences food intake, energy expenditure, body weight, and body composition. Moreover, both estrogens and androgens modulate central nervous system effectors of energy homeostasis that are targets for the action of leptin, including pathways that contain neuropeptide Y, pro-opiomelanocortin, or melanin-concentrating hormone. Sex steroids and leptin also regulate one another's production. Although gonadal steroids, unlike leptin, are clearly not critical to the maintenance of normal energy homeostasis, they do appear to function as physiologic modulators of this process. Identifying the specific central mediators of their effects will contribute to our understanding of their role in energy homeostasis. Topics: Body Weight; Eating; Energy Metabolism; Gonadal Steroid Hormones; Gonads; Homeostasis; Humans; Leptin; Steroids | 2000 |
[Monogenic forms of obesity: from mice to human].
The cloning of five rodent obesity genes has constituted a major advance in our understanding of body weight homeostasis. Breakthroughs in human molecular genetics have identified mutations disrupting either rodent homologue/analogue genes or genes involved in the same pathways in obese patients. Three rare cases of human morbid obesity of early onset associated with hypogodatropic hypogodanism are due to mutations in the leptin and the leptin receptor genes. These studies have confirmed that leptin plays not only a crucial role in the control of body weight in the human but also in several endocrine functions. Other Human obesity syndromes are linked to mutations in the genes encoding brain-expressed targets of leptin, particularly some key components of the melanocortin system. Patients compound heterozygous for mutations in the POMC gene display severe obesity of early onset, congenital adrenal insufficiency and red hair. Another genetic cause of obesity is due to mutation in the Proconvertase gene (PC1), the enzyme required for the cleavage of POMC into ACTH and alpha MSH, and also of Proinsulin to insulin. The subject compound heterozygous for the PC1 mutation displays besides obesity, a partial ACTH deficiency, elevated POMC and late post absorptive hypoglycemia due to the accumulation of high pro-insulinemia. Contrasting largely with these rare syndromic forms of obesity, several mutations located in the melanocortin 4 receptor gene have been showed to cause an early onset dominant form of obesity with no other associated abnormalities indifferent populations. These mutations in MC4-R could represent a "frequent" cause of common monogenic forms of obesity in human. More generally, these researches into human obesity have opened new exciting understandings in some of the pathways regulating body fat mass. Topics: Adrenocorticotropic Hormone; alpha-MSH; Animals; Body Weight; Carrier Proteins; Disease Models, Animal; Genes, Regulator; Heterozygote; Humans; Leptin; Mice; Mice, Obese; Obesity; Pedigree; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin | 2000 |
[Leptin and the feedback regulation of body weight].
Body weight may be controlled by a negative feedback loop. Recent studies have identified that the ob gene product, leptin, apparently and exclusively expressed in adipose tissue, is a part of the negative feedback loop. Leptin is proposed to act as an afferent signal in the negative feedback loop to hypothalamus that limiting food-intake, controlling energy homeostasis and regulating the mass of adipose tissue. The dificiency of or resistance to leptin causes severe obesity. Topics: Animals; Body Weight; Feedback; Humans; Leptin; Obesity; Receptors, Cell Surface; Receptors, Leptin | 1999 |
Physiological perspectives on leptin as a regulator of reproduction: role in timing puberty.
How nutrition regulates reproductive activity remains a major unsolved question of reproductive biology. Reducing the level of nutrition during adulthood can lead to infertility, primarily through reduction of GnRH secretion. Inquiry about such a mechanism has its roots in the search for cues timing the onset of fertility, because the tempo of sexual maturation is much more closely associated with body growth than with chronological age. Growth depends on the quantity and quality of food intake. When food availability is low, small, short-lived species with high metabolism and reduced growth may not even attain puberty before they die. In longer-lived species, puberty is delayed for months or even years until more food becomes available. To appreciate fully how the pubertal progression is timed will require understanding how peripheral signals relating information about energy metabolism are sensed by the brain and how such information is routed through pathways controlling GnRH secretion. Here, we provide some background and physiologic perspective on the question of whether the fat-derived hormone leptin is the unique peripheral signal, is an important signal, is but one of a constellation of signals, or is not a signal timing puberty. Topics: Aging; Animals; Body Weight; Female; Gonadotropin-Releasing Hormone; Humans; Leptin; Male; Nutritional Physiological Phenomena; Proteins; Puberty; Reproduction; Sexual Maturation | 1999 |
Interacting appetite-regulating pathways in the hypothalamic regulation of body weight.
Various aspects of the complex spatio-temporal patterning of hypothalamic signaling that leads to the development of synchronized nocturnal feeding in the rat are critically examined. Undoubtedly, as depicted in Fig. 7, a distinct ARN in the hypothalamus is involved in the control of nocturnal appetite. At least four basic elements operate within this ARN. These are: 1) A discrete appetite-driving or orexigenic network of NPY, NE, GABA, GAL, EOP, and orexin transduces and releases appetite-stimulating signals. 2) Similarly, anorexigenic signal-producing pathways (e.g., CRH, GLP-1, alpha MSH, and CART) orchestrate neural events for dissipation of appetite and to terminate feeding, possibly by interrupting NPY efflux and action at a postsynaptic level within the hypothalamus. It is possible that some of these may represent the physiologically relevant "off" switches under the influence of GABA alone, or AgrP alone, or in combination with NPY released from the NPY-, GABA-, and AgrP-coproducing neurons. 3) Recent evidence shows that neural elements in the VMN-DMN complex tonically restrain the orexigenic signals during the intermeal interval; the restraint is greatly aided by leptin's action via diminution of orexigenic (NPY) and augmentation of anorexigenic (GLP-1, alpha MSH, and CART) signals. Since interruption of neurotransmission in the VMN resulted in hyperphagia and development of leptin resistance, it seems likely that the VMN is an effector site for the restraint exercised by leptin. The daily rhythms in leptin synthesis and release are temporally dissociable because the onset of daily rise in leptin gene expression in adipocytes precedes that in leptin secretion. Nevertheless, these rhythms are in phase with daily ingestive behavior because the peak in circulating leptin levels occurs during the middle of the feeding period. These observations, coupled with the fact that circulating levels of leptin are directly related to adiposity, pose a new challenge for elucidating the precise role of leptin in daily patterning of feeding in the rat. 4) A neural timing mechanism also operates upstream from the ARN in the daily management of energy homeostasis. Although the precise anatomical boundaries are not clearly defined, this device is likely to be composed of a group of neurons that integrate incoming internal and external information for the timely onset of the drive to eat. Evidently, this network operates independently in primates, but it is entrained Topics: Animals; Appetite Regulation; Body Weight; Homeostasis; Humans; Hypothalamus; Leptin; Peptides; Proteins | 1999 |
Leptin and reproduction.
In the few years since leptin was identified as a satiety factor in rodents, it has been implicated in the regulation of various physiological processes. Leptin has been shown to promote sexual maturation in rodent species and a role in reproduction has been investigated at various sites within the hypothalamo-pituitary-gonadal axis. This review considers the evidence that leptin (or alteration in amount of body fat) can affect reproduction. There is evidence that leptin plays a permissive role in the onset of puberty, probably through action on the hypothalamus, where leptin receptors are found in cells that express appetite-regulating peptides. There is little evidence that leptin has a positive effect on the pituitary gonadotrophs and the gonads. There is also very little indication that leptin acts in an acute manner to regulate reproduction in the short term. It seems more likely that leptin is a 'barometer' of body condition that sends signals to the brain. Studies in vitro have shown negative effects on ovarian steroid production and there are no reports of effects on testicular function. Leptin concentrations in plasma increase in women during pregnancy, owing to production by the placenta but the functional significance of this is unknown. A number of factors that affect the production and action of leptin have yet to be studied in detail. Topics: Animals; Body Weight; Female; Gonadotropins; Humans; Hypothalamus; Leptin; Male; Nutritional Status; Obesity; Ovary; Pituitary Gland; Proteins; Sexual Maturation; Testis | 1999 |
From lesions to leptin: hypothalamic control of food intake and body weight.
Topics: Animals; Body Weight; Eating; Hypothalamus; Leptin; Models, Neurological; Proteins; Receptors, Corticotropin; Receptors, Melanocortin; Satiety Response | 1999 |
The control of appetite: basic concepts and practical implications.
Over the last decade physiological mechanisms have been revealed which have increased our understanding of the role of biology in controlling energy balance through processes of inhibition and termination of eating. However, in the majority of cases, these mechanisms do not constitute a biological imperative. The expression of appetite remains dependent upon an interaction between biology and the environment [4] and, at the present time, the environment contains extremely potent factors which for many people (adults and children) can readily overcome biological processes operating to maintain body weight. Topics: Adult; Animals; Appetite; Body Weight; Child; Energy Metabolism; Food Preferences; Humans; Leptin; Proteins; Psychophysiology; Satiety Response; Social Environment | 1999 |
Feeding and body-weight regulation by hypothalamic neuropeptides--mediation of the actions of leptin.
Neuropeptides are essential for the regulation of appetite and body weight within the hypothalamus. The understanding of the neuropeptide regulation of energy homeostasis has been greatly advanced by the recent discovery of leptin, the protein product of the obese gene (ob). Significant new insights into the relationship between peripheral adiposity signals and their impact on the hypothalamic neuropeptide signaling circuitry have provided some crucial missing links in the negative-feedback regulation of appetite and body weight. The neuropeptide Y orexigenic network is a final common pathway for this signaling cascade and, along with feeding-inhibitory neuropeptides such as melanocortin, corticotropin-releasing factor and glucagon-like peptide 1, it is a major target through which leptin exerts a regulatory tonic restraint on body adiposity. Topics: Animals; Body Weight; Corticotropin-Releasing Hormone; Eating; Humans; Hypothalamus; Leptin; Neuropeptide Y; Neuropeptides; Proteins | 1999 |
Melanocortin-4 receptor: a novel signalling pathway involved in body weight regulation.
For many years, genetically obese mouse strains have provided models for human obesity. The Avy/-agouti mouse, one of the oldest obese mouse models, is characterized by maturity-onset obesity and diabetes as a result of ectopic expression of the secreted protein hormone, agouti protein. Agouti protein is normally expressed in hair follicles to regulate pigmentation through antagonism of the melanocortin-1 receptor, but in-vitro studies have demonstrated that the hormone also has potent antagonist activity for the melanocortin-4 receptor (MC4-R). Subsequent development of the MC4-R knockout mouse model demonstrated that MC4-R plays a role in weight homeostasis as these mice recapitulated the metabolic defects of the agouti mouse. Further evidence for this hypothesis was obtained from pharmacological studies utilizing peptides with MC4-R agonist activity, that inhibited food intake (when administered intracerebrally). Additional studies with peptide antagonists have now implicated the MC4-R in the leptin signalling pathway. Finally, evidence that the MC4-R may play a role in human obesity has been obtained from the identification of a dis-functional variant of the receptor in genetically obese subjects. Topics: Animals; Body Weight; Humans; Leptin; Mice; Mice, Inbred Strains; Models, Biological; Obesity; Phenotype; Proteins; Receptor, Melanocortin, Type 4; Receptors, Peptide; Signal Transduction | 1999 |
Regulation of body weight in humans.
The mechanisms involved in body weight regulation in humans include genetic, physiological, and behavioral factors. Stability of body weight and body composition requires that energy intake matches energy expenditure and that nutrient balance is achieved. Human obesity is usually associated with high rates of energy expenditure. In adult individuals, protein and carbohydrate stores vary relatively little, whereas adipose tissue mass may change markedly. A feedback regulatory loop with three distinct steps has been recently identified in rodents: 1) a sensor that monitors the size of adipose tissue mass is represented by the amount of leptin synthesized by adipose cells (a protein encoded by the ob gene) which determines the plasma leptin levels; 2) hypothalamic centers, with specific leptin receptors, which receive and integrate the intensity of the signal; and 3) effector systems that influence the two determinants of energy balance, i.e., energy intake and energy expenditure. With the exception of a few very rare cases, the majority of obese human subjects have high plasma leptin levels that are related to the size of their adipose tissue mass. However, the expected regulatory responses (reduction in food intake and increase in energy expenditure) are not observed in obese individuals. Thus obese humans are resistant to the effect of endogenous leptin, despite unaltered hypothalamic leptin receptors. Whether defects in the leptin signaling cascade play a role in the development of human obesity is a field of great actual interest that needs further research. Present evidences suggest that genetic and environmental factors influence eating behavior of people prone to obesity and that diets that are high in fat or energy dense undermine body weight regulation by promoting an overconsumption of energy relative to need. Topics: Adipose Tissue; Adult; Animals; Body Weight; Humans; Leptin; Obesity; Proteins | 1999 |
The role of agouti-related protein in regulating body weight.
Defects in signaling by leptin, a hormone produced primarily by adipose tissue that informs the brain of the body's energy reserves, result in obesity in mice and humans. However, the majority of obese humans do not have abnormalities in leptin or its receptor but instead exhibit leptin resistance that could result from defects in downstream mediators of leptin action. Recently, two potential downstream mediators, agouti-related protein (Agrp) and its receptor, the melanocortin-4 receptor (Mc4r), have been identified. Agrp and Mc4r are excellent candidates for human disorders of body weight regulation and represent promising targets for pharmacological intervention in the treatment of these disorders. Topics: Agouti-Related Protein; Animals; Body Weight; Humans; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Transgenic; Obesity; Proteins; Receptor, Melanocortin, Type 4; Receptors, Peptide | 1999 |
The leptin era: new insight into the mechanisms of body weight homeostasis.
Topics: Adolescent; Body Weight; Child; Child, Preschool; Environment; Homeostasis; Humans; Infant; Leptin; Models, Biological; Obesity; Proteins | 1999 |
Cancer anorexia-cachexia syndrome: are neuropeptides the key?
Progressive wasting is common in many types of cancer and is one of the most important factors leading to early death in cancer patients. Weight loss is a potent stimulus to food intake in normal humans and animals. The persistence of anorexia in cancer patients, therefore, implies a failure of this adaptive feeding response, although the weight loss in the patients differs from that found in simple starvation. Tremendous progress has been made in the last 5 years with regard to the regulation of feeding and body weight. It has been demonstrated that leptin, a hormone secreted by adipose tissue, is an integral component of the homeostatic loop of body weight regulation. Leptin acts to control food intake and energy expenditure via neuropeptidergic effector molecules within the hypothalamus. Complex interactions among the nervous, endocrine, and immune systems affect the loop and induce behavioral and metabolic responses. A number of cytokines, including tumor necrosis factor-alpha, interleukins 1 and 6, IFN-gamma, leukemia inhibitory factor, and ciliary neurotrophic factor have been proposed as mediators of the cachectic process. Cytokines may play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin. This could be done by persistent stimulation of anorexigenic neuropeptides such as corticotropin-releasing factor, as well as by inhibition of the neuropeptide Y orexigenic network that consists of opioid peptides and galanin, in addition to the newly identified melanin-concentrating hormone, orexin, and agouti-related peptide. Information is being gathered, although it is still insufficient, on such abnormalities in the hypothalamic neuropeptide circuitry in tumor-bearing animals that coincide with the development of anorexia and cachexia. Characterization of the feeding-associated gene products have revealed new biochemical pathways and molecular targets for pharmacological intervention that will likely lead to new treatments. Although therapeutic intervention using neuropeptide agonists/antagonists is now directed at obesity treatment, it may also have an effect on treating cancer anorexia-cachexia, especially when combined with other agents that have effects on muscle and protein breakdown. Topics: Animals; Anorexia; Body Weight; Cachexia; Humans; Leptin; Neoplasms; Neuropeptides; Proteins; Syndrome | 1999 |
Leptin: physiological actions.
Leptin, a peptide hormone (167 aa) mainly expressed in adipocytes, and its hypothalamic receptors are integral components of a complex physiological system evolved to regulate fuel stores and energy expenditure. Thus, leptin discovery has constituted a great breakthrough in the understanding of body weight regulation and in the role of the fat tissue as an endocrine organ. Increasing scientific evidences suggest that, leptin has overall effects on metabolism. Leptin mRNA and/or protein are produced by placenta, fetal tissues, gastric mucosa and hepatic stellate cells and can participate in many physiological functions such as fetal growth, gut-derived satiety, immune or proinflammatory responses, reproduction, nutrient intestinal absorption, angiogenesis and lipolysis. The leptin participation in body weight homeostasis and obesity as well as other peripheral actions are revisited. Topics: Animals; Body Weight; Carrier Proteins; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Mutation; Obesity; Proteins; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction | 1999 |
Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight.
Insulin and leptin are hypothesized to be 'adiposity signals' for the long-term regulation of body weight by the brain. Accordingly, a change in the plasma levels of leptin or insulin indicates a state of altered energy homeostasis and adiposity, and the brain responds by adjusting food intake to restore adipose tissue mass to a regulated level. The candidate site for the brain's detection of leptin adiposity signaling is the hypothalamic arcuate nucleus, where leptin inhibits expression neuropeptide Y and increases expression of the pro-opiomelanocortin (POMC) precursor of alphaMSH. Insulin also inhibits arcuate nucleus expression of neuropeptide Y but its effects on other hypothalamic signaling systems are not known. Leptin-responsive neurons in the arcuate nucleus are hypothesized to project to the paraventricular nucleus and lateral hypothalamic area where they are proposed to influence the expression of peptides that regulate food intake. Future development of this model will incorporate brain pathways for integration of leptin and insulin adiposity signaling to the hypothalamus with meal-related signals that act in the caudal brainstem. Recent research showing that leptin and insulin enhance the satiety action of peripheral CCK, thereby causing meals to be terminated earlier and reducing cumulative food intake, suggests that hypothalamic pathways that are sensitive to leptin and insulin adiposity signals have anatomical connections with caudal brainstem neurons that respond to meal-related signals and regulate meal size. The recent findings that insulin alters the expression and function of neural transporters for dopamine and norepinephrine indicate that adiposity signals may influence food intake by acting on non-peptide neurotransmitter systems. Topics: Adipose Tissue; Animals; Body Weight; Brain; Eating; Humans; Insulin; Leptin; Signal Transduction | 1999 |
Leptin: molecular biology, physiology, and relevance to pediatric practice.
Topics: Adolescent; Body Composition; Body Weight; Child; Energy Metabolism; Exercise; Humans; Hunger; Insulin; Leptin; Molecular Biology; Mutation; Obesity; Pediatrics; Puberty | 1999 |
The physiology of body weight regulation: relevance to the etiology of obesity in children.
The prevalence of obesity in children and adults in the United States has increased by more than 30% over the past decade. Recent studies of the physiology and molecular genetics of obesity in humans have provided evidence that body weight (fat) is regulated. Some of the genes encoding the molecular components of this regulatory system have been isolated from rodents. The increasing prevalence of obesity in the United States apparently represents the interaction of these genes with an environment that encourages a sedentary lifestyle and consumption of calories. The rapid increase in the prevalence of obesity emphasizes the role of environmental factors, because genetic changes could not occur at this rate. Thus, understanding of the relevant genes and how their effects are mediated by environment and development should lead to more effective prophylaxis and therapy of obesity. Although no clear environmental factors have been identified as causative of obesity, the rapid increases in the prevalence of obesity and the seeming voluntary immutability of adult body fatness can be taken as tacit evidence that the pediatric environment can be altered in a way that affects adult body weight. Topics: Adipose Tissue; Age Factors; Agouti Signaling Protein; Animals; Body Mass Index; Body Weight; Energy Metabolism; Health Surveys; Humans; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Molecular Biology; Neuropeptide Y; Nutrition Surveys; Obesity; Paraventricular Hypothalamic Nucleus; Prevalence; Proteins; Rats; United States | 1998 |
[Progress in the study of obesity gene].
The study of obesity is one of the most active and fast moving area in the basic biomedical research. In the past three years, scientists had cloned the obese gene, clarified the structure of leptin, nailed down and cloned the gene of leptin receptor, partly revealed the mechanisms of leptin's effects which make the study of obesity entering the molecular age. It shows an attractive perspective for human being to control the body weight and increase the health level. The recent progress of all these aspects is discussed in this review. Topics: Animals; Body Weight; Gene Expression Regulation; Humans; Leptin; Neuropeptide Y; Obesity; Receptors, Cell Surface; Receptors, Leptin | 1998 |
Recently identified peptides involved in the regulation of body weight.
The application of molecular and genetic techniques to the study of body weight regulation have produced exciting new insights into the physiological systems governing energy expenditure, appetite, and metabolic signaling. A number of new peptides have been identified that play important roles in these regulatory systems. These include the hormone leptin, the short and long forms of the leptin receptor, uncoupling proteins, agouti protein, melanocortin receptor isoforms, melanin-concentrating hormone, and the proteins responsible for tub and fat, two monogenic mouse models of obesity. This article reviews some of the new insights gained from studies of these peptides. Although much of this new knowledge has come from studies of obesity, there may be implications for the clinical syndromes associated with weight loss. As more is learned about these systems, potential new targets for therapeutic intervention will likely become evident. These interventions may develop first as obesity treatments, but investigators and clinicians involved in the care of cachectic patients should follow these scientific developments as well. Topics: Animals; Appetite; Body Weight; Cachexia; Disease Models, Animal; Energy Intake; Humans; Leptin; Melanins; Metabolism; Mice; Obesity; Proteins; Receptors, Peptide; Uncoupling Agents | 1998 |
Pivotal role of leptin in insulin effects.
The OB protein, also known as leptin, is secreted by adipose tissue, circulates in the blood, probably bound to a family of binding proteins, and acts on central neural networks regulating ingestive behavior and energy balance. The two forms of leptin receptors (long and short forms) have been identified in various peripheral tissues, a fact that makes them possible target sites for a direct action of leptin. It has been shown that the OB protein interferes with insulin secretion from pancreatic islets, reduces insulin-stimulated glucose transport in adipocytes, and increases glucose transport, glycogen synthesis and fatty acid oxidation in skeletal muscle. Under normoglycemic and normoinsulinemic conditions, leptin seems to shift the flux of metabolites from adipose tissue to skeletal muscle. This may function as a peripheral mechanism that helps control body weight and prevents obesity. Data that substantiate this hypothesis are presented in this review. Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Carrier Proteins; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Muscle, Skeletal; Obesity; Proteins; Rats | 1998 |
Leptin and the regulation of body weight in mammals.
The assimilation, storage and use of energy from nutrients constitute a homeostatic system that is essential for life. In vertebrates, the ability to store sufficient quantities of energy-dense triglyceride in adipose tissue allows survival during the frequent periods of food deprivation encountered during evolution. However, the presence of excess adipose tissue can be maladaptive. A complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level. Leptin, a hormone secreted by adipose tissue, and its receptor are integral components of this system. Leptin also signals nutritional status to several other physiological systems and modulates their function. Here we review the role of leptin in the control of body weight and its relevance to the pathogenesis of obesity. Topics: Adipose Tissue; Animals; Body Weight; Carrier Proteins; Efferent Pathways; Humans; Leptin; Mammals; Nervous System Physiological Phenomena; Obesity; Protein Biosynthesis; Proteins; Receptors, Cell Surface; Receptors, Leptin | 1998 |
Hypothalamic serotonin in control of eating behavior, meal size, and body weight.
Serotonin (5-HT) has been implicated in the control of eating behavior and body weight. Stimulants of this monoamine reduce food intake and weight gain and increase energy expenditure, both in animals and in humans. This article reviews evidence that supports a role for hypothalamic serotonergic receptor mechanisms in the mediation of these effects. A variety of studies in rodents indicate that, at low doses, 5-HT or drugs that enhance the release of this neurotransmitter preferentially inhibit the ingestion of carbohydrate, more than fat or protein. This phenomenon is mediated, in part, by 5-HT receptors located in various medial hypothalamic nuclei. A negative feedback loop exists between the consumption of this macronutrient and the turnover of 5-HT in the hypothalamus. That is, carbohydrate ingestion enhances the synthesis and release of hypothalamic 5-HT, which in turn serves to control the size of carbohydrate-rich meals. A model is described that proposes the involvement of circulating hormones and glucose in this feedback process. These hormones, including insulin, corticosterone, and the adipose tissue-derived hormone, leptin, have impact on serotonergic function as well as satiety. This model further suggests that 5-HT exerts its strongest effect on appetite at the start of the natural feeding cycle, when carbohydrate is normally preferred. Clinical studies provide evidence that is consistent with the proposed model and that implicates 5-HT in disturbances of eating and body weight disorders. Topics: Animals; Appetite Regulation; Body Weight; Choice Behavior; Circadian Rhythm; Dietary Carbohydrates; Dietary Fats; Disease Models, Animal; Eating; Energy Metabolism; Feedback; Feeding and Eating Disorders; Feeding Behavior; Humans; Hypothalamus; Leptin; Models, Neurological; Obesity; Proteins; Receptors, Serotonin; Satiation; Serotonin; Serotonin Agents; Sex Factors | 1998 |
Leptin and cardiac cachexia: marker or mediator?
Topics: Adipose Tissue; Animals; Biomarkers; Body Weight; Cachexia; Heart Failure; Humans; Leptin; Proteins | 1998 |
Is there a role for leptin in human reproduction?
Leptin is a protein product from the obesity gene (ob gene). It has been shown that leptin significantly correlates with body mass index in humans. In contrast to the obesity of genetically obese (ob/ob) mice, human obesity is not generally caused by gene mutations. It is possible that human obesity results from central leptin resistance. Leptin can serve as a metabolic cue in the neuronal activation of gonadotropin releasing hormone (GnRH) at the end of the prepubertal period. The concentration of leptin is higher in pubertal girls than pubertal boys, and it is supposed that sexual dimorphism might be established in the prepubertal period or even in earlier developmental phases. This dimorphism could be explained by a suppressive action of androgens on leptin. Decreased leptin levels were found in undernourished women of reproductive age, mainly presenting with oligo- or amenorrhea. Leptin concentrations fluctuate according to the phase of the menstrual cycle. It is suggested that the complex relationship of leptin with other hormones, such as insulin, can have etiopathogenetic importance in some enigmatic reproductive disturbances such as the polycystic ovary syndrome. Recent findings of leptin in non-adipose tissue of the placenta could indicate its potential role in developmental physiology and human reproduction. Topics: Animals; Body Weight; Female; Humans; Leptin; Male; Obesity; Proteins; Puberty; Reproduction | 1998 |
[From Claude Bernard to the regulatory system between the hypothalamus and the periphery: implications for homeostasis of body weight and obesity].
The concept of interrelationships between the central nervous system and the periphery aimed at maintaining normal body weight homeostasis has been strengthened by the discovery of hypothalamic neuropeptide Y (NPY) and adipose tissue leptin. NPY, when infused intracerebroventricularly in normal animals produces hyperphagia and hormono-metabolic changes (hyperinsulinemia, hypercorticism) channeling nutrients preferentially toward lipogenesis and storage in adipose tissue and away from their utilization by muscles (muscle insulin resistance). Storage in NPY-infused rats is further favored by the observed decrease in the expression of uncoupling proteins. NPY-induced hyperinsulinemia and hypercorticosteronemia also promote leptin over-secretion. Released leptin, acting within the hypothalamus, decreases hypothalamic NPY levels (probably those of other hypothalamic neuropeptides as well), food intake, insulinemia, insulin sensitivity of white adipose tissue, while increasing that of muscles. Leptin acting centrally additionally favors the expression of uncoupling protein 1, 2, and 3, in keeping with an eflect on energy dissipating mechanisms. The respective hormono-metabolic eflects of NPY and leptin maintain a normal body homeostasis. In most obesity syndromes, the functional relationships between NPY and leptin are altered. Due to hypothalamic leptin receptor mutations or dysfunctions, leptin cannot exert its eflects: NPY levels (possibly those of other neuropeptides) remain elevated, maintaining excess storage, insulin as well as leptin resistance. Topics: Adipose Tissue; Animals; Body Weight; Carrier Proteins; France; History, 19th Century; History, 20th Century; Homeostasis; Humans; Hypothalamus; Leptin; Models, Biological; Neuropeptide Y; Obesity; Physiology; Proteins; Rats; Receptors, Cell Surface; Receptors, Leptin | 1998 |
[Possible pathophysiologic, diagnostic and therapeutic implications of new findings on leptin secretion within the scope of anorexia nervosa].
Leptin is a hormone synthesized in adipocytes and secreted into the bloodstream. It plays an important role in the regulation of body weight, the adaptation to semi-starvation and in reproductive function. Hence, clinical studies pertaining to anorexia nervosa can serve to further elucidate the functions of this hormone in light of the unique features of this disorder.. Circulating concentrations of leptin are exceedingly low during the acute stage of anorexia nervosa. Which symptoms result from these diminished concentrations must be clarified. Furthermore, research is required to evaluate whether or not a too rapid weight gain might induce a physiological counter-regulation which would predispose to renewed loss of weight.. This review summarizes findings to date pertaining to leptin secretion in patients with anorexia nervosa. In addition, possible diagnostic, pathophysiological and therapeutic implications are discussed. Topics: Adipose Tissue; Adolescent; Animals; Anorexia Nervosa; Body Weight; Child; Female; Homeostasis; Humans; Leptin; Mice; Mice, Obese; Proteins | 1998 |
CNS regulation of energy balance and body weight: insights from rodent models.
Topics: Animals; Body Weight; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Mice; Mice, Obese; Proteins | 1998 |
The new biology of body weight regulation.
A growing body of evidence suggests that energy balance (the difference between energy intake and expenditure) and body fuel stores in the form of adipose tissue are maintained by the body within a narrow range. This regulation of adiposity is mediated by the secretion of hormonal signals into the circulation in proportion to body adipose stores and their subsequent actions on brain systems that control caloric intake and energy expenditure. As a result, changes in energy balance sufficient to alter fuel stores elicit compensatory changes in energy intake and expenditure that return fat stores to their regulated level. Recent scientific break-through have identified the key components of this physiologic system. These include the circulating signals, leptin (the hormone encoded by the ob gene that is secreted by fat cells) and the pancreatic hormone insulin; and brain peptides such as neuropeptide Y, which is released from nerve terminals in the hypothalamus to elicit changes in feeding behavior and energy expenditure that mediate adaptive changes in energy balance. This article reviews the discovery of leptin and its receptor and discusses the interaction of leptin and insulin with the hypothalamic neuropeptide Y system. These observations provide a basis for understanding how weight lost during a period of negative energy balance (because of the inability to consume and/or store sufficient energy to meet ongoing energy demands) is eventually recovered. As our understanding of this weight-regulatory system increases, new insights into the causes of human obesity are likely to follow. Such insights may yield improvements in the medical and nutrition management of obese patients. Topics: Animals; Body Weight; Brain; Corticotropin-Releasing Hormone; Feedback; Humans; Insulin; Leptin; Neuropeptide Y; Obesity; Proteins | 1997 |
Leptin, leptin receptors and the control of body weight.
Topics: Adipose Tissue; Animals; Body Weight; Carrier Proteins; Cloning, Molecular; Homeostasis; Humans; Hypothalamus; Leptin; Mice; Mice, Mutant Strains; Mice, Obese; Obesity; Proteins; Receptors, Cell Surface; Receptors, Leptin | 1997 |
The leptin receptor.
Topics: Animals; Body Weight; Carrier Proteins; Cloning, Molecular; Forecasting; Homeostasis; Humans; Leptin; Mice; Obesity; Proteins; Rats; Receptors, Cell Surface; Receptors, Cytokine; Receptors, Leptin; Signal Transduction | 1997 |
Seminars in medicine of the Beth Israel Deaconess Medical Center. Neuroendocrine responses to starvation and weight loss.
Topics: Adipose Tissue; Animals; Body Weight; Endocrine System Diseases; Homeostasis; Humans; Hypothalamo-Hypophyseal System; Leptin; Neuropeptide Y; Pituitary-Adrenal System; Proteins; Starvation; Wasting Syndrome; Weight Loss | 1997 |
Regulation of appetite and body weight.
Short-term variations in caloric intake and energy expenditure-including attempts by obese patients to lose weight-tend to be modified by the body's long-term weight regulatory system. Hormones such as leptin and insulin participate in this system, which links changes in body fat content to appropriate compensatory responses in the hypothalamus. Correction of defects in the system might permit sustained weight loss in obese patients. Topics: Appetite Regulation; Body Weight; Energy Intake; Energy Metabolism; Humans; Hypothalamus; Insulin; Leptin; Neuropeptide Y; Obesity; Proteins | 1997 |
Central nervous system and body weight regulation.
The discovery of both neuropeptide Y and of leptin has led to a better understanding of the pathophysiology of obesity syndromes in animal models. It has strengthened the concept of the importance of the hypothalamus in the etiology of these syndromes. Due to alterations in the regulation of the hypothalamus, e.g. by insulin, by leptin or by decreases in the availability of glucose in specific brain areas, most animal models of obesity have higher than normal hypothalamic neuropeptide Y levels. As neuropeptide Y is a potent orexigenic agent, this hypothalamic defect explains why obese rodents are hyperphagic. Increased hypothalamic neuropeptide Y levels produce hyperinsulinemia and hypercorticism, two abnormalities previously reported in obesity, but whose origin is now known to be driven by neuropeptide Y. As hyperinsulinemia favors lipid accretion and muscle insulin resistance, and as hypercorticism favors the occurrence of both high circulating triglyceride levels and muscle insulin resistance, it may be appreciated that most disorders previously reported in obesity can now be explained by high hypothalamic neuropeptide Y levels. Leptin, produced and secreted by adipose tissue, is a potent anorectic agent whose main action is exerted within the hypothalamus in which it has been shown to decrease neuropeptide Y, therefore food intake. Leptin secretion is favored, in particular, by insulin as well as by glucocorticoids. When leptin is administered to obese mice of the ob/ob strain (which do not produce nor secrete leptin due to a gene mutation), their food intake, body weight and most metabolic abnormalities are normalized. However, in the majority of genetically obese rodents, as well as in obese humans, circulating levels of leptin are high. This is related to hyperinsulinemia- and hypercorticosteronemia-induced leptin oversecretion, as well as to central leptin receptor dysfunctions preventing normal leptin access to and action within specific brain areas. Under these conditions and to prevent the effects of elevated hypothalamic neuropeptide Y levels, neuropeptide Y antagonists or active leptin agonists must be found. Neuropeptide Y and leptin further underline the existence of functional relationship between the brain (hypothalamus) and the periphery (adipose tissue, muscle). Lack of leptin (mutated leptin gene) or inefficient leptin action (leptin receptor defect) results in increased hypothalamic neuropeptide Y levels. The latter favor hyperinsuli Topics: Adipose Tissue; Animals; Body Weight; Central Nervous System; Leptin; Mice; Mice, Obese; Muscle, Skeletal; Neuropeptide Y; Obesity; Proteins | 1997 |
Neurobiology.
The role of neuropeptide Y (NPY), leptin and 5-HT and other neurotransmitters implicated in the regulation of energy balance are only now being fully investigated. Little is known about how they may interact with each other in this complex process. In evolutionary terms, the availability of excess food, and the risk of obesity, is only a recent occurrence in humans. Man, and perhaps other species, may not have developed a specialised neurochemical system for adjusting food intake during obesity. Hence perturbation of a single system, such as hypothalamic NPY or leptin, is unlikely to be directly responsible for the development of most obesity. In contrast, periods of food deprivation and partial starvation have been common in the animal kingdom and the multitude of neurotransmitters implicated in energy balance are more likely to be directed towards increasing food consumption and conserving energy than reducing appetite and increasing thermogenesis in the presence of excess. The last few years have witnessed rapid advances in the understanding of the fundamental mechanisms that regulate body weight and fat content. This progress will undoubtedly continue in the future, and it is hoped that this will be rewarded with the development of new drugs to treat obesity. At present, however, it is unclear whether NPY, leptin, or other apparently strong candidates will be the winner in the lucrative race for the ideal anti-obesity drug. Topics: Body Weight; Diet; Humans; Hypothalamus; Leptin; Neuropeptide Y; Neurotransmitter Agents; Obesity; Proteins; Receptors, Neurotransmitter | 1997 |
Leptin: the voice of the adipose tissue.
Leptin is a newly discovered hormone that acts as a feedback signal from the adipose tissue. It plays a pivotal role in the modulation of neuronal and hormonal systems involved in the regulation of body weight and reproductive functions. This brief overview focuses on the regulation of circulating leptin levels and leptin in extreme clinical states of body weight, summarizing mainly results from the University of Giessen in collaboration with other groups. Finally, a possible role for leptin is presented. Topics: Adipose Tissue; Animals; Body Weight; Feedback; Female; Humans; Leptin; Male; Neurons; Obesity; Proteins; Reproduction | 1997 |
[Progress in obesity research].
Topics: Adipose Tissue; Animals; Body Temperature Regulation; Body Weight; Humans; Leptin; Mice; Mice, Obese; Obesity; Prognosis; Proteins | 1997 |
Weight regulation, leptin and growth hormone.
Leptin, the product of the adipose tissue-specific ob gene, is a newly recognized hormone involved in the regulation of metabolism and body composition. Leptin appears to provide information to the central nervous system on the amount of energy stored in the adipose tissue. Serum leptin levels are highly correlated with body fat mass in adults, children and newborns. Obese individuals have significantly higher circulating leptin than normal, lean subjects. In addition, females have higher serum leptin than males with equivalent fat mass. Although leptin correlates with fat mass, circulating concentrations are altered by extremes in energy intake, such as fasting and overfeeding. Defects in leptin or its receptor in the hypothalamus lead to the development of obesity in several rodent models; however, no such deleterious defects have been identified in humans to date. Taken together, these observations suggest that humans may be resistant to their endogenous leptin levels. Despite this, studies in rodents demonstrating that leptin administration can cause weight loss in both ob/ob mice, and in normal weight controls suggest that leptin may be useful in the treatment of human obesity. This review will summarize the current understanding of leptin and its role in the regulation of body composition. In addition, the interaction of leptin with other metabolic hormones including growth hormone will be discussed. Topics: Adult; Animals; Body Weight; Child; Growth Hormone; Humans; Leptin; Mice; Obesity; Proteins | 1997 |
Regulation of circulating leptin in humans.
Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Humans; Leptin; Obesity; Proteins | 1997 |
Leptin and the regulation of body weight.
Leptin has received considerable attention as a newly recognized metabolic hormone and for its potential for therapeutic use in the treatment of human obesity. Furthermore, defects in the leptin signal pathway that result in obesity in animal models have raised the possibility of a similar etiology for obesity in humans. This review will summarize the current findings on leptin in both humans and rodents. These findings will be discussed with respect to our view of the physiology and potential for pathophysiology in leptin-mediated regulation of body weight and composition. Topics: Body Weight; Carrier Proteins; Feedback; Homeostasis; Humans; Leptin; Obesity; Proteins; Receptors, Cell Surface; Receptors, Cytokine; Receptors, Leptin; Signal Transduction | 1997 |
Molecular approaches to the discovery of new treatments for obesity.
The treatment of obesity requires modulation of both energy intake and energy expenditure, and pharmaceutical treatments are being developed to complement the traditional means of dietary restriction and exercise. The recent discovery of the protein leptin, which modulates both food intake and energy expenditure, has provided a new tool with which to define and analyze potential pathways for pharmacological intervention. Neurotransmitters, such as neuropeptide Y (NPY) and norepinephrine, act downstream of leptin to modulate energy homeostasis. Specific subtypes of the receptors for these neurotransmitters represent promising molecular targets for the discovery of new drugs for the treatment of obesity. Topics: Anti-Obesity Agents; Appetite; Body Weight; Energy Metabolism; Humans; Leptin; Models, Molecular; Obesity; Proteins | 1997 |
Leptin: the tale of an obesity gene.
Topics: Adipose Tissue; Animals; Appetite; Body Temperature Regulation; Body Weight; Cloning, Molecular; Humans; Leptin; Mice; Mice, Mutant Strains; Models, Biological; Obesity; Proteins | 1996 |
Regulation of energy balance by leptin.
The high prevalence of obesity and its well documented association with the cardiovascular risk factors diabetes mellitus, dyslipidemia and hypertension represents a major problem for the general health status of industrialized societies. Although numerous studies have shown that genetic factors have a major influence on the regulation of energy homeostasis and the susceptibility to obesity, the genes and predisposing mutations involved are insufficiently understood. Among several known rodent models of obesity due to single gene mutations, mice homozygous for the obese (ob) gene exhibit massive early-onset obesity, hyperphagia, non-insulin-dependent diabetes mellitus, defective thermoregulation and infertility. Recently the ob gene was identified by positional cloning and shown to be mutated in ob/ob mice. Leptin, the product of the ob gene, is a 167-amino acid secreted protein that is synthesized exclusively in adipose tissue. With the exception of ob/ob mice, circulating plasma leptin is elevated in obesity. Administration of recombinant leptin to ob/ob mice reduces fat mass, food intake, hyperglycemia and hyperinsulinemia. The various effects of the hormone are mediated by leptin receptors expressed at high levels in the hypothalamus, but also in several other non-neuronal tissues. A mutation in the leptin receptor gene is responsible for the obese phenotype of db/db mice. Plasma leptin in humans is positively correlated with body fat mass, suggesting that leptin resistance rather than leptin deficiency is a common feature of human obesity. This review briefly summarizes the current status of the rapidly growing evidence that leptin plays an important role in the regulation of body weight and fat deposition. Topics: Adipocytes; Animals; Body Mass Index; Body Weight; Carrier Proteins; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Mice; Mice, Mutant Strains; Neuropeptide Y; Obesity; Protein Biosynthesis; Proteins; Receptors, Cell Surface; Receptors, Leptin | 1996 |
[The molecular pathogenesis of obesity. The physiological and pathophysiological role of leptin].
Topics: Animals; Body Weight; Carrier Proteins; Humans; Leptin; Obesity; Proteins; Receptors, Cell Surface; Receptors, Cytokine; Receptors, Leptin | 1996 |
Leptin and OB-R: body weight regulation by a cytokine receptor.
There has been intense recent interest in the molecules and pathways governing mammalian body weight regulation. Leptin (OB), an ancestral member of the cytokine family, is an adipocyte-secreted circulating hormone exhibiting weight regulatory properties. Recently, the leptin receptor (OB-R) was identified and shown to exhibit sequence homology and functional similarity to members of the class I cytokine receptor family. The mechanisms governing OB-R triggering and signal transduction have begun to be elucidated, providing new insight into the pathways controlling mammalian body weight homeostasis. Topics: Adipose Tissue; Animals; Body Weight; Carrier Proteins; Cloning, Molecular; Hypothalamus; Leptin; Mice; Mice, Mutant Strains; Mice, Obese; Parabiosis; Proteins; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction | 1996 |
Regulation of energy balance and adiposity: a model with new approaches.
Obesity etiology and treatment have been fraught with disappointment for researchers, because the mechanisms regulating fuel homeostasis and adiposity are incompletely understood. It can now be hypothesized in the light of new evidences that the control of body weight and composition depends upon an axis with three interrelated and self-controlled components: 1) food intake; 2) nutrient turnover and thermogenesis and 3) body fat stores, all of which underly complex feedback mechanisms. This approach considers two of the most relevant recent findings in the field (leptin and beta 3-adrenoceptors), adding new views to previous metabolic models of obesity. This perspective supplies some additional clues to the understanding of body composition regulation as well as the potential involvement of genetic and hypothalamic disorders in the onset of obesity. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Eating; Energy Metabolism; Hormones; Humans; Leptin; Models, Biological; Neuropeptide Y; Neuropeptides; Neurotransmitter Agents; Obesity; Proteins; Substrate Cycling | 1996 |
206 trial(s) available for leptin and Body-Weight
Article | Year |
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Effect of Lactobacillus plantarum LMT1-48 on Body Fat in Overweight Subjects: A Randomized, Double-Blind, Placebo-Controlled Trial.
We investigated whether Lactobacillus plantarum strain LMT1-48, isolated from Korean fermented foods and newborn feces, is a suitable probiotic supplement to treat overweight subjects.. In this randomized, double-blind, placebo-controlled clinical trial, 100 volunteers with a body mass index of 25 to 30 kg/m2 were assigned randomly (1:1) to receive 2×1010 colony forming units of LMT1-48 or to a placebo treatment group. Body composition was measured by dual-energy X-ray absorptiometry, and abdominal visceral fat area (VFA) and subcutaneous fat area were measured by computed tomography scanning. Changes in body fat, VFA, anthropometric parameters, and biomarkers were compared between the two treatment groups (ClinicalTrials.gov number: NCT03759743).. After 12 weeks of treatment, the body weight decreased significantly from 76.6±9.4 to 75.7±9.2 kg in the LMT1-48 group but did not change in the placebo group (P=0.022 between groups). A similar pattern was found in abdominal VFA between the two groups (P=0.041). Serum insulin levels, the corresponding homeostasis model assessment of insulin resistance, and leptin levels decreased in the LMT1-48 group but increased in the placebo group (all P<0.05). Decrease in body weight and body mass index by treatment with LMT1-48 was correlated with increase in Lactobacillus levels significantly. LMT1-48 also increased Oscillibacter levels significantly, which were negatively correlated with triglyceride and alanine transaminase levels.. Administration of LMT1-48 decreased body weight, abdominal VFA, insulin resistance, and leptin levels in these subjects with overweight, suggesting its anti-obesogenic therapeutic potential. Topics: Adipose Tissue; Body Weight; Humans; Insulin Resistance; Lactobacillus plantarum; Leptin; Overweight | 2023 |
Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.
Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations. Topics: Animals; Antibodies; Body Weight; Compassionate Use Trials; Humans; Insulin Resistance; Leptin; Lipodystrophy, Congenital Generalized; Mice; Obesity; Receptors, Leptin | 2023 |
Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function.
Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular complications, and growth hormone resistance with short stature. Small, uncontrolled studies suggest that 1-year treatment with recombinant leptin (metreleptin) improves glycemia in RMS.. This study aimed to determine effects of long-term metreleptin in RMS on glycemia, anthropometrics, the growth hormone axis, and kidney function.. We compared RMS patients during nonrandomized open-label treatment with metreleptin (≥ 0.15 mg/kg/day) vs no metreleptin over 90 months (5 subjects in both groups at different times, 4 only in metreleptin group, 2 only in control group). Main outcome measures were A1c; glucose; insulin; 24-hour urine glucose; standard deviation scores (SDS) for height, weight, body mass index (BMI), and insulin-like growth factor 1 (IGF-1); growth hormone; and estimated glomerular filtration rate.. Over time, metreleptin-treated subjects maintained 1.8 percentage point lower A1c vs controls (P = 0.007), which remained significant after accounting for changes in insulin doses. Metreleptin-treated subjects had a reduction in BMI SDS, which predicted decreased A1c. Growth hormone increased after metreleptin treatment vs control, with no difference in SDS between groups for IGF-1 or height. Reduced BMI predicted higher growth hormone, while reduced A1c predicted higher IGF-1.. Metreleptin alters the natural history of rising A1c in RMS, leading to lower A1c throughout long-term follow-up. Improved glycemia with metreleptin is likely attributable to appetite suppression and lower BMI SDS. Lower BMI after metreleptin may also worsen growth hormone resistance in RMS, resulting in a null effect on IGF-1 and growth despite improved glycemia. Topics: Antigens, CD; Blood Glucose; Body Height; Body Mass Index; Body Weight; Donohue Syndrome; Glomerular Filtration Rate; Glycated Hemoglobin; Human Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Kidney; Leptin; Receptor, Insulin; Treatment Outcome | 2022 |
Cavitation and radiofrequency versus cryolipolysis on leptin regulation in central obese subjects: A randomized controlled study.
To investigate the efficacy of adding ultrasound cavitation and radiofrequency versus cryolipolysis to weight reduction program on leptin, insulin, waist circumference, skinfold, body weight in central obese subjects.. Sixty centrally obese participants were randomly allocated into three equal groups. Subjects in the study group (I) received cavitation and radiofrequency plus dietary regimen, subjects in the second study group (II) received cryolipolysis in conjunction with the same diet program, and subjects in the control group (III) received the same dietary regimen only. Leptin, insulin level, waist circumference, skinfold, body weight, and body mass index were measured shortly before intervention techniques and 3 months afterward.. There were no statistically significant differences between cavitation plus radiofrequency and cryolipolysis on leptin and insulin levels after 3 months of intervention. However, statistically significant differences were found in waist circumference, skinfold, weight reduction, and body mass index in favor of the cavitation group (p < 0.05). In addition, both cavitation-radiofrequency and cryolipolysis were statistically significantly different than the diet alone in favor of the study groups (p < 0.05) in all the outcome measures. Furthermore, there were statistically significant differences in all outcome measures (p < 0.05) when comparing the baseline and postintervention results in each group except for leptin level in the diet group (p = 0.14).. Subjects who underwent cavitation plus radiofrequency had better improvement on waist circumference, skinfold, and body mass index than subjects who received cryolipolysis. However, no differences were found between cavitation plus radiofrequency and cryolipolysis on leptin and insulin levels. Topics: Body Mass Index; Body Weight; Humans; Insulin; Leptin; Obesity; Waist Circumference | 2022 |
Adiponectin/leptin ratio increases after a 12-week very low-carbohydrate, high-fat diet, and exercise training in healthy individuals: A non-randomized, parallel design study.
This study aimed to investigate the effect of a 12-week very low-carbohydrate, high-fat (VLCHF) diet and exercise on biomarkers of inflammation in healthy individuals. Since the anti-inflammatory effects of a ketogenic diet have been established, we hypothesized that the VLCHF diet, along with exercise, would have an additional favorable effect on biomarkers of inflammation. Twenty-four healthy individuals were allocated to the VLCHF diet (VLCHF: N = 12, age 25.3 ± 2.0 years, body mass 66.7 ± 9.8 kg, fat mass 21.5% ± 4.9%), or habitual diet (HD: N = 12, age 23.9 ± 3.8 years, body mass 72.7 ± 15.0 kg, fat mass 23.4 ± 8.4 %) group. Biomarkers of inflammation (adiponectin, leptin, and high-sensitive interleukin-6 [hs-IL-6]) and substrate metabolism (glycated hemoglobin, fasting glucose, triacylglycerides, and cholesterol) were analyzed from blood at baseline and after 12 weeks. The adiponectin-leptin ratio significantly increased in the VLCHF group after the intervention period (ES [95% CL]: -0.90 [-0.96, -0.77], P ≤ .001, BF Topics: Adiponectin; Adipose Tissue; Adult; Biomarkers; Body Weight; Cholesterol; Diet, Carbohydrate-Restricted; Diet, High-Fat; Exercise; Female; Humans; Leptin; Male; Young Adult | 2021 |
Antagonistic Autoantibodies to Insulin-Like Growth Factor-1 Receptor Associate with Poor Physical Strength.
Natural autoantibodies to the IGF1 receptor (IGF1R-aAb) have been described in relation to Graves' ophthalmopathy. Other physiological roles of natural IGF1R-aAb are not known. We hypothesized that IGF1R-aAb may be related to muscle development. Serum samples ( Topics: Adolescent; Autoantibodies; Biomarkers; Body Weight; Child; Exercise; Female; Hand Strength; HEK293 Cells; Humans; Leptin; Male; Muscle, Skeletal; Physical Fitness; Receptor, IGF Type 1 | 2020 |
The effects of flaxseed supplementation on metabolic status in women with polycystic ovary syndrome: a randomized open-labeled controlled clinical trial.
Polycystic Ovary Syndrome (PCOS) is known as the most common endocrine disorder of women in reproductive ages. With the increasing prevalence of PCOS in different countries, the use of herbal medicine as an alternative treatment is growing in these patients. This study aimed to evaluate the effects of flaxseed powder supplementation on metabolic biomarkers of patients with PCOS.. This randomized open-labeled controlled clinical trial was conducted on 41 patients with PCOS. The participants were randomized to take either flaxseed powder (30 g/day) plus lifestyle modification or only lifestyle modification for 12 weeks. Anthropometric and biochemical evaluations were performed for all patients at the beginning and end of the study.. The flaxseed group showed a significant reduction in body weight, insulin concentration, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Triglycerides (TG), high-sensitivity C-Reactive Protein (hs-CRP), and leptin and an increase in Quantitative Insulin-Sensitivity Check Index (QUICKI), High Density Lipoprotein (HDL), and adiponectin compared to the baseline (p < 0.05). Flaxseed supplementation also led to a significant reduction in insulin concentration, HOMA-IR, TG, hs-CRP, Interleukin 6 (IL- 6), and leptin and an increase in QUICKI, HDL, and adiponectin compared to the control group (p < 0.05). No significant changes were observed in other parameters.. Flaxseed supplementation plus lifestyle modification was more effective compared to lifestyle modification alone in biochemical and anthropometric variables in patients with PCOS.. The trial protocol was approved by the Ethics Board at Ahvaz Jundishapur University of Medical Sciences and was registered at Iranian Registry of Clinical Trials (code: IRCT20120704010181N11). Topics: Adiponectin; Adolescent; Adult; Biomarkers; Body Weight; C-Reactive Protein; Dietary Supplements; Female; Flax; Humans; Insulin; Iran; Leptin; Lipoproteins, HDL; Male; Middle Aged; Polycystic Ovary Syndrome; Triglycerides; Young Adult | 2020 |
Insulin Resistance Is Associated with Reduced Food Odor Sensitivity across a Wide Range of Body Weights.
The worldwide obesity epidemic is a major health problem driven by the modern food environment. Recently, it has been shown that smell perception plays a key role in eating behavior and is altered in obesity. However, the underlying mechanisms of this phenomenon are not well understood yet. Since the olfactory system is closely linked to the endocrine system, we hypothesized that hormonal shifts in obesity might explain this relationship. In a within-subject, repeated-measures design, we investigated sensitivity to a food and a non-food odor in the hungry and sated state in 75 young healthy (26 normal weight, 25 overweight, and 24 obese) participants (37 women). To determine metabolic health status and hormonal reactivity in response to food intake, we assessed pre- and postprandial levels of insulin, leptin, glucose, and ghrelin. Odor sensitivity did not directly depend on body weight status/body mass index (BMI) or hunger state. However, we could establish a strong negative mediating effect of insulin resistance on the relationship between BMI/waist-hip ratio and olfactory sensitivity for the food odor. These findings indicate an impact of metabolic health status on sensitivity to food odors. Our results contribute to a better understanding of the mechanisms behind altered smell perception in obesity. Topics: Adolescent; Adult; Blood Glucose; Body Weight; Eating; Feeding Behavior; Female; Food; Ghrelin; Humans; Hunger; Insulin; Insulin Resistance; Leptin; Male; Obesity; Odorants; Olfactory Perception; Overweight; Postprandial Period; Satiation; Sensory Thresholds; Young Adult | 2020 |
Empagliflozin decreases the plasma concentration of plasminogen activator inhibitor-1 (PAI-1) in patients with type 2 diabetes: Association with improvement of fibrinolysis.
Elevation of the plasma concentration of plasminogen activator inhibitor-1 (PAI-1), a rapid-acting inhibitor of fibrinolysis, is associated with development of vascular thrombotic diseases, including coronary artery disease and stroke. We investigated the effects of empagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, on the plasma concentration of PAI-1 and fibrinolytic activity in patients with type 2 diabetes.. In a randomized, active-controlled, open-label trial, 51 patients with type 2 diabetes were randomly allocated at a 2:1 ratio to receive empagliflozin (10 mg/day, n = 31) or standard therapy (n = 18) for 12 weeks. We measured the plasma concentrations of PAI-1 and plasmin-α2-antiplasmin complex (PAP) as indicators of fibrinolytic activity. Serum leptin and high-molecular weight (HMW) adiponectin were also measured.. In 49 patients who completed the trial, baseline plasma PAI-1 showed a positive correlation with body weight, visceral fat area (VFA), γ-glutamyltranspeptidase (GGT), leptin, and the platelet count, while it showed a negative correlation with HDL cholesterol and PAP. Body weight and VFA decreased significantly in the empagliflozin group, but not in the control group. The serum level of GGT showed a significant decrease at 12 weeks in the empagliflozin group, while it was unchanged in the control group. Serum HMW adiponectin increased significantly in the empagliflozin group. Plasma PAI-1 decreased significantly by 25% in the empagliflozin group, but not in the control group. In the empagliflozin group, the change of plasma PAI-1 was positively correlated with the changes of body weight and leptin, but was negatively correlated with the change of PAP.. Empagliflozin reduced the plasma PAI-1 concentration through its synergistic actions of a glucose-lowering effect, VFA loss, and restoring the adipokine balance. (Clinical trial registry: UMIN000025418). Topics: Adiponectin; Benzhydryl Compounds; Body Weight; Diabetes Mellitus, Type 2; Fibrinolysis; Glucosides; Humans; Leptin; Plasminogen Activator Inhibitor 1 | 2020 |
Effect of probiotic and prebiotic versus placebo on appetite in patients with major depressive disorder: post hoc analysis of a randomised clinical trial.
Poor appetite and weight loss are common in melancholic depression. Probiotics and prebiotics have the capacity to affect host behaviour, appetite and weight change by modulating the gut microbiome. The aim of this post hoc analysis was to investigate the effect of supplementation with probiotic and prebiotic on appetite, in parallel with body mass index (BMI), weight and energy intake, in patients with major depressive disorder (MDD).. We extracted data from a clinical trial with 81 patients. The participants were randomly assigned to receive probiotic (Lactobacillus helveticus and Bifidobacterium longum), prebiotic (galactooligosaccharide) or placebo for 8 weeks. Appetite, weight, BMI, dietary intake, serum leptin and physical activity were measured. Subjective appetite rating was evaluated every 2 weeks using visual analogue scales (VAS) to assess satiety, hunger, fullness and desire to eat. Serum leptin was measured by an enzyme-linked immunosorbent assay. Physical activity was measured using the international physical activity questionnaire. A repeated measures analysis of variance model was used to analyse VAS data and analysis of variance/analysis of covariance models for dietary intake, BMI, weight and leptin data.. VAS data analyses indicated no significant intervention-time interactions but did show a significant increase over time for desire to eat within the probiotic group (P = 0.025). No significant difference in either BMI or weight was seen among the groups. Energy intake and leptin were significantly increased in the probiotic group compared to the prebiotic.. Overall, probiotic supplementation for 8 weeks among MDD patients resulted in improvement of appetite, whereas prebiotic administration had no significant effect on appetite. Topics: Accelerometry; Adult; Analysis of Variance; Appetite; Bifidobacterium longum; Body Mass Index; Body Weight; Depressive Disorder, Major; Double-Blind Method; Energy Intake; Exercise; Female; Galactose; Humans; Lactobacillus helveticus; Leptin; Male; Oligosaccharides; Prebiotics; Probiotics; Treatment Outcome; Visual Analog Scale | 2020 |
Effects of medium chain triglycerides on body fat distribution and adipocytokine levels in children with acute lymphoblastic leukemia under chemotherapy.
Glucocorticoids used to treat acute lymphoblastic leukemia (ALL) are associated with cytotoxicity and obesity. The aim of the study was to investigate the effects of high-proportion medium chain triglyceride (MCT) on body fat distribution and levels of leptin and adiponectin during chemotherapy of children with ALL.New-onset ALL children treated at the Guangzhou Women and Children's Medical Center between March 2016 and March 2017 were enrolled. Children were divided into the MCT and control groups. For the MCT group, high-proportion MCT nutrition preparation was added to the diet, while no MCT was added for the control group. The MCT group was further divided into subgroups A and B based on the amount of supplement. Waist circumference, hip circumference, waist-to-hip ratio, bone marrow concentrations of leptin and adiponectin, and leptin-to-adiponectin ratio were measured before and on days 19 and 46 of chemotherapy. Body weight and body mass index (BMI) were measured on admission and discharge.Waist circumference in the control group increased by day 46 (P = .047), but did not change in the MCT group. The BMI of the children in the control group was higher than those in the MCT group on admission (P = .003), but not different at discharge. No significant differences in hip circumference, leptin levels, adiponectin levels, and body weight were observed between the 2 groups.This preliminary study suggests that short-term supplementation of high-proportion MCT nutrition preparation may help reduce the centripetal distribution of adipose induced by the application of glucocorticoids in children with ALL. This will have to be confirmed in future studies. Topics: Adiponectin; Adiposity; Body Fat Distribution; Body Mass Index; Body Weight; Child; Child, Preschool; Dietary Supplements; Female; Glucocorticoids; Humans; Leptin; Male; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Triglycerides; Waist Circumference | 2019 |
The effect of Cornus mas fruit extract consumption on lipid profile, glycemic indices, and leptin in postmenopausal women- A randomized clinical trial.
Menopause, which occurs following a declined ovarian activity and reduced estrogen levels, can lead to long-term changes in lipid and glycemic profiles and increases the risk of cardiovascular disease and osteoporosis. Cornelian cherry (Cornus mas) is rich in phytochemicals and antioxidants, which appears to be useful in reducing the postmenopausal complications. This interventional, double-blinded, randomized clinical trial carried out on 84 menopaused women aged 45-60 years old. They were randomly divided into two groups. The treatment group received three capsules of 300 mg of Cornus mas extract (CME), and control group received three capsules of 300 mg of starch powder per day for 8 weeks. Then, BMI, waist circumference, glycemic indices, lipid profile, serum apoproteinase, apoprotein B100, fibrinogen, and leptin were measured. The dietary intakes were evaluated using 24-hr dietary recall questionnaire. The consumption of CME in comparison with the control group resulted in a significant reduction in weight, body mass index, waist circumference, LDL to HDL ratio, total cholesterol to HDL ratio, and fibrinogen. There was also a significant increase in HDL and ApoA1 levels in the treatment group. Furthermore, there was a significant decrease in BMI, waist circumference, fasting insulin, and insulin resistance index after 8 weeks of using CME. Summing up the results, it can be concluded that CME can have possible effects on decreasing BMI, waist circumference, and improving some aspects of lipid profile and glycemic indices in postmenopausal women. Topics: Antioxidants; Blood Glucose; Body Mass Index; Body Weight; Cornus; Female; Fruit; Humans; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Middle Aged; Plant Extracts; Postmenopause | 2019 |
Effects of metformin administration on endocrine-metabolic parameters, visceral adiposity and cardiovascular risk factors in children with obesity and risk markers for metabolic syndrome: A pilot study.
Metformin treatment (1000-2000 mg/day) over 6 months in pubertal children and/or adolescents with obesity and hyperinsulinism is associated with a reduction in body mass index (BMI) and the insulin resistance index (HOMA-IR). We aimed to ascertain if long-term treatment (24 months) with lower doses of metformin (850 mg/day) normalizes the endocrine-metabolic abnormalities, improves body composition, and reduces the carotid intima-media thickness (cIMT) in pre-puberal and early pubertal children with obesity.. A pilot double-blind, placebo-controlled trial was conducted on 18 pre-puberal and early pubertal (Tanner stage I-II) children with obesity and risk markers for metabolic syndrome. Patients were randomly assigned (1:1) to receive metformin (850 mg/day) or placebo for 24 months. Clinical, biochemical (insulin, lipids, leptin, and high-sensitivity C-reactive protein [hsCRP]), and imaging (body composition [dual-energy X-ray absorptiometry and magnetic resonance imaging]) parameters as well as cIMT (ultrasonography) were assessed at baseline and at 6, 12, and 24 months.. The 12-month treatment tend to cause a reduction in weight standard deviation scores (SDS), BMI-SDS, leptin, leptin-to-high-molecular-weight (HMW) adiponectin ratio, hsCRP, cIMT, fat mass, and liver fat in metformin-treated children compared with placebo. The effect of metformin on the reduction of BMI-SDS, leptin, leptin-to-HMW adiponectin ratio, hsCRP, and liver fat seemed to be maintained after completing the 24 months of treatment. No changes in insulin sensitivity (HOMA-IR) or adverse effects were detected.. In this pilot study, metformin treatment in pre-puberal and early pubertal children with obesity seemed to improve body composition and inflammation markers. Our data encourage the development of future fully powered trials using 850 mg/day metformin in young children, highlighting its excellent tolerance and potential long-term benefits. Topics: Adolescent; Body Mass Index; Body Weight; C-Reactive Protein; Carotid Intima-Media Thickness; Child; Double-Blind Method; Female; Humans; Hyperinsulinism; Insulin; Leptin; Male; Metabolic Syndrome; Metformin; Obesity; Pilot Projects; Spain; White People | 2019 |
Short-term DHEA administration in recreational athletes: impact on food intake, segmental body composition and adipokines.
Dehydroepiandrosterone (DHEA) administration is potentially therapeutic because it has been shown to decrease fat mass and adipokines and improve eating and mood disturbances. However, its impact on these parameters has never been investigated in a young healthy population. This study therefore sought to determine whether short-term DHEA administration would alter food intake, segmental body composition, adipokine secretion and mood in young healthy male and female volunteers with regular sport practice.. Following a double-blind and randomized protocol, 20 young healthy recreational athletes (10 men and 10 women) received treatment with either oral placebo or DHEA (100 mg/day for 4 weeks). Body weight, segmental body composition and adipokines (i.e., leptin, adiponectin and resistin) were determined before and at the end of each treatment. In parallel, spontaneous food intake was assessed at the end of each treatment, and mood was assessed before and at the end of treatment with the positive and negative affect schedule (PANAS).. Body weight and segmental body composition showed no significant change in the men or women. Similarly, no change in adipokine secretion was found after DHEA administration. Total food intake was not affected by DHEA in any subject, despite an increase in fat intake by male subjects under DHEA (P<0.05). Positive and negative affect were not altered.. In conclusion, in contrast to pathological populations, a young healthy population of men and women was not significantly affected by short-term DHEA administration with regard to total food intake, segmental body composition, adipokines or mood. Topics: Adipokines; Adiponectin; Athletes; Body Composition; Body Weight; Cross-Over Studies; Dehydroepiandrosterone; Diet; Double-Blind Method; Feeding Behavior; Female; Humans; Leptin; Male; Resistin; Sports Nutritional Physiological Phenomena; Young Adult | 2019 |
The effect of single-nucleotide polymorphisms at the ADIPOQ gene locus rs1501299 on metabolic parameters after 9 mo of a high-protein/low-carbohydrate versus a standard hypocaloric diet.
Some adiponectin gene (ADIPOQ) single-nucleotide polymorphisms (SNPs) have been related to basal and adiponectin levels and metabolic parameters. The aim of this study was to evaluate the effect of the genetic variant rs1501299 ADIPOQ gene on biochemical changes after weight loss secondary to a high-protein and low-carbohydrate diet versus a standard severe hypocaloric diet over 9 mo as the primary endpoint.. A white population of 270 obese patients was enrolled in a randomized clinical trial with two hypocaloric diets (high-protein and low carbohydrate diet [HP] versus standard diet [S]) over 9 mo of intervention. The statistical analysis was performed for the combined GT and TT as a group (T-allele carriers) and GG as second group (non-T-allele carriers). Before and after 12 wk on each hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake, and a biochemical analysis were realized.. With both dietary interventions, body weight, body mass index (BMI), fat mass, waist circumference, systolic blood pressure, and leptin levels decreased. In non-T-allele carriers after both diets, the decrease in total cholesterol levels -12.3 ± 2.2 mg/dL (T-allele carriers -6.9 ± 2.1 mg/dL; P = 0.01 diet HP) and 12.2 ± 3.1 mg/dL (T-allele carriers -4.7 ± 1.2 mg/dL; P = 0.02 after diet S), low-density lipoprotein cholesterol -13.2 ± 2.7 mg/dL (T-allele carriers -6.1 ± 2.1 mg/dL; P = 0.02 after diet HP) and -9.3 ± 1.8 mg/dL (T-allele carriers -4.8 ± 2.9 mg/dL; P = 0.01 after diet S), triacylglycerol levels -12.7 ± 6.1 mg/dL (T-allele carriers -6 ± 2.9 mg/dL; P = 0.01 after diet HP) and -16.3 ± 7.2 mg/dL (T-allele carriers -5.3 ± 1.4 mg/dL; P = 0.03 after diet S), insulin levels -5 ± 1.1 mUI/L (in T-allele -1.7 ± 0.9 mUI/L; P = 0.02 after diet HP) and -3.2 1.1 mUI/L (T-allele carriers -0.7 ± 0.7 mUI/L; P = 0.02 after diet S), and homeostatic model assessment of insulin resistance levels -0.4 ± 0.2 units (T-allele group -0.1 ± 0.1; P = 0.04 after diet HP) and -0.7 ± 0.1 units (T-allele carriers -0.1 ± 0.5 mg/dL; P = 0.01 after diet S) was higher than T-allele carriers. Only no T-allele carriers showed an increase in adiponectin levels after both diets.. After two different hypocaloric diets during 9 mo of intervention, the GG genotype of an ADIPOQ gene variant (rs1501299) is related to better improvement in adiponectin levels, insulin resistance, and lipid profile than T-allele carriers. Topics: Adiponectin; Adult; Alleles; Anthropometry; Body Mass Index; Body Weight; Diet, Carbohydrate-Restricted; Diet, High-Protein; Diet, Reducing; Female; Genetic Loci; Genotype; Humans; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Treatment Outcome; Waist Circumference | 2019 |
Effect of Phytosomal Curcumin on Circulating Levels of Adiponectin and Leptin in Patients with Non-Alcoholic Fatty Liver Disease: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
Non-alcoholic fatty liver disease (NAFLD) is associated with insulin resistance and changes in serum adipocytokine levels. The aim of the current study was to evaluate the effect of phytosomal curcumin on serum adiponectin and leptin levels in patients with NAFLD.. In this randomized double-blind, placebo-controlled trial, 65 eligible patients were randomly allocated into curcumin and placebo recipient groups using a blocked randomized technique. Parameters of weight, height, body mass index (BMI), fasting blood sugar (FBS), lipid profile, aspartate aminotransferase (AST), alanine aminotransferase (ALT), adiponectin, leptin, and the leptin:adiponectin ratio were measured at baseline and eight weeks after intervention.. High-density lipoprotein cholesterol (HDL-C) levels increased significantly in the curcumin group compared to the placebo group (p=0.01). Serum adiponectin levels increased significantly (p<0.001) and serum leptin levels decreased significantly (p<0.001) with a decrease in the leptin: adiponectin ratio in the curcumin group compared to the placebo group after 8 weeks of intervention.. Non-alcoholic fatty liver disease was associated with changes in serum adipokines levels. Phytosomal curcumin effectively improved leptin and adiponectin levels. It is possible that curcumin efficacy will increase with long-term use of higher doses of this substance. Topics: Adiponectin; Adult; Alanine Transaminase; Anti-Inflammatory Agents, Non-Steroidal; Aspartate Aminotransferases; Blood Glucose; Body Mass Index; Body Weight; Curcumin; Dietary Supplements; Double-Blind Method; Female; Humans; Leptin; Lipids; Male; Middle Aged; Non-alcoholic Fatty Liver Disease | 2019 |
Comparison of the effects of a liquid breakfast meal with varying doses of plant-based soy protein on appetite profile, energy metabolism and intake.
A dose dependent satiating and thermogenic effect of animal-based protein has been observed, however, less is known wherever plant-based protein elicits same response. The purpose of the study was to examine the effects of a breakfast meal containing varying doses of plant-based soy protein (SP) on appetite profile, hormone response, energy metabolism and energy intake.. Seventeen participants (age: 27 ± 7 y, body fat: 21.5 ± 6.9%) in randomized order consumed one of three isoenergetic liquid breakfast meals (482 ± 5 kcals): high SP (HSP; 50 g), low SP (LSP; 25 g) and control (CON; 50 g carbohydrate) followed by an ad libitum lunch 3 h later. Appetite profile was measured before, immediately after and hourly during the 3 h postprandial period. Plasma concentrations of leptin and insulin were measured before, at 30 and 180 min.. Energy intake at lunch per kilogram of body weight was significantly higher after CON (11 ± 3.6 kcal/kg) compared to HSP (9.1 ± 3.0 kcal/kg) but not compared to LSP (10.2 ± 2.7 kcal/kg). Participants hunger was higher, whereas, satiety and fullness were lower after CON (p < 0.05). There were no significant differences (p > 0.05) observed in leptin or insulin responses between meals, however, a significant change over time was observed for insulin (p = 0.02) but not leptin (p > 0.05).. Liquid breakfast meals with higher dose of soy protein reduced energy intake when adjusted by body weight at lunch and was rated as more satiating compared to an isoenergetic CON meal. Topics: Adult; Appetite; Body Weight; Breakfast; Dose-Response Relationship, Drug; Energy Intake; Energy Metabolism; Female; Humans; Insulin; Leptin; Lunch; Male; Postprandial Period; Satiation; Soybean Proteins | 2019 |
Effects of alternate-day fasting or daily calorie restriction on body composition, fat distribution, and circulating adipokines: Secondary analysis of a randomized controlled trial.
Indirect comparisons suggest that alternate-day fasting (ADF) may produce greater improvements in body composition, fat distribution, and/or the adipokine profile compared to daily calorie restriction (CR), but this has not been tested directly. In a pre-planned secondary analysis of a randomized controlled trial, we compared changes in the VAT:SAT ratio, FFM:total mass ratio, and the adipokine profile between ADF and CR.. Overweight and obese participants (n = 100) were randomized to 1) ADF (alternating every 24-h between consuming 25% or 125% of energy needs); 2) CR (consuming 75% of needs every day); or 3) control (consuming 100% of needs every day) for 24 wk.. The VAT:SAT ratio did not change in any group. The FFM:total mass ratio increased in both ADF (0.03 ± 0.00) and CR (0.03 ± 0.01) compared to the control group (P < 0.01), with no differences between the intervention groups. Circulating leptin decreased in both the ADF group (-18 ± 6%) and CR group (-31 ± 10%) relative to the control group (P < 0.05), with no differences between the intervention groups. Circulating levels of adiponectin, resistin, IL-6, and TNF-α did not change in either intervention group relative to the control group.. ADF and CR similarly improve the FFM:total mass ratio and reduce leptin after a 24-wk intervention.. Clinicaltrials.gov, number NCT00960505. Topics: Adipokines; Adult; Body Composition; Body Weight; Caloric Restriction; Diet, Reducing; Exercise; Fasting; Female; Humans; Leptin; Male; Middle Aged; Obesity; Overweight; Treatment Outcome; Weight Loss | 2018 |
Aspartame Consumption for 12 Weeks Does Not Affect Glycemia, Appetite, or Body Weight of Healthy, Lean Adults in a Randomized Controlled Trial.
Low-calorie sweeteners are often used to moderate energy intake and postprandial glycemia, but some evidence indicates that they may exacerbate these aims.. The trial's primary aim was to assess the effect of daily aspartame ingestion for 12 wk on glycemia. Effects on appetite and body weight were secondary aims.. One hundred lean [body mass index (kg/m2): 18-25] adults aged 18-60 y were randomly assigned to consume 0, 350, or 1050 mg aspartame/d (ASP groups) in a beverage for 12 wk in a parallel-arm design. At baseline, body weight and composition were determined, a 240-min oral-glucose-tolerance test (OGTT) was administered, and measurements were made of appetite and selected hormones. Participants also collected a 24-h urine sample. During the intervention, the 0-mg/d ASP group consumed capsules containing 680 mg dextrose and 80 mg para-amino benzoic acid. For the 350-mg/d ASP group, the beverage contained 350 mg aspartame and the 1050-mg/d ASP group consumed the same beverage plus capsules containing 680 mg dextrose and 700 mg aspartame. Body weight, blood pressure, heart rate, and waist circumference were measured weekly. At weeks 4, 8, and 12, participants collected 24-h urine samples and kept appetite logs. Baseline measurements were repeated at week 12.. With the exception of the baseline OGTT glucose concentration at 60 min (and resulting area under the curve value), there were no group differences for glucose, insulin, resting leptin, glucagon-like peptide 1, or gastric inhibitory peptide at baseline or week 12. There also were no effects of aspartame ingestion on appetite, body weight, or body composition. Compliance with the beverage intervention was ∼95%.. Aspartame ingested at 2 doses for 12 wk had no effect on glycemia, appetite, or body weight among healthy, lean adults. These data do not support the view that aspartame is problematic for the management of glycemia, appetite, or body weight. This trial was registered at www.clinicaltrials.gov as NCT02999321. Topics: Adult; Appetite; Aspartame; Blood Glucose; Body Composition; Body Weight; Diet; Feeding Behavior; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Leptin; Male; Non-Nutritive Sweeteners; Postprandial Period; Young Adult | 2018 |
Use of principle component analysis to quantitatively score the equine metabolic syndrome phenotype in an Arabian horse population.
Equine metabolic syndrome (EMS), like human metabolic syndrome, comprises a collection of clinical signs related to obesity, insulin dysregulation and susceptibility to secondary inflammatory disease. Although the secondary conditions resulting from EMS can be life-threatening, diagnosis is not straightforward and often complicated by the presence of other concurrent conditions like pituitary pars intermedia dysfunction (PPID). In order to better characterize EMS, we sought to describe the variation within, and correlations between, typical physical and endocrine parameters for EMS. Utilizing an unsupervised statistical approach, we evaluated a population of Arabian horses using a physical examination including body measurements, as well as blood plasma insulin, leptin, ACTH, glucose, and lipid values. We investigated the relationships among these variables using principle component analysis (PCA), hierarchical clustering, and linear regression. Owner-assigned assessments of body condition were one full score (on a nine-point scale) lower than scores assigned by researchers, indicating differing perception of healthy equine body weight. Rotated PCA defined two factor scores explaining a total of 46.3% of variation within the dataset. Hierarchical clustering using these two factors revealed three groups corresponding well to traditional diagnostic categories of "Healthy", "PPID-suspect", and "EMS-suspect" based on the characteristics of each group. Proxies estimating up to 93.4% of the composite "EMS-suspect" and "PPID-suspect" scores were created using a reduced set of commonly used diagnostic variables, to facilitate application of these quantitative scores to horses of the Arabian breed in the field. Use of breed-specific, comprehensive physical and endocrinological variables combined in a single quantitative score may improve detection of horses at-risk for developing EMS, particularly in those lacking severe clinical signs. Quantification of EMS without the use of predetermined reference ranges provides an advantageous approach for future studies utilizing genomic or metabolomics approaches to improve understanding of the etiology behind this troubling condition. Topics: Animals; Blood Glucose; Body Weight; Female; Horse Diseases; Horses; Insulin; Leptin; Lipids; Male; Metabolic Syndrome; Phenotype | 2018 |
Insulin Pump Therapy - Influence on Body Fat Redistribution, Skeletal Muscle Mass and Ghrelin, Leptin Changes in T1D Patients.
To report changes in body composition and biochemical parameters in patients with type 1 diabetes mellitus (T1D) after switching from multiple daily injection (MDI) to continuous subcutaneous insulin infusion (CSII).. 31 patients switched over from MDI to CSII. Body composition, biochemical parameters, glycaemic variability (GV) and level of physical activity were evaluated before and 6 months on CSII.. In both sexes, we found an increase in skeletal muscle mass (SMM), (p = 0.008; 0.008). In men, there was mainly a decrease in visceral fat area (VFA), (p = 0.028) and in women there was decrease of total body fat (TBF), (p = 0.020) and non-significant decrease of VFA (p = 0.098). SMM inversely correlated with VFA in men (p = -0.001) and with TBF in women (p = -0.005 ). GV was decreased generally and correlated inversely with TBF in men only (p = -0.026). Physical activity was increased and correlated inversely with VFA in men (p = -0.002) and in women (p = -0.006).. Using CSII in T1D leads to a significant increase of SMM in both sexes to a decrease of VFA in men and to a non-significant decrease of VFA in women. Changes in adipose tissue and SMM were also related to increased physical activity and to decreased GV. Topics: Adipose Tissue; Adult; Aged; Blood Glucose; Body Composition; Body Fat Distribution; Body Weight; Diabetes Mellitus, Type 1; Female; Ghrelin; Glycated Hemoglobin; Humans; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Leptin; Male; Middle Aged; Muscle, Skeletal; Organ Size; Waist Circumference | 2018 |
Evaluating Weight Status and Sex as Moderators of the Association of Serum Leptin with Bone Mineral Density in Children and Adolescents
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Animal studies suggest that leptin may adversely affect bone mineral density (BMD). Clinical studies have yielded conflicting results. We therefore investigated associations between leptin and bone parameters in children.. 830 healthy children (age = 11.4 ± 3.1 years; 75% female; BMI standard deviation score [BMIz] = 1.5 ± 1.1) had fasting serum leptin measured with ELISA and body composition by dual-energy X-ray absorptiometry. The main effects for leptin and BMIz plus leptin's interactions with sex and BMIz were examined using hierarchical linear regressions for appendicular, pelvis, and lumbar spine BMD as well as bone mineral content (BMC), and bone area (BA).. Accounting for demographic, pubertal development, and anthropometric variables, leptin was negatively and independently associated with lumbar spine BMC and BA, pelvis BA, and leg BA (p < 0.05 for all). Sex, but not BMIz, moderated the associations of leptin with bone parameters. In boys, leptin was negatively correlated with leg and arm BMD, BMC at all bone sites, and BA at the subtotal and lumbar spine (p < 0.01 for all). In girls, leptin was positively correlated with leg and arm BMD (p < 0.05 for both).. Independent of body size, leptin is negatively associated with bone measures; however, these associations are moderated by sex: boys, but not girls, have a negative independent association between leptin and BMD. . Topics: Adolescent; Body Weight; Bone Density; Child; Female; Humans; Leptin; Male; Puberty; Sex Characteristics | 2017 |
The effect of meal frequency in a reduced-energy regimen on the gastrointestinal and appetite hormones in patients with type 2 diabetes: A randomised crossover study.
Appetite and gastrointestinal hormones (GIHs) participate in energy homeostasis, feeding behavior and regulation of body weight. We demonstrated previously the superior effect of a hypocaloric diet regimen with lower meal frequency (B2) on body weight, hepatic fat content, insulin sensitivity and feelings of hunger compared to the same diet divided into six smaller meals a day (A6). Studies with isoenergetic diet regimens indicate that lower meal frequency should also have an effect on fasting and postprandial responses of GIHs. The aim of this secondary analysis was to explore the effect of two hypocaloric diet regimens on fasting levels of appetite and GIHs and on their postprandial responses after a standard meal. It was hypothesized that lower meal frequency in a reduced-energy regimen leading to greater body weight reduction and reduced hunger would be associated with decreased plasma concentrations of GIHs: gastric inhibitory peptide (GIP), glucagon-like peptide-1(GLP-1), peptide YY(PYY), pancreatic polypeptide (PP) and leptin and increased plasma concentration of ghrelin. The postprandial response of satiety hormones (GLP-1, PYY and PP) and postprandial suppression of ghrelin will be improved.. In a randomized crossover study, 54 patients suffering from type 2 diabetes (T2D) underwent both regimens. The concentrations of GLP-1, GIP, PP, PYY, amylin, leptin and ghrelin were determined using multiplex immunoanalyses.. Fasting leptin and GIP decreased in response to both regimens with no difference between the treatments (p = 0.37 and p = 0.83, respectively). Fasting ghrelin decreased in A6 and increased in B2 (with difference between regimens p = 0.023). Fasting PP increased in B2with no significant difference between regimens (p = 0.17). Neither GLP-1 nor PYY did change in either regimen. The decrease in body weight correlated negatively with changes in fasting ghrelin (r = -0.4, p<0.043) and the postprandial reduction of ghrelin correlated positively with its fasting level (r = 0.9, p<0.001). The postprandial responses of GIHs and appetite hormones were similar after both diet regimens.. Both hypocaloric diet regimens reduced fasting leptin and GIP and postprandial response of GIP comparably. The postprandial responses of GIHs and appetite hormones were similar after both diet regimens. Eating only breakfast and lunch increased fasting plasma ghrelin more than the same caloric restriction split into six meals. The changes in fasting ghrelin correlated negatively with the decrease in body weight. These results suggest that for type 2 diabetic patients on a hypocaloric diet, eating larger breakfast and lunch may be more efficient than six smaller meals during the day. Topics: Adult; Aged; Body Weight; Caloric Restriction; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Insulin Resistance; Leptin; Male; Meals; Middle Aged; Pancreatic Polypeptide; Peptide YY; Time Factors; Treatment Outcome | 2017 |
A 12-week intervention with nonivamide, a TRPV1 agonist, prevents a dietary-induced body fat gain and increases peripheral serotonin in moderately overweight subjects.
A bolus administration of 0.15 mg nonivamide has previously been demonstrated to reduce energy intake in moderately overweight men. This 12-week intervention investigated whether a daily consumption of nonivamide in a protein-based product formulation promotes a reduction in body weight in healthy overweight subjects and affects outcome measures associated with mechanisms regulating food intake, e.g. plasma concentrations of (an)orexigenic hormones, energy substrates as well as changes in fecal microbiota.. Nineteen overweight subjects were randomly assigned to either a control (C) or a nonivamide (NV) group. Changes in the body composition and plasma concentrations of satiating hormones were determined at fasting and 15, 30, 60, 90, and 120 min after a glucose load. Participants were instructed to consume 0.15 mg nonivamide per day in 450 mL of a milk shake additionally to their habitual diet. After treatment, a group difference in body fat mass change (-0.61 ± 0.36% in NV and +1.36 ± 0.38% in C) and an increase in postprandial plasma serotonin were demonstrated. Plasma metabolome and fecal microbiome read outs were not affected.. A daily intake of 0.15 mg nonivamide helps to support to maintain a healthy body composition. Topics: Adiponectin; Adiposity; Adult; Blood Glucose; Body Composition; Body Mass Index; Body Weight; Capsaicin; Cholesterol; Diet; Dietary Fats; Female; Gastrointestinal Hormones; Gastrointestinal Microbiome; Humans; Insulin; Leptin; Male; Overweight; Postprandial Period; Satiation; Sensory System Agents; Serotonin; Triglycerides; TRPV Cation Channels; Weight Gain; Young Adult | 2017 |
Changes of serum adipocytokines and body weight following Zingiber officinale supplementation in obese women: a RCT.
The present randomized, double-blind, placebo-controlled study aimed to evaluate the effect of Zingiber officinale (ginger) consumption on some metabolic and clinical features of obesity.. Eighty eligible obese women (aged 18-45 years) were randomly assigned to either ginger or placebo groups (receiving 2 g/day of ginger powder or corn starch as two 1 g tablets) for 12 weeks. Body mass index (BMI) and body composition were assessed every 4 weeks, and serum levels of leptin, adiponectin, resistin, insulin and glucose were determined before and after intervention. The homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were also calculated.. Ginger consumption significantly decreased BMI, serum insulin and HOMA-IR index, along with increasing QUICKIs as compared to the placebo. Moreover, significant reductions in serum leptin, resistin and glucose were observed in both groups, especially in ginger group with nonsignificant differences between groups. The body composition and serum levels of adiponectin were not significantly changed in study groups.. In conclusion, our findings demonstrate a minor beneficial effect of 2 g ginger powder supplementation for 12 weeks on weight loss and some metabolic features of obesity. However, given the lack of data in this area, ongoing clinical trials are needed to further explore ginger's effectiveness. Topics: Adipokines; Adiponectin; Adolescent; Adult; Blood Glucose; Body Composition; Body Mass Index; Body Weight; Diet; Double-Blind Method; Female; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Obesity; Resistin; Young Adult; Zingiber officinale | 2016 |
Green Tea Extract and Catechol-O-Methyltransferase Genotype Modify Fasting Serum Insulin and Plasma Adiponectin Concentrations in a Randomized Controlled Trial of Overweight and Obese Postmenopausal Women.
Green tea consumption has been associated with favorable changes in body weight and obesity-related hormones, although it is not known whether these changes result from green tea polyphenols or caffeine.. We examined the impact of decaffeinated green tea extract (GTE) containing 843 mg of (-)-epigallocatechin-3-gallate on anthropometric variables, obesity-associated hormones, and glucose homeostasis.. The Minnesota Green Tea Trial was a 12-mo randomized, double-blind, placebo-controlled clinical trial of 937 healthy postmenopausal women assigned to either decaffeinated GTE (1315 mg total catechins/d) or a placebo, stratified by catechol-O-methyltransferase (COMT) genotype. This study was conducted in a subset of 237 overweight and obese participants [body mass index (BMI) ≥25 kg/m(2)].. No changes in energy intake, body weight, BMI, or waist circumference (WC) were observed over 12 mo in women taking GTE (n = 117) or placebo (n = 120). No differences were seen in circulating leptin, ghrelin, adiponectin, or glucose concentrations at month 12. Participants randomly assigned to GTE with baseline insulin ≥10 μIU/mL (n = 23) had a decrease in fasting serum insulin from baseline to month 12 (-1.43 ± 0.59 μIU/mL), whereas those randomly assigned to placebo with baseline insulin ≥10 μIU/mL (n = 19) had an increase in insulin over 12 mo (0.55 ± 0.64 μIU/mL, P < 0.01). Participants with the homozygous high-activity (G/G) form of COMT had significantly lower adiponectin (5.97 ± 0.50 compared with 7.58 ± 0.53 μg/mL, P = 0.03) and greater insulin concentrations (7.63 ± 0.53 compared with 6.18 ± 0.36 μIU/mL, P = 0.02) at month 12 compared with those with the low-activity (A/A) genotype, regardless of treatment group.. Decaffeinated GTE was not associated with reductions in body weight, BMI, or WC and did not alter energy intake or mean hormone concentrations in healthy postmenopausal women over 12 mo. GTE decreased fasting insulin concentrations in those with elevated baseline fasting concentrations. The high-activity form of the COMT enzyme may be associated with elevations in insulin and a reduction in adiponectin concentrations over time. This trial was registered at http://www.clinicaltrials.gov as NCT00917735. Topics: Adiponectin; Administration, Oral; Aged; Blood Glucose; Body Mass Index; Body Weight; Caffeine; Catechin; Catechol O-Methyltransferase; Double-Blind Method; Energy Intake; Fasting; Female; Genotype; Ghrelin; Humans; Insulin; Leptin; Middle Aged; Motor Activity; Nutrition Assessment; Obesity; Overweight; Plant Extracts; Polyphenols; Postmenopause; Tea; Waist Circumference | 2016 |
Ghrelin, GLP-1, and leptin responses during exposure to moderate hypoxia.
Severe hypoxia has been indicated to cause acute changes in appetite-related hormones, which attenuate perceived appetite. However, the effects of moderate hypoxia on appetite-related hormonal regulation and perceived appetite have not been elucidated. Therefore, we examined the effects of moderate hypoxia on appetite-related hormonal regulation and perceived appetite. Eight healthy males (21.0 ± 0.6 years; 173 ± 2.3 cm; 70.6 ± 5.0 kg; 23.4 ± 1.1 kg/m(2)) completed two experimental trials on separate days: a rest trial in normoxia (FiO2 = 20.9%) and a rest trial in hypoxia (FiO2 = 15.0%). The experimental trials were performed over 7 h in an environmental chamber. Blood samples and scores of subjective appetite were collected over 7 h. Standard meals were provided 1 h (745 kcal) and 4 h (731 kcal) after initiating exposure to hypoxia or normoxia within the chamber. Although each meal significantly reduced plasma active ghrelin concentrations (P < 0.05), the response did not differ significantly between the trials over 7 h. No significant differences in the area under the curves for plasma active ghrelin concentrations over 7 h were observed between the two trials. No significant differences were observed in glucagon-like peptide 1 or leptin concentrations over 7 h between the trials. The subjective feeling of hunger and fullness acutely changed in response to meal ingestions. However, these responses were not affected by exposure to moderate hypoxia. In conclusion, 7 h of exposure to moderate hypoxia did not change appetite-related hormonal responses or perceived appetite in healthy males. Topics: Adult; Appetite; Appetite Regulation; Body Mass Index; Body Weight; Cross-Over Studies; Energy Intake; Ghrelin; Glucagon-Like Peptide 1; Humans; Hypoxia; Leptin; Male; Postprandial Period; Young Adult | 2016 |
Energy depletion by diet or aerobic exercise alone: impact of energy deficit modality on appetite parameters.
Millions of Americans attempt to lose weight each year, and it is unclear whether the modality of acute, tightly controlled energy depletions can differently affect appetite parameters and olfaction.. The objectives were to examine how the modality of an acute 3-d isocaloric 25% energy depletion by dieting alone or by aerobic exercise alone differently affects appetite and appetite-related hormones, ad libitum feeding, food reward (snack points), and olfaction.. Ten male participants with a mean ± SD age of 23.7 ± 5.1 y and an initial mean ± SD body weight of 83.2 ± 11.5 kg participated in this randomized crossover design. Baseline measurement [day 1 of the control condition (CON1)] was performed and repeated 3 d later [day 4 of the control condition (CON4)], after which randomization was applied to the order of the 2 experimental conditions: 25% daily needs energy deficits induced by diet only (DIET) and by exercise only (EX) and tested before [day 1 of DIET (DIET1) and day 1 of EX (EX1)] and after 3 d [day 4 of DIET (DIET4) and day 4 of EX (EX4)] of the intervention. Body weight, leptin and ghrelin concentrations, relative-reinforcing value of food, and olfaction were measured at days 1 and 4. Body composition (dual-energy X-ray absorptiometry), ad libitum energy intake (EI; buffet), and palatability (visual analog scale) were measured only at day 4.. Relative to CON4, EI (P= 0.001), palatability (P= 0.01), and odor threshold (P= 0.05) were higher at DIET4; relative to CON4, palatability (P= 0.03) was higher at EX4. Compared with EX4, EI was higher for DIET4 (P= 0.006). Relative to CON4, snack points earned were higher at DIET4 (P= 0.03) and EX4 (P= 0.001); more snack points were earned at EX4 relative to DIET4 (P= 0.001).. Compared with the control condition, DIET represented a greater acute challenge to appetite regulation than EX, as demonstrated by greater appetite and ad libitum EI. This study confirms that compared with depletions by exercise alone, acute caloric restriction results in rapid changes in appetite that result in compensatory eating, which may initially dissuade potential success in weight-loss efforts. This trial was registered at clinicaltrials.gov as NCT02653378. Topics: Absorptiometry, Photon; Adolescent; Adult; Appetite; Appetite Regulation; Body Composition; Body Mass Index; Body Weight; Caloric Restriction; Cross-Over Studies; Diet, Reducing; Energy Metabolism; Exercise; Ghrelin; Humans; Leptin; Male; Snacks; Surveys and Questionnaires; Young Adult | 2016 |
Comparative evaluation of the therapeutic effect of metformin monotherapy with metformin and acupuncture combined therapy on weight loss and insulin sensitivity in diabetic patients.
Obesity induces insulin resistance (IR), the key etiologic defect of type 2 diabetes mellitus (T2DM). Therefore, an incidence of obesity-induced diabetes is expected to decrease if obesity is controlled. Although Metformin is currently one of the main treatment options for T2DM in obese patients, resulting in an average of 5% weight loss, adequate weight control in all patients cannot be achieved with Metformin alone. Thus, additional therapies with a weight loss effect, such as acupuncture, may improve the effectiveness of Metformin.Subjective:We designed this randomized clinical trial (RCT) to compare the effects of Metformin monotherapy with that of Metformin and acupuncture combined therapy on weight loss and insulin sensitivity among overweight/obese T2DM patients, to understand whether acupuncture plus Metformin is a better approach than Metformin only on treating diabetes. To understand whether acupuncture can be an insulin sensitizer and, if so, its therapeutic mechanism.. Our results show that Metformin and acupuncture combined therapy significantly improves body weight, body mass index (BMI), fasting blood sugar (FBS), fasting insulin (FINS), homeostasis model assessment (HOMA) index, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), leptin, adiponectin, glucagon-like peptide-1 (GLP-1), resistin, serotonin, free fatty acids (FFAs), triglyceride (TG), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc) and ceramides.. Consequently, Metformin and acupuncture combined therapy is more effective than Metformin only, proving that acupuncture is an insulin sensitizer and is able to improve insulin sensitivity possibly by reducing body weight and inflammation, while improving lipid metabolism and adipokines. As a result, electro-acupuncture (EA) might be useful in controlling the ongoing epidemics in obesity and T2DM. Topics: Acupuncture Therapy; Adiponectin; Adult; Biomarkers; Body Mass Index; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Interleukin-6; Leptin; Male; Metformin; Obesity; Resistin; Serotonin; Triglycerides; Tumor Necrosis Factor-alpha; Weight Loss | 2016 |
Leptin administration in physiological or pharmacological doses does not alter circulating irisin levels in humans.
Leptin is an adipokine causing browning of adipose tissue, and it thus increases energy expenditure. The same is true for irisin. We studied whether exogenously administered metreleptin affects serum irisin concentrations in humans, which would suggest a direct interplay between leptin and irisin. We performed two studies: a dose-escalating 1-day-long study and a randomized placebo-controlled study. Study 1: 15 healthy, normal-weight and/or obese male and female individuals participated in three 1-day-long trials of metreleptin administration in the fed state. Metreleptin was administered once at physiological and pharmacological (0.01, 0.1 and 0.3 mg per kg body weight) doses. Study 2: 18 apparently healthy hypoleptinemic young women with hypoleptinemia and secondary amenorrhea took part in this study. Subjects received either metreleptin in replacement doses (0.08 and/or 0.12 mg kg(-1)) or placebo for 16 weeks. Blood samples were analyzed for leptin and irisin. We found no effect of metreleptin administration on irisin levels of subjects studied at either the fasting or the fed state either in the short or the long term. We provide evidence that leptin is not altering circulating irisin levels in humans. Topics: Adipose Tissue; Body Composition; Body Weight; Dose-Response Relationship, Drug; Double-Blind Method; Energy Metabolism; Female; Fibronectins; Humans; Leptin; Male; Obesity; Young Adult | 2016 |
Palaeolithic diet decreases fasting plasma leptin concentrations more than a diabetes diet in patients with type 2 diabetes: a randomised cross-over trial.
We have previously shown that a Palaeolithic diet consisting of the typical food groups that our ancestors ate during the Palaeolithic era, improves cardiovascular disease risk factors and glucose control compared to the currently recommended diabetes diet in patients with type 2 diabetes. To elucidate the mechanisms behind these effects, we evaluated fasting plasma concentrations of glucagon, insulin, incretins, ghrelin, C-peptide and adipokines from the same study.. In a randomised, open-label, cross-over study, 13 patients with type 2 diabetes were randomly assigned to eat a Palaeolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts, or a diabetes diet designed in accordance with current diabetes dietary guidelines during two consecutive 3-month periods. The patients were recruited from primary health-care units and included three women and 10 men [age (mean ± SD) 64 ± 6 years; BMI 30 ± 7 kg/m(2); diabetes duration 8 ± 5 years; glycated haemoglobin 6.6 ± 0.6 % (57.3 ± 6 mmol/mol)] with unaltered diabetes treatment and stable body weight for 3 months prior to the start of the study. Outcome variables included fasting plasma concentrations of leptin, adiponectin, adipsin, visfatin, resistin, glucagon, insulin, C-peptide, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and ghrelin. Dietary intake was evaluated by use of 4-day weighed food records.. Seven participants started with the Palaeolithic diet and six with the diabetes diet. The Palaeolithic diet resulted in a large effect size (Cohen's d = -1.26) at lowering fasting plasma leptin levels compared to the diabetes diet [mean difference (95 % CI), -2.3 (-5.1 to 0.4) ng/ml, p = 0.023]. No statistically significant differences between the diets for the other variables, analysed in this study, were observed.. Over a 3-month study period, a Palaeolithic diet resulted in reduced fasting plasma leptin levels, but did not change fasting levels of insulin, C-peptide, glucagon, incretins, ghrelin and adipokines compared to the currently recommended diabetes diet.. ClinicalTrials.gov NCT00435240. Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Diet; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Humans; Insulin; Leptin; Male; Middle Aged | 2016 |
Effects of Oral L-Carnitine Supplementation on Leptin and Adiponectin Levels and Body Weight of Hemodialysis Patients: a Randomized Clinical Trial.
Carnitine supplementation may improve the general health and quality of life of hemodialysis patients by improving adipokines levels. The aim of the study was to investigate the effects of L-carnitine supplementation on leptin levels, adiponectin levels, and body weight of hemodialysis patients.. Fifty hemodialysis patients were randomly divided into the carnitine group, who received oral L-carnitine, 1 g/L for 3 months, and the control group. Anthropometric measurements and serum levels of adipokines were measured at baseline and at the end of the intervention.. Forty-two participants completed the study. Serum leptin concentrations decreased after 12 weeks of the intervention in both groups, but these changes were not significant. The mean change of leptin concentration were, -1.7 ± 19.0 µg/mL and -7.1 ± 20.0 µg/mL in the carnitine group and the control group, respectively (P = .39). The mean adiponectin levels at baseline and after the intervention were 8.6 ± 11.19 µg/mL and 9.8 ± 4.1 µg/mL in the carnitine group (P = .67) and 5.0 ± 2.5 µg/mL and 11.2 ± 5.4 µg/mL in the control group, respectively (P < .001). Serum adiponectin levels increased significantly in the control group only. The decrease in body mass index was not significant.. This study showed that a daily supplementation of 1000 mg oral syrup of L-carnitine for 12 weeks did not affect leptin and adiponectin levels or the body weight or body mass index of hemodialysis patients. Topics: Adiponectin; Administration, Oral; Body Mass Index; Body Weight; Carnitine; Dietary Supplements; Female; Humans; Leptin; Male; Middle Aged; Quality of Life; Renal Dialysis | 2016 |
Phase II study of metformin for reduction of obesity-associated breast cancer risk: a randomized controlled trial protocol.
Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk.. This is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n = 75) or placebo (n = 75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored.. The study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases.. ClinicalTrials.gov Identifier: NCT02028221 . Registered on January 2, 2014. Grant #: 1R01CA172444-01A1 awarded on Sept 11, 2013. Topics: Adiponectin; Adult; Body Weight; Breast; Breast Neoplasms; Double-Blind Method; Humans; Hypoglycemic Agents; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Magnetic Resonance Imaging; Metformin; Middle Aged; Obesity; Outcome Assessment, Health Care; Risk Factors; Testosterone; Waist Circumference | 2016 |
Effect of dronabinol therapy on physical activity in anorexia nervosa: a randomised, controlled trial.
The level of physical activity is inappropriately high in up to 80% of the patients suffering of anorexia nervosa (AN), as a result of conscious efforts to lose weight, affect regulation and biological adaptive changes to starvation induced by hypothermia and neuroendocrine mechanisms. The purposes of this paper were to (1) assess the effect of dronabinol-a synthetic cannabinoid agonist-on physical activity in patients with chronic and stable AN, and to (2) unravel the role of leptin and cortisol in this process.. This prospective, randomised, double-blind, crossover study was conducted at a specialised care centre for eating disorders. Twenty-four adult women with AN of at least 5-year duration received either the dronabinol-placebo or placebo-dronabinol sequence. Physical activity was monitored during the fourth week of each intervention. Body weight, leptin and urinary free cortisol excretion were measured repeatedly during the trial. Changes in behavioural dimensions related to AN were assessed by Eating Disorder Inventory-2.. The total duration of physical activity did not change, while its average intensity increased by 20% (P = 0.01) during dronabinol therapy, resulting in an increased energy expenditure with 68.2 kcal/day (P = 0.01) above placebo.. This randomised, double-blind study revealed that cannabinoid agonist treatment was associated with a modest increase in physical activity in adult women with severe and longstanding AN. Additionally, we detected a strong relationship between the circulating levels of leptin and physical activity in these chronically undernourished patients. Topics: Actigraphy; Adult; Anorexia Nervosa; Body Weight; Cross-Over Studies; Double-Blind Method; Dronabinol; Energy Intake; Female; Humans; Leptin; Middle Aged; Motor Activity; Treatment Outcome; Young Adult | 2015 |
Acute Changes in Sleep Duration on Eating Behaviors and Appetite-Regulating Hormones in Overweight/Obese Adults.
There is considerable interest in the role of sleep in weight regulation, yet few studies have examined this relationship in overweight/obese (OW/OB) adults. Using a within-subject, counterbalanced design, 12 OW/OB women were studied in lab with two nights of short (5 hr time in bed [TIB]) and two nights of long (9 hr TIB) sleep. Hunger, consumption at a buffet, and fasting hormone levels were obtained. Significant polysomnographic differences occurred between conditions in total sleep time and sleep architecture (ps < .001). Percent energy from protein at the buffet increased following short sleep. No differences were observed for total energy intake or measured hormones. Further research is needed to determine how lengthening sleep impacts weight regulation in OW/OB adults. Topics: Adult; Appetite; Body Weight; Eating; Energy Intake; Fasting; Feeding Behavior; Female; Ghrelin; Glucose; Humans; Hunger; Insulin; Leptin; Male; Middle Aged; Obesity; Overweight; Polysomnography; Sleep; Time Factors | 2015 |
Step aerobic combined with resistance training improves cutaneous microvascular reactivity in overweight women.
The aim of the present study was to determine the effect of combined aerobic and resistance exercise training on body weight and cutaneous microvascular reactivity in overweight individuals.. A total of 41 overweight women aged 30-45 years (BMI 25-29.9 kg/m²) were randomized into sedentary time control (CON; N.=15), traditional aerobic dance (AD; N.=11), and step aerobic dance combined with upper-body resistance training (SAR; N.=15) groups. Exercise programs were 50 minutes/session, 3 times/week for 12 weeks.. Maximal oxygen consumption and 1-RM strength of lower body increased (P<0.05) in the AD and SAR groups. Body mass and BMI decreased (P<0.05) in the SAR group. Plasma concentration of adiponectin increased (P<0.05) whereas leptin concentration did not change. Peak postocclusive reactive hyperemia measured by laser-Doppler fluxmeter improved (P<0.05) in the SAR group. These changes were not observed in the CON or AD groups. Peak occlusive reactive hyperemia was positively and significantly correlated with adiponectin level (r=0.23).. The present findings suggest that simultaneously performed step aerobic dance and resistance training exerts more favorable effects on weight loss and improving cutaneous microvascular reactivity in overweight women. Topics: Adiponectin; Adult; Body Weight; Cardiovascular Diseases; Exercise; Female; Hemodynamics; Humans; Leptin; Microcirculation; Middle Aged; Overweight; Oxygen Consumption; Physical Endurance; Physical Fitness; Regional Blood Flow; Resistance Training; Skin; Time Factors | 2015 |
The effects of diet and arginine treatment on serum metabolites and selected hormones during the estrous cycle in sheep.
The aim of this study was to determine the effects of diet and arginine (Arg) treatment on serum concentrations of selected metabolites and metabolic and reproductive hormones in nonpregnant ewes. Sixty days before the onset of estrus (Day 0), Rambouillet ewes were randomly assigned to one of three dietary groups: maintenance control (C; N = 16; 100% National Research Council requirements), overfed (O; N = 16; 2 × C), or underfed (U; N = 16, 0.6 × C) to achieve and maintain three different body conditions during their estrous cycle(s). At Day 0, ewes from each nutritional group were randomly assigned to receive one of two treatments: saline (Sal) or Arg (L-Arg-HCl; 155 μmol Arg per kg of body weight [BW]; intravenous), which was administered three times per day for 21 or 26 days. Blood samples were collected on Days 0, 6, 10, 12, 16, 21, and 26 of Sal or Arg treatment for evaluation of Arg, nitric oxide metabolite, cholesterol, glucose, insulin, insulin-like growth factor 1, leptin, and progesterone. For a time-response trial, blood samples were collected at 0, 1, 2, 4, and 7 hours after Sal or Arg treatment at the mid-luteal phase to determine serum Arg concentrations. During the 11-week study, C maintained body weight, O gained 9.6 ± 0.7 kg, and U lost 13.9 ± 0.1 kg. Overall, serum concentrations of Arg, glucose, insulin, insulin-like growth factor 1, leptin, and progesterone were greater (P < 0.05) in O ewes than C and/or U ewes and were not affected by Arg treatment. Serum Arg concentration increased at 1 and 2 hours and decreased to basal level at 4 and 7 hours after Arg treatment. These data reinforce the importance of diet in regulation of metabolic and endocrine functions, and demonstrated that the dose and duration of Arg treatment used in this study does not alter serum metabolites or hormones in nonpregnant ewes of various nutritional planes. Topics: Administration, Intravenous; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Arginine; Body Weight; Diet; Estrous Cycle; Insulin; Leptin; Progesterone; Sheep | 2015 |
Fasting gut hormone levels change with modest weight loss in obese adolescents.
Gut hormones change with weight loss in adults but are not well studied in obese youth.. The primary aim was to evaluate how gut hormones and subjective appetite measure change with dietary weight loss in obese adolescents.. Participants were a subset of those taking part in the 'Eat Smart Study'. They were aged 10-17 years with body mass index (BMI) > 90th centile and were randomized to one of three groups: wait-listed control, structured reduced carbohydrate or structured low-fat dietary intervention for 12 weeks. Outcomes were fasting glucose, insulin, leptin, adiponectin, total amylin, acylated ghrelin, active glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide (GIP), pancreatic polypeptide (PP) and total peptide tyrosine-tyrosine. Pre- and postprandial subjective sensations of appetite were assessed using visual analogue scales.. Of 87 'Eat Smart' participants, 74 participated in this sub-study. The mean (standard deviation) BMI z-score was 2.1 (0.4) in the intervention groups at week 12 compared with 2.2 (0.4) in the control group. Fasting insulin (P = 0.05) and leptin (P = 0.03) levels decreased, while adiponectin levels increased (P = 0.05) in the intervention groups compared with control. The intervention groups were not significantly different from each other. A decrease in BMI z-score at week 12 was associated with decreased fasting insulin (P < 0.001), homeostatic model of assessment-insulin resistance (P < 0.001), leptin (P < 0.001), total amylin (P = 0.03), GIP (P = 0.01), PP (P = 0.02) and increased adiponectin (P < 0.001). There was no significant difference in appetite sensations.. Modest weight loss in obese adolescents leads to changes in some adipokines and gut hormones that may favour weight regain. Topics: Adiponectin; Adolescent; Adult; Appetite; Body Mass Index; Body Weight; Fasting; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Leptin; Male; Pediatric Obesity; Peptide YY; Postprandial Period; Weight Loss | 2015 |
Effects of short-term oral corticosteroid intake on dietary intake, body weight and body composition in adults with asthma - a randomized controlled trial.
Oral corticosteroids (OCS) are an efficacious treatment for asthma exacerbations, yet risk of adverse effects may decrease patient adherence to therapy. In particular, changes in appetite and dietary intake, which lead to weight gain and changes in body composition, are considered undesirable.. To determine whether 10-day OCS therapy in adults with asthma causes changes in leptin, appetite, dietary intake, body weight and body composition.. Double-blinded, placebo-controlled randomized cross-over trial of 10 days prednisolone (50 mg) in adults with stable asthma (n = 55) (ACTRN12611000562976). Pre- and post-assessment included spirometry, body weight, body composition measured by dual-energy X-ray absorptiometry and bioelectrical impedance analysis, appetite measured using a validated visual analogue scale (VAS) and dietary intake assessed using 4-day food records. Leptin was measured as a biomarker of appetite and eosinophils as an adherence biomarker. Outcomes were analysed by generalized linear mixed models.. Subject adherence was confirmed by a significant decrease in blood eosinophils (× 10(9) /L) following prednisolone compared to placebo [Coef. -0.29, 95% CI: (-0.39, -0.19) P < 0.001]. There was no difference in serum leptin (ng/mL) [Coef. 0.13, 95% CI: (-3.47, 3.72) P = 0.945] or appetite measured by VAS (mm) [Coef. -4.93, 95% CI: (-13.64, 3.79) P = 0.267] following prednisolone vs. placebo. There was no difference in dietary intake (kJ/day) [Coef. 255, 95% CI: (-380, 891) P = 0.431], body weight (kg) [Coef. -0.38, 95% CI: (-0.81, 0.05) P = 0.083] or body fat (%) [Coef. -0.31, 95% CI: (-0.81, 0.20) P = 0.230]. Symptoms including sleep and gastrointestinal disturbance were reported significantly more often during prednisolone vs. placebo.. Short-term OCS in stable asthma did not induce significant changes in appetite, dietary intake, body weight or composition, although other adverse effects may require medical management. This evidence may assist in increasing medication adherence of asthmatics prescribed OCS for exacerbations. Topics: Administration, Oral; Adrenal Cortex Hormones; Adult; Aged; Appetite; Asthma; Australia; Body Composition; Body Weight; Body Weights and Measures; Cross-Over Studies; Eosinophils; Female; Humans; Leptin; Leukocyte Count; Male; Middle Aged; Surveys and Questionnaires; Young Adult | 2015 |
Olanzapine for cachexia in patients with advanced cancer: an exploratory study of effects on weight and metabolic cytokines.
Olanzapine is used for treatment of psychiatric conditions but causes substantial weight gain. This study assessed safety, efficacy, and changes in metabolic cytokines associated with olanzapine administration in patients with cachexia due to advanced cancer.. Patients with cancer-related cachexia were treated with olanzapine (doses ranging from 2.5 to 20 mg daily by mouth). Patients also received anti-neoplastic treatments. Serum samples were collected at baseline and after weeks 1, 2, 4, and 8 for analysis of levels of leptin, growth hormone, ghrelin, and interleukin-6 (IL-6).. Of the 39 participants, 31 were evaluable for weight change (N = 6 excluded for new ascites; N = 2, incomplete body weight of data). Toxicities related to olanzapine were somnolence (n = 1), pancreatitis (n = 1), extrapyramidal symptoms (n = 1), and nausea/vomiting (n = 1) (all grade 2). The recommended dose of Olanzapine is 20 mg PO daily for cancer patients (same as FDA approved dose for psychiatric conditions). Samples from 29 patients were eligible for analysis of serum cytokine levels. Mean values of leptin, ghrelin, and growth hormone did not change on treatment, though IL-6 levels increased, perhaps due to tumor progression. There was no association between changes in cytokines and weight. The mean change in slope of weight loss before versus after therapy was 0.24 (95 % CI, -0.08, 0.56; p = 0.13) indicating a trend, albeit not reaching statistical significance, toward attenuation of weight loss.. Changes in metabolic cytokines and body weight did not correlate. Treatment with olanzapine had only a modest effect in altering the trajectory of weight loss. Topics: Adult; Aged; Benzodiazepines; Body Weight; Cachexia; Cytokines; Dose-Response Relationship, Drug; Female; Ghrelin; Humans; Interleukin-6; Leptin; Male; Middle Aged; Neoplasms; Olanzapine; Weight Gain; Weight Loss | 2015 |
Changes in IGF-I, urinary free cortisol and adipokines during dronabinol therapy in anorexia nervosa: Results from a randomised, controlled trial.
Anorexia nervosa (AN) is characterised by complex neuroendocrine disturbances due to severe underweight, physical hyperactivity and purging behaviour. Cannabinoid agonists are used to palliate cachexia of various causes, but their interactions with the hormonal systems that are involved in energy metabolism have not been previously described in humans. Therefore we found it of interest to assess interactions between the synthetic cannabinoid agonist dronabinol and insulin-like growth factor I (IGF-I), urinary free cortisol (UFC) and adipokines in patients with chronic AN.. This was a prospective, double-blind randomised crossover study, conducted at a specialised care centre for eating disorders. The results are based on twenty-four adult women with chronic AN, who completed the study. The participants received dronabinol (oral capsules, 5mg daily) and matching placebo over four weeks, separated by a four-week washout period. Bioactive IGF was determined by a cell-based bioassay, whereas total IGF-I, IGFBP-2 and -3 and the two adipokines leptin and adiponectines were measured by immunoassays. The UFC excretion was determined by mass spectrometry.. As previously reported, dronabinol treatment caused a small, yet significant increase in BMI as compared to placebo (+0.23 kg/m(2); P = 0.04). This modest weight gain predicted a corresponding increase in bioactive IGF-I, while the amount of daily energy expenditure due to physical activity had a comparable but opposite effect. Nevertheless, neither IGF-I, bioactive IGF nor the IGFBPs levels changed significantly during dronabinol intervention as compared to placebo. Adiponectin also remained unaffected by the weight gain, whereas plasma leptin showed a transient increase at three weeks (P < 0.05). UFC levels were decreased during dronabinol intervention.. Our results showed that low-dosage therapy with the synthetic cannabinoid agonist dronabinol affected neither the concentration nor the activity of the circulating IGF-system in women with severe and chronic AN. However, our results suggest that such treatment may alleviate the increased hypothalamic-pituitary-adrenal axis activity seen in these patients. Topics: Adipokines; Adiponectin; Adult; Anorexia Nervosa; Body Weight; Cannabinoid Receptor Agonists; Cross-Over Studies; Double-Blind Method; Dronabinol; Energy Metabolism; Female; Humans; Hydrocortisone; Insulin-Like Growth Factor I; Leptin; Prospective Studies; Young Adult | 2015 |
Role of Fatty Acid-Binding Protein 2 Ala54Thr Genotype on Weight Loss and Cardiovascular Risk Factors after a High-Protein/Low-Carbohydrate versus a Standard Hypocaloric Diet during 9 Months.
It has been found that the expression of fatty acid-binding protein 2 gene mRNA is under dietary control. The polymorphism Ala54Thr of this protein was associated with high insulin resistance.. The aim of our study was to investigate the influence of Thr54 polymorphism on metabolic response, weight loss and serum adipokine levels secondary to high-protein/low-carbohydrate vs. standard hypocaloric diets during 9 months.. A population of 193 obese subjects was analyzed in a randomized trial. A nutritional evaluation was performed at the beginning and at the end of a 9-month period in which subjects received 1 of 2 diets (diet HP: high-protein/low-carbohydrate vs. diet S: standard diet).. With both diets and in both genotype groups, body mass index, weight, fat mass, waist circumference, systolic blood pressure and leptin levels decreased. With both diets and only in wild genotype (diet HP vs. diet S), glucose (-6.2 ± 2.1 vs. -4.9 ± 2.0 mg/dl; p < 0.05), insulin levels (-5.0 ± 3.9 vs. -2.0 ± 2.1 UI/l; p < 0.05), homeostasis model assessment for insulin resistance (HOMA-R) (-1.1 ± 0.9 vs. -0.7 ± 1.0 units; p < 0.05) decreased. The improvement in these parameters was higher with diet HP than HS. With both diets and only in the wild genotype, total cholesterol and LDL-total cholesterol levels decreased.. Carriers of Thr54 allele have a different metabolic response after weight loss than wild type non-A carriers obese, with a lack of decrease of LDL-cholesterol, glucose, insulin levels and HOMA-R. Topics: Adipokines; Adult; Blood Pressure; Body Mass Index; Body Weight; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diet, Carbohydrate-Restricted; Diet, Reducing; Dietary Carbohydrates; Dietary Proteins; Fatty Acid-Binding Proteins; Female; Genotype; Genotyping Techniques; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Risk Factors; Waist Circumference; Weight Loss | 2015 |
Metabolic adaptation to caloric restriction and subsequent refeeding: the Minnesota Starvation Experiment revisited.
Adaptive thermogenesis (AT) is the fat-free mass (FFM)-independent reduction of resting energy expenditure (REE) to caloric restriction (CR). AT attenuates weight loss and favors weight regain. Its variance, dynamics, and control remain obscure.. Our aims were to address the variance and kinetics of AT, its associations with body composition in the context of endocrine determinants, and its effect on weight regain.. Thirty-two nonobese men underwent sequential overfeeding (1 wk at +50% of energy needs), CR (3 wk at -50% of energy needs), and refeeding (2 wk at +50% of energy needs). AT and its determinants were measured together with body composition as assessed with the use of quantitative magnetic resonance, whole-body MRI, isotope dilution, and nitrogen and fluid balances.. Changes in body weight were +1.8 kg (overfeeding), -6.0 kg (CR), and +3.5 kg (refeeding). CR reduced fat mass and FFM by 114 and 159 g/d, respectively. Within FFM, skeletal muscle (-5%), liver (-13%), and kidneys (-8%) decreased. CR also led to reductions in REE (-266 kcal/d), respiratory quotient (-15%), heart rate (-14%), blood pressure (-7%), creatinine clearance (-12%), energy cost of walking (-22%), activity of the sympathetic nervous system (SNS) (-38%), and plasma leptin (-44%), insulin (-54%), adiponectin (-49%), 3,5,3'-tri-iodo-thyronine (T3) (-39%), and testosterone (-11%). AT was 108 kcal/d or 48% of the decrease in REE. Changes in FFM composition explained 36 kcal, which left 72 kcal/d for true AT. The decrease in AT became significant at ≤3 d of CR and was related to decreases in insulin secretion (r = 0.92, P < 0.001), heart rate (r = 0.60, P < 0.05), creatinine clearance (r = 0.79, P < 0.05), negative fluid balance (r = 0.51, P < 0.01), and the free water clearance rate (r = -0.90, P < 0.002). SNS activity and plasma leptin, ghrelin, and T3 and their changes with CR were not related to AT.. During early weight loss, AT is associated with a fall in insulin secretion and body fluid balance. This trial was registered at clinicaltrials.gov as NCT01737034. Topics: Adaptation, Physiological; Adiponectin; Adult; Basal Metabolism; Body Composition; Body Mass Index; Body Weight; C-Peptide; Caloric Restriction; Creatinine; Energy Metabolism; Ghrelin; Heart Rate; Humans; Insulin; Insulin Secretion; Leptin; Male; Minnesota; Starvation; Testosterone; Thermogenesis; Triiodothyronine; Young Adult | 2015 |
Coleus forskohlii Extract Supplementation in Conjunction with a Hypocaloric Diet Reduces the Risk Factors of Metabolic Syndrome in Overweight and Obese Subjects: A Randomized Controlled Trial.
Limited studies have shown that Coleus forskohlii extract may aid in weight management. This randomized, double blind placebo-controlled clinical study assessed the effects of supplementation with C. forskohlii extract on key markers of obesity and metabolic parameters in overweight and obese individuals. Thirty participants completed the trial and they were randomly assigned to receive either 250 mg of C. forskohlii extract (n = 15) or a placebo twice daily for 12 weeks. All participants were advised to follow a hypocaloric diet throughout the study. Body weight, body mass index (BMI), waist and hip circumference, and waist to hip ratio, were monitored fortnightly. Dietary intake was assessed at the baseline and weeks 4, 8 and 12. Appetite was assessed using visual analogue scales and blood samples were analyzed for plasma lipids, ghrelin, leptin, glucose and insulin at the baseline and end of the intervention. Significant reductions to waist and hip circumference (p = 0.02; p = 0.01, respectively) were recorded in both experimental and placebo groups after the 12 week intervention. Furthermore, high density lipoprotein-cholesterol (HDL-C) was significantly increased (p = 0.01) in both groups. The experimental group showed a favorable improvement in insulin concentration and insulin resistance (p = 0.001; 0.01 respectively) compared to the placebo group. These findings suggest that C. forskohlii extract in conjunction with a hypocaloric diet may be useful in the management of metabolic risk factors. Topics: Adult; Aged; Appetite; Blood Glucose; Body Mass Index; Body Weight; Cholesterol, HDL; Diet, Reducing; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Energy Intake; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Plant Extracts; Plectranthus; Risk Factors; Waist Circumference; Waist-Hip Ratio; Young Adult | 2015 |
Effect of reducing the n-6/n-3 fatty acid ratio on the maternal and fetal leptin axis in relation to infant body composition.
To investigate the effect of reducing the n-6/n-3 fatty acid ratio in maternal nutrition on the maternal and cord blood leptin axis and their association with infant body composition up to 2 years.. 208 healthy pregnant women were randomized to either a dietary intervention to reduce the n-6/n-3 fatty acid ratio from 15th week of gestation until 4 months postpartum or a control group. Leptin, soluble leptin receptor and free leptin index were determined in maternal and cord plasma and related to infant body composition assessed by skinfold thicknesses up to 2 years.. The intervention had no effect on either the maternal or fetal leptin axis. Maternal leptin in late pregnancy was inversely related to infant weight and lean body mass (LBM) up to 2 years, after multiple adjustments. Cord leptin was positively related to weight, body fat, and LBM at birth, and inversely associated with weight, BMI, fat mass, and LBM at 2 years and weight gain up to 2 years. The contribution of cord leptin to infant outcomes was overall stronger compared with maternal leptin.. Both, maternal and fetal leptin were associated with subsequent infant anthropometry with a greater impact of fetal leptin. Topics: Adipose Tissue; Anthropometry; Body Composition; Body Mass Index; Body Weight; Child, Preschool; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Feeding Behavior; Female; Fetal Blood; Fetus; Humans; Infant; Lactation; Leptin; Linear Models; Maternal Nutritional Physiological Phenomena; Pregnancy; Receptors, Leptin; Skinfold Thickness | 2014 |
Effects of different physical exercises on leptin concentration in obese adolescents.
In order to compare the effects of leisure physical activity (LPA), aerobic training (AT) and aerobic plus resistance training (AT + RT) as part of a 6-month interdisciplinary therapy in body composition, insulin resistance and leptin concentrations in obese adolescents, 72 volunteers (n = 24 in each group) ages 15-19 years were evaluated. Delta (Δ) body mass (kg) and Δ BMI (kg/m(2)) was different between AT and LPA groups and in AT + RT group compared to both LPA and AT groups; Δ body fat mass (kg and %) was different only in AT + RT group compared to both LPA and AT; Δ body lean mass (%) was different only in AT + RT group; Δ body lean mass (kg) was negative only in AT and positive and different from AT in AT + RT group; ΔHOMA-IR did not differ among groups; Δ leptin (ng/ml) was negative and different from LPA for both AT and AT + RT groups. In conclusion, both AT and AT + RT promoted a reduction on leptin levels, however, the adolescents subjected to AT + RT presented better results in body composition than the AT group. These results highlight the importance of associating aerobic and resistance training with nutritional and psychological approaches in the treatment of obese adolescents. Topics: Adolescent; Body Composition; Body Mass Index; Body Weight; Diet; Energy Intake; Female; Humans; Insulin Resistance; Leisure Activities; Leptin; Male; Motor Activity; Obesity; Patient Education as Topic; Physical Conditioning, Human; Resistance Training; Young Adult | 2014 |
Is a child's growth pattern early in life related to serum adipokines at the age of 10 years?
Growth parameters during infancy and early childhood might predict adipokine levels later in life. This study investigates the association between peak growth velocities, body mass index (BMI) and age at adiposity rebound (AR), with leptin and adiponectin levels at age 10 years.. Peak height (PHV) and weight (PWV) velocities were calculated from height and weight measurements obtained between birth and age 2 years from 2880 children participating in the GINIplus (German Infant Nutritional Intervention plus environmental and genetic influences on allergy development) and LISAplus (Influences of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus Air Pollution and Genetics) birth cohorts. BMI and age at AR were calculated using BMI measurements between age 1.5 and 12 years. Blood samples were collected during a physical examination at age 10. Adiponectin and leptin levels were measured by radioimmunoassay. Linear regression models were fitted after adjustment for potential confounding factors and results are presented per interquartile range increase in the exposure.. Age at AR was negatively associated with leptin in males and females (percent difference β*: -41.71%; 95% confidence interval: (-44.34;-38.96) and β*: -43.22%; (-45.59; -40.75), respectively). For both males and females PWV (β*: 14.23%; (7.60; 21.26) and β*: 18.54%; (10.76; 26.87), respectively) and BMI at AR (β*: 63.08%; (55.04; 71.53) and β*: 67.02%; (59.30; 75.10), respectively) were positively associated with leptin levels. PHV showed a positive effect on leptin in females only (β*: 10.75%; (3.73; 18.25)). Growth parameters were not significantly associated with adiponectin except for age at AR among females (β: 0.75 ng/ml; (0.42; 1.09)) and PWV among males (β: 0.45 ng/ml; (0.11; 0.79)).. Growth patterns in early life may be associated with leptin levels at age 10 years. Topics: Adiponectin; Adiposity; Body Mass Index; Body Weight; Child; Child Development; Child, Preschool; Female; Humans; Infant; Leptin; Linear Models; Male; Obesity; Prospective Studies; Radioimmunoassay | 2014 |
Effects of pistachio nuts on body composition, metabolic, inflammatory and oxidative stress parameters in Asian Indians with metabolic syndrome: a 24-wk, randomized control trial.
The aim of this study was to evaluate the effects of pistachio nuts as an adjunct to diet and exercise on body composition, metabolic, inflammatory, and oxidative stress parameters in Asian Indians with metabolic syndrome.. In this 24-wk randomized control trial, 60 individuals with the metabolic syndrome were randomized to either pistachio (intervention group) or control group (diet as per weight and physical activity profile, modulated according to dietary guidelines for Asian Indians) after 3 wk of a diet and exercise run in. In the first group, unsalted pistachios (20% energy) were given daily. A standard diet and exercise protocol was followed for both groups. Body weight, waist circumference (WC), magnetic resonance imaging estimation of intraabdominal adipose tissue and subcutaneous abdominal adipose tissue, fasting blood glucose (FBG), fasting serum insulin, glycosylated hemoglobin, lipid profile, high-sensitivity C-reactive protein (hs-CRP), adiponectin, free fatty acids (FFAs), tumor necrosis factor (TNF)-α, leptin, and thiobarbituric acid reactive substances (TBARS) were assessed before and after the intervention.. Statistically significant improvement in mean values for various parameters in the intervention group compared with control group were as follows: WC (P < 0.02), FBG (P < 0.04), total cholesterol (P < 0.02), low-density lipoprotein cholesterol (P < 0.006), hs-CRP (P < 0.05), TNF-α (P < 0.03), FFAs (P < 0.001), TBARS (P < 0.01), and adiponectin levels (P < 0.001).. A single food intervention with pistachios leads to beneficial effects on the cardiometabolic profile of Asian Indians with metabolic syndrome. Topics: Adiponectin; Adiposity; Adult; Asian People; Blood Glucose; Body Composition; Body Weight; C-Reactive Protein; Cholesterol, LDL; Diet; Exercise; Fasting; Fatty Acids; Female; Hemoglobins; Humans; Insulin; Leptin; Male; Metabolic Syndrome; Middle Aged; Nuts; Oxidative Stress; Patient Compliance; Pistacia; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha | 2014 |
Nutrition, metabolic profiles and puberty in Brahman (Bos indicus) beef heifers.
The aim of the present study was to gain an improved understanding of the relationships between body weight (BW), body condition (BCS), and metabolic homeostasis, and the attainment of puberty in Brahman heifers in a subtropical environment. Brahman heifers (200±3kg BW; 2.00±0.0 BCS) were assigned to a moderate nutrition (MN, n=11) or improved nutrition (IN, n=11) treatment from 11 to 23 months-of-age. The heifers were monitored at regular intervals for circulating concentrations of GH, IGF-1, insulin, glucose and leptin, and ovarian follicular activity was recorded until the first ovulation. From approximately 16 months of age, heifers on IN had a greater (P<0.01) BW and greater (P<0.01) BCS than heifers on MN. Heifers on IN also had a generally improved metabolic homeostasis than heifers on MN which was reflected in greater circulating concentrations of insulin, leptin, IGF-1 and glucose in the former heifers. Heifers on IN attained puberty between 21 and 23 months of age and only one heifer on MN had reached puberty by 23 months. This study has shown that Brahman heifers on IN had a metabolic homeostasis that was supportive of reproductive maturation and puberty. Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Body Composition; Body Weight; Cattle; Diet; Energy Metabolism; Female; Insulin; Insulin-Like Growth Factor I; Leptin; Ovarian Follicle; Sexual Maturation | 2014 |
Timed-daily ingestion of whey protein and exercise training reduces visceral adipose tissue mass and improves insulin resistance: the PRISE study.
The present study examined the effects of timed ingestion of supplemental protein (20-g servings of whey protein, 3×/day), added to the habitual diet of free-living overweight/obese adults and subsequently randomized to either whey protein only (P; n = 24), whey protein and resistance exercise (P + RT; n = 27), or a whey protein and multimode exercise training program [protein and resistance exercise, intervals, stretching/yoga/Pilates, endurance exercise (PRISE); n = 28]. Total and regional body composition and visceral adipose tissue (VAT) mass (dual-energy X-ray absorptiometry), insulin sensitivity [homeostasis model assessment-estimated insulin resistance (HOMA-IR)], plasma lipids and adipokines, and feelings of hunger and satiety (visual analog scales) were measured before and after the 16-wk intervention. All groups lost body weight, fat mass (FM), and abdominal fat; however, PRISE lost significantly (P < 0.01) more body weight (3.3 ± 0.7 vs. 1.1 ± 0.7 kg, P + RT) and FM (2.8 ± 0.7 vs. 0.9 ± 0.5 kg, P + RT) and gained (P < 0.05) a greater percentage of lean body mass (2 ± 0.5 vs. 0.9 ± 0.3 and 0.6 ± 0.4%, P + RT and P, respectively). Only P + RT (0.1 ± 0.04 kg) and PRISE (0.21 ± 0.07 kg) lost VAT mass (P < 0.05). Fasting glucose decreased only in P + RT (5.1 ± 2.5 mg/dl) and PRISE (15.3 ± 2.1 mg/dl), with the greatest decline occurring in PRISE (P < 0.05). Similarly, HOMA-IR improved (0.6 ± 0.3, 0.6 ± 0.4 units), and leptin decreased (4.7 ± 2.2, 4.7 ± 3.1 ng/dl), and adiponectin increased (3.8 ± 1.1, 2.4 ± 1.1 μg/ml) only in P + RT and PRISE, respectively, with no change in P. In conclusion, we find evidence to support exercise training and timed ingestion of whey protein added to the habitual diet of free-living overweight/obese adults, independent of caloric restriction on total and regional body fat distribution, insulin resistance, and adipokines. Topics: Adipokines; Adiponectin; Adipose Tissue; Body Composition; Body Fat Distribution; Body Mass Index; Body Weight; Dietary Supplements; Eating; Exercise; Female; Humans; Hunger; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Milk Proteins; Obesity; Overweight; Physical Endurance; Satiety Response; Whey Proteins | 2014 |
Body weight loss, reduced urge for palatable food and increased release of GLP-1 through daily supplementation with green-plant membranes for three months in overweight women.
The frequency of obesity has risen dramatically in recent years but only few effective and safe drugs are available. We investigated if green-plant membranes, previously shown to reduce subjective hunger and promote satiety signals, could affect body weight when given long-term. 38 women (40-65 years of age, body mass index 25-33 kg/m(2)) were randomized to dietary supplementation with either green-plant membranes (5 g) or placebo, consumed once daily before breakfast for 12 weeks. All individuals were instructed to follow a three-meal paradigm without any snacking between the meals and to increase their physical activity. Body weight change was analysed every third week as was blood glucose and various lipid parameters. On days 1 and 90, following intake of a standardized breakfast, glucose, insulin and glucagon-like peptide 1 (GLP-1) in plasma were measured, as well as subjective ratings of hunger, satiety and urge for different palatable foods, using visual analogue scales. Subjects receiving green-plant membranes lost significantly more body weight than did those on placebo (p < 0.01). Mean weight loss with green-plant extract was 5.0 ± 2.3 kg compared to 3.5 ± 2.3 kg in the control group. Consumption of green-plant membranes also reduced total and LDL-cholesterol (p < 0.01 and p < 0.05 respectively) compared to control. Single-meal tests performed on day 1 and day 90 demonstrated an increased postprandial release of GLP-1 and decreased urge for sweet and chocolate on both occasions in individuals supplemented with green-plant membranes compared to control. Waist circumference, body fat and leptin decreased in both groups over the course of the study, however there were no differences between the groups. In conclusion, addition of green-plant membranes as a dietary supplement once daily induces weight loss, improves obesity-related risk-factors, and reduces the urge for palatable food. The mechanism may reside in the observed increased release of GLP-1. Topics: Adult; Aged; Blood Glucose; Body Mass Index; Body Weight; Cholesterol, LDL; Diet; Dietary Supplements; Female; Glucagon-Like Peptide 1; Humans; Insulin; Leptin; Meals; Middle Aged; Overweight; Postprandial Period; Satiation; Single-Blind Method; Surveys and Questionnaires; Triglycerides; Vegetables; Waist Circumference; Weight Loss | 2014 |
Leptin and smoking cessation: secondary analyses of a randomized controlled trial assessing physical activity as an aid for smoking cessation.
Smokers have a lower body weight compared to non-smokers. Smoking cessation is associated with weight gain in most cases. A hormonal mechanism of action might be implicated in weight variations related to smoking, and leptin might be implicated. We made secondary analyses of an RCT, with a hypothesis-free exploratory approach to study the dynamic of leptin following smoking cessation.. We measured serum leptin levels among 271 sedentary smokers willing to quit who participated in a randomized controlled trial assessing a 9-week moderate-intensity physical activity intervention as an aid for smoking cessation. We adjusted leptin for body fat levels. We performed linear regressions to test for an association between leptin levels and the study group over time.. One year after smoking cessation, the mean serum leptin change was +3.23 mg/l (SD 4.89) in the control group and +1.25 mg/l (SD 4.86) in the intervention group (p of the difference < 0.05). When adjusted for body fat levels, leptin was higher in the control group than in the intervention group (p of the difference < 0.01). The mean weight gain was +2.91 (SD 6.66) Kg in the intervention and +3.33 (SD 4.47) Kg in the control groups, respectively (p not significant).. Serum leptin levels significantly increased after smoking cessation, in spite of substantial weight gain. The leptin dynamic might be different in chronic tobacco users who quit smoking, and physical activity might impact the dynamic of leptin in such a situation. Clinical trial registration number: NCT00521391. Topics: Adult; Biomarkers; Body Weight; Exercise; Female; Humans; Leptin; Male; Research Design; Smoking Cessation; Weight Gain | 2014 |
Carbohydrate modified diet & insulin sensitizers reduce body weight & modulate metabolic syndrome measures in EMPOWIR (enhance the metabolic profile of women with insulin resistance): a randomized trial of normoglycemic women with midlife weight gain.
Progressive midlife weight gain is associated with multiple adverse health outcomes and may represent an early manifestation of insulin resistance in a distinct subset of women. Emerging data implicate hyperinsulinema as a proximate cause of weight gain and support strategies that attenuate insulin secretion.. To assess a previously reported novel hypocaloric carbohydrate modified diet alone (D), and in combination with metformin (M) and metformin plus low-dose rosiglitazone (MR), in diverse women with midlife weight gain (defined as >20lbs since the twenties), normal glucose tolerance, and hyperinsulinemia.. 46 women, mean age 46.6±1.0, BMI 30.5±0.04 kg/m2, 54.5% white, 22.7% black, 15.9% Hispanic, at 2 university medical centers.. A dietary intervention designed to reduce insulin excursions was implemented in 4 weekly nutritional group workshops prior to randomization.. Change in 6-month fasting insulin. Pre-specified secondary outcomes were changes in body weight, HOMA-IR, metabolic syndrome (MS) measures, leptin, and adiponectin.. Six-month fasting insulin declined significantly in the M group: 12.5 to 8.0 µU/ml, p = .026. Mean 6-month weight decreased significantly and comparably in D, M, and MR groups: 4.7, 5.4, and 5.5% (p's.049, .002, and.032). HOMA-IR decreased in M and MR groups (2.5 to 1.6 and 1.9 to 1.3, p's = .054, .013). Additional improvement in MS measures included reduced waist circumference in D and MR groups and increased HDL in the D and M groups. Notably, mean fasting leptin did not decline in a subset of subjects with weight loss (26.15±2.01 ng/ml to 25.99±2.61 ng/ml, p = .907. Adiponectin increased significantly in the MR group (11.1±1.0 to 18.5±7.4, p<.001) Study medications were well tolerated.. These findings suggest that EMPOWIR's easily implemented dietary interventions, alone and in combination with pharmacotherapies that target hyperinsulinemia, merit additional investigation in larger, long-term studies.. ClinicalTrials.gov NCT00618072. Topics: Blood Glucose; Body Mass Index; Body Weight; Diet, Carbohydrate-Restricted; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Metabolic Syndrome; Middle Aged; Patient Compliance; Risk Factors; Treatment Outcome | 2014 |
High protein intake from meat as complementary food increases growth but not adiposity in breastfed infants: a randomized trial.
High intake of cow-milk protein in formula-fed infants is associated with higher weight gain and increased adiposity, which have led to recommendations to limit protein intake in later infancy. The impact of protein from meats for breastfed infants during complementary feeding may be different.. We examined the effect of protein from meat as complementary foods on growth and metabolic profiles of breastfed infants.. This was a secondary analysis from a trial in which exclusively breastfed infants (5-6 mo old from the Denver, CO, metro area) were randomly assigned to receive commercially available pureed meats (Meat group; n = 14) or infant cereal (Cereal group; n = 28) as their primary complementary feedings for ∼ 5 mo. Anthropometric measures and diet records were collected monthly from 5 to 9 mo of age; intakes from complementary feeding and breast milk were assessed at 9 mo of age.. The Meat group had significantly higher protein intake, whereas energy, carbohydrate, and fat intakes from complementary feeding did not differ by group over time. At 9 mo of age, mean (± SEM) intakes of total (complementary feeding plus breast milk) protein were 2.9 ± 0.6 and 1.4 ± 0.4 g · kg(-1) · d(-1), ∼ 17% and ∼ 9% of daily energy intake, for Meat and Cereal groups, respectively (P < 0.001). From 5 to 9 mo of age, the weight-for-age z score (WAZ) and length-for-age z score (LAZ) increased in the Meat group (ΔWAZ: 0.24 ± 0.19; ΔLAZ: 0.14 ± 0.12) and decreased in the Cereal group (ΔWAZ: -0.07 ± 0.17; ΔLAZ: -0.27 ± 0.24) (P-group by time < 0.05). The change in weight-for-length z score did not differ between groups. Total protein intake at 9 mo of age and baseline WAZ were important predictors of changes in the WAZ (R(2) = 0.23, P = 0.01).. In breastfed infants, higher protein intake from meats was associated with greater linear growth and weight gain but without excessive gain in adiposity, suggesting that potential risks of high protein intake may differ between breastfed and formula-fed infants and by the source of protein. Topics: Adiposity; Biomarkers; Blood Glucose; Body Weight; Breast Feeding; Child Development; Cholesterol, HDL; Diet Records; Dietary Proteins; Energy Intake; Female; Humans; Infant; Infant Formula; Infant Nutritional Physiological Phenomena; Insulin; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Linear Models; Male; Meat; Milk, Human; Triglycerides; Tumor Necrosis Factor-alpha; Weight Gain | 2014 |
Leptin mediates seasonal variation in some but not all symptoms of sickness in Siberian hamsters.
Many seasonally breeding species, including Siberian hamsters (Phodopus sungorus), exhibit seasonal variation in sickness responses. One hypothesis regarding the mechanism of this variation is that sickness intensity tracks an animal's energetic state, such that sickness is attenuated in the season that an animal has the lowest fat stores. Energetic state may be signaled via leptin, an adipose hormone that provides a signal of fat stores. Siberian hamsters respond to extended housing in short, winter-like days by reducing fat stores and leptin levels, relative to those housed in long, summer-like days. Sickness responses are also attenuated in short-day hamsters as compared to long-day hamsters. We hypothesized that leptin provides a physiological signal by which seasonally breeding animals modulate sickness responses, such that animals with higher leptin levels show increased sickness intensity. To test this, we provided short-day hamsters with a long-day-like leptin signal and assessed their responses to lipopolysaccharide (LPS), a sickness-inducing antigen. We compared these responses to short-day vehicle-, long-day vehicle-, and long-day leptin-treated hamsters. Unexpectedly, LPS induced a hypothermic response (rather than fever) in all groups. Short-day vehicle-treated hamsters exhibited the greatest LPS-induced hypothermia, and leptin treatment attenuated this response, making hypothermia more long-day-like. Contrary to our hypothesis, short-day leptin-treated hamsters showed the least pronounced LPS-induced anorexia among all groups. These results suggest that leptin may mediate some but not all aspects of seasonal sickness variation in this species. Future studies should be targeted at determining roles of other energetic hormones in regulating seasonal sickness response variation. Topics: Anhedonia; Animals; Anorexia; Behavior, Animal; Body Weight; Cricetinae; Fever; Illness Behavior; Infusion Pumps, Implantable; Leptin; Lipopolysaccharides; Male; Nesting Behavior; Phodopus; Photoperiod; Seasons | 2014 |
[Change of peripheral blood appetite regulation factor of anorexia children and infect of child anorexia granule].
Study the infect of child anorexia granule on serum ghrelin and leptin of anorexia children and its clinical efficacy. Selected 81 cases of anorexia children aged 1-6 years old into treatment group (42 cases) and control group (39 cases), in addition, 30 case healthy children as healthy control group. The control group children were treated with domperidone suspension 0.3 mg x kg(-1) x d(-1), tid, orally 30 minutes before meals. Treatment group were treated with child anorexia granule, 1-3 years 1 package, bid; 4-6 years 1 package, tid; po, 4 weeks as a course of treatment. Study the change of serum ghrelin and leptin before and after therapy. The study demonstrates that before treatment, the serum ghrelin level of disease group was lower than healthy group (P < 0.01), and the serum leptin level was higher than healthy group (P < 0.01). After treatment, the serum ghrelin level both increase, and the serum leptin decline. And the change of treatment group was significantly different with control group (P < 0.01). And the clinical effective rate are 95.23% and 74.35% (P < 0.01). After 6 months of follow-up visit, the children weight significantly increase in treatment group (P < 0.01). Results indicate that child anorexia granule can facilitate secretion of ghrelin, and inhibit secretion of leptin, so as to work up an appetite. And the molecular mechanism is its infect on serum ghrelin, leptin. Topics: Anorexia; Appetite Regulation; Body Weight; Child; Child, Preschool; Drugs, Chinese Herbal; Female; Ghrelin; Humans; Infant; Leptin; Male | 2014 |
Endothelial function and weight loss: comparison of low-carbohydrate and low-fat diets.
The effect of weight loss on obesity-associated endothelial dysfunction is not clear because of conflicting data, demonstrating both improvement and no change in endothelial function after weight loss in obese subjects. A 2-year prospective study (n = 121) was conducted to examine: (1) the effect of obesity and weight loss (either a low-carbohydrate or and low-fat diet) on flow mediated vasodilatation (FMD), a measure of endothelial function.. Participants reduced body weight by 7.1% ± 4.4%, 8.7% ± 6.8%, 7.1% ± 7.8%, and 4.1% ± 7.7% at 3, 6, 12, and 24 months, respectively with no significant differences between the low-fat and low-carbohydrate groups.. Endothelial function was inversely correlated with waist circumference, triglyceride level, and directly correlated with leptin in obese persons prior to weight loss. These weight losses did not confer any improvements in FMD. There were no differences between the low-fat and low-carbohydrate diets in FMD at any time point. At 6 months (r = 0.26, P = 0.04) and 1 year (r =0.28, P = 0.03), there were positive correlations between change in FMD and change in leptin but not at 2 years.. There was no significant improvement in endothelial function after 7.1% ± 7.8% weight loss at 1 year and 4.1% ± 7.7% at 2 years, achieved by either a low carbohydrate or a low fat diet. Topics: Adult; Blood Pressure; Body Mass Index; Body Weight; Brachial Artery; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Endothelium; Female; Humans; Image Processing, Computer-Assisted; Leptin; Male; Middle Aged; Obesity; Prospective Studies; Risk Factors; Triglycerides; Vasodilation; Waist Circumference; Weight Loss | 2013 |
Moderate-intensity aerobic training program improves insulin sensitivity and inflammatory markers in a pilot study of morbidly obese minority teens.
We initiated a pilot study to investigate the effects of 8 wks of aerobic exercise training (ET) on insulin sensitivity and inflammatory markers in obese and insulin-resistant minority adolescents. Eleven morbidly obese (BMI 41.4 ± 1.8 kg/m2) minority adolescents were entered into a supervised ET intervention (~180 min/wk at 40-55%VO2PeakR [(VO2Peak-VO2Rest)/VO2Rest]). The effects of training on insulin sensitivity (SI), inflammation and other metabolic syndrome features were examined.. Insulin action improved in response to training, as indicated by a ~37% increase in SI (p = .018). Plasma levels of several proinflammatory cytokines were reduced in response to ET, as indicated by significant decrements in sTNF-R, CCL2, MPO, IL-6, resistin, and leptin, with no significant changes in hsCRP. ET induced reductions in BMI and percent total body fat.. The present study supports the efficacy of ET interventions on metabolic syndrome features in morbidly obese minority youth. Topics: Adolescent; Black or African American; Body Composition; Body Weight; Chemokine CCL2; Exercise; Exercise Test; Exercise Therapy; Female; Glucose Tolerance Test; Hispanic or Latino; Humans; Insulin Resistance; Leptin; Male; Obesity, Morbid; Oxygen Consumption; Peroxidase; Pilot Projects; Receptors, Tumor Necrosis Factor; Resistin; Statistics, Nonparametric | 2013 |
The effect of leptin, caffeine/ephedrine, and their combination upon visceral fat mass and weight loss.
To evaluate the effects of combination caffeine/ephedrine and leptin A-200 on visceral fat mass and weight loss over 24 weeks.. In this randomized, double-blind, parallel-arm trial, 90 obese subjects received one of the three treatments for 24 weeks: 200 mg caffeine/20 mg ephedrine t.i.d. (CE), leptin A-200 (recombinant methionyl human Fc-leptin, 20 mg q.d.) (L), or combination leptin A-200 and caffeine/ephedrine (LCE). Outcomes included change in weight, visceral fat mass by computed tomography, lean mass and fat mass by dual energy X-ray absorptiometry.. Groups treated with CE and LCE lost significant amounts of weight (-5.9 ± 1.2% and -6.5 ± 1.1%, P < 0.05) and whole body fat mass (-9.6 ± 2.4% and -12.4 ± 2.3%, P < 0.05) compared to leptin only group. Only treatment with LCE significantly reduced visceral fat mass (-11.0 ± 3.3%, P < 0.05). There were no differences in lean mass between treatment groups.. Our study provides evidence that CE is a modestly effective weight loss agent and produces significant reductions in fat mass. Leptin A-200 was not effective in producing weight loss and did not have any significant additive or synergistic actions when combined with CE. Topics: Absorptiometry, Photon; Adolescent; Adult; Body Composition; Body Weight; Caffeine; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Ephedrine; Female; Humans; Intra-Abdominal Fat; Leptin; Male; Middle Aged; Obesity; Weight Loss; Young Adult | 2013 |
Increased protein intake and meal frequency reduces abdominal fat during energy balance and energy deficit.
Unrefined, complex carbohydrates and lean protein diets are used to combat obesity, although it's unknown whether more frequent meals may improve this response. The effects of consuming traditional (~15%) versus higher (~35%) protein intakes as three or six meals/day on abdominal fat, postprandial thermogenesis (TEM), and cardiometabolic biomarkers in overweight individuals during 28 days of energy balance (BAL) and deficit (NEG), respectively were compared.. Overweight individuals (n = 30) were randomized into three groups: two high-protein groups (35% of energy) consumed as three (HP3) or six (HP6) meals/day and one group consumed three meals/day of a traditional intake (TD3). Following a 5-day baseline control (CON), subjects consumed their respective diets throughout a 56-day intervention consisting of two, 28 day phases: a BAL followed by a NEG phase (75% of energy needs). Total body fat (BF) and abdominal BF (ABF), body weight (BW), TEM, and fasting biomarkers were assessed at the end of CON, BAL, and NEG phases.. BW remained stable throughout CON and BAL in all groups, whereas BF (P < 0.001) and ABF (P < 0.01) decreased in HP groups and lean body mass (LBM) and leptin increased in HP6. Following NEG, BW decreased in all groups. BF, ABF, and leptin decreased in HP groups; LBM remained higher (P < 0.05), and TEM was highest in HP6 (P < 0.05).. Consuming increased protein (∼35%) more frequently (6×) throughout the day decreases BF and ABF, increases LBM and TEM, and favorably affects adipokines more than current recommendations for macronutrients consumed over three meals/day in overweight individuals during both BAL and NEG. Topics: Abdominal Fat; Adult; Blood Glucose; Body Composition; Body Fat Distribution; Body Weight; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; Energy Metabolism; Fasting; Humans; Hunger; Insulin; Leptin; Meals; Middle Aged; Obesity; Overweight; Patient Compliance; Postprandial Period; Satiation; Thermogenesis | 2013 |
Effects of a multidisciplinary childhood obesity treatment intervention on adipocytokines, inflammatory and growth mediators.
To examine the effects of a 3-month multidisciplinary intervention on anthropometric measures, physical activity patterns and fitness, inflammatory cytokines, adipocytokines, and growth mediators in obese children.. 21 obese subjects completed the 3-month intervention and were compared with 20 age-, gender- and maturity-matched controls. Subjects underwent anthropometric measurements (weight, height, BMI percentile and waist circumference), blood tests (IL-6, CRP, leptin, adiponectin, insulin, IGF-I and glucose), a progressive treadmill exercise test to evaluate fitness, and habitual activity assessment before and after the intervention.. The intervention led to a significant change of differences in body weight (-1.3 ± 4.1 vs. 2.5 ± 3.3 kg), BMI percentile (-0.96 ± 1.29 vs. 0.19 ± 0.8), waist circumference (-2.1 ± 2.7 vs. 2.9 ± 3.0 cm) and running time (149.9 ± 86.3 vs. -8.2 ± 88.0 s) in the intervention compared to control. There was a significant increase in leisure-time physical activity (Godin questionnaire, 29.04 ± 6.8 vs. -1.3 ± 9.2) and a decrease in sedentary activity (-1.4 ± 0.73 vs. 0.02 ± 0.62 h/day) in the intervention compared to control. Significant change differences in adiponectin (2,308 ± 1,640 vs. -801 ± 465 ng/ml), IGF-I (33.8 ± 37.8 vs. -1.0 ± 36.2 ng/ml), CRP (-0.06 ± 0.29 vs. 0.5 ± 0.86 mg/dl) and HOMA-IR (-0.15 ± 0.57 vs. 0.55 ± 0.84) were found in the intervention group compared to control.. Our results highlight the short-term beneficial effects of a childhood obesity multidisciplinary intervention on anthropometrics, habitual activity, fitness, inflammatory and metabolic measures. The longer-term effects of these changes on obesity-associated metabolic risks are yet to be determined. Topics: Adipokines; Adiponectin; Adolescent; Body Mass Index; Body Weight; C-Reactive Protein; Child; Diet, Reducing; Exercise; Female; Humans; Inflammation Mediators; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Male; Pediatric Obesity; Physical Fitness | 2013 |
Effects of electroacupuncture and Chinese kidney-nourishing medicine on polycystic ovary syndrome in obese patients.
To explore the effect of electroacupuncture and Chinese kidney-nourishing medicine on insulin (INS), adiponectin (APN), leptin (LEP), and glucolipid metabolism of obese patients with polycystic ovary syndrome (PCOS).. Sixty-seven obese PCOS patients were randomly divided into two groups. Thirty-three patients in the acupuncture-medicine group were treated three times a week with electroacupuncture at the Tianshu (ST 25), Zhongwan (CV 12), Qi-hai (CV 6), Sanyinjiao (SP 6), Geshu (BL 17), and Ciliao (BL 32) acupoints. They also took the Chinese drug, Tiankui capsule, for 3 months as a course of treatment. Point-taking and treatment in the electroacupuncture group of 34 patients was the same as those in the acupuncture-medicine group. We observed and compared the changes in the obesity-related indexes of body weight (BW), body mass index (BMI), and waist-hip ratio (WHR), as well as fasting plasma glucose (FPG), fasting insulin (FINS), APN, and LEP.. BW, BMI, WHR, and FINS decreased and insulin sensitivity index (ISI) and APN were higher in the acupuncture-medicine group than in the electroacupuncture group (P < 0.01). There was no obvious difference in LEP between the two groups (P > 0.05).. Acupuncture combined with medicine is better than just electroacupuncture for obese PCOS patients by improving obesity-related indexes, insulin sensitivity, and APN level. This indicates that acupuncture-medicine therapy is worth clinical popularization. Topics: Adiponectin; Adolescent; Adult; Body Weight; Combined Modality Therapy; Drugs, Chinese Herbal; Electroacupuncture; Female; Glucose; Humans; Insulin Resistance; Leptin; Obesity; Polycystic Ovary Syndrome; Waist-Hip Ratio; Young Adult | 2013 |
Changes in children's sleep duration on food intake, weight, and leptin.
To examine the effect of experimental changes in children's sleep duration on self-reported food intake, food reinforcement, appetite-regulating hormones, and measured weight.. Using a within-subjects, counterbalanced, crossover design, 37 children, 8 to 11 years of age (27% overweight/obese) completed a 3-week study. Children slept their typical amount at home for 1 week and were then randomized to either increase or decrease their time in bed by 1.5 hours per night for 1 week, completing the alternate schedule on the third week. Primary outcomes were dietary intake as assessed by 24-hour dietary recalls, food reinforcement (ie, points earned for a food reward), and fasting leptin and ghrelin. The secondary outcome was child weight.. Participants achieved a 2 hour, 21 minute difference in the actigraph defined sleep period time between the increase and decrease sleep conditions (P < .001). Compared with the decrease sleep condition, during the increase condition, children reported consuming an average of 134 kcal/day less (P < .05), and exhibited lower fasting morning leptin values (P < .05). Measured weights were 0.22 kg lower during the increase sleep than the decrease sleep condition (P < .001). There were no differences in food reinforcement or in fasting ghrelin.. Compared with decreased sleep, increased sleep duration in school-age children resulted in lower reported food intake, lower fasting leptin levels, and lower weight. The potential role of sleep duration in pediatric obesity prevention and treatment warrants further study. Topics: Actigraphy; Appetite Regulation; Biomarkers; Body Weight; Child; Choice Behavior; Cross-Over Studies; Diet Surveys; Dietary Fats; Eating; Energy Intake; Female; Ghrelin; Humans; Leptin; Male; Obesity; Overweight; Reward; Self Report; Sleep Deprivation; Time Factors | 2013 |
A gene variation (rs12691) in the CCAT/enhancer binding protein α modulates glucose metabolism in metabolic syndrome.
CCAAT/enhancer-binding protein alpha (CEBPA) is a transcription factor involved in adipogenesis and energy homeostasis. Caloric restriction reduces CEBPA protein expression in patients with metabolic syndrome (MetS). A previous report linked rs12691 SNP in CEBPA to altered concentration of fasting triglycerides. Our objective was to assess the effects of rs12691 in glucose metabolism in Metabolic Syndrome (MetS) patients.. Glucose metabolism was assessed by static (glucose, insulin, adiponectin, leptin and resistin plasma concentrations) and dynamic (disposition index, insulin sensitivity index, HOMA-IR and acute insulin response to glucose) indices, performed at baseline and after 12 weeks of 4 dietary interventions (high saturated fatty acid (SFA), high monounsaturated fatty acid (MUFA), low-fat and low-fat-high-n3 polyunsaturated fatty acid (PUFA)) in 486 subjects with MetS. Carriers of the minor A allele of rs12691 had altered disposition index (p = 0.0003), lower acute insulin response (p = 0.005) and a lower insulin sensitivity index (p = 0.025) indicating a lower insulin sensitivity and a lower insulin secretion, at baseline and at the end of the diets. Furthermore, A allele carriers displayed lower HDL concentration.. The presence of the A allele of rs12691 influences glucose metabolism of MetS patients. Topics: Adiponectin; Adult; Aged; Alleles; Blood Glucose; Body Mass Index; Body Weight; CCAAT-Enhancer-Binding Proteins; Dietary Fats; Dietary Supplements; DNA; Fasting; Fatty Acids; Fatty Acids, Monounsaturated; Fatty Acids, Omega-3; Female; Genotype; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Lipid Metabolism; Male; Metabolic Syndrome; Middle Aged; Polymorphism, Single Nucleotide; Resistin; Triglycerides | 2013 |
Evaluation of the influence of whole and defatted flaxseed on satiety, glucose, and leptin levels of women in the late postoperative stage of bariatric surgery.
Satiety decline is one of the factors that are involved in weight regain in the postoperative period of bariatric surgery. Nutrients such as long-chain n-3 polyunsaturated fatty acid and fibers could assist in food intake control by increasing satiety. Flaxseed is a source of these nutrients, and its consumption could help with possible glycemic control and increased satiety. The aim of this study was to evaluate the influence of whole flaxseed and defatted flaxseed on satiety, postprandial blood glucose, and leptin in post-bariatric women.. A single-blind crossover and randomized study was performed with 18 women in the late postoperative of Roux-en-Y gastric bypass (RYGBP). All women received three test meals containing whole flaxseed, defatted flaxseed, and placebo with 1 week of washout. Satiety was evaluated by a Visual Analog Scale during the fasting period; immediately after ingestion; and 60, 120, and 180 min after meals.. There was no difference between test meals for the variables of hunger, satisfaction, fullness, and desire to eat. The basal and postprandial glucose and leptin levels did not differ between the test meals. The intake of defatted flaxseed and placebo muffins resulted in reduced postprandial blood glucose. Postprandial leptin was higher than the baseline (p = 0.02); however, only defatted flaxseed showed increased postprandial leptin levels (p = 0.044).. Whole flaxseed and defatted flaxseed did not promote satiety in women in the late postoperative of RYGBP. However, the test meals with a lower fat content increased the serum leptin levels. Topics: Adult; Aged; Blood Glucose; Body Weight; Brazil; Cross-Over Studies; Diet Records; Eating; Female; Flax; Gastric Bypass; Humans; Leptin; Meals; Middle Aged; Obesity, Morbid; Postoperative Period; Satiation; Single-Blind Method; Time Factors; Treatment Outcome; Weight Loss | 2013 |
Effects of three weeks of mild sleep restriction implemented in the home environment on multiple metabolic and endocrine markers in healthy young men.
Evidence for a causal relationship between sleep-loss and metabolism is derived primarily from short-term sleep deprivation studies in the laboratory. The objective of this study was to investigate whether small changes in sleep duration over a three week period while participants are living in their normal environment lead to changes in insulin sensitivity and other metabolic parameters.. Nineteen healthy, young, normal-weight men were randomised to either sleep restriction (habitual bedtime minus 1.5h) or a control condition (habitual bedtime) for three weeks. Weekly assessments of insulin sensitivity by hyperinsulinaemic-euglycaemic clamp, anthropometry, vascular function, leptin and adiponectin were made. Sleep was assessed continuously using actigraphy and diaries.. Assessment of sleep by actigraphy confirmed that the intervention reduced daily sleep duration by 01:19 ± 00:15 (SE; p<0.001). Sleep restriction led to changes in insulin sensitivity, body weight and plasma concentrations of leptin which varied during the three week period. There was no effect on plasma adiponectin or vascular function.. Even minor reductions in sleep duration lead to changes in insulin sensitivity, body weight and other metabolic parameters which vary during the exposure period. Larger and longer longitudinal studies of sleep restriction and sleep extension are warranted. Topics: Adiponectin; Adult; Blood Pressure; Body Composition; Body Weight; Glucose Clamp Technique; Humans; Insulin Resistance; Leptin; Longitudinal Studies; Male; Sleep; Sleep Deprivation; Young Adult | 2013 |
Massage improves growth quality by decreasing body fat deposition in male preterm infants.
To assess the effect of massage on weight gain and body fat deposition in preterm infants.. Preterm infants (29-32 weeks) were randomized to the massage group (n = 22, 12 girls, 10 boys) or the control group (n = 22, 12 girls, 10 boys). Treatment was masked with massage or control care administered twice-daily by licensed massage therapists (6 d/wk for 4 weeks). Body weight, length, Ponderal Index (PI), body circumferences, and skinfold thickness (triceps, mid-thigh, and subscapular [SSF]) were measured. Circulating insulin-like growth factor I, leptin, and adiponectin levels were determined by enzyme-linked immunosorbent assay. Daily dietary intake was collected.. Energy and protein intake as well as increase in weight, length, and body circumferences were similar. Male infants in the massage group had smaller PI, triceps skinfold thickness, mid-thigh skinfold thickness, and SSF and increases over time compared with control male infants (P < .05). Female infants in the massage group had larger SSF increases than control female infants (P < .05). Circulating adiponectin increased over time in control group male infants (group × time × sex interaction, P < .01) and was correlated to PI (r = 0.39, P < .01).. Twice-daily massage did not promote greater weight gain in preterm infants. Massage did, however, limit body fat deposition in male preterm infants. Massage decreased circulating adiponectin over time in male infants with higher adiponectin concentrations associated with increased body fat. These findings suggest that massage may improve body fat deposition and, in turn, growth quality of preterm infants in a sex-specific manner. Topics: Adiponectin; Anthropometry; Body Fat Distribution; Body Weight; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant, Newborn; Infant, Premature; Insulin-Like Growth Factor I; Leptin; Male; Massage; Weight Gain | 2013 |
Treatment with pioglitazone is associated with decreased preprandial ghrelin levels: a randomized clinical trial.
The effects of metformin and pioglitazone on ghrelin, a physiologic regulator of appetite and food intake, have not been clearly established. In a randomized clinical trial, we randomly assigned 60 type 2 diabetic patients to either metformin (Group A; n=30) or pioglitazone (Group B; n=30) treatment groups. The groups were similar in their baseline characteristics. A standard fasting 75 g oral glucose tolerance test was performed at time zero before starting metformin or pioglitazone, and 3 months later. After 3 months of treatment, pioglitazone, but not metformin, was significantly associated with weight gain. Both groups experienced a significant reduction in fasting plasma glucose (p<0.01), hemoglobin A1c (p<0.01 in Group A and p<0.05 in Group B), and insulin resistance (p<0.01). The effect of metformin on preprandial ghrelin and its response to glucose challenge was not significant, while the pioglitazone group had a significant reduction in preprandial ghrelin levels after treatment (p<0.05). The effect of pioglitazone on ghrelin was independent of changes in body weight, body mass index, glucose control, insulin resistance, and plasma insulin. In conclusion, treatment with pioglitazone is associated with a decrease in preprandial ghrelin levels and therefore, the weight gain and increased food intake related to pioglitazone use cannot be explained by its effects on ghrelin. The effect of pioglitazone on ghrelin is independent of changes in body weight, body mass index, plasma insulin, insulin resistance, or glucose control. Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Female; Ghrelin; Glucose Tolerance Test; Humans; Insulin; Leptin; Male; Metformin; Middle Aged; Pioglitazone; Thiazolidinediones | 2013 |
Effect of chronic infusion of leptin and nutrition on sexual maturation of zebu heifers.
The amount of fat in the carcass has been proposed as a regulator of initiation of puberty in cattle. To test if changes in energy intake and in circulating leptin concentration are each capable of altering age, BW, and body composition at puberty, 36 prepubertal Nellore heifers, 18 to 20 mo old, 275.8 ± 17.2kg BW, and BCS of 5 ± 0.5 (1 to 9 scale), were randomly assigned to each of 3 treatments (n = 12): High (high energy diet), Low (low energy diet), and LL [low energy diet + ovine leptin (oLeptin)]. Diets were formulated to promote BW gain of 0.4 kg/d (groups Low and LL) or 1.2 kg/d (High group). After 14 d of adjustment to diet, heifers in LL group received subcutaneous injections of oLeptin at 4.8 μg/kg BW twice a day for 56 d. Groups High and Low received similar injections of 2 mL saline solution. Age at puberty was considered to be the age on first detection of a corpus luteum, confirmed by plasma concentrations of progesterone of >1 ng/mL. Heifers were slaughtered on the second day after first corpus luteum detection. Expression of leptin gene was quantified by real-time PCR using ribosomal protein-L19 (RP-L19) as a control gene. Leptin administration increased (P = 0.04) leptin serum concentration but had no effect (P > 0.05) on age, BW, or BCS at puberty. High energy intake increased (P < 0.01) leptin concentration, accelerated (P = 0.02) puberty, and increased (P < 0.01) BCS at puberty, without altering (P = 0.17) BW at puberty. High energy intake also accelerated (P = 0.04) follicular development. Leptin administration caused a significant (P < 0.05) but transient increase in follicular development, which was similar to the transient increase in leptin serum concentration. Results from leptin gene expression demonstrated that high energy intake increased (P < 0.01) and leptin administration decreased (P < 0.01) leptin expression in 3 adipose tissues. The observed decrease in leptin gene expression after administration of leptin could explain the reduction in leptin serum concentration after 30 d of treatment and consequently the failure of leptin to accelerate puberty. Our findings did not support the hypothesis that reduced serum concentration of leptin is an important hindrance for puberty onset in malnourished zebu heifers. Although exogenous administration of leptin temporarily enhanced rate of follicular growth, it did not accelerate puberty. Topics: Adipose Tissue; Aging; Animal Feed; Animals; Body Constitution; Body Weight; Cattle; Diet; Energy Intake; Female; Gene Expression Regulation; Leptin; Ovarian Follicle; Radioimmunoassay; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Sexual Maturation; Sheep | 2013 |
Anti-inflammatory effect of exercise, via reduced leptin levels, in obese women with Down syndrome.
Recent studies have reported that obese young people with Down syndrome suffer from low-grade systemic inflammation. Whereas this condition may be improved in the general population by regular exercise, the problem has received no attention in the case of people with intellectual disability. Therefore, the authors' aim was to assess the influence of aerobic training on plasma adipokines in obese women with Down syndrome. Twenty obese young women with Down syndrome volunteered for this study, 11 of whom were randomly assigned to a 10-wk aerobic-training program. They attended 3 sessions/wk, which consisted of warm-up exercises followed by the main activity on a treadmill (30-40 min) at a work intensity of 55-65% of peak heart rate and ended with a cooling-down period. The control group included 9 women with Down syndrome matched for age, sex, and body-mass index. Fat-mass percentage and distribution were measured, and plasma adipokine levels (leptin and adiponectin) were assessed. In addition, each participant performed a maximal graded continuous treadmill exercise test. These parameters were assessed pre- and postintervention. Aerobic training produced a significant increase in participants' maximal oxygen uptake (20.2 ± 5.8 vs.23.7 ± 6.3 ml · kg-1 · min-1; p < .001), and plasma leptin levels were significantly reduced in the intervention group (54.2 ± 6.7 vs.45.7 ± 6.1 ng/ml; p = .026). Further significant correlations between plasma leptin and indices of obesity were found. In contrast, no significant changes were found in adiponectin levels (p > .05). None of the tested parameters changed in the control group. In conclusion, a 10-week training program reduced leptin levels in obese young women with Down syndrome. Topics: Adiponectin; Adolescent; Adult; Body Composition; Body Height; Body Mass Index; Body Weight; Down Syndrome; Exercise; Exercise Test; Female; Humans; Inflammation; Leptin; Obesity; Waist-Hip Ratio; Young Adult | 2013 |
Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety.
Leptin replacement therapy improves metabolic complications in patients with lipodystrophy and severe hypoleptinemia (SH), but whether the response is related to the degree of hypoleptinemia remains unclear.. The aim of the study was to compare efficacy of leptin therapy in familial partial lipodystrophy, Dunnigan variety (FPLD) patients with SH (serum leptin<7th percentile of normal) vs. those with moderate hypoleptinemia (MH; serum leptin in 7th to 20th percentiles).. We conducted an open-label, parallel group, observational study in 14 SH (mean±sd, serum leptin, 1.9±1.1 ng/ml) and 10 MH (serum leptin, 5.3±1.0 ng/ml) women with FPLD.. Patients received 0.08 mg/kg·d of metreleptin by twice daily sc injections for 6 months.. The primary outcome variable was change in fasting serum triglycerides. Other secondary variables were fasting plasma glucose and insulin, insulin sensitivity, hemoglobin A1c, and hepatic triglyceride content.. Median fasting serum triglycerides decreased from 228 to 183 mg/dl in the SH group (P=0.04) and from 423 to 339 mg/dl in the MH group (P=0.02), but with no difference between the groups (P value for interaction=0.96). Hepatic triglyceride levels similarly declined significantly from 8.8 to 4.9% in the SH group and from 23.7 to 9.2% in the MH group (P value for interaction=0.9). Loss of body weight and body fat occurred in both groups. Fasting glucose, insulin, glucose tolerance, and hemoglobin A1c levels did not change. K value on insulin tolerance test improved slightly in the SH group (0.98 to 1.24%; P=0.01), but not in the MH group (1.1 to 1.27%; P=0.4).. Metreleptin replacement therapy is equally effective in FPLD patients with both SH and MH in reducing serum and hepatic triglyceride levels, but did not improve hyperglycemia. Topics: Adipose Tissue; Adult; Aged; Blood Glucose; Body Weight; Energy Metabolism; Female; Hormone Replacement Therapy; Humans; Insulin; Leptin; Lipids; Lipodystrophy, Familial Partial; Middle Aged; Treatment Outcome | 2012 |
Gender-specific early postnatal catch-up growth after intrauterine growth retardation by food restriction in swine with obesity/leptin resistance.
The effects of undernutrition during pregnancy on prenatal and postnatal development of the offspring were evaluated in sows with obesity/leptin resistance. Females were fed, from day 35 of pregnancy onwards, a diet fulfilling either 100% (group control, n=10) or 50% of the nutritional requirements (group underfed, n=10). In the control group, maternal body weight increased during pregnancy (P<0.05) while it decreased or remained steady in the underfed group. At days 75 and 100 of gestation, plasma triglycerides were lower but urea levels were higher in restricted than in control sows (P<0.05 for both). Assessment of the offspring indicated that the trunk diameter was always smaller in the restricted group (P<0.01 at day 50, P<0.005 at days 75 and 100 and P<0.0001 at birth) while head measurements were similar through pregnancy, although smaller in the restricted than in the control group at birth (P<0.05). Newborns from restricted sows were also lighter than offspring from control females (P<0.01) and had higher incidence of growth retardation (P<0.01). Afterwards, during lactation, early postnatal growth in restricted piglets was modulated by gender. At weaning, males from restricted sows were still lighter than their control counterparts (P<0.05), while females from control and underfed sows were similar. Thus, the current study indicates a gender-related differential effect in the growth patterns of the piglets, with females from restricted sows evidencing catch-up growth to neutralise prenatal retardation and reaching similar development than control counterparts. Topics: Animals; Animals, Newborn; Body Weight; Caloric Restriction; Drug Resistance; Female; Fetal Growth Retardation; Food; Leptin; Male; Obesity; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Sex Characteristics; Swine | 2012 |
Short sleep duration, glucose dysregulation and hormonal regulation of appetite in men and women.
To determine the hormonal effects of reducing sleep duration under controlled feeding conditions.. Randomized, crossover study.. Inpatient.. Twenty-seven normal weight, 30- to 45-yr-old men and women habitually sleeping 7-9 hr/night.. PARTICIPANTS WERE STUDIED UNDER TWO SLEEP CONDITIONS: short (4 hr in bed) or habitual (9 hr in bed) sleep. A controlled diet was provided for each 4-day study period.. Fasting blood samples were obtained daily and frequent blood samples were obtained throughout day 4. The main outcomes measures included glucose, insulin, leptin, ghrelin, adiponectin, total glucagon-like peptide 1 (GLP-1) and peptide YY(3-36) (PYY(3-36)) concentrations. Body weights were reduced by 2.2 ± 0.4 lb and 1.7 ± 0.4 lb during the habitual and short sleep phases, respectively (both P < 0.0001). There was no effect of sleep duration on glucose, insulin, and leptin profiles (all P > 0.05). Ghrelin and GLP-1 responses differed by sex. Short sleep increased fasting (P = 0.054) and morning (08:00-12:00) (P = 0.042) total ghrelin in men but not women. The reverse was observed for GLP-1: afternoon levels (12:30-19:00) were lower (P = 0.016) after short sleep compared with habitual sleep in women but not men.. These data suggest that, in the context of negative energy balance, short sleep does not lead to a state of increased insulin resistance, but may predispose to overeating via separate mechanisms in men and women.. Trial registration on http://www.clinicaltrials.gov. #NCT00935402. Topics: Adiponectin; Adult; Blood Glucose; Body Weight; Cross-Over Studies; Female; Ghrelin; Humans; Insulin; Leptin; Male; Middle Aged; Sex Factors; Sleep Deprivation | 2012 |
Effects of combination of sibutramine and L-carnitine compared with sibutramine monotherapy on inflammatory parameters in diabetic patients.
The aim of the study was to evaluate the effects of 12-month treatment with sibutramine plus L-carnitine compared with sibutramine alone on body weight, glycemic control, insulin resistance, and inflammatory state in type 2 diabetes mellitus patients. Two hundred fifty-four patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA(1c)] >8.0%) in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA(1c), fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, tumor necrosis factor-α, adiponectin, vaspin, and high-sensitivity C-reactive protein. Sibutramine plus L-carnitine gave a faster improvement of fasting plasma glucose, postprandial plasma glucose, lipid profile, leptin, tumor necrosis factor-α, and high-sensitivity C-reactive protein compared with sibutramine alone. Furthermore, there was a better improvement of body weight, HbA(1c), fasting plasma insulin, homeostasis model assessment of insulin resistance index, vaspin, and adiponectin with sibutramine plus L-carnitine compared with sibutramine alone. Sibutramine plus L-carnitine gave a better and faster improvement of all the analyzed parameters compared with sibutramine alone without giving any severe adverse effect. Topics: Aged; Appetite Depressants; Blood Glucose; Body Weight; C-Reactive Protein; Carnitine; Cholesterol; Cyclobutanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Longitudinal Studies; Male; Middle Aged; Tumor Necrosis Factor-alpha; Vitamin B Complex | 2011 |
Variation of inflammatory parameters after sibutramine treatment compared to placebo in type 2 diabetic patients.
The efficacy of sibutramine has been demonstrated in randomized trials in obese/overweight patients including those with type 2 diabetes mellitus (T2DM). Our objective was to evaluate the effects of 1-year treatment with sibutramine compared to placebo on body weight, glycaemic control, lipid profile, and inflammatory parameters in type 2 diabetic patients.. Two hundred and forty-six patients with uncontrolled T2DM [glycated haemoglobin (HbA(1c) ) > 8·0%] in therapy with different oral hypoglycaemic agents or insulin were randomized to take 10 mg of sibutramine or placebo for 12 months. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), HbA(1c) , fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), leptin, tumour necrosis factor-α (TNF-α), adiponectin (ADN), vaspin, high sensitivity C-reactive protein (Hs-CRP).. We observed a decrease of body weight after 9 and 12 months in the group treated with sibutramine, but not in the control group. Regarding glycaemic and lipid profile, although there are differences seen over time within each of the groups, we did not obtain any significant differences between the two groups. Both placebo and sibutramine gave a similar improvement of HOMA-IR, leptin, TNF-α, ADN, and Hs-CRP. No vaspin variations were observed in either group.. Sibutramine resulted in a decrease in body weight at 9 months and at 12 months that was not observed with placebo. Although there were differences seen over time within each of the groups, there were no significant differences between groups for any other parameter that we measured. Topics: Adiponectin; Appetite Depressants; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Comorbidity; Cyclobutanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Leptin; Lipids; Male; Middle Aged; Obesity; Placebos; Randomized Controlled Trials as Topic; Thiazolidinediones; Time Factors | 2011 |
Comparison between orlistat plus l-carnitine and orlistat alone on inflammation parameters in obese diabetic patients.
To evaluate the effects of 1-year treatment with orlistat plus L-carnitine compared to orlistat alone on body weight, glycemic and lipid control, and inflammatory parameters in obese type 2 diabetic patients. Two hundred and fifty-eight patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA(1c)) > 8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take orlistat 120 mg three times a day plus L-carnitine 2 g one time a day or orlistat 120 mg three times a day. We evaluated the following parameters at baseline and after 3, 6, 9, and 12 months: body weight, body mass index (BMI), glycated hemoglobin (HbA(1c) ), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (Tg), adiponectin (ADN), leptin, tumor necrosis factor-α (TNF-α), vaspin, and high-sensitivity C-reactive protein (Hs-CRP). We observed a better decrease in body weight, glycemic profile, HOMA-IR, LDL-C, and ADN and a faster improvement in FPI, TC, Tg, leptin, TNF-α, Hs-CRP with orlistat plus L-carnitine compared to orlistat alone. We also recorded an improvement in vaspin with orlistat plus l-carnitine not reached with orlistat alone. Orlistat plus L-carnitine gave a better improvement in body weight, glycemic and lipid profile compared to orlistat alone; furthermore, a faster and better improvement in inflammatory parameters was observed with orlistat plus L-carnitine compared to orlistat alone. Topics: Adiponectin; Anti-Inflammatory Agents; Anti-Obesity Agents; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Carnitine; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Lactones; Leptin; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Obesity; Orlistat; Thiazolidinediones; Time Factors | 2011 |
Somatotropic axis and concentrate supplementation in grazing dairy cows of genetically diverse origin.
Supplementing pasture-fed dairy cows with concentrates in early lactation was hypothesized to result in an earlier postpartum recoupling of the somatotropic axis in New Zealand (NZ)-type Holstein-Friesian dairy cows than in North American (NA)-type cows. To test this hypothesis, NA (n=30) and NZ (n=30) cows were allocated to 1 of 3 supplementation strategies (0, 3, or 6 kg of dry matter concentrate/d) for the first 12 wk of lactation in a completely randomized design and a 2×3 factorial arrangement. Production traits and characteristics of the somatotropic axis were studied at phenotypic, hormonal, and gene expression levels. Milk production and plasma metabolite concentrations were measured weekly, and liver was biopsied in wk 1, 4, 8, and 12 postcalving. North American cows produced more milk and displayed a larger degree of somatotropic axis uncoupling than did NZ cows. This was evident in strain differences in body condition score, blood growth hormone, and insulin-like growth factor-1 concentrations, and hepatic expression of growth hormone receptor-1a. No strain×diet interactions were observed for any characteristic of the somatotropic axis at either the blood metabolite or gene expression level; however, blood insulin concentrations during wk 7 to 11 postpartum increased with concentrate supplementation in NZ but not NA cows. These results demonstrate that feeding supplements does not result in an earlier recoupling of the somatotropic axis; however, the greater blood insulin concentrations with concentrate feeding in NZ cows from wk 7 may result in an earlier recoupling in this genetic strain, after the period investigated in this study. Further research is required to understand differences in insulin control between these genetic strains. Topics: Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Body Constitution; Body Weight; Cattle; Dietary Supplements; Fatty Acids, Nonesterified; Feeding Methods; Female; Growth Hormone; Hormones; Insulin; Lactation; Leptin; Milk | 2011 |
A high-legume low-glycemic index diet reduces fasting plasma leptin in middle-aged insulin-resistant and -sensitive men.
Fasting leptin and ghrelin levels were measured in 36 insulin-sensitive (IS) and 28 insulin-resistant (IR) men who consumed a legume-enriched low-glycemic index (LG) diet or healthy American (HA) diet in a randomly ordered cross-over feeding study consisting of two 4-week periods. Weight remained stable over the entire study. Fasting plasma leptin was significantly reduced from pre-study levels by both the LG (18.8%, P < 0.001) and HA (16.1%, P < 0.001) diets, whereas fasting ghrelin did not change. By subgroup analysis according to prestudy insulin status, leptin was reduced in IR subjects after both the LG (17.1%, P < 0.01) and the HA (33.3%, P < 0.001) diets, whereas IS subjects responded only after the LG diet (23.1%, P < 0.01). Thus, a legume-rich LG index diet may be a beneficial strategy for reducing circulating leptin concentrations, even under conditions of weight maintenance. Topics: Body Weight; Cross-Over Studies; Fabaceae; Ghrelin; Glycemic Index; Humans; Insulin; Insulin Resistance; Leptin; Male | 2011 |
Improvements in vascular health by a low-fat diet, but not a high-fat diet, are mediated by changes in adipocyte biology.
Low-fat (LF) and high-fat (HF) weight loss diets improve brachial artery flow-mediated dilation (FMD) in obese individuals, although results are conflicting. Moreover, the role that adipose tissue plays in mediating these diet-related effects are unknown.. This study examined how modulations in FMD by HF and LF diets relate to changes in adipocyte parameters.. Obese subjects (n = 17) were randomized to a HF diet (60% kcal as fat) or a LF diet (25% kcal as fat) for 6 weeks. Both groups were restricted by 25% of energy needs.. Body weight decreased (P <0.05) in both groups (HF: -6.6 ± 0.5 kg, LF: -4.7 ± 0.6 kg). Fat mass and waist circumference were reduced (P <0.05) in the LF group only (-4.4 ± 0.3 kg; -3.6 ± 0.8 cm, respectively). FMD improved (P <0.05) in the LF group (7.4 ± 0.8% to 9.8 ± 0.8; 32% increase) and was impaired in the HF group (8.5 ± 0.6% to 6.9 ± 0.7; 19% reduction). Increases in plasma adiponectin (P <0.05, 16 ± 5%), and decreases in resistin (P <0.05, -26 ± 11%), were shown by the LF diet only. Greater decreases in leptin were observed with LF (-48 ± 9%) versus HF (-28 ± 12%) (P <0.05, diet × time). Increased FMD by the LF diet was associated with increased adiponectin, and decreased fat mass, waist circumference, leptin, and resistin.. Beneficial modulations in vascular health by LF diets may be mediated by improvements in adipocyte parameters. Topics: Adipocytes; Adiponectin; Adipose Tissue; Adult; Analysis of Variance; Body Composition; Body Weight; Cardiovascular Diseases; Diet, Fat-Restricted; Dietary Fats; Female; Humans; Leptin; Male; Obesity; Random Allocation; Risk Factors; Weight Loss | 2011 |
Leptin treatment reduces body fat but does not affect lean body mass or the myostatin-follistatin-activin axis in lean hypoleptinemic women.
Animal studies in vivo indicate that leptin treatment in extremely leptin-sensitive ob/ob mice reduces body weight exclusively by reducing fat mass and that it increases muscle mass by downregulating myostatin expression. Data from human trials are limited. Therefore, we aimed at characterizing the effects of leptin administration on fat mass, lean body mass, and circulating regulators of muscle growth in hypoleptinemic and presumably leptin-sensitive human subjects. In an open-label, single-arm trial, seven lean, strenuously exercising, amenorrheic women with low leptin concentrations (≤5 ng/ml) were given recombinant methionyl human leptin (metreleptin; 0.08 mg·kg(-1)·day(-1)) for 10 wk. In a separate randomized, double-blind, placebo-controlled trial, seven women were given metreleptin (initial dose: 0.08 mg·kg(-1)·day(-1) for 3 mo, increased thereafter to 0.12 mg·kg(-1)·day(-1) if menstruation did not occur), and six were given placebo for 9 mo. Metreleptin significantly reduced total body fat by an average of 18.6% after 10 wk (P < 0.001) in the single-arm trial and by 19.5% after 9 mo (placebo subtracted; P for interaction = 0.025, P for metreleptin = 0.004) in the placebo-controlled trial. There were no significant changes in lean body mass (P ≥ 0.33) or in serum concentrations of myostatin (P ≥ 0.35), follistatin (P ≥ 0.30), and activin A (P ≥ 0.20) whether in the 10-wk trial or the 9-mo trial. We conclude that metreleptin administration in lean hypoleptinemic women reduces fat mass exclusively and does not affect lean body mass or the myostatin-follistatin-activin axis. Topics: Activins; Adipose Tissue; Adult; Body Composition; Body Weight; Double-Blind Method; Down-Regulation; Female; Follistatin; Humans; Leptin; Metabolic Diseases; Myostatin; Placebos; Signal Transduction; Thinness; Young Adult | 2011 |
Leptin is better than any other biological parameter for monitoring the efficacy of renutrition in hospitalized malnourished elderly patients.
Despite malnutrition being a major problem in hospitalized elderly patients, there is a lack of studies focusing on the comparative value of biological parameters for monitoring renutrition. The aim of this study was to determine which biological parameter(s) could best monitor successful renutrition in hospitalized malnourished elderly patients.. The objective of the study was to explore the impact of a 6-week renutrition process on anthropometric and biological parameters in elderly patients and to define the biological parameters associated with weight regain.. A total of 72 hospitalized malnourished elderly patients admitted to a hospital-based geriatric rehabilitation unit.. Patients were evaluated at admission and at 6 weeks for anthropometric measurements of weight, sum of the four subcutaneous skinfold thicknesses, calf circumference and biological serum parameters including albumin, transthyretin, leptin, IGF-1, IGFBP-1 and IGFBP-3. Renutrition was considered successful if a patient gained at least 5% of body weight over 6 weeks.. Leptin was the only biological parameter that increased at 6 weeks in successful renutrition. Leptin variations were not influenced by C-reactive protein variations, in contrast to transthyretin which can be modified by the inflammatory states frequently encountered in geriatric patients.. Serum leptin is a more appropriate parameter than transthyretin for monitoring renutrition. Topics: Aged, 80 and over; Biomarkers; Body Weight; Female; Food; Geriatric Assessment; Hospitalization; Humans; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Malnutrition; Monitoring, Physiologic; Nutrition Assessment; Nutritional Status; Prealbumin; Serum Albumin; Skinfold Thickness; Time Factors; Treatment Outcome | 2011 |
[Low doses of megestrol acetate increase weight and improve nutrition status in patients with severe chronic obstructive pulmonary disease and weight loss].
Weight loss in patients with severe chronic obstructive pulmonary disease (COPD) is a prognostic bad factor. The objective of this study is to analyze the effectively of megestrol acetate (MA) to increase appetite of these patients.. Randomized double blind placebo controlled trial to study the effect of 160 mg/bid of MA, for 8 weeks, on nutritional, functional, analytical and quality of life parameters, in 38 patients with severe COPD and body mass index (BMI) < 21 kg/m(2), or between 21-25 with involuntary weight loss of 5% in the last 3 months.. At 8 weeks, in the MA group the body weight increased (2.3 kg) with respect to the control group (0.1 kg) (p<0.04). MA improved significantly the triceps skin-fold thickness (p < 0.04), prealbumin (p<0.004), lymphocytes (p<0.0006), C3 (p<0.04), PCO(2) (p<0.007) and bicarbonate levels (p<0.008). MA did not increase the MRC and SGRQ scales, the distance of 6 MWT nor BODE index. The IL-6 and TNF alpha levels were not modified in the MA group, but leptin did increase (p<0.043). MA improved the sense of wellbeing (p<0.02) and the appetite (p<0.008), compared to the control group. Adverse effects were similar in both groups.. MA safely increases the body weight and the appetite in severe COPD patients with weight loss. MA improves blood gases and nutritional parameters and the sense of wellbeing, but it does not improve the respiratory muscular function or exercise tolerance. Topics: Adult; Aged; Aged, 80 and over; Appetite; Appetite Stimulants; Bicarbonates; Body Weight; Cachexia; Double-Blind Method; Female; Humans; Hydrocortisone; Interleukin-6; Leptin; Male; Megestrol Acetate; Middle Aged; Nutritional Status; Prealbumin; Pulmonary Disease, Chronic Obstructive; Quality of Life; Skinfold Thickness; Testosterone; Tumor Necrosis Factor-alpha | 2011 |
Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance.
Metreleptin has been efficacious in improving metabolic control in patients with lipodystrophy, but its efficacy has not been tested in obese patients with type 2 diabetes.. We studied the role of leptin in regulating the endocrine adaptation to long-term caloric deprivation and weight loss in obese diabetic subjects over 16 weeks in the context of a double-blinded, placebo-controlled, randomized trial. We then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro.. In obese patients with diabetes, metreleptin administration for 16 weeks did not alter body weight or circulating inflammatory markers but reduced HbA(1c) marginally (8.01 ± 0.93-7.96 ± 1.12, P = 0.03). Total leptin, leptin-binding protein, and antileptin antibody levels increased, limiting free leptin availability and resulting in circulating free leptin levels of ∼50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at ∼50 ng/mL, with no major differences in timing or magnitude of leptin-activated STAT3 phosphorylation in tissues from male versus female or obese versus lean humans in vivo, ex vivo, or in vitro. We also observed for the first time that endoplasmic reticulum (ER) stress in human primary adipocytes inhibits leptin signaling.. In obese patients with diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA(1c) marginally. ER stress and the saturable nature of leptin signaling pathways play a key role in the development of leptin tolerance in obese patients with diabetes. Topics: Adipocytes; Adult; Blotting, Western; Body Weight; Cells, Cultured; Diabetes Mellitus, Type 2; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Humans; Immunohistochemistry; Leptin; Male; Middle Aged; Obesity; Phosphorylation; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor | 2011 |
Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women.
Strenuously exercising young women with hypothalamic amenorrhea are hypoleptinemic and have low bone mineral density (BMD) and content (BMC), which predispose them to increased fracture risk. Short-term leptin replacement in these women corrects many neuroendocrine abnormalities and increases circulating levels of bone formation markers. Whether treatment with recombinant methionyl human leptin (metreleptin) for a long period improves BMD and BMC remains unknown. We studied 20 strenuously exercising young women with hypoleptinemia (leptin concentration <5 ng/mL) and hypothalamic amenorrhea of at least 6 months' duration. Eleven were randomized to metreleptin (initial dose, 0.08 mg/[kg·d] for 3 months; altered thereafter to 0.12 mg/kg for lack of efficacy or 0.04 mg/[kg d] for more than 5% weight loss) and 9 were randomized to placebo for 9 months. After a 3-month washout period, subjects were reexamined at the 1-year time point. Six subjects elected to continue on open-label metreleptin treatment for another 12 months. Two subjects dropped out after 18 months, and 4 completed the entire 2-year study. The BMD and BMC of the total body, lumbar spine (L1-L4), hip, and radius were assessed by using dual-energy x-ray absorptiometry at baseline and at 3, 6, 9, 12, 18, and 24 months of treatment. Metabolic and hormonal parameters and bone markers were measured in blood and urine. Metreleptin significantly increased BMC (P = .034) and tended to increase BMD (P = .069) at the lumbar spine at 9 months in the entire study group (intention-to-treat analysis). In subjects who completed the entire 2-year study (n = 4), metreleptin significantly increased BMD (P = .024) and BMC (P = .049) at the lumbar spine by 4% to 6%. Changes were not significant at the whole body, hip, and radius. Changes in hormonal and metabolic parameters and bone markers were moderate during the first year of treatment, but metreleptin further increased insulin-like growth factor 1 and decreased cortisol and cross-linked C-terminal telopeptide of type 1 collagen concentrations in serum during the second year of treatment (P < .05). The incremental area under the estradiol concentration curve over the 2-year course of the study correlated positively with the corresponding increase in lumbar spine BMD (ρ = 0.42, P = .039). Long-term metreleptin administration in strenuously exercising young women with hypothalamic amenorrhea and hypoleptinemia increases lumbar spine BMD and BMC and alters bone rem Topics: Adult; Body Composition; Body Weight; Bone Density; Bone Remodeling; Exercise; Female; Humans; Insulin-Like Growth Factor I; Leptin; Lumbar Vertebrae | 2011 |
Preadipocyte factor-1 levels are higher in women with hypothalamic amenorrhea and are associated with bone mineral content and bone mineral density through a mechanism independent of leptin.
Preadipocyte factor 1 (pref-1) is increased in anorexia nervosa and is associated negatively with bone mineral density (BMD). No previous studies exist on pref-1 in women with exercise-induced hypothalamic amenorrhea (HA), which similar to anorexia nervosa, is an energy-deficiency state associated with hypoleptinemia.. Our objective was to evaluate whether pref-1 levels are also elevated and associated with low BMD and to assess whether leptin regulates pref-1 levels in women with HA.. Study 1 was a double-blinded, placebo-controlled randomized clinical trial of metreleptin administration in women with HA. Study 2 was an open-label study of metreleptin administration in low physiological, supraphysiological, and pharmacological doses in healthy women volunteers.. At Beth Israel Deaconess Medical Center, 20 women with HA and leptin levels higher than 5 ng/ml and nine healthy control women participated in study 1, and five healthy women participated in study 2.. For study 1, 20 HA subjects were randomized to receive either 0.08 mg/kg metreleptin (n = 11) or placebo (n = 9). For study 2, five healthy subjects received 0.01, 0.1, and 0.3 mg/kg metreleptin in both fed and fasting conditions for 1 and 3 d, respectively.. Circulating pref-1 and leptin levels were measured.. Pref-1 was significantly higher in HA subjects vs. controls (P = 0.035) and negatively associated with BMD (ρ = -0.38; P < 0.01) and bone mineral content (ρ = -0.32; P < 0.05). Metreleptin administration did not alter pref-1 levels in any study reported herein.. Pref-1 is higher in HA subjects than controls. Metreleptin administration at low physiological, supraphysiological, and pharmacological doses does not affect pref-1 levels, suggesting that hypoleptinemia is not responsible for higher pref-1 levels and that leptin does not regulate pref-1. Topics: Adult; Amenorrhea; Body Composition; Body Mass Index; Body Weight; Bone Density; Calcium-Binding Proteins; Cross-Sectional Studies; Dose-Response Relationship, Drug; Double-Blind Method; Energy Metabolism; Estradiol; Exercise; Female; Humans; Hypothalamic Diseases; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Leptin; Membrane Proteins; Young Adult | 2011 |
Alterations in downstream mediators involved in central control of eating behavior in obese adolescents submitted to a multidisciplinary therapy.
The aim of this study was to verify the effects of a multidisciplinary therapy (24 weeks) on neurohormonal control of food intake, specifically in orexigenic (total ghrelin, agouti-related protein [AgRP], neuropeptide Y [NPY], and melanin-concentrating hormone) and anorexigenic factors (leptin, insulin, and alpha-melanocyte stimulating hormone [α-MSH]), in obese adolescents.. A total of 88 adolescents (38 boys and 50 girls), including 62 obese and 26 normal-weight, aged 15-19 years were recruited. Obese adolescents were submitted to a 24-week multidisciplinary therapy. AgRP, NPY, melanin-concentrating hormone, leptin, insulin, glucose, α-MSH, total ghrelin, and food intake were measured at three stages (at baseline, after 12 weeks, and after 24 weeks).. At baseline, obese adolescents showed hyperleptinemia (circulating leptin levels, which were, in boys and girls, 40 and 35 times higher than in normal-weight subjects, respectively). After 24 weeks, these values decreased in all obese patients. Our results showed no differences in ghrelin levels between obese and normal-weight adolescents, in both genders. However, obese boys reduced their plasma ghrelin concentration after 24 weeks of therapy (p < .05). The multidisciplinary therapy decreased NPY and AgRP values and increased α-MSH; simultaneously with these changes there was a decrease in total food intake after 24 weeks of therapy.. We can conclude that the multidisciplinary therapy was efficient to modulate neurohormonal control of food intake in obese adolescents. Topics: Adolescent; Adolescent Health Services; Agouti-Related Protein; alpha-MSH; Body Weight; Combined Modality Therapy; Diet, Reducing; Exercise; Feeding Behavior; Female; Ghrelin; Humans; Hypothalamic Hormones; Leptin; Male; Melanins; Neuropeptide Y; Obesity; Peptide Hormones; Pituitary Hormones; Weight Loss | 2011 |
A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers.
Atypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans.. A double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18-30 years old, BMI 18.5-25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged.. Olanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics.. ClinicalTrials.gov NCT00741026. Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cross-Over Studies; Double-Blind Method; Dyslipidemias; Fatty Acids, Nonesterified; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Leptin; Male; Olanzapine; Triglycerides; Young Adult | 2011 |
Short-term energy deprivation alters activin a and follistatin but not inhibin B levels of lean healthy women in a leptin-independent manner.
Leptin is a potent modulator of the hypothalamic-pituitary-gonadal axis mediating the effect of energy deprivation on several hypothalamic-pituitary-peripheral axes. Activin A, inhibin B, and follistatin (FST) also regulate the hypothalamic-pituitary-gonadal axis in humans. It remains unknown whether energy deprivation affects these hormone levels in a leptin-dependent or -independent manner.. We investigated 1) day-night variability patterns of activin, inhibin, and FST in the fed state, 2) whether their levels are affected by fasting, and 3) whether such an effect is mediated by leptin in physiological replacement or pharmacological doses.. We conducted two studies in healthy, eumenorrheic females, each comprising three separate admissions. In study 1, six women were maintained for 72 h 1) on isocaloric diet, 2) fasting while receiving placebo, or 3) fasting while receiving metreleptin in physiological replacement doses. In study 2, five women were administered physiological or pharmacological metreleptin doses (0.01, 0.1, or 0.3 mg/kg i.v. four times daily).. Neither activin A nor FST had a pulsatile or day-night variability pattern. Inhibin B levels were also nonpulsatile, but a trend toward a day-night pattern was noted. When compared with the fed state, inhibin B levels remained unchanged, whereas FST levels increased (P = 0.01) and activin A decreased (P = 0.01) in the fasting state. These changes were not corrected with metreleptin administered in replacement or pharmacological doses.. Short-term energy deprivation alters levels of activin A and FST, but these effects are not mediated by leptin. Topics: Activins; Adult; Body Weight; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follistatin; Food Deprivation; Humans; Inhibins; Leptin | 2011 |
Effects of nutritional cues on the duration of the winter anovulatory phase and on associated hormone levels in adult female Welsh pony horses (Equus caballus).
Mares have an annual reproductive rhythm, with a phase of inactivity in midwinter. The aim of this study was to determine the impact of food restriction on physiological and metabolic hallmarks of this rhythm.. Over three successive years, 3 groups of 10 mares were kept under natural photoperiod. A 'well-fed' group was fed to maintain the mares in good body condition; a 'restricted' group received a diet calculated to keep the mares thin and a 'variable' group was fed during some periods like the 'restricted' group and during some other periods like the 'well-fed' group, with the aim of mimicking the natural seasonal variation of pasture availability, but a few months in advance of this natural rhythm.. Winter ovarian inactivity always occurred and was long in the restricted group. In contrast, in the 'well-fed' group, 40% of mares showed this inactivity, which was shorter than in the other groups. Re-feeding the 'variable' group in autumn and winter did not advance the first ovulation in spring, compared with the 'restricted' group. Measurements of glucose and insulin concentrations in mares from the 'restricted' group during two 24 h periods of blood sampling, revealed no post-prandial peaks. For GH (Growth hormone), IGF-1 and leptin levels, large differences were found between the 'well-fed' group and the other groups. The glucose, insulin, GH and leptin levels but not melatonin level are highly correlated with the duration of ovulatory activity.. The annual rhythm driven by melatonin secretion is only responsible for the timing of the breeding season. The occurrence and length of winter ovarian inactivity is defined by metabolic hormones. Topics: Adiposity; Animals; Anovulation; Blood Glucose; Body Weight; Caloric Restriction; Circadian Rhythm; Female; France; Growth Hormone; Horses; Insulin; Insulin-Like Growth Factor I; Leptin; Melatonin; Ovulation; Photoperiod; Seasons; Subcutaneous Fat, Abdominal; Time Factors | 2011 |
Long-term persistence of hormonal adaptations to weight loss.
After weight loss, changes in the circulating levels of several peripheral hormones involved in the homeostatic regulation of body weight occur. Whether these changes are transient or persist over time may be important for an understanding of the reasons behind the high rate of weight regain after diet-induced weight loss.. We enrolled 50 overweight or obese patients without diabetes in a 10-week weight-loss program for which a very-low-energy diet was prescribed. At baseline (before weight loss), at 10 weeks (after program completion), and at 62 weeks, we examined circulating levels of leptin, ghrelin, peptide YY, gastric inhibitory polypeptide, glucagon-like peptide 1, amylin, pancreatic polypeptide, cholecystokinin, and insulin and subjective ratings of appetite.. Weight loss (mean [±SE], 13.5±0.5 kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin (P<0.001 for all comparisons), and amylin (P=0.002) and to increases in levels of ghrelin (P<0.001), gastric inhibitory polypeptide (P=0.004), and pancreatic polypeptide (P=0.008). There was also a significant increase in subjective appetite (P<0.001). One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin (P<0.001), peptide YY (P<0.001), cholecystokinin (P=0.04), insulin (P=0.01), ghrelin (P<0.001), gastric inhibitory polypeptide (P<0.001), and pancreatic polypeptide (P=0.002), as well as hunger (P<0.001).. One year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss do not revert to the levels recorded before weight loss. Long-term strategies to counteract this change may be needed to prevent obesity relapse. (Funded by the National Health and Medical Research Council and others; ClinicalTrials.gov number, NCT00870259.). Topics: Body Mass Index; Body Weight; Cholecystokinin; Diet, Reducing; Female; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Intention to Treat Analysis; Leptin; Male; Middle Aged; Obesity; Peptide YY; Peptides; Postmenopause; Weight Loss | 2011 |
Sex differences in the endocrine system in response to protein intake early in life.
Nutritional factors during a sensitive period can influence child development in a sex-related manner.. Our aim was to investigate whether sex modulates the responses of relevant biochemical parameters and growth to different protein intakes early in life.. In a randomized controlled trial, formula-fed infants were assigned to receive formula with higher protein (HP) or lower protein (LP) content. The main outcome measures were insulin-like growth factor (IGF)-1 axis parameters, weight, length, BMI, leptin, and C-peptide/creatinine ratio at 6 mo of age. Dietary intake during the first 6 mo of life was also assessed.. The IGF-1 axis response to HP feeding was modulated by sex. Total and free IGF-1 and IGF binding protein 3 concentrations were higher in girls than in boys. Compared with the LP diet, the HP diet was associated with higher IGF-1 and lower IGF binding protein 2 secretion. The response to this HP content formula tended to be stronger in girls than in boys. The HP diet was associated with a higher C-peptide/creatinine ratio. The leptin concentration was higher in girls than in boys and was correlated to the IGF-1 axis parameters. No interaction between sex and nutritional intervention was shown on growth.. Our findings show that the endocrine response to a high protein diet early in life may be modulated by sex. The IGF-1 axis of female infants shows a stronger response to the nutritional intervention than does that of male infants, but there is no enhanced effect on growth. This trial was registered at clinicaltrials.gov as NCT00338689. Topics: Body Height; Body Mass Index; Body Weight; Child Development; Creatinine; Dietary Proteins; Double-Blind Method; Endocrine System; Female; Humans; Infant; Infant Formula; Infant Nutritional Physiological Phenomena; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor I; Leptin; Male; Nutritional Status; Sex Factors | 2011 |
Effects of exercise program on appetite-regulating hormones, inflammatory mediators, lipid profiles, and body composition in healthy men.
Exercise can improve appetite, inflammatory mediators, lipid profiles, and body composition in overweight or obese patients. However, it has not yet been clearly elucidated how exercise affects healthy people in relation to these variables. Thus, we investigated the effects of an exercise program on appetite-regulating hormones, inflammatory mediators, lipid profiles, and body composition in healthy men.. Thirty sedentary men were recruited and randomly assigned to two groups (exercise group, EG, N.=15 and control group, CG, N.=15). Total plasma ghrelin, leptin, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were determined by radioimmunoassay and immunoassay. Total cholesterol (TC), triglyceride (TG), high- and low-density lipoprotein cholesterol (HDL-C and LDL-C) were determined by enzymatic assay. Body composition was determined by bioelectrical impedance analysis.. After 8 weeks, the ghrelin and leptin levels of CG showed a tendency to increase, whereas those of EG were significantly decreased. Although TNF-α and CRP, except for IL-6, showed a tendency to increase in CG, all three tended to decrease in EG after 8 weeks. TG and LDL-C were significantly increased in CG. The TC, TG, and LDL-C levels of EG were remarkably decreased, whereas HDL-C was significantly increased. In EG, body weight, fat mass, percent fat, and waist/hip ratio were significantly decreased, whereas muscle mass was significantly increased after 8 weeks.. The present study results have demonstrated the beneficial effects of an exercise program by altering appetite-regulating hormones, decreasing inflammatory factors, and improving lipid profiles and body composition in healthy young men. Topics: Adult; Body Composition; Body Weight; C-Reactive Protein; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Exercise; Ghrelin; Humans; Interleukin-6; Leptin; Lipids; Male; Physical Fitness; Sedentary Behavior; Triglycerides; Tumor Necrosis Factor-alpha; Young Adult | 2011 |
Effects of the regular consumption of wholemeal wheat foods on cardiovascular risk factors in healthy people.
The intake of wholemeal foods is consistently associated with reduced risk of type 2 diabetes and cardiovascular diseases in epidemiological studies, although the mechanisms of this association are unclear. Here we aim to compare in healthy subjects the metabolic effects of a diet rich in wholemeal wheat foods versus one based on the same products in refined form.. Fifteen healthy individuals (12 M/3 F), mean age 54.5+/-7.6 years, BMI 27.4+/-3.0 kg/m(2) (mean+/-SD), participated in a randomized sequential crossover study. After 2 weeks run-in, participants were randomly assigned to two isoenergetic diets with similar macronutrient composition, one rich in wholemeal wheat foods and the other with the same foods but in refined form (cereal fibre 23.1 vs. 9.8 g/day). After the two treatment periods (each lasting 3 weeks) plasma glucose and lipid metabolism, antioxidant activity, acetic acid, magnesium, adipokines, incretins and high-sensitivity C-reactive protein (hs-CRP) were measured at fasting and for 4h after a standard test meal (kcal 1103, protein 12%, CHO 53%, fat 35%) based on wholemeal or refined wheat foods, respectively. After the two diets there were no differences in fasting nor in postprandial plasma parameter responses; only glucose was slightly but significantly lower at 240 min after the refined wheat food meal compared to the wholemeal wheat food meal. Conversely, after the wholemeal diet both total (-4.3%; p<0.03) and LDL (-4.9%; p<0.04) cholesterol levels were lower than after the refined wheat diet at fasting.. Consumption of wholemeal wheat foods for 3 weeks reduces significantly fasting plasma cholesterol as well as LDL cholesterol levels in healthy individuals without major effects on glucose and insulin metabolism, antioxidant status and sub-clinical inflammation markers. Topics: Blood Glucose; Blood Pressure; Body Weight; C-Peptide; Cardiovascular Diseases; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Diet; Fasting; Female; Food Handling; Gastric Inhibitory Polypeptide; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Risk Factors; Triticum | 2010 |
Pubertal metformin therapy to reduce total, visceral, and hepatic adiposity.
Puberty is part of a critical window in which adiposity and its correlates can be fine-tuned toward reproduction, which implies that puberty provides an opportunity to reprogram a misprogramming that occurred in early life. We tested this hypothesis in low-birthweight (LBW) girls with precocious pubarche (PP), who are at risk for hyperinsulinemic body adiposity during and beyond puberty.. LBW girls with PP (n = 38; mean age 8 years) were randomized to remain untreated or to receive metformin across puberty (425 mg/d for 2 years, then 850 mg/d for 2 years); subsequently, all girls were monitored for 1 year without intervention. Here we report on the latter year.. The benefits of metformin were mostly maintained during the posttreatment year so that, after 5 years, metformin therapy was associated with more lean mass; with less total, visceral, and hepatic fat; with lower circulating levels of androgens and leptin; and with elevated levels of high-molecular-weight adiponectin and undercarboxylated osteocalcin.. In LBW girls with PP, pubertal metformin therapy was followed by a favorable adipokine profile and by a reduction of total, visceral, and hepatic adiposity beyond puberty. Topics: Adiposity; Adolescent; Body Weight; Child; Comorbidity; Female; Follow-Up Studies; Humans; Hyperinsulinism; Hypoglycemic Agents; Infant, Low Birth Weight; Infant, Newborn; Intra-Abdominal Fat; Leptin; Liver; Magnetic Resonance Imaging; Metformin; Puberty, Precocious | 2010 |
Improved appetite after multi-micronutrient supplementation for six months in HIV-infected South African children.
The aim of the study was to assess the effect of multi-micronutrient supplementation on the appetite of HIV-infected children. HIV-infected children (6-24 months) who had previously been hospitalized were enrolled into a double-blind randomized trial, and given daily multi-micronutrient supplements or placebos for six months. Appetite tests were performed at enrollment and after three and six months. Appetite was measured as ad libitum intake of a commercial cereal test food served after an overnight fast according to standardized procedures. Body weights and total amount of test food eaten were measured. In total, 99 children completed the study (50 on supplements and 49 on placebos). Amounts eaten per kilogram body weight in the supplement group at enrollment and after six months were 36.7+/-17.7 g/kg (mean+/-SD) and 41.3+/-15.0 g/kg respectively, while the amounts in the placebo group were 47.1+/-14.9 g/kg and 45.7+/-13.1g/kg respectively. The change in amount eaten per kilogram body weight over six months was significantly higher in the supplement group (4.7+/-14.7 g/kg) than in the placebo group (-1.4+/-15.1g/kg). Multi-micronutrient supplementation for six months seems to significantly improve the appetite of HIV-infected children. Topics: Analysis of Variance; Appetite; Biomarkers; Body Weight; Child Nutrition Disorders; Child Nutritional Physiological Phenomena; Child, Preschool; Dietary Supplements; Double-Blind Method; Edible Grain; Feeding Behavior; Female; Ferritins; Follow-Up Studies; Food, Fortified; HIV Infections; Humans; Infant; Insulin; Iron, Dietary; Leptin; Male; Micronutrients; South Africa; Zinc | 2010 |
Changes in circulating satiety hormones in obese children: a randomized controlled physical activity-based intervention study.
The aims of this study are to examine in children: (i) obesity-related alterations in satiety factors such as leptin, ghrelin, and obestatin; (ii) the link between satiety factors and cardiometabolic risk factors; and (iii) the impact of a physical activity-based lifestyle intervention on the levels of these satiety factors in the obese. We studied a total of 21 adolescents (BMI percentile, 99.0 +/- 0.6 for 15 obese and 56.2 +/- 1.1 for 6 lean). The obese subjects underwent a 3-month randomized controlled physical activity-based lifestyle intervention. Leptin, soluble leptin receptor (sOB-R), ghrelin, and obestatin levels were determined as the primary outcome measures. Other markers of cardiometabolic disease such as inflammation and insulin resistance were also determined. Body composition was measured by dual-energy X-ray absorptiometry. The concentrations of ghrelin, obestatin, and sOB-R were significantly lower in the obese children compared to the lean controls, whereas that of leptin was higher (all P < 0.05). Although intervention led to a net increase in obestatin (P < 0.01) and no change in ghrelin levels, the balance between ghrelin and obestatin (ratio of ghrelin to obestatin, G/O) decreased (P < 0.02). Intervention reduced leptin and increased sOB-R (P < 0.01 for both). Significant associations between satiety factors and other cardiometabolic risk factors were also observed. Taken together, alterations in the levels of satiety factors are evident early in the clinical course of obesity, but physical activity-based lifestyle intervention either prevented their continued increase or normalized their levels. These beneficial effects appear to aid in the maintenance of body weight and reduction in cardiovascular risk. Topics: Adolescent; Biomarkers; Body Weight; Cardiovascular Diseases; Exercise; Female; Ghrelin; Humans; Inflammation; Insulin Resistance; Leptin; Life Style; Male; Motor Activity; Obesity; Receptors, Leptin; Satiation | 2010 |
Hypobaric hypoxia causes body weight reduction in obese subjects.
The reason for weight loss at high altitudes is largely unknown. To date, studies have been unable to differentiate between weight loss due to hypobaric hypoxia and that related to increased physical exercise. The aim of our study was to examine the effect of hypobaric hypoxia on body weight at high altitude in obese subjects. We investigated 20 male obese subjects (age 55.7 +/- 4.1 years, BMI 33.7 +/- 1.0 kg/m(2)). Body weight, waist circumference, basal metabolic rate (BMR), nutrition protocols, and objective activity parameters as well as metabolic and cardiovascular parameters, blood gas analysis, leptin, and ghrelin were determined at low altitude (LA) (Munich 530 m, D1), at the beginning and at the end of a 1-week stay at high altitude (2,650 m, D7 and D14) and 4 weeks after returning to LA (D42). Although daily pace counting remained stable at high altitude, at D14 and D42, participants weighed significantly less and had higher BMRs than at D1. Food intake was decreased at D7. Basal leptin levels increased significantly at high altitude despite the reduction in body weight. Diastolic blood pressure was significantly lower at D7, D14, and D42 compared to D1. This study shows that obese subjects lose weight at high altitudes. This may be due to a higher metabolic rate and reduced food intake. Interestingly, leptin levels rise in high altitude despite reduced body weight. Hypobaric hypoxia seems to play a major role, although the physiological mechanisms remain unclear. Weight loss at high altitudes was associated with clinically relevant improvements in diastolic blood pressure. Topics: Altitude; Atmospheric Pressure; Basal Metabolism; Blood Pressure; Body Mass Index; Body Weight; Energy Intake; Exercise; Humans; Hypoxia; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Weight Loss | 2010 |
Effects of increasing dietary protein and fibre intake with lupin on body weight and composition and blood lipids in overweight men and women.
Lupin kernel flour (LKF) is a novel food ingredient that is high in protein and fibre. We have previously shown that partial substitution of refined wheat-derived carbohydrate in bread with protein and fibre from LKF can reduce appetite and energy intake acutely. In addition, several studies have suggested that lupin may reduce cholesterol concentrations and benefit glucose and insulin metabolism.. The aim of this study was to investigate the effects on body weight and composition and blood lipids, glucose and insulin of an ad libitum LKF-enriched diet higher in dietary protein and fibre.. A total of 88 overweight and obese men and women were recruited for a 16-week parallel-design randomized controlled trial. Participants replaced 15-20% of their usual daily energy intake with white bread (control) or LKF-enriched bread (lupin) in an ad libitum diet. Measurements of body weight and composition, and fasting blood biochemical measurements were performed at baseline and 16 weeks. The primary analysis included 74 participants (37 per group) who completed the intervention.. At baseline, mean (+/-s.d.) body mass index and total cholesterol were 30.6+/-3.5 kg m(-2) and 5.37+/-0.94 mmol l(-1), respectively. Estimated (mean between-group difference (95% confidence interval)) protein (13.7 (2.28, 25.0) g per day) and fibre (12.5 (8.79, 16.2) g per day) intakes were higher during the intervention with lupin than with control. For lupin relative to control, the net effects on body weight (-0.4 (-1.3, 0.6) kg), fat mass (-0.5 (-1.1, 0.2) kg) and percentage (-0.5 (-1.1, 0.1)%), plasma leptin (-1.66 (-4.91, 1.59) ng ml(-1)) and adiponectin (0.20 (-0.73, 1.13) mg l(-1), as well as serum total cholesterol (-0.08 (-0.38, 0.22) mmol l(-1)), triglycerides (0.09 (-0.10, 0.21) mmol l(-1)), glucose (0.10 (-0.11, 0.30) mmol l(-1)) and insulin (0.40 (-1.20, 2.00) mU l(-1)) were not significant.. This study does not support the proposal that an ad libitum diet enriched in LKF resulting in moderate changes in both protein and fibre intakes can benefit body weight and composition or fasting blood lipids, glucose and insulin concentrations in overweight men and women with mildly elevated total cholesterol concentrations. Topics: Adult; Aged; Blood Glucose; Body Mass Index; Body Weight; Bread; Diet; Dietary Carbohydrates; Dietary Fiber; Dietary Proteins; Energy Intake; Female; Humans; Leptin; Lipids; Lupinus; Male; Middle Aged; Overweight; Triglycerides | 2010 |
The use of LeptiCore in reducing fat gain and managing weight loss in patients with metabolic syndrome.
LeptiCore is a proprietary combination of various ingredients which have been shown to have properties which could be beneficial to weight loss in obese and overweight human subjects. This study evaluates the effect of Lepticore on bodyweight as well as parameters associated with obesity and metabolic syndrome.. The study was an 8 week randomized, double-blind, placebo-controlled design involving 92 obese (mean BMI > 30 kg/m2) participants (37 males; 55 females; ages 19-52; mean age = 30.7). The participants were randomly divided into three groups: placebo (n = 30), LeptiCore formula A (low dose) (n = 31) and LeptiCore formula B (high dose) (n = 31). Capsules containing the placebo or active formulations were administered twice daily before meals with 300 ml of water. None of the participants followed any specific diet nor took any weight-reducing medications for the duration of the study. A total of 12 anthropomorphic and serological measurements were taken at the beginning of the study and after 2, 4, 6, and 8 weeks of treatment.. Compared to the placebo group, the two active groups showed statistically significant differences on all 12 variables by week 8. These included four anthropomorphic variables (body weight, body fat, waist and hip size) and eight measures of serological levels (plasma total cholesterol, LDL, HDL, triglycerides, blood glucose, serotonin, leptin, C-reactive protein). The two active groups also showed significant intra-group differences on all 12 variables between study onset and week 8.. The LeptiCore formulation at both the low and high dosages appears to be helpful in the management of fat gain and its related complications. The higher dosage resulted in significantly greater reductions in body weight and triglyceride, blood glucose, and C-reactive protein levels, as well as increased serotonin levels. Topics: Adult; Anthropometry; Antioxidants; Body Weight; C-Reactive Protein; Double-Blind Method; Fatty Acids; Female; Humans; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Placebos; Polysaccharides | 2010 |
Risperidone associated weight, leptin, and anthropometric changes in children and adolescents with psychotic disorders in early treatment.
To document prospective weight and anthropometric changes in children and adolescents during the first 12 weeks of treatment with risperidone and evaluate metabolic outcomes including plasma leptin levels.. Eight patients with psychotic disorders (ages 11-17) who had started risperidone (mean: 1.80 mg/day; sd = 1.04) in the prior 4 weeks participated in this observational study. Fasting morning blood samples were obtained at baseline and week 8 to assess glucose, leptin, cortisol, insulin, and triglycerides. Measures of body mass index (BMI), weight, waist and hip circumference, blood pressure, and heart rate were obtained weekly.. Participants increased in mean weight (4.16 kg; sd = 4.36; p = 0.03) and BMI (1.47 kg/m(2); sd = 1.53; p = 0.03) with five out of eight gaining at least 7% of baseline body weight. They had a 4.03 cm (sd = 3.82; p = 0.02) increase in waist circumference and a 5.17 cm (sd = 3.68; p = 0.01) increase in hip circumference. Leptin trended higher, but did not reach statistical significance. There were no significant changes in glucose, insulin, cortisol, blood pressure, or heart rate.. Subjects experienced significant increases in weight, BMI, hip and waist circumference during the first 3 months of treatment. Better powered research with more advanced anthropometric assessment is warranted to further elucidate mechanisms of antipsychotic associated weight gain in youth. Topics: Adolescent; Anthropometry; Antidepressive Agents, Second-Generation; Body Mass Index; Body Size; Body Weight; Child; Day Care, Medical; Diagnostic and Statistical Manual of Mental Disorders; Female; Hip; Humans; Insulin Resistance; Leptin; Male; Pilot Projects; Psychotic Disorders; Risperidone; Waist Circumference; Weight Gain | 2010 |
Metabolic outcome of GH treatment in prepubertal short children with and without classical GH deficiency.
Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic short stature (ISS). Moreover, children with ISS appear to need higher GH doses than children with GH deficiency (GHD) to achieve the same amount of growth and may therefore be at increased risk of adverse events during treatment. The individualized approach using prediction models for estimation of GH responsiveness, on the other hand, has the advantage of narrowing the range of growth response, avoiding too low or high GH doses.. Short prepubertal children with either isolated GHD (39) or ISS (89) participated in a 2-year randomized trial of either individualized GH treatment with six different GH doses (range, 17-100 microg/kg/day) or a standard dose (43 microg/kg/day).. To evaluate if individualized GH treatment reduced the variance of the metabolic measures as shown for growth response and to compare changes in metabolic variables in children with ISS and GHD.. Individualized GH dose reduces the range of metabolic outcomes, and metabolic outcomes are similar in children with ISS and GHD.. We observed a narrower variation for fasting insulin (-34.2%) and for homoeostasis model assessment (HOMA) (-38.9%) after 2 years of individualized GH treatment in comparison with standard GH dose treatment. Similar metabolic changes were seen in ISS and GHD. Delta (Delta) height SDS correlated with Deltainsulin-like growth factor I (IGF-I), Deltaleptin and Deltabody composition. Principal component analysis identified an anabolic and a lipolytic component. Anabolic variables [Deltalean body mass (LBM) SDS and DeltaIGF-I SDS] clustered together and correlated strongly with Deltaheight SDS and GH dose, whereas lipolytic variables [Deltafat mass (FM) SDS and Deltaleptin] were clustered separately from anabolic variables. Regression analysis showed GH dose dependency in ISS, and to a lesser degree in GHD, for DeltaLBM SDS and Deltaheight SDS, but not for changes in FM.. Individualized GH dosing during catch-up growth reduces the variance in insulin and HOMA and results in equal metabolic responses irrespective of the diagnosis of GHD or ISS. Topics: Adiponectin; Analysis of Variance; Body Composition; Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Dwarfism, Pituitary; Female; Growth Disorders; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Principal Component Analysis; Prospective Studies; Time Factors; Treatment Outcome | 2010 |
Comparison of orlistat treatment and placebo in obese type 2 diabetic patients.
To evaluate the effects of 1-year treatment with orlistat compared with placebo on different inflammatory parameters in type 2 obese diabetic patients.. Two hundred and fifty-four type 2 diabetic patients were randomized to take orlistat 120 mg three times a day or placebo for 12 months. We evaluated at baseline and after 3, 6, 9 and 12 months: leptin, tumor necrosis factor (TNF)-alpha, adiponectin (ADN), vaspin and high-sensitivity C-reactive protein (HS-CRP), body weight, waist circumference, body mass index (BMI), lipid profile, glycemic profile, fasting plasma insulin (FPI) and homeostasis model assessment insulin resistance index (HOMA-IR).. Regarding inflammatory parameters, there was a significant improvement of ADN and TNF-alpha, and a faster decrease of leptin and HS-CRP in the orlistat group compared with the control group. We also recorded a significant reduction of body weight and BMI with orlistat, but not with placebo. A faster improvement of glycemic profile and FPI was obtained with orlistat compared with the controls. Also, there was a significant reduction of lipid profile with orlistat, not reached with placebo.. Orlistat was more effective than placebo in ameliorating inflammatory parameters such as ADN and TNF-alpha, and anthropometric parameters. Topics: Adiponectin; Anti-Obesity Agents; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Inflammation Mediators; Insulin; Insulin Resistance; Italy; Lactones; Leptin; Lipids; Male; Middle Aged; Obesity; Orlistat; Placebo Effect; Serpins; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Waist Circumference | 2010 |
[Effects of acupuncture combined with dietary adjustments and aerobic exercise on body weight, body mass index and serum leptin level in simple obesity patients].
To observe the effect of acupuncture combined with dietary adjustments and aerobic exercise on the body weight, body mass index (BMI) and serum leptin content of patients with simple obesity, so as to evaluate the efficacy of the present therapy in the treatment of simple obesity.. A total of 61 cases of out-patients were randomly divided into control (n=30) and treatment (n=31) groups. Patients in the control group were treated with dietary adjustments and aerobic exercise everyday (30 min/d), continuously for 51 days, and those of the treatment group were treated with acupuncture [Zhong-wan (CV 12), Tianshu (ST 25), Guanyuan (CV 4), etc.] plus dietary adjustment and aerobic exercise everyday, with 15 days being a course of treatment, 3 days' interval between every two courses, and 3 courses altogether. Serum leptin content was detected by using radioimmunoassay.. Compared with pre-treatment, the body weight and BMI and serum leptin levels in the control and treatment groups were all decreased significantly (P < 0.01). Comparison between the two groups showed that the body weight at the end of the 1st and 3rd course of treatment, the BMI at the end of the 1st, 2nd and 3rd course of treatment, and serum leptin level after the treatment in the treatment group were all significantly lower than those in the control group (P < 0.05, P < 0.01). The difference values of body weight and BMI between pre-treatment and post-treatment of the treatment group were obviously higher than those of the control group (P < 0.01), suggesting a better therapeutic effect of acupuncture combined with dietary adjustments and aerobic exercise in the treatment of simple obesity.. Acupuncture combined with dietary adjustments and aerobic exercise can reduce the body weight, BMI and serum leptin level, which is better than dietary adjustments plus aerobic exercise. Topics: Acupuncture Therapy; Adolescent; Adult; Body Mass Index; Body Weight; Combined Modality Therapy; Exercise; Exercise Therapy; Female; Humans; Leptin; Male; Middle Aged; Obesity; Young Adult | 2010 |
Effect of valproic acid on body weight, food intake, physical activity and hormones: results of a randomized controlled trial.
The objective of this study was to identify mechanisms through which valproic acid (VPA) causes weight gain. Healthy participants (N = 52) were randomized to VPA or placebo in a double-blind study. Energy intake (EI) was measured in the laboratory at lunch and dinner, and physical activity (PA) was measured with accelerometry. Glucose levels and hormones [Peptide YY(3-36), glucagon-like peptide-1 (GLP-1), leptin, ghrelin, insulin] that regulate EI were measured. Assessments occurred at baseline and week 3. Change from baseline was evaluated with mixed models (alpha = 0.05). Weight significantly increased in the VPA group (+0.49 kg), but not the placebo group. The VPA group increased fast food fats cravings and decreased glucose levels compared with placebo. Change in weight, EI and PA did not differ by group. Within group analyses indicated that the VPA group increased PA, hunger, binge eating, depression and GLP-1. VPA-associated weight gain is not likely due to changes in PA or the gut hormones studied. Although EI did not increase when measured after 3 weeks of treatment, VPA decreased glucose levels and increased motivation to eat; hence, EI might have increased in the short-term. Research testing VPA on short-term (1 week) EI, metabolism, and substrate partitioning is warranted. Topics: Adolescent; Adult; Anticonvulsants; Attitude; Blood Glucose; Body Weight; Creatinine; Delayed-Action Preparations; Eating; Feeding Behavior; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Leptin; Lipids; Male; Middle Aged; Motor Activity; Patient Compliance; Peptide Fragments; Peptide YY; Serum Albumin; Valproic Acid | 2009 |
Antiandrogenic contraceptives increase serum adiponectin in obese polycystic ovary syndrome patients.
Increasing evidence suggests that adipocyte function is altered in the polycystic ovary syndrome (PCOS) as a result of androgen excess, providing an explanation for its frequent association with abdominal adiposity and insulin resistance. We here compared the response of serum adiponectin and leptin levels to the amelioration of androgen excess by means of treatment with an antiandrogenic oral contraceptive pill, as compared with the response to insulin sensitization with metformin. Thirty-four women presenting with PCOS were randomized to treatment with an oral contraceptive containing 35 microg ethinyl-estradiol plus 2 mg cyproterone acetate (Diane(35) Diario) or with metformin (850 mg twice daily). Serum adiponectin and leptin levels were evaluated at baseline and after 12 and 24 weeks of treatment. In obese PCOS women, treatment with Diane(35) Diario resulted in an increase in serum adiponectin levels and in the adiponectin/leptin ratio, in parallel with a marked decrease in serum androgen concentrations, whereas no statistically significant changes were observed during treatment with metformin. On the contrary, leptin concentrations did not show any statistically significant change during the study with any of the drugs studied here. In summary, our present results might suggest a direct inhibitory effect of androgen excess on adiponectin secretion by adipocytes in obese PCOS women, supporting the hypothesis that androgen excess contributes to adipocyte dysfunction in these women. Topics: Adipocytes; Adiponectin; Adipose Tissue; Adult; Androgen Antagonists; Area Under Curve; Body Weight; Contraceptives, Oral; Dehydroepiandrosterone Sulfate; Female; Humans; Insulin; Leptin; Metformin; Obesity; Polycystic Ovary Syndrome; Testosterone; Young Adult | 2009 |
Sleep curtailment is accompanied by increased intake of calories from snacks.
Short sleep is associated with obesity and may alter the endocrine regulation of hunger and appetite.. We tested the hypothesis that the curtailment of human sleep could promote excessive energy intake.. Eleven healthy volunteers [5 women, 6 men; mean +/- SD age: 39 +/- 5 y; mean +/- SD body mass index (in kg/m(2)): 26.5 +/- 1.5] completed in random order two 14-d stays in a sleep laboratory with ad libitum access to palatable food and 5.5-h or 8.5-h bedtimes. The primary endpoints were calories from meals and snacks consumed during each bedtime condition. Additional measures included total energy expenditure and 24-h profiles of serum leptin and ghrelin.. Sleep was reduced by 122 +/- 25 min per night during the 5.5-h bedtime condition. Although meal intake remained similar (P = 0.51), sleep restriction was accompanied by increased consumption of calories from snacks (1087 +/- 541 compared with 866 +/- 365 kcal/d; P = 0.026), with higher carbohydrate content (65% compared with 61%; P = 0.04), particularly during the period from 1900 to 0700. These changes were not associated with a significant increase in energy expenditure (2526 +/- 537 and 2390 +/- 369 kcal/d during the 5.5-h and 8.5-h bedtime periods, respectively; P = 0.58), and we found no significant differences in serum leptin and ghrelin between the 2 sleep conditions.. Recurrent bedtime restriction can modify the amount, composition, and distribution of human food intake, and sleeping short hours in an obesity-promoting environment may facilitate the excessive consumption of energy from snacks but not meals. Topics: Adult; Appetite; Body Composition; Body Weight; Cross-Over Studies; Eating; Energy Intake; Energy Metabolism; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Obesity; Sleep Deprivation | 2009 |
Consumption of medium- and long-chain triacylglycerols decreases body fat and blood triglyceride in Chinese hypertriglyceridemic subjects.
To investigate the effects of medium- and long-chain triacylglycerol (MLCT) on blood triglyceride (TG) in Chinese hypertriglyceridemic subjects.. A double-blind controlled clinical trial was carried out, in which 112 subjects with hypertriglyceridemia were randomly divided into two dietary oil groups: (1) long-chain triacylglycerol (LCT) and (2) MLCT. All subjects were requested to ingest fixed energy and to continue their normal activity levels, and to consume LCT or MLCT oil at 25-30 g daily during the study period. Anthropometric measurements of body weight, body mass index (BMI), body fat, body fat percentage, waist and hip circumference (WC and HC), areas of subcutaneous and visceral fat by computed tomography scanning and blood biochemical markers were measured at the beginning and end of the study.. There were 50 and 51 subjects left in LCT and MLCT groups, respectively. There were no significant differences in daily intake of energy, protein, fat and carbohydrate, as well as the daily physical activity between the two groups during the study. After 8 weeks, MLCT group showed a significant decrease in body weight, BMI, WC, HC, ratio of WC and HC, body fat, body fat percentage and subcutaneous fat when compared with the initial values. The decrease in body weight, BMI, WC, body fat and subcutaneous and visceral fat was significantly greater in MLCT group than that in the LCT group. Furthermore, the serum concentrations of TG in MLCT group were significantly lower than those in the LCT group.. Consumption of MLCT may reduce body weight, body fat and blood TG in hypertriglyceridemic subjects under an appropriate dietary regime. Topics: Abdominal Fat; Adiponectin; Biomarkers; Body Weight; Caprylates; China; Decanoates; Diet; Dietary Fats, Unsaturated; Double-Blind Method; Fatty Acids; Humans; Hypertriglyceridemia; Leptin; Lipids; Physical Exertion; Subcutaneous Fat; Tomography, X-Ray Computed; Triglycerides | 2009 |
Green tea catechin plus caffeine supplementation to a high-protein diet has no additional effect on body weight maintenance after weight loss.
Green tea (epigallocatechin gallate + caffeine) and protein each were shown to improve body weight maintenance after weight loss.. We investigated the effect of a green tea-caffeine mixture added to a high-protein (HP) diet on weight maintenance (WM) after body weight loss in moderately obese subjects.. A randomized, placebo-controlled, double-blind parallel trial was conducted in 80 overweight and moderately obese subjects [age (mean +/- SD): 44 +/- 2 y; body mass index (BMI; in kg/m(2)): 29.6 +/- 2.0] matched for sex, age, BMI, height, body mass, and with a habitually low caffeine intake. A very-low-energy diet intervention during 4 wk was followed by 3 mo of WM; during the WM period, the subjects received a green tea-caffeine mixture (270 mg epigallocatechin gallate + 150 mg caffeine/d) or placebo, both in addition to an adequate protein (AP) diet (50-60 g protein/d) or an HP diet (100-120 g protein/d).. Subjects lost 7.0 +/- 1.6 kg, or 8.2 +/- 2.0%, body weight (P < 0.001). During the WM phase, WM, resting energy expenditure, and fat-free mass (FFM) increased relatively in both the HP groups and in the AP + green tea-caffeine mixture group (P < 0.05), whereas respiratory quotient and body fat mass decreased, all compared with the AP + placebo group. Satiety increased only in both HP groups (P < 0.05). The green tea-caffeine mixture was only effective with the AP diet.. The green tea-caffeine mixture, as well as the HP diet, improved WM independently through thermogenesis, fat oxidation, sparing FFM, and, for the HP diet, satiety; a possible synergistic effect failed to appear. Topics: Adolescent; Adult; Appetite; Blood Glucose; Body Composition; Body Weight; Caffeine; Catechin; Dietary Proteins; Fatty Acids, Nonesterified; Female; Glycerol; Humans; Insulin; Leptin; Male; Middle Aged; Tea; Thermogenesis; Triglycerides; Weight Loss; Young Adult | 2009 |
Hypercaloric diets differing in fat composition have similar effects on serum leptin and weight gain in female subjects with anorexia nervosa.
Weight regain in subjects with anorexia nervosa is associated with an increase in serum leptin concentrations that is hypothesized to impair full weight restoration. As diets rich in n-3 polyunsaturated fatty acids (PUFA) have been described to lower serum leptin concentrations, we tested the hypothesis that consumption of a hypercaloric diet rich in n-3 PUFA is associated with an attenuated increase in serum leptin and a higher efficiency of body weight gain in subjects with anorexia nervosa. Twenty-five female subjects with anorexia nervosa were enrolled into this controlled dietary intervention study. Four subjects discontinued therapy or participation in the study prematurely, and six were excluded. 15 subjects completed the study. Subjects consumed hypercaloric diets rich in either saturated fatty acids (SFA, n = 8) or n-3 PUFA (n = 7) for 5 weeks. Primary endpoints were the change in serum leptin concentrations and body weight gain relative to energy consumed. Serum leptin concentrations increased distinctly throughout the study (P < .001), and to a similar extend in both groups [+2.9 (SD 2.4) vs. +2.8 (SD 3.4) ng/mL in the SFA- and n-3 PUFA group, respectively; P = .487]. The efficiency of body weight gain also did not differ significantly between groups, with a body weight gain of 63.1 (SD 12.4) vs. 79.2 (SD 26.0) g per 4.2 MJ (1000 kcal) consumed in the SFA- and n-3 PUFA group, respectively (P = .132). Hypercaloric diets rich in either SFA or n-3 PUFA do not differ in their effects on serum leptin concentrations and the efficiency of body weight gain in female subjects with anorexia nervosa. Topics: Adolescent; Adult; Anorexia Nervosa; Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diet; Dietary Fats; Energy Intake; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; Ghrelin; Humans; Insulin; Leptin; Middle Aged; Triglycerides; Weight Gain; Young Adult | 2009 |
IGOB131, a novel seed extract of the West African plant Irvingia gabonensis, significantly reduces body weight and improves metabolic parameters in overweight humans in a randomized double-blind placebo controlled investigation.
A recent in vitro study indicates that IGOB131, a novel seed extract of the traditional West African food plant Irvingia gabonensis, favorably impacts adipogenesis through a variety of critical metabolic pathways including PPAR gamma, leptin, adiponectin, and glycerol-3 phosphate dehydrogenase. This study was therefore aimed at evaluating the effects of IGOB131, an extract of Irvingia gabonensis, on body weight and associated metabolic parameters in overweight human volunteers.. The study participants comprised of 102 healthy, overweight and/or obese volunteers (defined as BMI > 25 kg/m2) randomly divided into two groups. The groups received on a daily basis, either 150 mg of IGOB131 or matching placebo in a double blinded fashion, 30-60 minutes before lunch and dinner. At baseline, 4, 8 and 10 weeks of the study, subjects were evaluated for changes in anthropometrics and metabolic parameters to include fasting lipids, blood glucose, C-reactive protein, adiponectin, and leptin.. Significant improvements in body weight, body fat, and waist circumference as well as plasma total cholesterol, LDL cholesterol, blood glucose, C-reactive protein, adiponectin and leptin levels were observed in the IGOB131 group compared with the placebo group.. Irvingia gabonensis administered 150 mg twice daily before meals to overweight and/or obese human volunteers favorably impacts body weight and a variety of parameters characteristic of the metabolic syndrome. This is the first double blind randomized placebo controlled clinical trial regarding the anti-obesity and lipid profile modulating effects of an Irvingia gabonensis extract. The positive clinical results, together with our previously published mechanisms of gene expression modulation related to key metabolic pathways in lipid metabolism, provide impetus for much larger clinical studies. Irvingia gabonensis extract may prove to be a useful tool in dealing with the emerging global epidemics of obesity, hyperlipidemia, insulin resistance, and their co-morbid conditions. Topics: Adiponectin; Adult; Africa, Western; Anti-Obesity Agents; Blood Glucose; Body Weight; Cellulose; Cholesterol; Double-Blind Method; Fasting; Feeding Behavior; Female; Humans; Leptin; Male; Middle Aged; Overweight; Phytotherapy; Placebos; Plant Extracts; Seeds; Waist Circumference | 2009 |
Carbohydrate restriction (with or without additional dietary cholesterol provided by eggs) reduces insulin resistance and plasma leptin without modifying appetite hormones in adult men.
Carbohydrate-restricted diets (CRDs) have been shown to reduce body weight, whereas whole egg intake has been associated with increased satiety. The purpose of this study was to evaluate the effects of additional dietary cholesterol and protein provided by whole eggs while following a CRD on insulin resistance and appetite hormones. Using a randomized blind parallel design, subjects were allocated to an egg (640 mg/d additional dietary cholesterol) or placebo (0 mg/d additional dietary cholesterol) group for 12 weeks while following a CRD. There were significant reductions in fasting insulin (P < .025) and fasting leptin concentrations (P < .01) for both groups, which were correlated with the reductions in body weight and body fat (P < .05 and P < .01, respectively). Both groups reduced insulin resistance as measured by the homeostatic model assessment of insulin resistance (P < .025). There was a significant decrease in serum glucose levels observed after the intervention. We did not observe the expected increases in plasma ghrelin levels associated with weight loss, suggesting a mechanism by which subjects do not increase appetite with CRD. To confirm these results, the subjective measures of satiety using visual analog scale showed that both groups felt more "full" (P < .05), "satisfied" (P < .001), and "wanted to eat less" (P < .001) after the intervention. These results indicate that inclusion of eggs in the diet (additional dietary cholesterol) did not modify the multiple beneficial effects of CRD on insulin resistance and appetite hormones. Topics: Adult; Aged; Analysis of Variance; Appetite; Blood Glucose; Body Composition; Body Weight; Cholesterol, Dietary; Diet, Carbohydrate-Restricted; Diet, Reducing; Dietary Proteins; Eggs; Energy Intake; Ghrelin; Hormones; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Pancreatic Polypeptide; Peptide YY; Satiation | 2009 |
Extended release metformin for metabolic control assistance during prolonged clozapine administration: a 14 week, double-blind, parallel group, placebo-controlled study.
Clozapine is the most effective agent in treatment-resistant schizophrenia. However, it is frequently associated with excessive body weight (BW) gain, type 2 diabetes mellitus and hyperlipidemia. The antidiabetic metformin (MET) has proved effective to assist in BW control during olanzapine administration. Therefore, we aimed to test whether MET may improve the metabolic profile in patients under prolonged clozapine administration.. In a double-blind, parallel group protocol, 61 patients (94.4% with schizophrenia) receiving clozapine (196.8+/-132 mg daily, range: 25-500) for more than 3 consecutive months (86.5+/-40.6 months, range: 4-168) were randomly allocated to extended release MET (n=31; 500 to 1000 mg daily) or placebo (n=30) group for 14 weeks. The BW, the body mass index, waist circumference, serum glucose, insulin, lipids, glycated hemoglobin (HBA1c), leptin and cortisol, and the HOMA-IR index were assessed at baseline, and weeks 7 and 14.. MET was well tolerated and the mental state was not impaired during the study. The protocol was completed by all the placebo subjects and by 24 MET-treated patients. In a complete analysis at week 14, without including data of the 7 dropouts, the MET group lost -1.87+/-2.9 kg, whereas the placebo group had a stable BW: 0.16+/-2.9 kg, p=0.01 for the between group comparisons (effect size: 0.70). Leptin levels also tended to decrease after MET (p=0.08). Insulin and the triglyceride-HDL-C ratio significantly decreased (p<0.05, effect size 0.59 and 1.99 respectively) and the HDL-C significantly increased (p=0.001, effect size 0.95) after MET.. MET improves metabolic control during prolonged clozapine administration. Topics: Adult; Anthropometry; Antipsychotic Agents; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Cholesterol, HDL; Clozapine; Double-Blind Method; Drug Delivery Systems; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Metformin; Middle Aged; Schizophrenia; Statistics, Nonparametric; Waist Circumference | 2009 |
Plasma concentrations of fibroblast growth factors 19 and 21 in patients with anorexia nervosa.
Fibroblast growth factor 19 (FGF19) and FGF21 are novel metabolic regulators that improve insulin sensitivity and decrease adiposity in mice. However, little is known about the nutritional regulation of these factors in humans.. The objective of this study was to measure plasma FGF19 and FGF21 levels in patients with anorexia nervosa (AN) and to explore its relationship with anthropometric and endocrine parameters.. This was a single-center cross-sectional study.. The study was performed in a university hospital.. Seventeen untreated women with a restrictive type of AN and 17 healthy women (control group) were included.. Fasting plasma FGF19 and FGF21, serum insulin, leptin, soluble leptin receptor, adiponectin, resistin, and C-reactive protein were the main outcome measures.. Plasma FGF19 levels did not significantly differ between the groups studied, whereas plasma FGF21 levels were significantly reduced in AN relative to the control group. Plasma FGF21 positively correlated with body mass index and serum leptin and insulin and was inversely related to serum adiponectin in both groups. In contrast, plasma FGF19 was not related to any of parameters studied. Partial realimentation significantly reduced plasma FGF21 levels in AN.. Circulating levels of FGF21 but not FGF19 are strongly related to body weight and serum levels of leptin, adiponectin, and insulin in both anorectic and normal-weight women. We suggest that reduced plasma FGF21 levels could be involved in the pathophysiology of AN or in a complex adaptive response to this disease. Topics: Adaptation, Biological; Adiponectin; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Case-Control Studies; Cross-Sectional Studies; Eating; Female; Fibroblast Growth Factors; Humans; Insulin; Leptin; Triiodothyronine | 2008 |
Effect of diet and exercise on body composition, energy intake and leptin levels in overweight women and men.
To investigate the effect of diet alone (D), exercise alone (E), and a combination of diet and exercise (DE) on body weight, body composition, energy intake, blood pressure, serum lipid and leptin levels, and fitness levels in mildly obese sedentary women and men.. The three interventions were compared in a randomized longitudinal study design. The exercise programs were supervised for six months, after which participants in E and DE were provided with exercise equipment to take home.. 90 adult overweight women and men (age: 44.2 +/- 7.2 years; BMI = 30.5 +/- 2.7 kg/m(2)).. Body weight, body composition, waist and hip circumferences, blood pressure, serum lipid levels, and fitness levels were evaluated at 0, 3, 6, 9, and 12 months. Serum leptin concentrations were measured at 0 and 6 months only.. At 6 and 9 months in women, and 9 months in men, DE demonstrated a significant loss of body weight compared to both D and E (p < 0.05). Serum leptin levels significantly decreased from baseline to 6 months in women in D (p = 0.05) and DE (p = 0.0003) and men in E (p = 0.038). At one year, no significant differences existed among groups in any of the measures.. A combination of diet and exercise resulted in a significant decrease in body weight in women and men; but this decrease was not maintained at one year follow-up. Serum leptin concentrations showed significant within-group decreases, but were not different among groups. A supervised diet and exercise program is effective for weight loss; however, once intensive participant-investigator and participant-participant contact is discontinued, weight regain ensures. Topics: Adult; Blood Pressure; Body Composition; Body Weight; Cholesterol; Diet; Energy Intake; Exercise; Female; Humans; Leptin; Longitudinal Studies; Male; Middle Aged; Obesity; Physical Fitness; Triglycerides | 2008 |
The effects of the surgical removal of subcutaneous adipose tissue on energy expenditure and adipocytokine concentrations in obese women.
To analyze the effects of the surgical removal of subcutaneous adipose tissue by ultrasound-assisted megalipoplasty (UAM) on energy expenditure and adipocytokine concentrations in obese women.. Fifteen premenopausal obese women with BMI 37.5+/-6.3 kg/m(2) (range: 30.7-53.6 kg/m(2)) underwent UAM. Body composition (by DEXA), resting metabolic rate (REE) by indirect calorimetry, insulin resistance (by the HOMA method), leptin, C-reactive protein, interleukin-6, resistin and adiponectin were measured before and 1, 3, 28 and 180 days after the procedure.. UAM significantly reduced fat mass at day 3, without further changes in the following days. REE increased at day 3 after UAM, returned to baseline levels at day 28 and significantly declined at day 180. Leptin levels transiently increased after UAM and then declined according to fat mass reduction. C-reactive protein, interleukin-6 and resistin levels acutely increased after UAM and then returned to the baseline levels. Adiponectin levels acutely declined after the procedure and then stabilized to a plasma level slightly lower than at baseline. Insulin resistance deteriorated in the acute post-operative phase and then improved.. The surgical removal of subcutaneous fat was associated to an acute inflammatory reaction with high REE and insulin-resistance. Later on, the metabolic effects of fat mass removal appeared, with a reduction of leptin levels and REE and an improvement of insulin resistance. Topics: Adipokines; Adiponectin; Adolescent; Adult; Blood Glucose; Body Composition; Body Weight; C-Reactive Protein; Calorimetry, Indirect; Energy Metabolism; Female; Humans; Insulin Resistance; Interleukin-6; Leptin; Lipectomy; Middle Aged; Obesity; Premenopause; Resistin; Severity of Illness Index; Subcutaneous Fat; Time Factors; Treatment Outcome; Ultrasonography, Interventional | 2008 |
Effect of selective and non-selective beta-blockers on body weight, insulin resistance and leptin concentration in chronic heart failure.
Chronic heart failure (CHF) is characterized by increased insulin resistance and hyperleptinaemia. We aimed to study effects of selective and non-selective beta-blockers on body weight, insulin resistance, plasma concentrations of leptin and resistin in patients with CHF.. Twenty-six non-cachectic beta-blocker-naive patients with CHF were randomized and treated with either carvedilol or bisoprolol. Body weight, plasma concentrations of leptin, resistin, fasting glucose and insulin were measured at baseline and after 6 months of therapy. Insulin resistance was estimated by homeostasis model assessment- estimated insulin resistance (HOMA-IR).. Body weight increased significantly in the carvedilol group (mean change + 2.30 kg, p = 0.023) while it did not change in the bisoprolol group (mean change -0.30 kg, p = 0.623) (ns between groups). Plasma leptin concentration increased only in the carvedilol group (mean change + 4.20 ng/ml, p = 0.019) (ns between groups). Fasting glucose and resistin remained unchanged in both groups. After 6 months, mean plasma insulin concentration changed significantly differently (p = 0.015) in the bisoprolol (mean change +3.1 microU/ml) compared to the carvedilol group (mean change -6.3 microU/ml) and HOMA-IR was consequently higher in the bisoprolol compared to the carvedilol group (5.2 +/- 4.2 vs 2.8 +/- 1.6, p = 0.046).. This study found different metabolic effects of carvedilol and bisoprolol in non-cachectic patients with CHF. With unchanged fasting plasma glucose concentration after 6 months of treatment, carvedilol significantly decreased plasma insulin concentration and insulin resistance compared to bisoprolol. Topics: Adrenergic beta-Antagonists; Aged; Bisoprolol; Blood Glucose; Body Weight; Carbazoles; Carvedilol; Chronic Disease; Female; Heart Failure; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Propanolamines; Resistin | 2008 |
Restoration of acute insulin response in T2DM subjects 1 month after biliopancreatic diversion.
Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes.. Twenty-one consecutive morbid obese subjects, 9 with type 2 diabetes (T2DM) and 12 with normal fasting glucose (NFG) were evaluated, just before and 1 month after BPD, by measuring body weight (BW), glucose, adipocitokines, homeostasis model assessment of insulin resistance (HOMA-IR), acute insulin response (AIR) to e.v. glucose and the insulinogenic index adjusted for insulin resistance ([DeltaI5/DeltaG5]/HOMA-IR).. Preoperatively, those with T2DM differed from those with NFG in showing higher levels of fasting glucose, reduced AIR (57.9 +/- 29.5 vs. 644.9 +/- 143.1 pmol/l, P < 0.01) and reduced adjusted insulinogenic index (1.0 +/- 0.5 vs. 17.6 +/- 3.9 1/mmol(2), P < 0.001). One month following BPD, in both groups BW was reduced (by approximately 11%), but all subjects were still severely obese; HOMA-IR and leptin decreased significanlty, while high-molecular weight (HMW) adiponectin and adjusted insulinogenic index increased. In the T2DM group, fasting glucose returned to non-diabetic values. AIR did not change in the NFG group, while in the T2DM group it showed a significant increase (from 58.0 +/- 29.5 to 273.8 +/- 47.2 pmol/l, P < 0.01). In the T2DM group, the AIR percentage variation from baseline was significantly related to changes in fasting glucose (r = 0.70, P = 0.02), suggesting an important relationship exists between impaired AIR and hyperglycaemia.. BPD is able to restore AIR in T2DM even just 1 month after surgery. AIR restoration is associated with normalization of fasting glucose concentrations. Topics: Adiponectin; Adult; Biliopancreatic Diversion; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Fasting; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Male; Obesity; Weight Loss | 2008 |
Ghrelin - growth hormone releasing and orexigenic hormone in men declines with age, insulin and with decrease in testosterone concentration.
Ghrelin, a natural ligand of the growth-hormone secretagouges receptor is the peptide known because of its growth hormone (GH)-releasing as well as orexigenic actions. THE AIM of the study was to examine the relationship between ghrelin levels and age, weight, glucose metabolism markers, GH, IGF-1 and androgens in men.. The study included 19 healthy men aged 16-73 yrs, mean 46,8 +/-18,5 (mean +/- SD). The height, weight, and body mass index (BMI) of the study subjects were assessed and serum concentration of fasting ghrelin, leptin, GH, IGF-1, glucose, insulin, estradiol, testosterone and DHA-S were measured.. The negative correlation between age and serum ghrelin levels (r=-0,52; p<0,04) in men was found. In men under 30 years old serum ghrelin levels were significantly higher compared to men over 60 years old (p<0,02). Serum ghrelin levels in men were significantly lower compared to healthy women aged 43,5 +/- 12 years old (p<0,008). Serum insulin levels correlated negatively with ghrelin levels (r= -0,87; p<0,0006) and serum testosterone concentrations correlated with ghrelin levels (r= 0,69; p<0,00006).. Our findings demonstrate that the serum ghrelin levels in men decline with age, is lower than in women and correlate negatively with fasting insulin levels. We demonstrated, for the first time, that serum testosterone levels in men correlate with total ghrelin levels. Topics: Adolescent; Adult; Aged; Aging; Blood Glucose; Body Weight; Dehydroepiandrosterone Sulfate; Estradiol; Ghrelin; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Testosterone | 2008 |
Leptin, ghrelin and TNF-alpha before and after hypo-caloric traditional Chinese diet and auricular acupuncture.
Topics: Acupuncture, Ear; Adult; Body Weight; Caloric Restriction; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Obesity; Tumor Necrosis Factor-alpha | 2008 |
Metabolic parameters and adipokine profile during GH replacement therapy in children with GH deficiency.
GH replacement therapy in children with GH deficiency (GHD) mainly promotes linear growth. Not only have very few studies fully analyzed the metabolic consequences of GH therapy, but also the question as to whether GH may affect adipokine secretion has been insufficiently investigated. Our aim was to study the effects of GH replacement therapy on auxological data, lipid and glycemic profiles, insulin homeostasis (HOMA-IR) and serum adipokines in children.. This was a 1-year prospective study. Thirty-four GHD children (11.6 +/- 2.6 years) and thirty healthy matched controls were enrolled. Children affected by GHD were studied both before beginning continuous GH replacement therapy and again at 12 months.. At the beginning of the study, total and LDL cholesterol were higher in GHD children than in controls (P<0.001), whereas HDL cholesterol, triglycerides, insulin, HOMA-IR, leptin, and adiponectin were similar. At 12 months of continuous GH replacement therapy in the GHD group, there was a significant increase in both auxological data and IGF-I (P<0.001); total cholesterol (P<0.001), LDL (P<0.001), triglycerides (P<0.005), and leptin (P<0.001) decreased significantly; HDL (P<0.003), insulin (P<0.001), HOMA-IR (P<0.001) increased while adiponectin was unmodified. Furthermore, IGF-IDelta showed an inverse correlation with leptin Delta (rho = -0.398, P = 0.02).. In GHD children, the evaluation of metabolic parameters proves to be a useful tool for the evaluation of auxological parameters during GH replacement therapy. In our study, GH replacement therapy in GHD children improved final height, restored IGF-I levels, reduced leptin levels, and improved the lipid profile, without producing any unfavorable effects on glucose metabolism. Topics: Adiponectin; Adolescent; Body Height; Body Mass Index; Body Weight; Child; Cholesterol, LDL; Female; Growth Disorders; Hormone Replacement Therapy; Human Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Time Factors; Treatment Outcome; Triglycerides | 2007 |
Pharmacokinetics of recombinant methionyl human leptin after subcutaneous administration: variation of concentration-dependent parameters according to assay.
Recombinant human leptin (r-metHuLeptin) has demonstrated efficacy in improving hormonal and metabolic parameters in leptin-deficient states, but pharmacokinetic parameters after sc administration have not yet been published. In addition, the effect of potential variability across different leptin assays on concentration-dependent pharmacokinetic parameters remains unknown.. The objective of the study was to characterize pharmacokinetic parameters after sc r-metHuLeptin administration using three commercially available leptin assays (Linco, Diagnostic Systems Laboratories, and Alpco).. We analyzed pharmacokinetic profiles in five lean and five obese men after sc administration of physiological (0.01 mg/kg) and pharmacological (0.3 mg/kg) doses of r-metHuLeptin.. Leptin pharmacokinetic parameters were measured.. Measurement of leptin produced typical pharmacokinetic profiles in all assays with time to maximal concentration and half-life of approximately 3 h. Diagnostic Systems Laboratories consistently measured leptin higher than Linco, with Alpco measuring intermediate between or similar to Linco. There was high correlation among assays (R(2) ranging from 0.89 to 0.98, all P < 0.01). Concentration-dependent parameters such as maximal concentration, area under the curve, and clearance were significantly different among assays, whereas concentration-independent parameters such as time to maximal concentration and half-life were generally not different.. We report novel data on leptin pharmacokinetic parameters after sc administration, which will be relevant for the future therapeutic use of r-metHuLeptin. Although commercially available assays demonstrated high correlation, they can provide substantially different measures of leptin levels. This demonstrates the importance of standardizing leptin assays for diagnosing patients with relative leptin deficiency, determining appropriate doses of r-metHuLeptin for administration, and monitoring response to therapy. Topics: Adult; Body Weight; Humans; Immunoassay; Injections, Subcutaneous; Leptin; Male; Obesity; Reagent Kits, Diagnostic; Regression Analysis | 2007 |
Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: a multicentric, double-blind, placebo-controlled trial.
Excessive body weight gain (BWG) is a clinically relevant side effect of olanzapine administration. The primary objective of this study was to assess whether metformin prevents or reverses BWG in patients with schizophrenia or bipolar disorder under olanzapine administration. Secondarily we evaluated diverse metabolic variables.. Eighty patients taking olanzapine (5-20 mg daily for more than 4 consecutive months) were randomly allocated to metformin (n=40; 850 to 2550 mg daily) or placebo (n=40) group in a 12-week double-blind protocol. Waist circumference (WC) body weight (BW), body mass index (BMI) fasting glucose, glycated hemoglobin (Hb1c), insulin, an insulin resistance index (HOMA-IR) lipids, leptin, c-reactive protein, fibrinogen, cortisol and the growth hormone (GH) were evaluated at baseline and at week 12 of treatment.. The metformin group lost 1.4+/-3.2 kg (p=0.01) and tended to decrease its leptin levels, whereas the placebo group maintained a stable weight: -0.18+/-2.8 kg (p=0.7). The HOMA-IR significantly increased after placebo (p=0.006) and did not change after metformin (p=0.8). No ostensible differences were observed in the other variables, even though metformin did not improve the lipid profile and the Hb1c levels.. Metformin may safely assist olanzapine-treated patients in body weight and carbohydrate metabolism control. Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Blood Glucose; Body Mass Index; Body Weight; Brief Psychiatric Rating Scale; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Energy Metabolism; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipids; Male; Metformin; Middle Aged; Olanzapine; Schizophrenia; Statistics as Topic | 2007 |
Effect of macronutrient composition on postprandial peptide YY levels.
Peptide YY (PYY) is released from the distal small intestine and colon after meals and reduces appetite by increasing satiety. The amount of PYY released is proportional to calories ingested. Fat ingestion has also been reported to stimulate PYY release.. The objective of the study was to determine whether macronutrient composition influences postprandial serum PYY levels by comparing 1 wk of a weight-maintenance low-carbohydrate, high-fat (LCHF) diet with a low-fat, high-carbohydrate (LFHC) diet.. In this randomized crossover study, 18 obese subjects (14 females, 4 males, mean body mass index 35.6 +/- 2.9 kg/m(2)) were randomly assigned initially to 1 wk of a weight-maintenance LCHF or LFHC diet, after which a test meal of identical composition was given and serum PYY levels were assessed for 2.5 h postprandially. After a 1-wk washout period, subjects were crossed over and retested.. After 1 wk, mean postprandial area under the curve PYY after the LCHF test meal was 1.5-fold greater than after the LFHC test meal (P < 0.001). The LCHF diet led to 55% higher levels of postprandial serum PYY levels, compared with the LFHC diet (P = 0.005).. These data show that a LCHF diet stimulates PYY secretion more than a LFHC diet in obese individuals. Topics: Adiponectin; Adult; Blood Glucose; Body Weight; Cross-Over Studies; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Dietary Carbohydrates; Dietary Fats; Energy Intake; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period | 2007 |
Longitudinal measures of circulating leptin and ghrelin concentrations are associated with the growth of young Peruvian children but are not affected by zinc supplementation.
Leptin, ghrelin, and insulin are hormonal regulators of energy balance and, therefore, may be related to growth during infancy. Zinc is essential for growth, and its growth effects may be mediated through these hormones.. We examined the effects of supplemental zinc on plasma leptin, ghrelin, and insulin concentrations among young children at risk of zinc deficiency and examined the relations between these hormones and physical growth.. Children (n = 142) aged 6-8 mo were randomly assigned to receive 3 mg Zn/d as a supplement, in a fortified food, or as a placebo for 6 mo. Relations between hormones and anthropometric z scores, body composition, and growth rates were examined at baseline and 3 and 6 mo after the start of the intervention.. No treatment group-related differences were found in plasma leptin, ghrelin, or glucose concentrations or in anthropometric z scores at 3 or 6 mo after the start of the zinc intervention. Neither plasma leptin nor ghrelin concentrations at baseline or 3 mo were predictive of subsequent changes in growth. However, changes in weight-for-age z scores over the two 3-mo time intervals were positively associated with subsequent leptin concentrations and inversely associated with subsequent plasma ghrelin concentrations.. Supplemental zinc did not affect the children's growth, anthropometric indexes, or plasma hormone concentrations in this study population. Our results suggest that plasma leptin and ghrelin concentrations in later infancy are a consequence of previous weight changes rather than predictors of short-term growth. Topics: Body Composition; Body Height; Body Weight; Child Development; Dietary Supplements; Double-Blind Method; Energy Metabolism; Female; Food, Fortified; Ghrelin; Growth; Humans; Infant; Infant Nutritional Physiological Phenomena; Insulin; Leptin; Male; Nutritional Status; Peru; Time Factors; Trace Elements; Zinc | 2007 |
The role of ghrelin in weight gain and growth in epileptic children using valproate.
Ghrelin is a major hormone, regulating the energy balance of the body. Weight gain is a significant side effect of valproic acid, which has not been clearly identified pathogenetically. The aim of this study was to investigate the effect of valproic acid on ghrelin and its potential effects on weight gain and growth. Each patient and control group consisted of 35 children aged 3 to 15 years. Fasting serum glucose, insulin, C-peptide, leptin, ghrelin, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 levels were measured in patients treated with valproic acid before and at month 6 of treatment. A significant increase in body weight, body mass index, height, and height standard deviation scores was observed in all patients after 6 months of treatment. Significant increases in growth velocity and weight gain were observed in the patient group compared with controls at 6 months of therapy. A significant increase in serum ghrelin levels (P < .01) was detected at the same time in the study group. A negative correlation of ghrelin with insulin-like growth factor-1 and insulin-like growth factor binding protein-3 was detected. Serum ghrelin levels were significantly increased (P < .05), and insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels were significantly decreased (P < .01 and P < .05, respectively) in the prepubertal group at 6 months of treatment, but no significant change was observed in the pubertal group. Consequently, ghrelin levels significantly increase in the prepubertal children treated with valproic acid. The weight gain in using valproic acid may be associated with the increase in ghrelin level in the early treatment period. Topics: Adolescent; Anticonvulsants; Blood Glucose; Body Height; Body Mass Index; Body Weight; C-Peptide; Child; Child, Preschool; Epilepsy; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Puberty; Valproic Acid; Weight Gain | 2007 |
Effects of short-term hypocaloric diet on sympatho-vagal interaction assessed by spectral analysis of heart rate and blood pressure variability during stress tests in obese hypertensive patients.
We examined the effects of a short-term low-calorie diet on the activity of the autonomic nervous system during stress tests in obese patients with hypertension by analysis of heart rate and blood pressure variability. Eighteen obese inpatients with essential hypertension were given a regular-calorie diet (1,600 kcal, NaCl 7 g) for 4 days, and then a low-calorie diet (1,100 kcal, NaCl 7 g) for 11 days. During both the regular-calorie diet and low-calorie diet, power spectral analysis of heart rate and blood pressure variability at rest and during mental arithmetic test, deep breathing test, isometric handgrip test or cold pressor test was performed. Body weight and 24-h ambulatory blood pressure were significantly lower during the low-calorie diet than during the regular-calorie diet. Systolic and diastolic blood pressure significantly increased over the handgrip test and cold pressor test during both diets. The low frequency component (LF) of systolic blood pressure, a marker of sympathetic activity to the vasculature, during the deep breathing test and cold pressor test were significantly lower on the low-calorie diet than the regular-calorie diet. The blood leptin concentration was also significantly lower on the low-calorie diet than the regular-calorie diet. The decrease in body weight was positively correlated with the decrease in blood leptin concentration. The LF/high frequency component (HF) ratio of the RR interval at rest on the regular-calorie diet was negatively correlated with the decrease in blood leptin concentration. These results suggest that the autonomic nervous function assessed by analysis of heart rate and blood pressure variability during stress tests may be improved by weight loss due to a short-term low-calorie diet in obese patients with hypertension. Topics: Blood Pressure; Body Weight; Caloric Restriction; Diet, Reducing; Exercise Test; Female; Heart Rate; Humans; Hypertension; Leptin; Male; Middle Aged; Obesity; Sympathetic Nervous System; Vagus Nerve | 2007 |
Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia.
Although treatment with antipsychotics, particularly olanzapine and clozapine, has been implicated in weight gain and higher incidence of diabetes, the mechanism of these adverse reactions remains unclear. The purposes of this study were to explore the early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin, three recently identified hormones that play crucial roles in the regulation of energy balance and glucose metabolism. Thirteen patients with schizophrenia who had not received any medication in the 4 weeks prior to this study were included. The patients received olanzapine at an average dose of 14.5mg/day. Serum levels of ghrelin, adiponectin, leptin and insulin, as well as weight and fasting glucose, were investigated at the baseline and at 4 weeks. Serum ghrelin levels had decreased (p 0.03) and leptin had increased (p 0.02), while adiponectin and insulin levels had not significantly changed at Week 4 (p 0.29 and p 0.25, respectively). Weight had increased (p 0.01), while fasting glucose had not significantly changed (p 0.46). These findings suggest that ghrelin levels decrease and leptin levels increase after initiation of olanzapine therapy. Weight gain is also considered to be an early change, while change in insulin sensitivity is not an early change of treatment with olanzapine. Further large-scale and longitudinal studies are warranted to elucidate metabolic changes involving ghrelin, adiponectin, leptin and insulin and their impact on weight and glucose metabolism during treatment with olanzapine and other antipsychotics. Topics: Adiponectin; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Olanzapine; Peptide Hormones; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology | 2006 |
Changes of sleep architecture, spectral composition of sleep EEG, the nocturnal secretion of cortisol, ACTH, GH, prolactin, melatonin, ghrelin, and leptin, and the DEX-CRH test in depressed patients during treatment with mirtazapine.
The noradrenergic and specific serotoninergic antidepressant mirtazapine improves sleep, modulates hormone secretion including blunting of hypothalamic-pituitary-adrenocortical (HPA) activity, and may prompt increased appetite and weight gain. The simultaneous investigation of sleep electroencephalogram (EEG) and hormone secretion during antidepressive treatment helps to further elucidate these effects. We examined sleep EEG (for later conventional and quantitative analyses) and the nocturnal concentrations of cortisol, adrenocorticotropin (ACTH), growth hormone (GH), prolactin, melatonin and the key factors of energy balance, ghrelin, and leptin before and after 28 days of treatment of depressed patients (seven women, three men, mean age 39.9+/-4.2 years) with mirtazapine. In addition, a sleep EEG was recorded at day 2 and the dexamethasone-corticotropin-releasing hormone (DEX-CRH) test was performed to assess HPA activity at days -3 and 26. Psychometry and mirtazapine plasma concentrations were measured weekly. Already at day 2, sleep continuity was improved. This effect persisted at day 28, when slow-wave sleep, low-delta, theta and alpha activity, leptin and (0300-0700) melatonin increased, and cortisol and ghrelin decreased. ACTH and prolactin remained unchanged. The first two specimens of GH collected after the start of quantitative EEG analysis were reduced at day 28. The DEX-CRH test showed, at day 26, a blunting of the overshoot of ACTH and cortisol found at day -3. The Hamilton Depression score decreased from 32.1+/-7.3 to 15.5+/-6.7 between days -1 and 28. A weight gain of approximately 3 kg was observed. This unique profile of changes is compatible with the action of mirtazapine at 5-HT-2 receptors, at presynaptic adrenergic alpha 2 receptors, at the HPA system, and on ghrelin and leptin. Topics: Adrenocorticotropic Hormone; Adult; Animals; Antidepressive Agents, Tricyclic; Area Under Curve; Body Weight; Circadian Rhythm; Depression; Dexamethasone; Dose-Response Relationship, Drug; Electroencephalography; Endocrine System; Female; Ghrelin; Growth Hormone; Hormones; Humans; Hydrocortisone; Immunoradiometric Assay; Leptin; Male; Melatonin; Mianserin; Middle Aged; Mirtazapine; Peptide Hormones; Prolactin; Psychometrics; Sleep; Time Factors | 2006 |
Effect of sex hormone administration on circulating ghrelin levels in peripubertal children.
Ghrelin levels gradually decrease throughout childhood and with advancing pubertal stage. The change during puberty is more pronounced in boys than girls.. The objective of the study was to investigate whether the pubertal drop in ghrelin secretion is modified by the increase in sex hormones.. Ghrelin levels were measured in 34 short peripubertal children (17 boys and 17 girls) aged 8-12.5 yr before and after sex hormone priming for GH stimulation testing.. In boys, priming with testosterone increased testosterone to pubertal levels (23.7 +/- 7.1 nmol/liter), which in turn induced a marked decrease in ghrelin (from 1615.8 +/- 418.6 to 1390.0 +/- 352.0 pg/ml) and leptin (from 8.0 +/- 4.5 to 5.8 +/- 3.2 ng/ml) and an increase in IGF-I (from 162.7 +/- 52.8 to 291.1 +/- 101.6 ng/ml) (P < 0.001 for all parameters). In girls, priming with estrogen led to a supraphysiological increase in estradiol levels (1313.8 +/- 438.0 pmol/liter), which had no effect on ghrelin, leptin, or IGF-I. There was no correlation between ghrelin levels and levels of sex hormones, leptin, or body mass index in either boys or girls.. A pharmacological increase in sex hormones is associated with a marked decline in circulating levels of ghrelin in boys but not girls. Additional longitudinal studies through puberty are needed to elucidate the physiological interaction between sex hormones and ghrelin. Topics: Body Height; Body Mass Index; Body Weight; Child; Exercise Test; Female; Follicle Stimulating Hormone, Human; Ghrelin; Gonadal Steroid Hormones; Growth Hormone; Hormones; Humans; Leptin; Luteinizing Hormone; Male; Peptide Hormones; Puberty; Sex Characteristics | 2006 |
Metabolic effects of green tea and of phases of weight loss.
The effect of ingestion of green tea (GT) extract along with a low-energy diet (LED) on health-related blood parameters, and the relationships among changes in metabolic parameters and phases of weight loss were assessed. A double-blind, placebo-controlled, parallel design was used. 46 female subjects (BMI 27.7+/-1.8 kg/m(2)) were fed in energy balance from days 1 to 3, followed by a LED with GT (n=23) or placebo (PLAC, n=23) from days 4 to 87. The LED-period consisted of a phase 1 of 4 weeks (days 4-32) followed by a phase 2 of 8 weeks (days 32-87). Body composition and fasting blood samples were determined on days 4, 32 and 87. No significant differences were observed between the blood parameters of the PLAC and GT group. In phase 1 compared to phase 2 the rate of weight loss was 0.09+/-0.05 kg/day vs. 0.03+/-0.03 kg/day (p<0.001); Fat free mass (FFM) was 21% of weight loss in phase 1 vs. 7% in phase 2 (ns). Surprisingly, favourable changes in free fatty acids, triacylglycerol, beta-hydroxybutyrate, glucose and total cholesterol in phase 1 were reversed in phase 2 (p<0.01). Taken together, GT supplementation during a LED had no effect on health-related blood parameters. Initial improvements in several blood measures at day 32 were reversed by day 87, despite continued weight loss. Modest weight loss improved HDL cholesterol and blood pressure. Topics: Administration, Oral; Adult; Analysis of Variance; Anthropometry; Body Mass Index; Body Weight; Camellia sinensis; Catechin; Double-Blind Method; Energy Intake; Energy Metabolism; Female; Humans; Leptin; Middle Aged; Plant Extracts; Reference Values; Regression Analysis; Tea; Triglycerides; Weight Loss | 2006 |
Leptin secretion in horses: effects of dexamethasone, gender, and testosterone.
Five experiments were performed to evaluate the effects of dexamethasone (DEX), gender, and testosterone on plasma leptin concentrations in horses. In experiment 1, plasma leptin, insulin, glucose, and IGF-1 concentrations were increased (P < 0.01) in stallions following five daily injections of DEX (125 microg/kg BW). In experiment 2, leptin concentrations increased (P < 0.01) in mares, geldings, and stallions following a single injection of DEX, and the response was greater (P < 0.01) in mares and geldings than in stallions. The gender effect was confounded by differences in body condition scores and diet; however, based on stepwise regression analysis, both BCS and gender were significant sources of variation in the best fit model for pre-DEX leptin concentrations (R(2) = 0.65) and for maximum leptin response to DEX (R(2) = 0.75). In experiment 3, in which mares and stallions were pair-matched based on age and body condition and fed similar diets, mares again had higher (P < 0.01) leptin concentrations than stallions after DEX treatment as used in experiment 2. In experiment 4, there was no difference (P > 0.1) in plasma leptin response in mares following four single-injection doses of DEX from 15.6 to 125 microg/kg BW. In experiment 5, treatment of mares with testosterone propionate every other day for 5 days did not alter (P > 0.1) plasma leptin concentrations or the leptin response to DEX. In conclusion, multiple injections of DEX increase leptin concentrations in stallions, as does a single injection in mares (as low as 15.6 microg/kg BW), geldings and stallions. The greater leptin levels observed in mares and geldings relative to stallions were due partially to their greater body condition and partially to the presence of hyperleptinemic individuals; however, even after accounting for body condition and diet, mares still had greater leptin concentrations than stallions after DEX administration. Elevation of testosterone levels in mares for approximately 10 days did not alter leptin concentrations in mares. Topics: Adipose Tissue; Animals; Body Weight; Dexamethasone; Female; Glucocorticoids; Horses; Leptin; Male; Sex Factors; Testosterone Propionate | 2006 |
Overweight humans are resistant to the weight-reducing effects of melanocortin4-10.
By enhancing energy expenditure and suppressing appetite, melanocortin peptides derived from proopiomelanocortin play a primary role in the hypothalamic regulation of body weight. In a recent study in normal-weight adults, the 6-wk intranasal administration of the MSH/ACTH(4-10) core fragment of proopiomelanocortin resulted in a distinct reduction of body weight and body fat, accompanied by significant decreases in leptin and insulin plasma concentrations.. The present study aimed to generalize this finding to overweight patients.. MSH/ACTH(4-10) (0.5 mg) and placebo were intranasally administered once in the morning and once in the evening over a period of 12 wk in 23 overweight men (body mass index, mean +/- sem: 29.72 +/- 0.43 kg/m(2)).. MSH/ACTH(4-10) did not induce any significant reduction in body weight, body fat, and plasma levels of insulin and leptin as compared with the effects of placebo. Melanocortin treatment was accompanied by reduced cortisol concentrations.. We conclude that contrasting with normal-weight humans, overweight subjects are not susceptible to the effects of melanocortin administration on hypothalamic weight regulatory systems. In overweight subjects, a decreased sensitivity to ACTH/MSH peptides may derive from alterations at the level of the melanocortin receptor or at subsequent steps in the processing of the body fat signal. Topics: Administration, Intranasal; Adrenocorticotropic Hormone; Adult; Body Composition; Body Weight; Double-Blind Method; Drug Resistance; Humans; Hydrocortisone; Insulin; Leptin; Male; Middle Aged; Overweight; Peptide Fragments | 2006 |
Determinants of coronary flow velocity reserve in healthy young men.
The objective of this study was to identify risk markers for attenuated coronary flow velocity reserve (CFVR) that exist in healthy young men without evident atherosclerotic risk factors. Coronary blood flow velocity was measured with transthoracic Doppler echocardiography at baseline and during adenosine infusion in 37 healthy nonsmoking men [mean age, 27 yr (SD 4.0)]. Body composition and distribution of fat tissue were assessed with anthropometric measures and regulation of fat metabolism by determination of adiponectin and leptin levels. Physical performance capacity was tested with ergospirometry. The mean body mass index was 23 kg/m2 (SD 1.9), waist-to-hip ratio was 0.84 (SD 0.04), and CFVR was 3.5 (SD 0.61). Obesity indexes at study outset, leptin, adiponectin, maximal load (Max load in W/kg) and maximal oxygen consumption (Vo2 peak in ml x kg(-1) x min(-1)) in ergospirometry, rate-pressure product, and heart rate at rest were significantly associated with CFVR. In multivariate analysis, Max load (in W/kg) and waist-to-hip ratio were the only independent predictors of CFVR. We found no relationship between CFVR and serum lipids or body mass index. We conclude that abdominal fat accumulation and low aerobic fitness are independently associated with CFVR in men. Topics: Adiponectin; Adipose Tissue; Adult; Anthropometry; Body Composition; Body Mass Index; Body Weight; Coronary Circulation; Echocardiography; Ergometry; Hemodynamics; Humans; Leptin; Lipids; Male; Reference Values; Spirometry; Waist-Hip Ratio | 2006 |
Correlations between measures of insulin sensitivity and weight loss.
Many formulas have been proposed to calculate insulin sensitivity and studies have shown their effectiveness. However, few studies have been done to compare formulas.. Seventy-two obese participants completed a randomized weight loss study. Weight loss, change in body fat and change in waist circumference were used as surrogates for change in insulin sensitivity. Correlation coefficients were calculated for each of these surrogates with proposed formulas for insulin sensitivity found in the literature.. The change in insulin sensitivity using the formula proposed by McAuley (exp(2.63-0.28 x ln(fasting insulin)-0.31 x ln(fasting triglyceride in mmol/l)) showed the greatest correlation with weight loss (r=-0.59, p<0.0001) and was statistically superior to change in fasting glucose, fasting insulin and homeostasis model assessment (HOMA).. The insulin sensitivity formula proposed by McAuley provides an accurate means of detecting insulin resistance. As it does not require a glucose tolerance test, it is also easier and less expensive than most other formulas. Use of this formula rather than fasting glucose would detect many more patients with insulin resistance who are at risk for subsequent diabetes and other complications. Topics: Adipose Tissue; Blood Glucose; Body Mass Index; Body Size; Body Weight; C-Reactive Protein; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Obesity; Weight Loss | 2006 |
The effects of Goami No. 2 rice, a natural fiber-rich rice, on body weight and lipid metabolism.
Increased intake of dietary fiber reduces the risk of obesity and type 2 diabetes. We assessed the effects of a fiber-rich diet on body weight, adipokine concentrations, and the metabolism of glucose and lipids in non-obese and obese subjects in Korea, where rice is the main source of dietary carbohydrates.. Eleven healthy, non-obese and 10 obese subjects completed two 4-week phases of individual isoenergetic food intake. During the control diet phase, subjects consumed standard rice; during the modified diet phase, subjects consumed equal proportions of fiber-rich Goami No. 2 rice and standard rice. We used a randomized, controlled, crossover study design with a washout period of 6 weeks between the two phases.. After the modified diet phase, body weight was significantly lower in both the non-obese and obese subjects (non-obese, 57.0 +/- 2.9 vs. 56.1 +/- 2.8 kg, p = 0.001; obese, 67.7 +/- 2.1 vs. 65.7 +/- 2.0 kg, p < 0.001 for before vs. after). The BMI was significantly lower in obese subjects (26.9 +/- 0.5 vs. 26.0 +/- 0.6 kg/m2, p < 0.001). The modified diet was associated with lower serum triacylglycerol (p < 0.01), total cholesterol (p < 0.01), low-density lipoprotein cholesterol (p < 0.05), and C-peptide (p < 0.05) concentrations in the obese subjects.. These results indicate that fiber-rich Goami No. 2 rice has beneficial effects and may be therapeutically useful for obese subjects. Topics: Adiponectin; Adult; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Cholesterol; Cross-Over Studies; Dietary Carbohydrates; Dietary Fiber; Female; Glycated Hemoglobin; Humans; Leptin; Lipid Metabolism; Male; Obesity; Oryza; Resistin; Triglycerides | 2006 |
Effect of mirtazapine treatment on body composition and metabolism.
Weight gain is a common side effect of psychotropic medications. Mirtazapine, a widely used antidepressant, induces adverse metabolic effects such as an increase in body weight. The aim of this study was to investigate the influence of mirtazapine treatment on body weight, body fat mass, glucose metabolism, lipoprotein profile, and leptin and its soluble receptor in a prospective, controlled study design.. Seven women who met the ICD-10 diagnostic criteria for a depressive episode (ICD-10: F31-F33) were assigned to monotherapy with mirtazapine and observed for a 6-week period. Seven mentally and physically healthy female volunteers matched for age and body weight served as a control group. Data were collected from November 2002 to December 2003.. The mean +/- SD body weight increased from 63.6 +/- 13.1 kg to 66.6 +/- 11.9 kg during mirtazapine treatment (p = .027). Fat mass increased in study subjects from 20.9 +/- 9.6 kg to 22.1 +/- 9.3 kg (p = .018). Insulin, glucose, and the homeostasis model assessment (HOMA) index for insulin resistance and lipid parameters remained stable. Leptin concentrations increased from 23.0 +/- 17.1 ng/mL to 40.9 +/- 27.2 ng/mL (p = .018), whereas the soluble leptin receptor concentrations remained stable during mirtazapine treatment. In the control subjects, the investigated parameters remained stable. Between-group analyses of change scores revealed significant differences for body weight (p = .010), body mass index (p = .013), fat mass (p = .035), and leptin (p = .013).. The antidepressant therapy with mirtazapine was associated with a significant increase in body weight, body fat mass, and leptin concentration. In contrast to other psychotropic medications inducing weight gain, such as some second-generation antipsychotics, mirtazapine treatment did not influence the glucose homeostasis. Topics: Adipose Tissue; Adult; Antidepressive Agents, Tricyclic; Blood Glucose; Body Composition; Body Fat Distribution; Body Weight; Depressive Disorder; Female; Follow-Up Studies; Homeostasis; Humans; International Classification of Diseases; Leptin; Lipoproteins; Mianserin; Mirtazapine; Obesity; Prospective Studies; Receptors, Cell Surface; Receptors, Leptin; Treatment Outcome | 2006 |
Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans.
To elucidate whether the role of leptin in regulating neuroendocrine and immune function during short-term starvation in healthy humans is permissive, i.e., occurs only when circulating leptin levels are below a critical threshold level, we studied seven normal-weight women during a normoleptinemic-fed state and two states of relative hypoleptinemia induced by 72-h fasting during which we administered either placebo or recombinant methionyl human leptin (r-metHuLeptin) in replacement doses. Fasting for 72 h decreased leptin levels by approximately = 80% from a midphysiologic (14.7 +/- 2.6 ng/ml) to a low-physiologic (2.8 +/- 0.3 ng/ml) level. Administration of r-metHuLeptin during fasting fully restored leptin to physiologic levels (28.8 +/- 2.0 ng/ml) and reversed the fasting-associated decrease in overnight luteinizing hormone pulse frequency but had no effect on fasting-induced changes in thyroid-stimulating hormone pulsatility, thyroid and IGF-1 hormone levels, hypothalamic-pituitary-adrenal and renin-aldosterone activity. FSH and sex steroid levels were not altered. Short-term reduction of leptin levels decreased the number of circulating cells of the adaptive immune response, but r-metHuLeptin did not have major effects on their number or in vitro function. Thus, changes of leptin levels within the physiologic range have no major physiologic effects in leptin-replete humans. Studies involving more severe and/or chronic leptin deficiency are needed to precisely define the lower limit of normal leptin levels for each of leptin's physiologic targets. Topics: Adaptation, Physiological; Adipose Tissue; Adult; Body Fat Distribution; Body Weight; Cells, Cultured; Fasting; Female; Hormones; Humans; Immunity; Immunity, Innate; Insulin-Like Growth Factor I; Leptin; Leukocyte Count; Neurosecretory Systems; T-Lymphocytes; Time Factors | 2006 |
Effects of oral continuous 17beta-estradiol plus norethisterone acetate replacement therapy on abdominal subcutaneous fat, serum leptin levels and body composition.
To evaluate the effects of oral continuous 17beta-estradiol plus norethisterone acetate (E2/NETA) replacement therapy on abdominal subcutaneous fat, serum leptin level (SLL) and body composition in postmenopausal women.. A 6-month, prospective, randomized, double-blind and placebo-controlled study was conducted. Forty-three healthy naturally postmenopausal women aged 43-65 years were randomly assigned to receive E2/NETA (2 mg E2 plus 1 mg NETA, n = 22) or placebo (n = 21). Fasting SLL by enzyme-linked immunosorbent assay, subcutaneous abdominal fat thickness (STh) by ultrasound and the anthropometric indices of body weight (BW), body mass index (BMI), waist and hip circumference (WC, HC) and waist-to-hip ratio (WHR) were recorded at the beginning and the end of the study.. After 6 months of therapy, BW and SLL increased in the placebo group (p = 0.043 and 0.033, respectively). WC, HC and STh decreased significantly in the E2/NETA group (p = 0.002, 0.006 and 0.000, respectively) and they were also significantly lower in women receiving E2/NETA than in women taking placebo (p = 0.000, 0.034 and 0.000, respectively). At baseline, SLL and STh were positively correlated with all anthropometric indices except WHR.. Oral continuous combined regimen of E2/NETA significantly reduced central fat accumulation as assessed by WC and STh, and attenuated the increase in SLL. The observed changes in SLL were highly and positively related to changes in STh. The oral continuous combined E2/NETA regimen appears to have protective effects on cardiovascular function and probably on metabolic diseases by its slimming effect upon WC in postmenopausal women. Topics: Administration, Oral; Adult; Aged; Body Composition; Body Mass Index; Body Weight; Double-Blind Method; Drug Therapy, Combination; Estradiol; Estrogen Replacement Therapy; Female; Humans; Leptin; Middle Aged; Norethindrone; Norethindrone Acetate; Osteoporosis, Postmenopausal; Placebos; Postmenopause; Subcutaneous Fat, Abdominal; Waist-Hip Ratio | 2006 |
Effects of short-term caloric restriction on circulating free IGF-I, acid-labile subunit, IGF-binding proteins (IGFBPs)-1-4, and IGFBPs-1-3 protease activity in obese subjects.
Decreased levels of GH and total IGF-I have been reported in obesity. It has been hypothesized that increased free (biologically active) IGF-I levels generated from IGF-binding protein (IGFBP) protease activity could be the mechanism for the low GH release in dieting obese subjects. However, no published data exist on free IGF-I levels, acid labile subunit (ALS), or IGFBP protease activity in relation to GH release during a hypocaloric diet. The main purpose of this study was to determine free IGF-I, ALS, IGFBPs-1-4, and IGFBPs-1-3 protease activity in relation to 24-h GH release before and after a short-term very low-calorie diet (VLCD).. Six obese subjects before weight loss, five after an average weight loss of 36.1 kg, and five age-and sex-matched lean controls underwent a 4-day VLCD. All subjects were studied on two occasions, once during normal basic diet and again during the last day of the VLCD (1.6 MJ).. Free IGF-I was determined by a non-competitive immunoradiometric assay.. Free IGF-I levels decreased in concert with increased ALS and unchanged blunted GH release after a VLCD in the obese subjects. IGFBPs-1-3 proteolytic activity was found to be unchanged by hypocaloric diet in all groups.. We conclude that free IGF-I decreases after a short-term hypocaloric diet in obese subjects with no concomitant change in 24-h GH release. Circulating free IGF-I per se cannot be the main mechanism of the attenuated GH release in dieting obese subjects. Topics: Adult; Body Mass Index; Body Weight; Caloric Restriction; Carrier Proteins; Diet, Reducing; Endopeptidases; Female; Glycoproteins; Human Growth Hormone; Humans; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Leptin; Male; Obesity; Protein Denaturation; Thinness; Time Factors; Weight Loss | 2006 |
Rise of plasma ghrelin with weight loss is not sustained during weight maintenance.
Ghrelin is postulated to be an orexigenic signal that promotes weight regain after weight loss (WL). However, it is not known whether this putative effect of ghrelin is sustained after weight stabilization. The objective of this study was to investigate the relationship of plasma ghrelin concentrations to active WL and weight maintenance in obese subjects.. This study was a randomized clinical trial, with a 12-month follow-up period. Obese Mexican-American women matched for age and BMI were randomized to a 12-month WL program (n = 25) or no intervention (controls, n = 23). Interventions included diet, exercise, and orlistat. Body weight and fasting ghrelin, leptin, insulin, and glucose concentrations were measured at baseline and 6 and 12 months.. The WL group lost 8.5% of body weight after 6 months and maintained the new weight for the next 6 months. Ghrelin concentrations increased significantly at 6 months but returned to baseline at 12 months. Baseline ghrelin concentrations were directly related to the degree of WL achieved after 12 months. Controls experienced no change in BMI or ghrelin levels. There were no associations between plasma ghrelin and leptin or insulin concentrations.. Consistent with previous results, ghrelin rises in response to WL, perhaps as a counterregulatory mechanism. However, the present results indicate that ghrelin concentrations return to baseline with sustained weight maintenance, suggesting that its effects are unlikely to regulate long-term energy balance. Baseline ghrelin concentrations are related to the degree of WL that can be achieved by active weight reduction. Topics: Adult; Analysis of Variance; Body Mass Index; Body Weight; Female; Follow-Up Studies; Ghrelin; Health Promotion; Humans; Insulin; Insulin Resistance; Leptin; Mexican Americans; Middle Aged; Obesity; Peptide Hormones; Radioimmunoassay; Time Factors; Waist-Hip Ratio; Weight Loss | 2006 |
Effects of high-fat diets on body composition, hypothalamus NPY, and plasma leptin and corticosterone levels in rats.
We investigated the adipogenic effects of high-fat diets with different fat sources, as well as their influence on hypothalamus NPY content (NPY) and plasma corticosterone (Cs) and leptin (Lep) concentrations. In a 6-wk experiment performed in 28 male Wistar rats, high-fat diets (approx 60% of energy as fat) containing sunflower oil (S), rapeseed oil (R), palm oil (P), or lard (L) as the fat source were applied. Carcass composition was analyzed by standard methods; NPY, Cs, and Lep were determined by RIA method. Gas chromatography was applied to measure fatty acid composition of dietary fats. S group had the highest body fat content and Lep and the lowest Cs and NPY, while L rats had high Lep and the highest Cs and NPY. We conclude that the fatty acid composition of dietary fat is of high importance where effects of high fat diets on adiposity, as well as on plasma levels of both hormones and hypothalamus NPY content are concerned. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Corticosterone; Dietary Fats; Eating; Energy Intake; Hypothalamus; Leptin; Male; Neuropeptide Y; Plant Oils; Rats | 2006 |
[The role of fat tissue in development of metabolic disorders in patients with diabetes mellitus type 2 and obesity].
To specify changes in clinicolaboratory parameters in reduction of obesity in patients with diabetes mellitus type 2 (DM-2).. Antropometry, densitometry of fat tissue (FT) were made and parameters of fat and carbohydrate metabolism (lipidogram, glycated hemoglobin, immunoreactive insulin), FT secretory activity (leptin, adiponectin, TNF-alpha) were studied in 75 obese DM-2 patients. After the above primary examination all the patients were randomized into 2 groups: group 1 (n = 55) received xenical (120 mg 3 times a day) and kept moderate hypocaloric diet; group 2 (n = 20) received only the above diet therapy. Active treatment lasted 24 weeks.. In addition to symptoms of metabolic syndrome (MS) the patients were found to have secretory disturbances of FT activity: elevation of leptin and TNF-alpha levels, subnormal adiponectin. These alterations directly correlated with body mass, FT mass gain, increase in waist circumference. Hyperleptinemia, hyperinsulinemia and hypoadiponectinemia were considered as markers of insulin resistance (IR) and related conditions. Xenical promoted a significant weight loss resulting in a positive trend in the parameters of adipokines, fat and carbohydrate metabolism, in reduction of IR.. Xenical is beneficial for patients with DM-2 and obesity because it improves metabolic processes. Topics: Adiponectin; Adipose Tissue; Anthropometry; Anti-Obesity Agents; Biomarkers; Body Weight; Caloric Restriction; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Lactones; Leptin; Lipids; Male; Metabolic Syndrome; Middle Aged; Obesity; Orlistat; Tumor Necrosis Factor-alpha | 2006 |
Olanzapine increases plasma ghrelin level in patients with schizophrenia.
Increased appetite and weight gain are frequently reported in treatment with olanzapine. However, the mechanism behind this appetite gain remains unclear. Ghrelin is a newly discovered appetite-stimulating peptide that has a role in the regulation of feeding behavior. Ghrelin is synthesized principally in the stomach, and the concentration of circulating ghrelin is negatively correlated with leptin and body fat mass. To elucidate the mechanism of appetite and weight gain during olanzapine treatment, we investigated the circulating ghrelin levels.. Seven patients with schizophrenia were examined before and after 6-month administration of olanzapine. The concentrations of circulating ghrelin, leptin, glucose and lipid metabolic parameters were measured.. Body fat percentage (P=0.0121) and serum leptin (P=0.0284) were significantly increased after 6-month administration of olanzapine. Both plasma total ghrelin (P=0.0188) and active ghrelin levels (P=0.0057) were significantly increased. Six of the seven patients reported increased appetite during olanzapine treatment. Other glucose and lipid parameters were not altered significantly.. Although, the leptin level and body fat percentage were significantly increased, the concentration of circulating ghrelin was also significantly increased. Olanzapine may directly act on the secretion of ghrelin and induce appetite, resulting in weight gain. Topics: Adult; Aged; Antipsychotic Agents; Appetite; Benzodiazepines; Body Composition; Body Mass Index; Body Weight; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Olanzapine; Peptide Hormones; Radioimmunoassay; Schizophrenia; Weight Gain | 2005 |
Does tibolone affect serum leptin levels and body weight in postmenopausal women?
Leptin has a significant role in body weight regulation and energy balance. We examined the effect of tibolone on the body weight and serum leptin levels in postmenopausal women.. Twenty women (aged 43-60 years) participated in this prospective study. All women in this study protocol received 2.5 mg/day of tibolone. Absolute and body mass index (BMI)-corrected serum leptin concentrations and BMI values were measured at baseline, after 3 months, and after 6 months of the tibolone therapy.. Tibolone did not affect absolute and BMI-corrected serum leptin levels, and BMI values during the treatment. A significant linear correlation between BMI values and serum leptin levels was observed (p<0.05, r=0.67).. Tibolone seems not to affect serum leptin levels, body weight and BMI values of postmenopausal women. There is a significant correlation between serum leptin levels and BMI values. Topics: Adult; Body Weight; Estrogen Receptor Modulators; Female; Humans; Leptin; Middle Aged; Norpregnenes; Postmenopause; Prospective Studies | 2005 |
Plasma levels of leptin and endogenous immune modulators during treatment with carbamazepine or lithium.
Several psychopharmacological agents induce weight gain. Recent studies have suggested that the tumor necrosis factor-alpha (TNF-alpha) cytokine system is pathophysiologically involved. To assess whether carbamazepine and lithium, which have been reported to lead to weight gain, have effects on the circulating levels of cytokines, we measured plasma levels of TNF-alpha, its soluble receptors sTNF-R p55 and p75, and leptin, as well as weight in 25 inpatients receiving lithium (n=10) or carbamazepine (n=15) weekly during the first 4 weeks of treatment. We found an increase in the body mass index and in TNF-alpha and its soluble receptor levels, but not in leptin levels over the 4 weeks of treatment. These changes did not differ between treatment groups. Changes of weight during the first week of treatment, but no other parameter, strongly predicted weight change until endpoint. We conclude that the mood stabilizers carbamazepine and lithium have similar effects on the TNF-alpha system and do not affect leptin levels. Topics: Adult; Antimanic Agents; Bipolar Disorder; Body Mass Index; Body Weight; Carbamazepine; Female; Humans; Immunologic Factors; Leptin; Lithium Carbonate; Male; Middle Aged; Mood Disorders; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha | 2005 |
Effect of administration of recombinant human leptin during the neonatal period on the plasma concentration and gene expression of leptin in the piglet.
Leptin is produced predominantly by white adipocytes and in adults it regulates both appetite and energy expenditure but its role in the neonate remains to be fully established. The aim of this, the first study of leptin administration to Meishan piglets, was to examine the effects of chronic leptin administration to neonatal pigs on their endocrine profile, growth and development. Six Meishan sows gave birth normally at term and 6 pairs of siblings (n = 12), matched by birth weight and gender (male, n = 6; female, n = 6) were randomly allocated to leptin (L: n = 6) or placebo (P: n = 6) administration groups. Piglets remained with their mother throughout the study and from day 3 to 8 of neonatal life each pig received either 4 microg ml(-1) kg(-1) body weight recombinant human leptin or a saline placebo. Plasma concentrations of key hormones and metabolites were determined in conjunction with messenger RNA (mRNA) for leptin, which was assessed by PCR. Recombinant leptin treatment improved growth performance and promoted skeletal growth in favour of adipose tissue accretion. Circulating plasma leptin concentrations were higher on days 4 and 7 in L pigs. Leptin administration altered the endocrine profile of the neonatal pig, although these changes were not maintained. There were no relationships between plasma leptin and body weight or mRNA leptin abundance, irrespective of treatment. Chronic leptin administration appeared to have a beneficial influence on growth rate and body conformation, which may in part be attributed to alterations in metabolism and nutrient partitioning. Topics: Adipose Tissue; Animals; Animals, Newborn; Biometry; Body Weight; Bone Development; Female; Gene Expression; Growth; Humans; Insulin; Lactic Acid; Leptin; Male; Placebos; Polymerase Chain Reaction; Recombinant Proteins; RNA, Messenger; Swine; Thyroxine; Triiodothyronine | 2005 |
Effect of increasing energy and protein intake on body growth and carcass composition of heifer calves.
The objective was to determine whether increased energy and protein intake between 2 and 14 wk of age would increase growth rates of heifer calves without fattening. At 2 wk of age, Holstein heifer calves were assigned to 1 of 4 treatments in a 2 x 2 factorial arrangement with 2 levels of protein and energy intake (moderate [M]; high [H]) in period 1 (2 to 8 wk of age) by 2 levels of protein and energy intake (low [L]; high [H]) in period 2 (8 to 14 wk of age) to produce similar initial BW for all 4 treatments. Treatments were ML, MH, HL, and HH, indicating moderate or high energy and protein intake during the first period and low or high intake during the second period. The M diet consisted of a standard milk replacer (21.3% CP, 21.3% fat) fed at 1.1% of BW on a DM basis and a 16.5% CP grain mix fed at restricted intake to promote 400 g of average daily gain (ADG), whereas the L diet consisted only of the grain mix. The H diet consisted of a high-protein milk replacer (30.3% CP, 15.9% fat) fed at 2% of BW on a DM basis and a 21.3% CP grain mix available ad libitum. Calves were weaned gradually from milk replacer by 7 wk and slaughtered at 8 (n = 11) or 14 wk of age (n = 41). In periods 1 and 2, ADG and the gain:feed ratio were greater for calves fed the H diet. Calves fed the H diet were taller after both periods 1 and 2. No difference was observed in carcass composition at 8 wk, but at 14 wk calves fed MH and HH had less water and more fat than calves fed ML and HL. Plasma IGF-I concentrations were greatest for calves fed the H diet during either period. Plasma leptin concentrations were increased in calves fed the H diet during period 1 from 4 to 6 wk of age. Increasing energy and protein intake from 2 to 8 wk and 8 to 14 wk of age increased BW, withers height, and gain:feed ratio. Calves fed the H diet from 8 to 14 wk of age had more body fat than calves fed the L diet. Increased energy and protein intake can increase the rate of body growth of heifer calves and potentially reduce rearing costs. Topics: Adipose Tissue; Animal Feed; Animals; Biometry; Body Composition; Body Weight; Cattle; Costs and Cost Analysis; Diet; Dietary Proteins; Energy Intake; Female; Health Status; Insulin-Like Growth Factor I; Leptin; Weight Gain | 2005 |
Ghrelin stimulates appetite, imagination of food, GH, ACTH, and cortisol, but does not affect leptin in normal controls.
Ghrelin, a growth hormone (GH) secretagogue receptor ligand was isolated from the stomach and hypothalamus of rats and humans. In rodents, ghrelin exerts distinct orexigenic action, probably as counterpart of the anorexigenic leptin. In humans, ghrelin infusion enhances appetite. It is unknown whether single intravenous (i.v.) injections of ghrelin affect human eating behavior. Therefore, we investigated the influence of a single i.v. bolus injection of 100 microg ghrelin on appetite, ideas about food, hormone levels, and glucose concentration in young control subjects. In order to test gender differences, we included five women and four men. After ghrelin administration, appetite was enhanced in eight of nine subjects. Seven probands reported a vivid, plastic image of their preferred meal. Furthermore, ghrelin stimulated an immediate increase in plasma levels of GH (area under the curve, mean+/-SEM 35+/-16 ng/ml x min after placebo [P] to 2808+/-533 ng/ml x min after ghrelin [G]; p<0.001), cortisol (5908+/-984 ng/ml x min [P] to 10179+/-1293 ng/ml x min [G]; p<0.001), and ACTH (922+/-103 pg/ml x min [P] to 3030+/-763 pg/ml x min [G]; p<0.02), whereas leptin levels remained unchanged. Contrary to placebo, glucose concentration did not decrease markedly after administration of ghrelin. Our data suggest that i.v. ghrelin stimulates appetite and images of food in young women and men. Obviously, leptin is not involved in these effects. Topics: Adrenocorticotropic Hormone; Adult; Aging; Appetite Stimulants; Blood Glucose; Body Weight; Female; Food; Ghrelin; Human Growth Hormone; Humans; Hunger; Hydrocortisone; Imagination; Individuality; Injections, Intravenous; Leptin; Male; Peptide Hormones; Sex Characteristics | 2005 |
Plasma leptin in men and women with seasonal affective disorder and in healthy matched controls.
Seasonal affective disorder (SAD) is a specific clinical entity characterized by recurrent episodes of depression, which typically occur during the winter with periods of remission during the spring and summer. These depression episodes are accompanied by hyperphagia with cravings for carbohydrates and moderate weight gain, and usually respond to light therapy. We examined potential relationships between leptin, a hormone known to affect appetite and weight regulation, and seasonal changes in mood and appetite by measuring plasma leptin, clinical severity of depression, appetite scores, and body mass index (BMI) in 19 women and 8 men with SAD and matched controls (20 women and 8 men) in the summer and winter. Plasma leptin was positively correlated with BMI in patients and controls during both seasons. Women and men with SAD both experienced depression in the winter, which was associated with increased appetite, caloric intake, and carbohydrate craving. Increased body weight during the winter in subjects with SAD was paralleled by a lack of concomitant changes in plasma leptin, which suggests that leptin sensitivity to changes in body weight may be influenced by seasons in subjects with SAD, similar to seasonal mammals. Topics: Adult; Appetite Regulation; Body Mass Index; Body Weight; Chronobiology Phenomena; Female; Humans; Leptin; Male; Matched-Pair Analysis; Middle Aged; Seasonal Affective Disorder; Seasons; Severity of Illness Index | 2005 |
Increased serum resistin levels in patients with type 2 diabetes are not linked with markers of insulin resistance and adiposity.
The role of resistin in human biology remains uncertain. We measured serum resistin levels in Japanese patients with (n=111) and without (n=98) type 2 diabetes mellitus and investigated the significance of this hormone in the pathophysiology of diabetes. The levels of serum adiponectin and leptin were also measured. Resistin levels were increased significantly in patients with type 2 diabetes compared with non-diabetic subjects (24.7+/-2.6 vs. 15.0+/-1.2 ng/ml, p=0.0013). However, there was no correlation in either patient group between serum resistin levels and markers of insulin resistance, obesity or hyperlipidaemia. These results were in direct contrast to the data of leptin or adiponectin, both of which were closely related to these clinical markers of diabetes. Multivariate regression analysis on the combined data of the two groups demonstrated that the presence of diabetes and HDL cholesterol levels were significant predictors of serum resistin levels (diabetes: beta=0.159, p=0.035; HDL: beta=-0.172, p=0.039). No correlation was observed between C-reactive protein and resistin adjusted for BMI. Taken together, these findings demonstrate that serum resistin levels are increased in patients with type 2 diabetes, but this increase is not linked to markers of insulin resistance or adiposity. Further studies are necessary to elucidate the significance of serum resistin concentration in human pathophysiology. Topics: Adiponectin; Aged; Biomarkers; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Hormones, Ectopic; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Patient Selection; Reference Values; Resistin | 2005 |
Plasma leptin concentration increases early during highly active antiretroviral therapy for acquired immunodeficiency syndrome, independent of body weight.
Leptin, the protein product of the obese gene (ob), is secreted by adipocytes. Circulating leptin levels correlate with fat mass in humans, including individuals infected with HIV. Leptin serves as an adipostatic hormone, a permissive factor for reproduction and a modulator of immune function. Leptin is a cytokine, and has been demonstrated to enhance CD4 cell proliferation and IL-2 secretion from CD4 cells in vitro. The role of leptin in HIV-positive patients treated with highly active antiretroviral therapy (HAART) has not been well defined. We haveevaluated leptin levels in HIV-infected individualsduringthe early phase of HAART. We measured plasma leptin levels in 15 antiretroviral-naive HIV positive patients at baseline and after 1 and 4 weeks of HAART. After the first week of therapy, mean leptin level and CD4 count were increased compared to baseline, 6.0 vs 7.2 ng/ml (p = 0.004) and 377 vs 432 cells/ul (p = 0.014), respectively. In contrast, mean body mass index (BMI) remained unchanged 27.0 vs 26.8 kg/m2 (p < 0.08). After four weeks of therapy, leptin and BMI values were unchanged compared to baseline, 6.0 vs 5.9 (p < 0.4) and 27.0 vs 26.9 (p < 0.5), respectively, whereas CD4 count continued to increase to 491 cells/ul (p < 0.012 compared to baseline). These data demonstrate an early transient increase in plasma leptin levels in HIV positive patients initiated on HAART, despite a lack of change in BMI. It is unclear if the transient increase in leptin is related to its role as a cytokine, a metabolic regulator, or reproductive factor. Topics: Antiretroviral Therapy, Highly Active; Body Mass Index; Body Weight; CD4 Lymphocyte Count; HIV Infections; HIV Seropositivity; Humans; Leptin | 2005 |
A high-protein diet induces sustained reductions in appetite, ad libitum caloric intake, and body weight despite compensatory changes in diurnal plasma leptin and ghrelin concentrations.
Ad libitum, low-carbohydrate diets decrease caloric intake and cause weight loss. It is unclear whether these effects are due to the reduced carbohydrate content of such diets or to their associated increase in protein intake.. We tested the hypothesis that increasing the protein content while maintaining the carbohydrate content of the diet lowers body weight by decreasing appetite and spontaneous caloric intake.. Appetite, caloric intake, body weight, and fat mass were measured in 19 subjects placed sequentially on the following diets: a weight-maintaining diet (15% protein, 35% fat, and 50% carbohydrate) for 2 wk, an isocaloric diet (30% protein, 20% fat, and 50% carbohydrate) for 2 wk, and an ad libitum diet (30% protein, 20% fat, and 50% carbohydrate) for 12 wk. Blood was sampled frequently at the end of each diet phase to measure the area under the plasma concentration versus time curve (AUC) for insulin, leptin, and ghrelin.. Satiety was markedly increased with the isocaloric high-protein diet despite an unchanged leptin AUC. Mean (+/-SE) spontaneous energy intake decreased by 441 +/- 63 kcal/d, body weight decreased by 4.9 +/- 0.5 kg, and fat mass decreased by 3.7 +/- 0.4 kg with the ad libitum, high-protein diet, despite a significantly decreased leptin AUC and increased ghrelin AUC.. An increase in dietary protein from 15% to 30% of energy at a constant carbohydrate intake produces a sustained decrease in ad libitum caloric intake that may be mediated by increased central nervous system leptin sensitivity and results in significant weight loss. This anorexic effect of protein may contribute to the weight loss produced by low-carbohydrate diets. Topics: Adult; Appetite; Area Under Curve; Body Composition; Body Weight; Circadian Rhythm; Dietary Proteins; Energy Intake; Ghrelin; Humans; Insulin; Leptin; Middle Aged; Peptide Hormones; Satiation | 2005 |
Megestrol acetate in a moderate dose for the treatment of malnutrition-inflammation complex in maintenance dialysis patients.
Malnutrition-inflammation complex syndrome and anorexia, common conditions in maintenance dialysis patients, are strongly associated with higher mortality and hospitalization and lower quality of life (QoL) in this population. Megestrol acetate, 800 mg/day, has been shown to increase appetite and food intake and to mitigate inflammation in cachectic AIDS and cancer patients, leading to weight gain, but it is also associated with side effects at this dose.. We evaluated the efficacy of the oral solution of megestrol acetate in half of its conventional dose in improving the nutritional state and inflammation in 10 hypoalbuminemic dialysis patients (albumin < 3.7 g/dL). Six women and 4 men, ages 60.2 years, took 400 mg of megestrol acetate solution daily for 16 weeks. Anthropometry, dual energy x-ray absorptiometry, 24-hour diet recalls, and biochemical measurements of nutrition and inflammation, including serum C-reactive protein and leptin, were performed.. At the end of the 16 weeks of intervention, weight and body mass index increased by 9%, body fat proportion by 31%, and triceps skinfold by 40% (P < .01). Serum albumin increased from 3.0 to 3.3 g/dL and continued to increase significantly to 3.6 g/dL after 3 months postintervention (P = .03). Serum leptin increased from 5.2 to 10.7 ng/mL (P = .09). Daily protein and energy intake increased progressively up to 27% to 42% by the end of the trial (P < or = .01). In 8 patients without acute infection, serum C-reactive protein declined from 1.24 to 0.78 mg/L (P = .06). QoL and appetite were reported to be improved. No major side effects were observed, and all 10 patients completed the 16 weeks of daily intake of megestrol acetate without interruption.. Megestrol acetate oral solution in half of its conventional dose is safe and improves the nutritional state, inflammation, and anorexia in maintenance dialysis patients. Larger-scale placebo-controlled randomized studies are needed to confirm the beneficial effects of 400 mg/day of megestrol acetate in dialysis patients. Topics: Adult; Aged; Aged, 80 and over; Anorexia; Anthropometry; Body Composition; Body Mass Index; Body Weight; C-Reactive Protein; Dietary Proteins; Energy Intake; Female; Humans; Hypoalbuminemia; Inflammation; Kidney Failure, Chronic; Leptin; Male; Megestrol Acetate; Middle Aged; Nutritional Status; Prospective Studies; Protein-Energy Malnutrition; Renal Dialysis; Serum Albumin; Syndrome; Treatment Outcome | 2005 |
Efficacy of a novel calcium/potassium salt of (-)-hydroxycitric acid in weight control.
The weight-loss efficacy of a novel, water-soluble, calcium-potassium salt of (-)-hydroxycitric acid (HCA-SX) was re-examined in 90 obese subjects (BMI: 30-50.8 kg/m2). We combined data from two previously reported randomized, double-blind, placebo-controlled clinical studies in order to achieve a better statistical evaluation based on a larger population. This re-examination of data also allowed us to reflect more intensely on various aspects of weight loss studies. Subjects were randomly divided into three groups: group A received a daily dose of HCA-SX 4, 667 mg (providing 2,800 mg HCA per day); group B was given a daily dose of a combination of HCA-SX 4,667 mg, niacin-bound chromium (NBC) 4 mg (providing 400 microg elemental chromium), and Gymnema sylvestre extract (GSE) 400 mg (providing 100 mg gymnemic acid); and group C received a placebo in three equally divided doses 30-60 min before each meal. All subjects were provided a 2,000 kcal diet/day and participated in a supervised walking program for 30 min/day, 5 days/week. Eighty-two subjects completed the study. At the end of 8 weeks, in group A, both body weight and BMI decreased by 5.4%, low-density lipoprotein and triglycerides levels were reduced by 12.9% and 6.9%, respectively, while high-density lipoprotein levels increased by 8.9%, serum leptin levels decreased by 38%, serotonin levels increased by 44.5% and urinary excretion of fat metabolites increased by 32-109%. Group B demonstrated similar beneficial changes, but generally to a greater extent. No significant adverse effects were observed. The combined results confirm that HCA-SX and, to a greater degree, the combination of HCA-SX plus NBC and GSE reduce body weight and BMI, suppress appetite, improve blood lipid profiles, increase serum leptin and serotonin levels and increase fat oxidation more than placebo. We conclude that dosage levels, timing of administration, subject compliance and bioavailability of HCA-SX significantly affect results and that when taken as directed, HCA-SX is a highly effective adjunct to healthy weight control. Topics: Adult; Anti-Obesity Agents; Body Mass Index; Body Weight; Calcium; Chromium; Citrates; Double-Blind Method; Drug Therapy, Combination; Gymnema sylvestre; Humans; Leptin; Lipids; Middle Aged; Niacin; Obesity; Plant Preparations; Potassium; Serotonin; Solubility; Treatment Outcome | 2005 |
High protein intake sustains weight maintenance after body weight loss in humans.
A relatively high percentage of energy intake as protein has been shown to increase satiety and decrease energy efficiency during overfeeding.. To investigate whether addition of protein may improve weight maintenance by preventing or limiting weight regain after weight loss of 5-10% in moderately obese subjects.. In a randomized parallel design, 148 male and female subjects (age 44.2 +/- 10.1 y; body mass index (BMI) 29.5 +/- 2.5 kg/m2; body fat 37.2 +/- 5.0%) followed a very low-energy diet (2.1 MJ/day) during 4 weeks. For subsequent 3 months weight-maintenance assessment, they were stratified according to age, BMI, body weight, restrained eating, and resting energy expenditure (REE), and randomized over two groups. Both groups visited the University with the same frequency, receiving the same counseling on demand by the dietitian. One group (n=73) received 48.2 g/day additional protein to their diet. Measurements at baseline, after weight loss, and after 3 months weight maintenance were body weight, body composition, metabolic measurements, appetite profile, eating attitude, and relevant blood parameters.. Changes in body mass, waist circumference, REE, respiratory quotient (RQ), total energy expenditure (TEE), dietary restraint, fasting blood-glucose, insulin, triacylglycerol, leptin, beta-hydroxybutyrate, glycerol, and free fatty acids were significant during weight loss and did not differ between groups. During weight maintenance, the 'additional-protein group' showed in comparison to the nonadditional-protein group 18 vs 15 en% protein intake, a 50% lower body weight regain only consisting of fat-free mass, a 50% decreased energy efficiency, increased satiety while energy intake did not differ, and a lower increase in triacylglycerol and in leptin; REE, RQ, TEE, and increases in other blood parameters measured did not differ.. A 20% higher protein intake, that is, 18% of energy vs 15% of energy during weight maintenance after weight loss, resulted in a 50% lower body weight regain, only consisting of fat-free mass, and related to increased satiety and decreased energy efficiency. Topics: Adolescent; Adult; Attitude to Health; Body Mass Index; Body Weight; Dietary Proteins; Energy Metabolism; Exercise; Female; Humans; Leptin; Male; Middle Aged; Obesity; Satiation; Secondary Prevention; Weight Loss | 2004 |
Unchanged fasting and postprandial adiponectin levels following a 4-day caloric restriction in young healthy men.
Adiponectin is an adipocyte-secreted protein that has been shown to promote fat oxidation and insulin sensitivity in animals. Whether acute energy restriction is associated with modulation of adiponectin in humans remains largely unknown. The purpose of this study was to examine the effects of a short-term caloric restriction on fasting and postprandial adiponectin levels in young healthy men.. Fifteen young healthy men were subjected to a 4-day energy restricted diet (-800 kcal/day). Before and after the intervention, anthropometric measurements, fasting and postprandial glucose, insulin and adiponectin were measured at 0, 30 and 60 min after a fixed breakfast.. While fat mass remained stable, minor but significant changes in weight were observed after the 4-day energy-restricted diet. Glucose and insulin levels increased postprandially, and patterns did not differ before and after the intervention. Fasting levels of adiponectin remained unchanged after the energy restriction, and postprandial levels were not significantly different from fasting levels either before, or after, the intervention.. Fasting and postprandial adiponectin levels are not acutely modulated by a short-term energy restriction in young healthy men. Topics: Adiponectin; Adult; Analysis of Variance; Blood Glucose; Body Composition; Body Weight; Caloric Restriction; Fasting; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Postprandial Period; Proteins; Time Factors | 2004 |
Leptin levels as function of age, gender, auxological and hormonal parameters in 202 healthy neonates at birth and during the first month of life.
Leptin signals to the brain energy stores and balance while integrating neuroendocrine functions. Leptin levels in adults are higher in females than in males, while a gender-related difference in newborns is controversial. To clarify this point, in 202 healthy neonates we measured dynamic changes in leptin levels over the first month of life and looked for correlation between leptin levels and auxological and hormonal parameters. Cord leptin concentration in females was higher (p < 0.001) than in males. IGF-I, IGF-II, insulin, testosterone and 17beta-estradiol levels were similar in both sexes while insulin-like growth factor binding protein 3 (IGF-BP3) levels in females were slightly higher than in males. Leptin levels were positively associated to body weight, gestational age, IGF-BP3 levels, insulin levels and maternal body mass index (BMI) at time of delivery. In a subset of subjects (no. = 65), in comparison with cord levels, serum leptin levels were decreased on the 5th day of life (p < 0.0001) and then increased at 1 month (p < 0.0001). Positive association between leptin and weight was lost on the 5th day of life but present again at 1 month. In conclusion, our findings in a large population of neonates definitely show that leptin levels at birth are functions of gender, body weight and gestational age but not of length, cranial circumference, IGF-I and IGF-II levels. These findings, coupled with weight-independent prompt decrease after birth followed by weight-dependent increase at one month of life, suggest that leptin secretion in neonates as well as in adults mainly signals the nutritional state to the brain. Topics: Adult; Aging; Body Constitution; Body Weight; Female; Gestational Age; Hormones; Humans; Infant, Newborn; Leptin; Male; Nutritional Status; Reference Values; Sex Factors; Somatomedins | 2004 |
Efficacy of orlistat as an adjunct to behavioral treatment in overweight African American and Caucasian adolescents with obesity-related co-morbid conditions.
This pilot study compared the efficacy of orlistat as an adjunctive treatment for obesity between African American and Caucasian adolescents. Twenty obese adolescents with obesity-related co-morbid conditions underwent measurements of body composition, glucose homeostasis by frequently sampled intravenous glucose tolerance test (FSIGT), and fasting lipids before and after 6 months treatment with orlistat 120 mg tid in conjunction with a comprehensive behavioral program. Weight (p < 0.05), BMI (p < 0.001), total cholesterol (p < 0.001), LDL cholesterol (p < 0.001), fasting insulin (p < 0.02) and fasting glucose (p < 0.003) were lower after treatment. Insulin sensitivity, measured during the FSIGT, improved significantly (p < 0.02), as did fasting indices such as the homeostasis model assessment for insulin resistance (p < 0.01). African American subjects exhibited significantly less improvement in weight (p < 0.05), BMI (p < 0.01), waist circumference (p = 0.03), and insulin sensitivity (p = 0.05). Improvements in cholesterol were not significantly different between African Americans and Caucasians. We conclude that Caucasians lost more weight and had greater improvements in insulin sensitivity than African Americans, but both exhibited improvements in plasma lipids. The true benefit of orlistat treatment over a comprehensive behavioral program remains to be determined in placebo-controlled trials. Topics: Administration, Oral; Adolescent; Behavior Therapy; Black or African American; Blood Glucose; Body Weight; Capsules; Cholesterol, LDL; Clinical Trials as Topic; Comorbidity; Drug Administration Schedule; Energy Metabolism; Female; Humans; Insulin Resistance; Lactones; Leptin; Male; Obesity; Orlistat; Pilot Projects; Treatment Outcome; White People | 2004 |
Weight and leptin changes among risperidone-treated youths with autism: 6-month prospective data.
The authors examined the developmental impact and temporal characteristics of risperidone-associated weight change.. Weight change was measured for 63 children and adolescents with autism treated with risperidone for 6 months. Change in serum leptin levels after 2 months was examined as a predictor of final weight gain in mixed regression models that controlled for site, gender, age, and risperidone dose.. Age- and gender-standardized weight increased after 6 months of treatment (gross: mean=5.6 kg [SD=3.9]; standardized: mean=0.6 z [SD=0.5]) and was positively correlated with weight gained after 1 month. Change in leptin levels after 2 months of treatment (mean=-0.3 ng/ml, SD=6.2) (N=48) did not predict final weight gain.. Chronic risperidone exposure in children with autism causes weight gain in excess of developmentally expected norms that follows a curvilinear trajectory and decelerates over time. Serum leptin change does not reliably predict risperidone-associated weight gain. Topics: Adolescent; Age Factors; Antipsychotic Agents; Autistic Disorder; Body Mass Index; Body Weight; Child; Child, Preschool; Female; Humans; Leptin; Male; Prospective Studies; Risperidone; Weight Gain | 2004 |
Adiponectin relationship with lipid metabolism is independent of body fat mass: evidence from both cross-sectional and intervention studies.
Adiponectin influences insulin sensitivity and lipid metabolism, but it is not clear whether these effects are correlated with fat mass or distribution. We studied the relationship between plasma adiponectin and leptin levels, insulin sensitivity, and serum lipids by a cross-sectional study (n = 242 subjects) and by an intervention study (95 of 242) to evaluate the effect of weight loss (WL). Considering all subjects both together and subdivided into nonobese (n = 107) and obese (n = 135) groups, plasma adiponectin, but not plasma leptin, was significantly (P < 0.01) correlated with insulin sensitivity [homeostasis model assessment of insulin-resistance index (HOMAIR), insulin sensitivity index (ISI) at oral glucose tolerance test, and clamp in 115 of 242 individuals], high-density lipoprotein cholesterol, and triglycerides. These relationships were still significant (P < 0.01) after adjusting for age, gender, body mass index (BMI), and ISI. After WL (-16.8 +/- 0.8%), plasma adiponectin increased, and plasma leptin decreased (P < 0.0001 for both). Their changes (Delta) were significantly correlated with Delta-BMI (P < 0.05 for both). Delta-Adiponectin, but not Delta-leptin, significantly (P < 0.001) correlated with Delta-high-density lipoprotein cholesterol and Delta-triglycerides; these correlations were independent of age, gender, Delta-BMI, and Delta-ISI (P < 0.005). In conclusion, both cross-sectional and intervention studies indicate that plasma adiponectin level correlates with serum lipids independently of fat mass. The intervention study also suggests that adiponectin increase after WL is correlated with serum lipid improvement independently of insulin sensitivity changes. Topics: Adiponectin; Adipose Tissue; Adolescent; Adult; Age Factors; Aged; Body Composition; Body Weight; Cholesterol, HDL; Cross-Sectional Studies; Female; Glucose Clamp Technique; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Obesity; Proteins; Triglycerides; Weight Loss | 2004 |
Effects of laparoscopic ovarian drilling on young adult women with polycystic ovarian syndrome.
To assess changes in serum hormone levels and ovarian stromal blood flow after laparoscopic ovarian drilling (LOD) in young adult women with polycystic ovary syndrome (PCOS).. Prospective, nonrandomized study (Canadian Task Force classification II-1).. Tertiary care, major teaching hospitals.. Anovulatory young women with PCOS who were resistant to clomiphene citrate.. Laparoscopic ovarian drilling.. To evaluate the endocrinological effects of LOD, serum leptin, insulin-like growth factor-1, estrone (E1), and estradiol were measured before and after ovarian drilling in the early follicular phase. Three-dimensional transabdominal power Doppler examinations were performed to determine the effects of LOD. Serum leptin was correlated with body mass index (BMI) before LOD. Levels of BMI, fasting blood sugar, and leptin were higher and LH, LH/FSH, and the sugar/insulin ratio were lower in the obese group. There were significant decreases in the free androgen index, and total testosterone, luteinizing hormone (LH), and LH/follicle-stimulating hormone (FSH) levels, and a significant increase in sex hormonebinding globulin (SHBG) concentration in the 3 months after the operation. The vascularization index and vascularization flow index of the intraovarian stroma significantly decreased after treatment. Reversed correlations between leptin and LH, LH/FSH, E1, thyroid-stimulating hormone, and SHBG were noted 3 months after the operation compared with levels obtained before the operation.. Treatment of young adult women with PCOS using LOD did not influence leptin levels but changed the ovarian stromal blood flow dynamics during short-term follow-up. The surgical procedure may be beneficial both to endocrine profiles and to intraovarian stromal flow in patients with PCOS. Topics: Adolescent; Adult; Age Factors; Body Mass Index; Body Weight; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Hormones; Humans; Laparoscopy; Leptin; Linear Models; Obesity; Polycystic Ovary Syndrome; Probability; Prospective Studies; Risk Assessment; Severity of Illness Index; Treatment Outcome; Ultrasonography, Doppler, Color | 2004 |
Effect of fish diets and weight loss on serum leptin concentration in overweight, treated-hypertensive subjects.
Leptin, a circulating hormone secreted from adipocytes, is an index of adiposity and is reduced by caloric restriction and weight loss. A recent population study suggested that dietary-derived omega3 fatty acids lower leptin levels independent of body fat.. To examine whether dietary fish enhanced the effects of weight loss on serum leptin levels, in 69 overweight, treated hypertensive men and women.. Participants were randomized to a daily fish meal, a weight-reduction regimen, the two regimens combined or a control group for 16 weeks.. A total of 63 individuals completed the study. Weight fell 5.6 +/- 0.8 kg with energy-restriction. Blood pressure (BP) reductions in the combined fish-weight loss group were twice that seen with either intervention alone. At baseline, in all groups combined, serum leptin levels correlated with serum insulin (r = 0.307, P = 0.014), but not with body weight. The greatest change in serum leptin occurred in the fish-weight loss group (control, 0.60 +/- 0.76 ng/ml; fish, 1.20 +/- 0.79 ng/ml; weight loss, -1.40 +/- 1.05 ng/ml; fish-weight loss, -5.08 +/- 1.64 ng/ml). In the fish-weight loss group, the change in serum leptin was predicted by changes in serum insulin (r = 0.488, P = 0.038), 24-h BP (systolic BP (SBP): r = 0.435, P = 0.060; diastolic BP (DBP): r = 0.563, P = 0.018) and 24-h heart rate (0.584, P = 0.028). Using general linear models, there was a significant fish x weight-loss interaction (P = 0.008) on post-intervention serum leptin after adjustment for baseline levels, independent of post-intervention insulin.. A daily fish meal as part of a weight-reducing regimen was more effective than either measure alone at reducing leptin levels. Reductions in leptin may be related to the substantial fall in BP seen with the fish-weight loss program. Topics: Animals; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Body Weight; Diet; Diet, Reducing; Energy Intake; Fatty Acids; Female; Fishes; Heart Rate; Humans; Hypertension; Insulin; Leptin; Lipids; Male; Middle Aged; Obesity; Phospholipids; Weight Loss | 2004 |
Serum leptin concentrations in children with mild protein-energy malnutrition and catch-up growth.
The aim of the present study was to clarify the relationship between changing nutritional anthropometric data and serum leptin concentrations during the catch-up growth process in children.. Thirty children with mild protein-energy malnutrition (PEM) were followed for 6 months and their anthropometric measurements and serum leptin concentrations were recorded during follow up.. Twenty-two (73.3%) of the 30 children showed catch-up growth. All parameters and serum leptin concentrations increased during the period of catch-up growth. In the remaining eight children, weight for height, percentage standard body mass index, percentage standard body height and mean serum leptin concentrations did not show any significant increase at the 6 month follow-up. Mean serum leptin concentration was higher in children with catch-up growth than in the controls.. During recovery from malnutrition, leptin concentrations increase in relation to fat mass if the fat mass reaches a critical point, and leptin might trigger catch-up growth with its regulator effects on growth. Although weight gain was noted in both groups, an increase in leptin concentration was observed only in children who showed catch-up growth. More interestingly, the mean leptin concentration was much higher in children with PEM who had catch-up growth compared to the control group and in children who failed to have catch-up growth. In children with catch-up growth, the higher serum leptin concentrations compared to healthy children and to children without catch-up growth despite significant weight gain suggests that leptin affects nutritional status in catch-up growth as a dynamic process, rather than merely being an index of body fat content. Topics: Body Height; Body Weight; Child; Child, Preschool; Female; Follow-Up Studies; Growth; Humans; Infant; Leptin; Male; Outpatients; Protein-Energy Malnutrition; Skinfold Thickness | 2004 |
Endocrine and metabolic effects of physiologic r-metHuLeptin administration during acute caloric deprivation in normal-weight women.
Leptin is a nutritionally regulated hormone that may modulate neuroendocrine function during caloric deficit. We hypothesized that administration of low-dose leptin would prevent changes in neuroendocrine function resulting from short-term caloric restriction. We administered physiologic doses of r-metHuLeptin [(0.05 mg/kg sc daily or identical placebo in divided doses (0800, 1400, 2000, and 0200 h)] to 17 healthy, normal-weight, reproductive-aged women during a 4-d fast. Leptin levels were lower in the placebo-treated group during fasting (3.3 +/- 0.2 vs. 9.6 +/- 1.0 ng/ml, P < 0.001, placebo vs. leptin-treated at end of study). Fat mass decreased more in the leptin than the placebo-treated group (-0.6 +/- 0.1 vs. -0.2 +/- 0.1 kg, P = 0.03). Both overnight LH area (38.9 +/- 21.5 vs. 1.2 +/- 11.1 microIU/ml.min, P = 0.05) and LH peak width increased (15.8 +/- 7.1 vs. -2.3 +/- 6.7 min, P = 0.06) and LH pulsatility decreased (-2.0 +/- 0.9 vs. 1.0 +/- 0.8 peaks/12 h, P = 0.03) more in the leptin vs. placebo group. LH pulse regularity was higher in the leptin-treated group (P = 0.02). Twenty-four-hour mean TSH decreased more in the placebo than the leptin-treated group, respectively (-1.06 +/- 0.27 vs. -0.32 +/- 0.18 microIU/ml, P = 0.03). No differences in 24-h mean GH, cortisol, IGF binding protein-1, and IGF-I were observed between the groups. Hunger was inversely related to leptin levels in the subjects randomized to leptin (r = -0.76, P = 0.03) but not placebo (r = -0.18, P = 0.70) at the end of the study. Diminished hunger was seen among subjects achieving the highest leptin levels. Our data provide new evidence of the important role of physiologic leptin regulation in the neuroendocrine response to acute caloric deprivation. Topics: Adult; Body Composition; Body Weight; Caloric Restriction; Double-Blind Method; Energy Metabolism; Female; Humans; Hunger; Leptin; Luteinizing Hormone; Thyroid Hormones; Thyrotropin | 2004 |
Carnitine and choline supplementation with exercise alter carnitine profiles, biochemical markers of fat metabolism and serum leptin concentration in healthy women.
We sought to determine the effects of supplementary choline, carnitine and a combination of the two with or without exercise on serum and urinary carnitine and biochemical markers of fatty acid oxidation in healthy humans. Nineteen women were placed in three groups: 1) placebo, choline or carnitine preloading period of 1 wk followed by 2) supplementation with choline plus carnitine during wk 2-wk 3 and 3) all groups exercised in wk 3. Although there were no changes in the placebo group, serum and urinary carnitine decreased in the choline-supplemented group during wk 1. Introduction of carnitine to the choline group restored serum and urinary carnitine. Serum and urinary carnitine increased during wk 1 in the carnitine-supplemented group and, although the introduction of choline to this group depressed serum and urinary carnitine, they remained significantly greater than control. Serum beta-hydroxybutyrate and serum as well as urinary acetylcarnitine were elevated by the supplements. A mild exercise regimen increased the concentration of serum beta-hydroxybutyrate, and serum and urinary acylcarnitines; it also decreased serum leptin concentrations in all groups. The effects of supplements were sustained until wk 2 after cessation of choline plus carnitine supplementation and exercise. We conclude that the choline-induced decrease in serum and urinary carnitine is buffered by carnitine preloading, and these supplements shift tissue partitioning of carnitine that favors fat mobilization, incomplete oxidation of fatty acids and disposal of their carbons in urine as acylcarnitines in humans. Topics: 3-Hydroxybutyric Acid; Adipose Tissue; Adult; Body Constitution; Body Weight; Carnitine; Choline; Diet; Exercise; Female; Humans; Leptin; Middle Aged | 2003 |
The conjugated linoleic acid (CLA) isomer, t10c12-CLA, is inversely associated with changes in body weight and serum leptin in subjects with type 2 diabetes mellitus.
Isomers of conjugated linoleic acid (CLA) are found in beef, lamb and dairy products. Diets containing CLA reduce adipose mass in various depots of experimental animals. In addition, CLA delays the onset of diabetes in the ZDF rat model for obesity-linked type 2 diabetes mellitus. We hypothesize that there would be an inverse association of CLA with body weight and serum leptin in subjects with type 2 diabetes mellitus. In this double-blind study, subjects with type 2 diabetes mellitus were randomized into one of two groups receiving either a supplement containing mixed CLA isomers (CLA-mix; 8.0 g daily, 76% pure CLA; n = 12) or a supplement containing safflower oil (placebo; 8.0 g daily safflower oil, n = 9) for 8 wk. The isomers of CLA in the CLA-mix supplement were primarily c9t11-CLA ( approximately 37%) and t10c12-CLA ( approximately 39%) in free fatty acid form. Plasma levels of CLA were inversely associated with body weight (P < 0.05) and serum leptin levels (P < 0.05). When levels of plasma t10c12-CLA isomer were correlated with changes in body weight or serum leptin, t10c12-CLA, but not c9t11-CLA, was inversely associated with body weights (P < 0.05) and serum leptin (P < 0.02). These findings strongly suggest that the t10c12-CLA isomer may be the bioactive isomer of CLA to influence the body weight changes observed in subjects with type 2 diabetes. Future studies are needed to determine a causal relationship, if any, of t10c12-CLA or c9t11-CLA to modulate body weight and composition in subjects with type 2 diabetes. Furthermore, determining the ability of CLA isomers to influence glucose and lipid metabolism as well as markers of insulin sensitivity is imperative to understanding the role of CLA to aid in the management of type 2 diabetes and other related conditions of insulin resistance. Topics: Adult; Animals; Body Weight; Diabetes Mellitus, Type 2; Humans; Leptin; Linoleic Acid; Obesity; Randomized Controlled Trials as Topic | 2003 |
Effect of heavy increase in training stress on the plasma leptin concentration in highly trained male rowers.
To characterize the effects of a heavy increase in training stress followed by a reduced stress on fasting plasma leptin levels in highly trained male rowers.. 12 rowers underwent a 3-week period of maximally increased training stress followed by a 2-week tapering period.. A mean 22% increase in training stress caused a significant decrease (by 8%) in the leptin concentrations. A further increase in training stress by 25% significantly reduced leptin further by 35%. A 1st tapering week, during which the training stress was rapidly reduced by approximately 50%, significantly increased the plasma leptin concentrations by 29%. Plasma leptin was significantly increased further (by 4%) during the 2nd tapering week.. Leptin is sensitive to pronounced changes in training stress in highly trained male rowers. Topics: Adult; Blood Glucose; Body Weight; Creatine Kinase; Fasting; Humans; Insulin; Leptin; Male; Physical Fitness; Stress, Physiological | 2003 |
In vivo assessment of the mitochondrial response to caloric restriction in obese women by the 2-keto[1-C]isocaproate breath test.
The 2-keto[1-(13)C]isocaproate breath test has been proposed as a tool to detect mitochondrial dysfunction in alcoholic liver disease. The aim of this study was to evaluate if the 2-keto[1-(13)C]isocaproate breath test could detect in vivo dynamic changes on mitochondrial activity due to caloric restriction in obese women. Fifteen obese women (body mass index [BMI] > 30 kg/m(2)) participated in the study at baseline. Ten of these women agreed to participate on a diet program to induce body weight loss. Fifteen lean women (BMI < 25 kg/m(2)) were included as a control group. The breath test was performed by the oral administration of the tracer measuring (13)CO(2) enrichment in breath before and after ingestion using isotope ratio mass spectrometry. Body composition, resting energy expenditure, and plasma levels of insulin and leptin were measured. There were no relationships observed between the 2-keto[1-(13)C]isocaproate breath test and the plasma insulin (before diet: P =.863; after diet: P =.879), or leptin (before diet: P =.500; after diet: P =.637). In obese women before treatment, kilograms of fat free mass (P =.108), resting energy expenditure adjusted for body composition (P =.312), and the 2-keto[1-(13)C]isocaproate breath test (P =.205) were similar in comparison to lean women. However, 2-keto[1-(13)C]isocaproate oxidation tended to increase after dieting and was significantly higher than in controls (P =.015). These data suggest that the 2-keto[1-(13)C]isocaproate breath test reflected the adaptive modifications in mitochondrial oxidation in response to caloric restriction in obese women. Topics: Adolescent; Adult; Body Composition; Body Weight; Breath Tests; Caloric Restriction; Energy Metabolism; Female; Humans; Insulin; Keto Acids; Kinetics; Leptin; Middle Aged; Mitochondria; Obesity; Oxidation-Reduction | 2003 |
The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men.
To elucidate the role of leptin in regulating neuroendocrine and metabolic function during an acute fast, six to eight healthy, lean men were studied under four separate conditions: a baseline fed state and three 72-hour fasting studies with administration of either placebo, low-dose recombinant-methionyl human leptin (r-metHuLeptin), or replacement-dose r-metHuLeptin designed to maintain serum leptin at levels similar to those in the fed state. Replacement-dose r-metHuLeptin administered during fasting prevents the starvation-induced changes in the hypothalamic-pituitary-gonadal axis and, in part, the hypothalamic-pituitary-thyroid axis and IGF-1 binding capacity in serum. Thus, in normal men, the fall in leptin with fasting may be both necessary and sufficient for the physiologic adaptations of these axes, which require leptin levels above a certain threshold for activation. In contrast to findings in mice, fasting-induced changes in the hypothalamic-pituitary-adrenal, renin-aldosterone, and growth hormone-IGF-1 axes as well as fuel utilization may be independent of leptin in humans. The role of leptin in normalizing several starvation-induced neuroendocrine changes may have important implications for the pathophysiology and treatment of eating disorders and obesity. Topics: Adult; Body Weight; Double-Blind Method; Eating; Energy Metabolism; Epinephrine; Fasting; Homeostasis; Human Growth Hormone; Humans; Hydrocortisone; Insulin-Like Growth Factor I; Leptin; Luteinizing Hormone; Male; Neurosecretory Systems; Testosterone; Thyroid Hormones | 2003 |
Relationship among systolic blood pressure, serum insulin and leptin, and visceral fat accumulation in obese children.
The aim of this study was to clarify the relation among systolic blood pressure (SBP), serum insulin, leptin, visceral fat accumulation and family history of hypertension, and to elucidate the pathophysiologic mechanism of blood pressure elevation in obese children. This study examined 109 obese children with a family history of hypertension (OF: 77 boys and 32 girls), and 83 obese children without such a history (ON: 60 boys and 23 girls). Body height and weight, and percent of body fat were measured and the percent of relative weight was calculated. Both boys and girls, the two groups were matched with respect to age, height, and weight. SBP was measured in the seated position using an automated recorder. Abdominal fat thickness (maximum preperitoneal fat thickness: Pmax; minimum subcutaneous fat thickness: Smin) were measured using ultrasonography. The fasting serum levels of insulin and leptin were measured by radioimmunoassay. All subjects were simply obese, without diabetic states. In both OF and ON, SBP was associated with insulin levels, leptin levels, and Pmax by simple regression analysis, and with insulin levels by stepwise regression analysis. Insulin levels were associated with leptin levels and Pmax by simple regression analysis, and with leptin levels by stepwise regression analysis. These findings indicated that SBP was associated with hyperinsulinemia, hyperleptinemia and visceral accumulation regardless of a family history of hypertension in obese children, as well as later in adult obesity. For primary prevention of hypertension, these results support the importance of implementation of a strategy to prevent obesity, especially visceral obesity. An effective strategy for preventing childhood obesity will contribute to a future decrement in cases of metabolic syndrome, including adulthood hypertension. Topics: Adipose Tissue; Adolescent; Blood Pressure; Body Height; Body Weight; Child; Female; Humans; Hypertension; Insulin; Leptin; Male; Obesity; Regression Analysis | 2003 |
Octreotide therapy of pediatric hypothalamic obesity: a double-blind, placebo-controlled trial.
Hypothalamic obesity is a devastating complication in children surviving brain tumors and/or cranial irradiation. These subjects are thought to exhibit autonomic dysregulation of the beta-cell, with insulin hypersecretion in response to oral glucose tolerance testing (OGTT). We report the results of a randomized, double-blind, placebo-controlled trial of octreotide therapy for pediatric hypothalamic obesity. Eighteen subjects [weight, 100.6 +/- 5.6 kg; body mass index (BMI), 37.1 +/- 1.3 kg/m(2)] received octreotide (5-15 microg/kg x d s.c.) or placebo for 6 months. With octreotide, Delta weight (mean +/- SEM) was +1.6 +/- 0.6 vs. +9.1 +/- 1.7 kg for placebo (P < 0.001). Delta BMI was -0.2 +/- 0.2 vs. +2.2 +/- 0.5 kg/m(2), respectively (P < 0.001). OGTT documented Delta insulin response (peak - basal) of -417 +/- 304 pM after octreotide vs. +216 +/- 215 pM after placebo (P = 0.034). Improvement in physical activity by parent report was noted with octreotide, but not placebo (P = 0.03). For the octreotide group, changes in quality of life positively correlated with changes in insulin response (P = 0.041). Complications and adverse events were mild and self-limited. These data demonstrate the beneficial effects of octreotide in pediatric hypothalamic obesity. Octreotide suppressed insulin, and stabilized weight and BMI. Improved quality of life correlated with the degree of insulin suppression. Octreotide was safe and well tolerated. Topics: Adolescent; Blood Glucose; Body Height; Body Mass Index; Body Weight; Child; Double-Blind Method; Energy Intake; Female; Hormones; Humans; Hypothalamic Diseases; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Obesity; Octreotide; Placebos; Quality of Life; Safety | 2003 |
Pathways linking depression, adiposity, and inflammatory markers in healthy young adults.
Despite mounting evidence that depression increases risk for cardiovascular morbidity and mortality, little is known about the mechanisms responsible for this association. The current study examined the inter-relationships between depression, adiposity, and inflammatory molecules implicated in the pathogenesis of coronary heart disease. One hundred adults were enrolled. Half were clinically depressed; the others were matched controls with no history of psychiatric illness. All subjects were in excellent health, defined as having no acute infectious disease, chronic medical illness, or prescribed medication regimen. Structural equation modeling yielded support for a model in which depressive symptoms promote weight accumulation, which in turn activates an inflammatory response through two distinct pathways: expanded adipose tissue release of interleukin-6 and leptin-induced upregulation of interleukin-6 release by white blood cells (CFI =.99; NNFI =.99; RMSEA =.05). It did not support a sickness behavior model in which the inflammatory molecules arising from expanded adipose tissue promote depressive symptoms. Topics: Adaptation, Physiological; Adult; Biomarkers; Body Weight; C-Reactive Protein; Depression; Evaluation Studies as Topic; Female; Humans; Inflammation; Interleukin-6; Leptin; Male; Matched-Pair Analysis; Models, Biological; Models, Statistical; Obesity; Psychoneuroimmunology; Signal Transduction | 2003 |
Circulating ghrelin levels in newborns are not associated to gender, body weight and hormonal parameters but depend on the type of delivery.
Ghrelin, a new gastric-derived hormone, probably plays a major role in managing energy balance and the neuroendocrine response to starvation. Information about the age-related variation in ghrelin secretion is scanty. We measured circulating ghrelin levels in 93 full term newborns adequate for gestational age, in 39 normal children and in 19 lean healthy adults. Our findings demonstrate that ghrelin levels are independent of age and gender from birth to adulthood. Interestingly, ghrelin secretion at birth is not associated to body weight and hormonal parameters such as GH, insulin and leptin levels. On the other hand, ghrelin levels seem dependent on the type of delivery, being lower in newborns after caesarean section with respect to those after normal delivery. Topics: Adult; Aging; Birth Weight; Blood Glucose; Body Weight; Cesarean Section; Child; Delivery, Obstetric; Energy Metabolism; Female; Fetal Blood; Ghrelin; Growth Hormone; Humans; Infant, Newborn; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Peptide Hormones; Sex Characteristics | 2003 |
Effects of recombinant human leptin treatment as an adjunct of moderate energy restriction on body weight, resting energy expenditure and energy intake in obese humans.
We explored the effects of recombinant human leptin (rL) as an adjunct of mild energy restriction (2092 kJ/day less than needed) in the treatment of obese humans as part of a larger multicentre trial. In a double blind, randomised, placebo (P)-controlled design, the effects of 10 mg of rL once daily vs twice daily (rL OD/BID, by s.c. injection) upon body weight, resting energy expenditure (REE) and energy intake were compared. The study groups comprised 9 (P), 15 (rL OD) and 6 (rL BID) healthy subjects (body mass index 27.5-35 kg/m2). We observed in both groups treated with rL a decline of body weight. [2.8+/-1.1 kg (P), 5.2+/-0.9 kg (rL OD), 7.9+/-1.4 kg (rL BID), p < 0.035]. No significant effects of rL treatment upon energy intake or REE were observed. However, rL tended to reduce the decline of energy expenditure associated with energy restriction, whereas the tendency of energy intake to increase back to baseline levels in placebo-treated subjects was largely prevented in subjects treated with rL. Thus, rL appears to enhance the loss of body weight in obese humans in a dose-dependent fashion if prescribed as an adjunct of energy restriction. This effect might be mediated by rL ability to counteract the behavioural and metabolic adaptations that accompany weight loss attempts. Topics: Adaptation, Physiological; Adult; Body Mass Index; Body Weight; Calorimetry, Indirect; Diet, Reducing; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Energy Intake; Energy Metabolism; Female; Humans; Injections, Subcutaneous; Leptin; Male; Middle Aged; Obesity; Recombinant Proteins | 2003 |
Circulating ghrelin levels are suppressed by meals and octreotide therapy in children with Prader-Willi syndrome.
Prader-Willi syndrome (PWS) is characterized by severe obesity, hyperphagia, hypogonadism, and GH deficiency. Unlike individuals with common obesity, who have low fasting-plasma ghrelin concentrations, those with PWS have high fasting-ghrelin concentrations that might contribute to their hyperphagia. Treatment with octreotide, a somatostatin agonist, decreases ghrelin concentrations in healthy and acromegalic adults and induces weight loss in children with hypothalamic obesity. This pilot study was performed to determine whether octreotide administration (5 microg/kg.d) for 5-7 d lowers ghrelin concentrations and affects body composition, resting energy expenditure, and GH markers in children with PWS. Octreotide treatment decreased mean fasting plasma ghrelin concentration by 67% (P < 0.05). Meal-related ghrelin suppression (-35%; P < 0.001) was still present after intervention but was blunted (-11%; P = 0.19). Body weight, body composition, leptin, insulin, resting energy expenditure, and GH parameters did not change. However, one subject's parent noted fewer tantrums over denial of food during octreotide intervention. In conclusion, short-term octreotide treatment markedly decreased fasting ghrelin concentrations in children with PWS but did not fully ablate the normal meal-related suppression of ghrelin. Further investigation is warranted to determine whether long-term octreotide treatment causes sustained ghrelin suppression, changes eating behavior, and induces weight loss in this population. Topics: Behavior; Body Composition; Body Weight; Child; Female; Food; Ghrelin; Hormones; Humans; Hyperphagia; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Obesity; Octreotide; Peptide Hormones; Pilot Projects; Prader-Willi Syndrome | 2003 |
Effect of insulin therapy on plasma leptin and body weight in patients with type 2 diabetes.
This study set out to define relationships between changes in plasma leptin and changes in body weight, plasma insulin and blood glucose control during a 12-month crossover study of once-daily Ultratard or twice-daily Insulatard insulin.. Fasting plasma leptin and insulin were measured during a multicentre cross-over study involving 60 subjects with type 2 diabetes (fasting glucose > 8 mM). After a 2-month run-in, there were two 6-month periods of treatment with Insulatard or Ultratard insulin.. Mean plasma leptin increased significantly in both groups after insulin therapy was instigated (12.8 +/- 8.1 to 22.9 +/- 13.1 ng/ml in the Insulatard group; 12.1 +/- 7.2 to 19.2 +/- 12.3 ng/ml in the Ultratard group). Weight also increased significantly in both groups (82.4 +/- 14.3 kg to 88.8 +/- 14.3 kg and 82.2 +/- 15.3 kg to 85.3 +/- 15.2 kg respectively). The increase in plasma leptin correlated well with the increase in weight (R = 0.416, p = 0.001), and this correlation continued after the crossover point. Plasma leptin correlated with BMI throughout the study (R = 0.540, p = 0.000).. The sustained rise in body weight despite a substantial increase in plasma leptin suggests that either resistance to the hypothalamic action of leptin develops when insulin therapy is begun in type 2 diabetes, or that resetting of the set point for body weight occurs such that a larger body mass is tolerated for a given level of plasma leptin. Topics: Body Mass Index; Body Weight; Cross-Over Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Humans; Insulin; Insulin, Isophane; Insulin, Long-Acting; Insulin, Regular, Human; Isophane Insulin, Human; Leptin; Male; Middle Aged | 2003 |
Serum leptin monitoring in anorectic patients during refeeding therapy.
Circulating concentrations of leptin are exceedingly low in severe malnutrition as seen in the acute state of anorexia nervosa (AN). During refeeding therapy plasma leptin levels increase to normal and in some cases peak at values in excess of the BMI of matched controls even before a normal body weight has been achieved. Peak leptin levels are possibly the cause of an increased energy expenditure during this stage of the disorder and might predispose to renewed weight loss (rebound phenomenon). In this study we investigated the role of leptin fluctuations as a prognostic factor of therapeutic success in AN. In 11 anorectic female patients serum leptin levels, BMI and body fat percentage were evaluated in four-week intervals during a conventional refeeding program over three months (group 1). The results of the first two measurements were used to determine a range of increases in leptin levels in relation to increases in BMI. The values between the 25th and 75th percentiles determined the reference range. In a second group of 9 anorectic female patients serum leptin levels, BMI, body fat percentage and the increase in the leptin level in relation to the BMI of each subject were investigated for three months every two weeks. These patients were also treated according to the same conventional refeeding program, but the caloric intake was reduced or increased (+/-250 kcal/d) if the increase in the leptin level, in relation to the increase in the BMI, had exceeded or fallen short of the reference range. During the refeeding therapy every subject of each group experienced increases in serum leptin levels, BMI and body fat percentage. Six subjects of group 1 and six subjects of the second group had an increase in leptin levels in relation to the increase of the BMI out of the reference range at least once. To investigate the therapeutic outcome of leptin monitoring and the following alteration of caloric intake, weight gain of the patients of both groups during the whole treatment was compared. No significant difference was found. Our results probably do not support the findings that high leptin levels predispose to a renewed loss of weight. The outcome in our patients whose caloric intake was modified due to their serum leptin levels was not significantly improved. Topics: Adipose Tissue; Anorexia; Biomarkers; Body Mass Index; Body Weight; Energy Intake; Fasting; Female; Humans; Leptin; Monitoring, Physiologic; Predictive Value of Tests; Prognosis; Reference Values; Time Factors; Weight Gain | 2003 |
Interleukin-6 levels in the central nervous system are negatively correlated with fat mass in overweight/obese subjects.
Recently, we demonstrated that intracerebroventricular injection of IL-6 increases energy expenditure and decreases body fat in rodents. Therefore, IL-6 may play a role in appetite and body weight control in the central nervous system. In the present study we evaluated cerebrospinal fluid (CSF) and serum IL-6 levels in humans in relation to body fat content and to CSF and serum levels of leptin. Thirty-two healthy overweight/obese male subjects with a body mass index range of 29.3-36.0 kg/m(2) were studied. Total and sc body fat were measured by dual energy x-ray absorptiometry and computed tomography, respectively. CSF IL-6 levels were in some individuals higher than serum IL-6 levels and correlated negatively with total body weight, sc and total body fat. In contrast, CSF leptin levels were 30-60 times lower than serum leptin levels and correlated positively with serum leptin, body weight, sc and total body fat. Furthermore, there was a negative correlation between CSF IL-6 and leptin. In conclusion, CSF IL-6 differs in many ways from CSF leptin. CSF IL-6 may be locally produced rather than serum derived, and body fat-regulating regions in the central nervous system may be exposed to insufficient IL-6 levels in more severe obesity. Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Body Composition; Body Weight; Central Nervous System; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Serum Albumin | 2003 |
The effects of human leptin fragment(126-140) on pituitary functions in man.
The effects of human leptin fragment(126-140) on pituitary function in eight healthy, non-obese men were studied.. The effects of the fragment on spontaneous secretion of pituitary hormones and endogenous leptin, as well as on GHRH-induced GH secretion were examined.. After the administration of the fragment (50 microg i.v. for 150 min), the mean nadir value and 45 min value were significantly lower than that of the control study. Endogenous leptin levels did not decrease significantly following the administration of the leptin fragment. Other pituitary hormones were not affected by the fragment. The area under the curve of the GH response to GHRH(1-44)NH(2) (10 microg, i.v. from 0 to 75 min) was also significantly inhibited by the combined administration of the leptin fragment (100 microg i.v. from -30 to 75 min) (P<0.001). Three subjects were re-examined with larger doses of the leptin fragment (200-400 microg), and even greater GH suppression was observed.. These results indicate that human leptin fragment(126-140) has an inhibitory role in GH secretion, since when administered exogenously this fragment significantly suppressed spontaneous and, in a dose-response manner, GHRH-induced GH secretion. Clear effects of the fragment on other pituitary hormones and an inhibitory effect on endogenous leptin secretion were not observed in this study. Topics: Adult; Body Weight; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Leptin; Male; Peptide Fragments; Pituitary Gland | 2003 |
Effects of growth hormone (GH) on ghrelin, leptin, and adiponectin in GH-deficient patients.
Ghrelin is a recently discovered gastric peptide that increases appetite, glucose oxidation, and lipogenesis and stimulates the secretion of GH. In contrast to ghrelin, GH promotes lipolysis, glucose production, and insulin secretion. Both ghrelin and GH are suppressed by intake of nutrients, especially glucose. The role of GH in the regulation of ghrelin has not yet been established. We investigated the effect of GH on circulating levels of ghrelin in relation to its effects on glucose, insulin, body composition, and the adipocyte-derived peptides leptin and adiponectin. Thirty-six patients with adult-onset GH deficiency received recombinant human GH for 9 months in a placebo-controlled study. Body composition and fasting serum analytes were assessed at baseline and at the end of the study. The GH treatment was accompanied by increased serum levels of IGF-I, reduced body weight (-2%) and body fat (-27%), and increased serum concentrations of glucose (+10%) and insulin (+48%). Ghrelin levels decreased in 30 of 36 subjects by a mean of -29%, and leptin decreased by a mean of -24%. Adiponectin increased in the women only. The decreases in ghrelin and leptin correlated with changes in fat mass, fat-free mass, and IGF-I. The reductions in ghrelin were predicted independently of the changes in IGF-I and fat mass. It is likely that the reductions in ghrelin and leptin reflect the metabolic effects of GH on lipid mobilization and glucose production. Possibly, a suppression of ghrelin promotes loss of body fat in GH-deficient patients receiving treatment. The observed correlation between the changes in ghrelin and IGF-I may suggest that the GH/IGF-I axis has a negative feedback on ghrelin secretion. Topics: Adiponectin; Adult; Blood Glucose; Body Composition; Body Weight; Female; Ghrelin; Growth Disorders; Human Growth Hormone; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Peptide Hormones; Proteins; Regression Analysis | 2003 |
[Effect of rosiglitazone on insulin resistance and hyperandrogenism in polycystic ovary syndrome].
To evaluate the effect of rosiglitazone on insulin resistance and hyperandrogenism in polycystic ovary syndrome (PCOS).. Rosiglitazone was given 4 mg daily to 30 patients with PCOS for 12 weeks. Before and after treatment, body mass index (BMI), plasma glucose, insulin, levels insulin resistance index (HOMA IR), blood lipid spectrum, leptin, neuropeptide Y, and sex hormone concentrations and ovulation rate were determined and compared.. After 12 weeks of treatment, basal insulin level decreased from (18 +/- 8) to (12 +/- 7) mIU/L (P < 0.01), HOMA IR decreased from 4.3 +/- 1.2 to 2.6 +/- 0.7 (P < 0.01). Luteinizing hormone, free testosterone and androstenedione levels decreased [(15.4 +/- 4.4) versus (7.9 +/- 2.1) U/L, (12.5 +/- 1.9) versus (8.9 +/- 1.4) pmol/L, (9.8 +/- 1.7) versus (7.4 +/- 1.2) nmol/L respectively, P < 0.01]; Dehydroepiandrosterone sulfate level also decreased [(8.7 +/- 3.5) versus (6.9 +/- 2.1) micromol/L, P < 0.05]; Sex hormone binding globulin level increased [(39 +/- 3) versus (58 +/- 5) nmol/L, P < 0.01]. Plasma leptin level was decreased [(18 +/- 4) versus (13 +/- 3) microg/L, P < 0.01]. Ovulation rate increased to 50%.. Rosiglitazone might decrease plasma leptin level and improve insulin sensitivity, which led to alleviation of hyperandrogenism and resumption of ovulation and menses in patients with PCOS. Topics: Administration, Oral; Adult; Androstenedione; Blood Glucose; Body Weight; Female; Follicle Stimulating Hormone; Humans; Hyperandrogenism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Lipids; Luteinizing Hormone; Menstruation; Neuropeptide Y; Ovulation; Polycystic Ovary Syndrome; Rosiglitazone; Testosterone; Thiazoles; Thiazolidinediones; Treatment Outcome | 2002 |
Body weight, the tumor necrosis factor system, and leptin production during treatment with mirtazapine or venlafaxine.
Weight gain is a frequent and important side effect of psychopharmacotherapy. Recent studies suggest that the fat-cell-derived hormone leptin and the tumor necrosis factor-alpha (TNF-alpha) cytokine system are pathophysiologically involved. No information is available concerning the influence of the antidepressants mirtazapine and venlafaxine on these immunoendocrine variables. An open-labeled study was performed in 20 patients suffering from major depression treated with either mirtazapine (N = 11) or venlafaxine (N = 9). During 4 weeks, the patients' weight, body mass index (BMI), and plasma levels of leptin, TNF-alpha, sTNF-R p55, and sTNF-R p75 were assessed. Mirtazapine induced a significant increase in weight (mean weight gain: 2.4 kg) that was evident after the first week of treatment. In parallel, the plasma levels of TNF-alpha and both soluble TNF receptors increased. In addition, a slight rise in leptin levels, which occurred slowly and was significant only at the end of the 4 th week of treatment, was observed. Weight decreased slightly but significantly in patients treated with venlafaxine (mean weight loss: 0.4 kg), whereas plasma levels of leptin, TNF-alpha, or soluble TNF receptors did not change significantly. The present results further support the notion that the activation of the TNF-alpha cytokine system is an early, sensitive, and specific marker of weight gain induced by psychotropic agents. In contrast, the effects of such drugs on leptin production seem to be less sensitive with respect to weight gain and more variable. Topics: Adult; Aged; Antipsychotic Agents; Body Mass Index; Body Weight; Cross-Over Studies; Cyclohexanols; Depressive Disorder, Major; Female; Humans; Leptin; Longitudinal Studies; Male; Mianserin; Middle Aged; Mirtazapine; Tumor Necrosis Factor-alpha; Venlafaxine Hydrochloride | 2002 |
Leptin, insulin-like growth factor (IGF)-I and IGF binding protein-3 levels in children with constitutional delay of growth.
This study was planned in order to investigate the role of insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) and leptin, the product of the ob gene synthesized by fat tissue cells, in constitutional delay of growth and puberty (CDGP) which is the most frequent cause of short stature in children. This study was conducted on 80 children with CDGP aged 6-15 years, and 60 healthy children served as controls. Serum IGF-I, IGFBP-3, insulin and plasma leptin levels were measured by immunoradiometric assay. Mean IGF-I and leptin levels were significantly lower in the CDGP group compared with the controls, but the mean IGFBP-3 level was not different in the two groups. Mean leptin levels were 3.72 +/- 2.29 in CDGP and 4.68 +/- 3.08 in the control group (p <0.05). There was a statistically significant relationship between leptin levels and height, weight, and body mass index. Leptin levels were also correlated with chronological age, bone age and height age. When evaluated according to pubertal status, a significant difference was found in IGF-I, leptin and IGFBP-3 levels between prepubertal and pubertal groups. Leptin levels were significantly different in the prepubertal CDGP group compared with controls but in the pubertal CDGP group only IGF-I levels were significantly different from controls. As the weight of children with CDGP was lower than in the control group, it is postulated that the reason for short stature and pubertal delay may be this decrease in weight which is also the cause of low levels of leptin and IGF-I. Topics: Adolescent; Body Height; Body Weight; Child; Female; Growth Disorders; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Radioimmunoassay | 2002 |
Short-term treatment with metformin decreases serum leptin concentration without affecting body weight and body fat content in normal-weight healthy men.
A weight-reducing effect of metformin has been demonstrated in obese subjects with and without diabetes. The mechanisms of this action are unclear, which may be partly due to the fact that in obese and diabetic patients the substance's effects result from a complex interaction with the distinct endocrine and metabolic disturbances in these patients. To dissociate primary from secondary action of metformin, we examined effects of the substance in normal-weight healthy subjects. Fifteen normal-weight men were treated with metformin (850 mg twice daily) or placebo for a 15-day period in a double-blind, placebo-controlled, cross-over study. Anthropometric, psychologic, cardiovascular, endocrine, and metabolic parameters were assessed before and at the end of the treatment period. Metformin did not affect body weight (P =.838) and body fat mass (P =.916). Yet, serum leptin concentration was distinctly reduced after metformin (P <.001). Also, metformin reduced the concentration of plasma glucose (P =.011), serum insulin (P=.044), and serum insulin-like growth factor -1 (IGF-1) (P=.013), while it increased serum glucagon concentration (P <.001). There were no effects of metformin on feelings of hunger, blood pressure, heart rate, resting energy expenditure, the respiratory quotient, free fatty acids, beta-hydroxybutyrate, glycerol, triglycerides, cholesterol, and uric acid (all P >.1). Data indicate that metformin decreases the serum leptin concentration even without affecting body weight and body composition in normal-weight men. Topics: Adipose Tissue; Adult; Blood Pressure; Body Weight; C-Peptide; Diabetes Mellitus; Glucagon; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Metformin; Obesity; Reference Values | 2002 |
Five-week, low-glycemic index diet decreases total fat mass and improves plasma lipid profile in moderately overweight nondiabetic men.
To evaluate whether a 5-week low-glycemic index (LGI) diet versus a high-glycemic index (HGI) diet can modify glucose and lipid metabolism as well as total fat mass in nondiabetic men.. In this study, 11 healthy men were randomly allocated to 5 weeks of an LGI or HGI diet separated by a 5-week washout interval in a crossover design.. The LGI diet resulted in lower postprandial plasma glucose and insulin profiles and areas under the curve (AUCs) than the HGI diet. A 5-week period of the LGI diet lowered plasma triacylglycerol excursion after lunch (AUC, P < 0.05 LGI vs. HGI). These modifications were associated with a decrease in the total fat mass by approximately 700 g (P < 0.05) and a tendency to increase lean body mass (P < 0.07) without any change in body weight. This decrease in fat mass was accompanied by a decrease in leptin, lipoprotein lipase, and hormone-sensitive lipase RNAm quantities in the subcutaneous abdominal adipose tissue (P < 0.05).. We concluded that 5 weeks of an LGI diet ameliorates some plasma lipid parameters, decreases total fat mass, and tends to increase lean body mass without changing body weight. These changes were accompanied by a decrease in the expression of some genes implicated in lipid metabolism. Such a diet could be of benefit to healthy, slightly overweight subjects and might play a role in the prevention of metabolic diseases and their cardiovascular complications. Topics: Adult; Blood Glucose; Body Weight; Cross-Over Studies; Humans; Insulin; Leptin; Lipids; Lipoprotein Lipase Activators; Male; Middle Aged; Obesity; Peptides; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Time Factors; Transcription Factors | 2002 |
The effect of pegylated recombinant human leptin (PEG-OB) on weight loss and inflammatory status in obese subjects.
To investigate whether weekly subcutaneous administration of 60 mg of long-acting pegylated human leptin (PEG-OB) for 8 weeks was able to influence weight loss, metabolic profile and inflammatory status of obese subjects on a mildly hypoenergetic diet (deficit: 3.2 MJ/day).. A prospective, randomized, double-blind and placebo-controlled single-center trial.. Twenty-eight healthy, obese subjects (16 women, 12 men; age 22-65 y; body mass index 27.7-38.7 kg/m2).. Bodyweight, metabolic profile (including lipids), C-reactive protein (CRP) and soluble TNF alpha-receptor (sTNF-R) 55 and 75 levels.. At the end of the study no significant differences in the delta or percentage weight loss between the placebo (n = 14) and PEG-OB (n = 14) groups was observed. Also the changes in metabolic profile, CRP, sTNF-R55 and R75 concentrations between the two groups after 8 weeks of treatment did not differ.. Weekly injection of 60 mg PEG-OB did not lead to additional weight loss after 8 weeks of treatment. Furthermore, PEG-OB administration did not affect the changes in metabolic profile and the inflammatory status of obese subjects. Topics: Adolescent; Adult; Aged; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Double-Blind Method; Female; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Placebos; Prospective Studies; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Weight Loss | 2002 |
Dopaminergic tone and obesity: an insight from prolactinomas treated with bromocriptine.
It has recently been shown that increased body weight is associated with prolactinomas and that weight loss occurs with normalization of prolactin levels. On the other hand, decreased dopaminergic tone in humans is well correlated with obesity. The objective of this study was to correlate changes in prolactin levels with leptin and body mass index (BMI) in patients with prolactinomas treated with the long-acting dopamine agonist bromocriptine (BC).. Eleven female and twelve male patients, aged 36.7+/-2.6 years with BMI in males of 30.4+/-1.7 kg/m(2) and in females of 24.4+/-1.2 kg/m(2), were evaluated after 1 and 6 months and 11 patients were further evaluated after 2 years of BC therapy. Plasma prolactin is presented as the mean of four samples taken daily. Serum leptin was determined in the pooled serum from three samples taken at 15-min intervals at 0800 h after an overnight fast. Multivariate linear regression and repeated measures analysis of covariance were used.. In males, pretreatment prolactin levels were 71 362+/-29 912 mU/l while leptin levels were 14.9+/-1.8 microg/l. In females, pretreatment prolactin levels were 11 395+/-5839 mU/l and leptin levels were 16.7+/-2.5 microg/l. The sexual dimorphism of serum leptin levels at initial presentation was preserved after adjusting for BMI and prolactin-induced hypogonadism. After 1 month of therapy, prolactin levels significantly decreased (males: 17 618+/-8736 mU/l, females: 3686+/-2231; P<0.05), BMI did not change (males: 30.2+/-1.7 kg/m(2), females: 24.1+/-1.2 kg/m(2); P>0.05), while serum leptin levels decreased (males: 12.5+/-1.5 microg/l, females: 13.6+/-2.1 microg/l; P<0.05). After 6 months of treatment, prolactin further decreased (males: 3456+/-2101 mU/l, females: 677+/-360 mU/l; P<0.05) as did BMI (males: 28.6+/-1.6 kg/m(2), females 23.1+/-1.0 kg/m(2); P<0.05). The difference was more pronounced in male patients. Leptin levels were 12.8+/-2.8 microg/l in males and 12.9+/-1.8 microg/l in females (P<0.05). After 2 years of BC treatment, prolactin levels were near normal (males: 665+/-439 mU/l, females 447+/-130 mU/l; P<0.05) and BMI remained 26.5+/-1.9 kg/m(2) for males and 23.6+/-0.8 kg/m(2) for females (P<0.05). Leptin levels were 9.5+/-2.2 microg/l in males and 18.7+/-3.1 microg/l in females (P<0.05). There was a gradual increase in the gender difference in serum leptin levels over time. Changes in serum leptin levels significantly correlated with changes in BMI (r=0.844, P<0.001) but did not correlate with changes in plasma prolactin levels after 1 month (r=0.166), 6 months (r=0.313) and 2 years (r=0.234, P>0.05).. The long-acting dopamine agonist BC, by increasing dopaminergic tone, may influence body weight and likely body composition by mechanisms in addition to reducing hyperprolactinemia in patients with prolactinomas. Topics: Adolescent; Adult; Basal Metabolism; Body Weight; Bromocriptine; Dopamine; Female; Hormone Antagonists; Humans; Hyperprolactinemia; Leptin; Male; Middle Aged; Obesity; Pituitary Neoplasms; Prolactin; Prolactinoma | 2002 |
Genomic scan for genes affecting body composition before and after training in Caucasians from HERITAGE.
An autosomal genomewide search for genes related to body composition and its changes after a 20-wk endurance-exercise training program has been completed in the HERITAGE Family Study. Phenotypes included body mass index (BMI), sum of eight skinfold thicknesses, fat mass (FM), fat-free mass, percent body fat (%Fat), and plasma leptin levels. A maximum of 364 sib-pairs from 99 Caucasian families was studied with the use of 344 markers with single-point and multipoint linkage analyses. Evidence of significant linkage was observed for changes in fat-free mass with the S100A and the insulin-like growth factor I genes (P = 0.0001). Suggestive evidence (2.0 < or = Lod < 3.0; 0.0001 < P < or = 0.001) was also observed for the changes in FM and %Fat at 1q31 and 18q21-q23, in %Fat with the uncoupling protein 2 and 3 genes, and in BMI at 5q14-q21. At baseline, suggestive evidence was observed for BMI at 8q23-q24, 10p15, and 14q11; for FM at 14q11; and for plasma leptin levels with the low-density lipoprotein receptor gene. This is the first genomic scan on genes involved in exercise-training-induced changes in body composition that could provide information on the determinants of weight loss. Topics: Adipose Tissue; Adolescent; Adult; Aged; Body Composition; Body Mass Index; Body Weight; Canada; Chromosome Mapping; Exercise; Female; Genetic Markers; Humans; Leptin; Lod Score; Male; Microsatellite Repeats; Middle Aged; Nuclear Family; Physical Fitness; Receptors, LDL; Sex Characteristics; Skinfold Thickness; United States; White People | 2001 |
Smoking related to plasma leptin concentration in pregnant women and their newborn infants.
Leptin, a hormone produced in adipose tissue and placenta, is potentially important in relation to energy metabolism and growth. We investigated the effect of cigarette smoking on maternal plasma leptin concentration during pregnancy, and on plasma leptin concentration and weight among infants up to 13 wk of age. Plasma leptin concentration was measured in women in week 18 (n = 203) and week 35 (n = 164) of pregnancy, while cotinine (nicotine metabolite) was measured in plasma sampled from mothers in week 35 of pregnancy (n = 159). Leptin concentration was also measured in plasma from the umbilical cord (n = 133) and from 4-wk-old (n = 129) and 13-wk-old (n = 130) infants. There was no difference in plasma leptin concentration between smoking and non-smoking mothers at 18 wk and at 35 wk of pregnancy. Plasma cotinine concentration was higher in smoking than in non-smoking mothers, and a negative correlation between plasma cotinine and leptin concentrations was found. The leptin concentrations in umbilical cord plasma were similar, although the birthweights of newborns from smoking mothers were significantly lower than those from non-smoking mothers. The plasma leptin concentrations were similar between the two groups also at 4 wk of age. At 13 wk of age, infants of smoking mothers had significantly higher plasma leptin concentrations than infants of non-smoking mothers.. Our results indicate that a lower birthweight of neonates among smoking mothers is not due to altered plasma leptin concentration. Topics: Adult; Body Mass Index; Body Weight; Cotinine; Female; Fetal Blood; Humans; Infant; Infant, Newborn; Leptin; Multivariate Analysis; Pregnancy; Smoking | 2001 |
The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes.
The prevalence of type 2 diabetes in American adolescents has increased markedly during the past generation. Although the factors that contribute to the development of type 2 diabetes are complex and not wholly elucidated, the triad of severe obesity, hyperinsulinemia, and a family history of type 2 diabetes places a child at an increased risk for development of the disease. Current approaches to the prevention of type 2 diabetes, including dietary counseling and exercise, have had limited success. We reasoned that drugs that increase glucose tolerance in diabetic patients might prove useful in preventing the progression to glucose intolerance in high-risk patients. To that end, we conducted a double-blind, placebo-controlled study of the effects of metformin on body mass index (BMI), serum leptin, glucose tolerance, and serum lipids in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes.. The study population consisted of 29 white and black adolescents aged 12 to 19 years. All had BMIs exceeding 30 kg/m(2). Criteria for enrollment included: 1) a fasting insulin concentration exceeding 15 microU/mL; and 2) at least 1 first- or second-degree relative with type 2 diabetes. All patients had fasting plasma glucose concentrations <110 mg% and hemoglobin A1c concentrations =6.0%. All had normal linear growth and sexual development for age, with no marked hirsutism, severe acne, or menstrual irregularities characteristic of polycystic ovary syndrome. Eight participants had acanthosis nigricans. After baseline laboratory studies including a rapidly sampled intravenous glucose tolerance test, patients were randomized to receive metformin (500 mg twice daily) or a placebo for a total of 6 months. The effects of metformin on BMI standard deviation score, serum leptin, glucose tolerance, and serum lipids were analyzed. The study was double-blinded and included no specific dietary restrictions.. Metformin caused a decline of 0.12 standard deviation in BMI in study participants (-1.3% from baseline), and a 5.5% reduction in serum leptin in girls. In contrast, BMI and serum leptin rose 0.23 standard deviation (2.3%) and 16.2%, respectively, in the placebo group during the treatment period. Metformin caused a progressive decline in fasting blood glucose (from a mean of 84.9 to 75.1 mg%) and a reduction in fasting insulin levels (from 31.3 to 19.3 microU/mL). In contrast, fasting glucose levels in the placebo group rose slightly from 77.2 to 82.3 mg%, and fasting insulin levels did not change. Insulin sensitivity, as assessed by the ratio of fasting insulin to glucose concentrations and the quantitative insulin sensitivity check index (1/[log fasting insulin + log fasting glucose]) and homeostasis model assessment insulin resistance index (fasting insulin x fasting glucose/22.5) indices, increased slightly in the metformin-treated participants. However, the insulin sensitivity measured using Bergman's minimal model did not change. There were also no significant changes in glucose effectiveness, hemoglobin A1c, serum lipids, or serum lactate in the metformin or placebo groups. Metformin was tolerated well by the majority of patients. Transient abdominal discomfort or diarrhea occurred in 40% of treated participants; there were no episodes of vomiting or lactic acidosis.. The treatment of obesity and insulin resistance in adults often proves ineffective because the vicious cycle leading to type 2 diabetes may have become entrenched and, to some extent, may be irreversible. Early detection and therapy of the obese adolescent with a family history of type 2 diabetes may interrupt the cycle of weight gain and insulin resistance that leads to glucose intolerance in adulthood. Through its ability to reduce fasting blood glucose and insulin concentrations and to moderate weight gain, metformin might complement the effects of dietary and exercise counseling and reduce the risk of type 2 diabetes in selected patients. Topics: Adolescent; Blood Glucose; Body Mass Index; Body Weight; Child; Comorbidity; Diabetes Mellitus; Diabetes Mellitus, Type 2; Family; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Obesity; Pilot Projects | 2001 |
Reduction of leptin gene expression by dietary polyunsaturated fatty acids.
Supplementation with n-3 polyunsaturated fatty acids (PUFA) for 6 weeks did not alter plasma leptin concentrations in male smokers. Changes in dietary intake of saturated fatty acids (FA) correlated positively, whereas changes in the intake of PUFA correlated negatively to changes in plasma leptin levels. A 3-week n-3 PUFA-enriched diet, as compared with a 3-week lard-enriched diet, induced lower plasma leptin concentration and reduced leptin mRNA expression in rat epididymal adipose tissue. In the human trophoblast cell line (BeWo), n-3 PUFA had a dose- and time-dependent effect on leptin expression. One mM of eicosapentaenoic acid or docosahexaenoic acid (DHA) reduced leptin expression by 71% and 78%, respectively, as compared with control, after 72 h. There was no effect on expression of the signal transducing form of the leptin receptor. In BeWo cells transfected with the human leptin promoter, we found that n-3 PUFA reduced leptin promoter activity; in contrast saturated and monounsaturated FA had no effect on leptin promoter activity. The transcription factors peroxysomal proliferator activated receptor gamma and sterol regulatory element binding protein-1 mRNAs were reduced after incubation with n-3 PUFA, whereas the expression of CCAAT/enhancer binding protein alpha was unchanged. DHA-reduced leptin expression was abolished in BeWo cells grown in cholesterol-free medium. In conclusion, n-3 FA decreased leptin gene expression both in vivo and in vitro. The direct effects of PUFA on leptin promoter activity indicate a specific regulatory action of FA on leptin expression. Topics: Adipose Tissue; Adult; Animals; Antioxidants; Body Weight; Carrier Proteins; CCAAT-Enhancer-Binding Proteins; Cell Line; Dietary Fats, Unsaturated; DNA-Binding Proteins; Double-Blind Method; Epididymis; Fatty Acids; Gene Expression Regulation; Humans; Infant; Leptin; Male; Middle Aged; Promoter Regions, Genetic; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; Smoking; Sterol Regulatory Element Binding Protein 1; Transcription Factors; Transfection | 2001 |
Relation of serum leptin levels to lipid profile in healthy children.
The association of leptin with body fat concentration is well established. There is also experimental evidence of a direct effect of leptin on lipid metabolism. The aim of this study was to evaluate whether leptin levels are related to the corresponding serum lipid levels independently of body fat mass. The study population consisted of 294 phenotypically healthy school children aged 6 to 12 years. Age, sex, body weight, height, Tanner stage, and triceps skinfold thickness were recorded for all participating subjects. A blood sample was drawn in the morning after a 12-hour fast, and serum total, high-density lipoprotein (HDL), and low-density lipoprotein cholesterol; triglyceride; and leptin levels were determined. Multiple regression analysis showed that triglyceride values were positively correlated with the ln(log(e))-transformed leptin levels (beta =.01, P <.001), whereas HDL levels were inversely associated with lnleptin values (beta = -.06, P =.05) after controlling for age, sex, Tanner stage, and body mass index when each of the lipid parameters was tested separately in the regression model. However, the introduction of both triglycerides and HDL values in the same model eliminated the significance of association of HDL with lnleptin, and the positive relationship of triglycerides with lnleptin remained significant. Our results indicate that triglycerides are independently associated with leptin levels after controlling for any known confounder. Topics: Adipose Tissue; Age Factors; Body Height; Body Mass Index; Body Weight; Child; Female; Humans; Leptin; Linear Models; Lipids; Male; Puberty; Reference Values; Sex Factors; Skinfold Thickness | 2001 |
Insulin resistance in obesity: body-weight or energy balance?
Weight reduction is recommended for the treatment of subjects with insulin resistance (IR) syndrome; however, the relative importance of the decrease in body fat or the negative energy balance achieved during a hypo-energetic diet in the improvement of this metabolic syndrome is still debated. Therefore, we undertook to study their relative impact on amelioration of the metabolic abnormalities associated with IR in obese subjects. Twelve obese subjects (six males and six females, mean+/-s.d. body mass index 36.1+/-4.7 kg/m(2)) aged 38-57 years were investigated. During the first phase they were fed a hypo-energetic diet for 6 weeks (week 0-6). During the second phase, lasting 4 weeks (week 6-10) they consumed an iso-energetic diet. During the third phase (week 10-16) the subjects were put again on a hypo-energetic diet. Insulin sensitivity (SI) was assessed by an insulin-enhanced, frequently sampled i.v. glucose tolerance test with minimal model analysis. All subjects reduced weight during both hypo-energetic periods: 5.49+/-0.75 and 2.32+/-0.37%, means+/-s.e.m., P<0.005, week 0-6 and 10-16 respectively. One-third of this loss was achieved within the first week of each period. SI increased by 353+/-121 and 147+/-38% (P<0.005), means+/-s.e.m., at the end of both hypo-energetic periods (week 6 vs 0 and 16 vs 10 respectively). Two-thirds of this improvement were observed within the first week of each period (week 1 vs 0 and 11 vs 10 respectively). During the iso-energetic weight-maintaining period (week 10 vs 6), SI decreased by 43.5+/-7.9% (P<0.002). Serum levels of leptin and triglyceride followed a similar pattern, but to a lesser extent. It may be concluded that negative energy balance is more effective when compared with maintaining a stable lower weight in achieving an improvement in the metabolic parameters of the IR syndrome. Topics: Adult; Analysis of Variance; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Dietary Carbohydrates; Energy Metabolism; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Triglycerides | 2001 |
Association between serum leptin concentrations and bone mineral density, and biochemical markers of bone turnover in adult men.
Leptin, the product of the ob gene, has been shown to inhibit bone formation in mice. We addressed whether leptin has any role in the regulation of bone mineral density (BMD) in humans. Subjects were 221 adult men with a mean (+/-SD) age and body mass index of 52.1 +/- 8.7 yr and 23.6 +/- 2.8 kg/m2. Serum leptin, carboxyterminal propeptide of type 1 procollagen (PICP; a marker of bone formation), and cross-linked carboxyterminal teleopeptide of type 1 collagen (a marker of bone resorption) were measured by RIA. BMD was assessed by single photon absorptiometry, and total fat mass was determined by bioimpedance analysis. BMD was inversely associated with serum leptin concentrations and total fat mass after adjustment for body weight. PICP, but not cross-linked carboxyterminal teleopeptide of type 1 collagen, was inversely correlated with serum leptin. These results may suggest that an increase in serum leptin reduces bone formation and decreases BMD in adult men. Leptin may be a regulator of BMD in humans. Topics: Adult; Aged; Biomarkers; Body Height; Body Weight; Bone and Bones; Bone Density; Humans; Japan; Leptin; Male; Middle Aged | 2001 |
Endocrine effects of lithium carbonate in healthy premenopausal women: relationship with body weight regulation.
The mechanisms involved in Li-induced weight gain remain unclear. The higher frequency of obesity in women than in men under Li treatment, suggests a role for reproductive hormones. The serum levels of the following hormones were evaluated in healthy young women at diverse stages of a control menstrual cycle, and during Li carbonate (900 mg/day) or placebo administration: prolactin, luteinizing hormone, follicle-stimulating hormone, 17-1 estradiol, progesterone, thyroxine, thyrotropin, cortisol, dehidroepiandrosterone sulfate, free testosterone, leptin and an oral glucose tolerance test, in order to measure the areas under the glucose and insulin curve. The body weight was assessed the day before and the last day of treatment. The Li serum levels 15 hours after the last dose were 0.31 +/- 0.1 mEq/L. No significant changes in body weight and in the normal fluctuations of the reproductive hormones along the menstrual cycle were observed during Li administration. An increase in the serum levels of thyrotropic hormone ( p = 0.0001) was the only significant effect of Li, which may predispose to excessive weight gain after prolonged administration of the cation. The remarkable lack of effects of Li on these hormones, question the pertinence of studies conducted in healthy volunteers for the comprehension of the obesity observed in psychiatric patients who may be particularly prone to gain weight under prolonged treatment with high dose of Li. Topics: Adult; Androgens; Blood Glucose; Body Weight; Endocrine Glands; Female; Glucose Tolerance Test; Gonadal Steroid Hormones; Humans; Leptin; Lithium; Lithium Carbonate; Premenopause | 2000 |
Serum leptin levels and body weight in postmenopausal women under transdermal hormone replacement therapy.
Leptin, the adipocyte-specific product of the ob gene, is implicated in body weight regulation and energy balance. We investigated the influence of hormone replacement therapy (HRT) on the body mass index (BMI) and serum leptin levels in 20 postmenopausal, nonobese women treated with transdermal HRT (delivery rate 50 microg 17beta-estradiol/24 h, 1 patch per week) for 6 months. Serum leptin levels were measured by ELISA and results were compared by means of the Student's paired t-test or Pearson's correlation. The mean patient age was 55+/-6.04 years. The mean body weight prior to the start of the study was 69.39+/-9.37 kg, and the BMI before HRT was 26.92+/-4.47 kg/m2. Both parameters remained unchanged under therapy. No significant change in absolute serum leptin values (18.8+/-8.4 ng/ml; 20.47+/-9.7 ng/ml; 17.92+/-8.7 ng/ml at 0, 4 and 6 months respectively) or in adiposity-corrected values (serum leptin/BMI) (0.68+/-0.24; 0.75+/-0.29; 0.67+/-0.26 at 0, 4 and 6 months respectively) were found. Serum leptin levels correlated well with BMI (r = 0.7193, p<0.0001). There was no significant correlation of estradiol with serum leptin levels before or during therapy. In summary, low dose, transdermal HRT exhibited no influence on serum leptin levels or BMI in postmenopausal women. These data suggest that low dose HRT does not influence body weight regulation in postmenopausal women. Topics: Administration, Cutaneous; Body Mass Index; Body Weight; Enzyme-Linked Immunosorbent Assay; Estradiol; Estrogen Replacement Therapy; Female; Follicle Stimulating Hormone; Humans; Leptin; Levonorgestrel; Middle Aged; Obesity; Postmenopause | 2000 |
Effect of coadministration of clozapine and fluvoxamine versus clozapine monotherapy on blood cell counts, plasma levels of cytokines and body weight.
Clozapine treatment is associated with side-effects such as blood cell dyscrasias and weight gain. Increased plasma levels of the cytokines and soluble cytokine receptors leptin, tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors p55 and p75, as well as toxic metabolites of clozapine, have been suggested as the basis for these side-effects,. This study examined whether the coadministration of the selective serotonine reuptake inhibitor fluvoxamine, which interferes with clozapine's hepatic metabolism, affects the immunomodulation by clozapine and some of its side-effects.. The following parameters were measured: circulating levels of the cytokines and soluble receptors, plasma concentrations of clozapine and its metabolite N-desmethylclozapine, body weight and blood cell counts in 11 and 12 schizophrenic inpatients on combined and monotherapy, respectively, before and during the first 6 weeks of medication.. On the basis of comparable plasma levels of clozapine and N-desmethylclozapine, the coadministration of fluvoxamine 1) attenuated and delayed the clozapine-induced increase in TNF-alpha plasma levels, 2) enhanced and accelerated the clozapine-induced increase in leptin plasma levels without significant effect on clozapine-induced weight gain, and 3) decreased granulocyte counts.. As clozapine, its metabolite N-desmethylclozapine and fluvoxamine are unlikely to make these differences, other metabolites might be responsible. The coadministration of clozapine and fluvoxamine offers the opportunity to investigate further the putative associations between certain metabolites, immunomodulation and these side-effects. Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Blood Cell Count; Body Weight; Clozapine; Cytokines; Drug Interactions; Drug Therapy, Combination; Female; Fluvoxamine; Granulocytes; Humans; Leptin; Male; Middle Aged; Schizophrenia; Selective Serotonin Reuptake Inhibitors | 2000 |
Fasting insulin levels influence plasma leptin levels independently from the contribution of adiposity: evidence from both a cross-sectional and an intervention study.
The aim of the present investigation was to determine whether leptinemia is only a reflection of the status of fat stores or if insulinemia has a significant influence over leptin levels. Study 1 focused on the association between fasting plasma insulin and leptin in subjects of the Quebec Family Study who were first classified as either high- or low-insulin individuals and were then individually matched on the basis of fat mass (FM). In Study 2, 19 men and 23 women took part in a 15-week weight loss program that consisted of drug therapy (fenfluramine, 60 mg/day) or placebo coupled to an energy-restricted diet (-2930 kJ/day). Body weight, FM, and fat-free mass (assessed by underwater weighing) as well as visceral and sc abdominal and mid-thigh adipose tissue measured by computed tomography were assessed before and after weight loss. Blood samples were drawn and analyzed for fasting plasma insulin and leptin before and after weight loss. In Study 1, significant positive associations were noted between log10 transformed fasting insulin and leptin in both men (r = 0.55, P < 0.0001) and women (r = 0.48, P < 0.0001). Moreover, after having carefully matched high-insulin to low-insulin individuals on the basis of FM, significantly lower leptin levels were observed in the low-insulin groups, in men (5.5 vs. 8.1 ng/mL, P < 0.05) as well as in women (18.7 vs. 24 ng/mL, P < 0.05). Results from Study 2 showed significant reductions of body weight, FM, fat-free mass, visceral abdominal tissue, sc abdominal tissue, and mid-thigh adipose tissue levels in men and women in response to the weight loss protocol. Moreover, the decrease in fasting plasma insulin was the only significant correlate of changes in fasting plasma leptin levels during weight loss, even after corrections for changes in FM in both men (r = 0.50, P < 0.05) and women (r = 0.46, P < 0.05). These results suggest that in a population characterized by a wide range of adiposity hyperinsulinemia has the potential to modulate leptin levels beyond what can be explained by total adiposity. Moreover, this relation also seems to exist in a dynamic setting (i.e. during weight loss) because changes in insulin were independent predictors of the changes in leptinemia in both men and women after correction for changes in FM. Topics: Adipose Tissue; Adult; Body Composition; Body Weight; Cross-Sectional Studies; Diet, Reducing; Energy Intake; Fasting; Female; Fenfluramine; Humans; Insulin; Leptin; Male; Multivariate Analysis; Placebos; Quebec; Regression Analysis; Selective Serotonin Reuptake Inhibitors; Sex Characteristics; Tomography, X-Ray Computed; Weight Loss; White People | 2000 |
Decreased serum leptin in bulimia nervosa.
The eating disorder bulimia nervosa has been associated with impaired satiety, decreased resting metabolic rate, and abnormal neuroendocrine regulation. Preclinical studies suggest that such alterations could be associated with impaired leptin function. Thus, the goal of this study was to assess whether leptin function is decreased in bulimia nervosa. Serum leptin levels measured in women with bulimia nervosa (n = 18) and in women who had maintained stable recovery from bulimia nervosa (n = 15) were compared with values in healthy female controls (n = 20). Subjects were studied during the follicular phase of their menstrual cycle after an overnight fast and bed rest. Baseline serum samples were analyzed for leptin concentration by RIA. Subject groups were matched for age and body weight. Analysis of covariance, adjusting for percent body fat, demonstrated abnormally low serum leptin levels in the bulimia nervosa group (P: = 0.02), with a trend toward an inverse correlation between frequency of binge episodes and serum leptin concentration (P: < 0.1). Additionally, the remitted patient group demonstrated abnormally low leptin values (P: = 0.01). These results are consistent with the hypothesis that decreased leptin function may be associated with alterations in eating patterns, metabolic rate, and neuroendocrine regulation in bulimia nervosa. Topics: Adult; Body Composition; Body Weight; Bulimia; Female; Follicular Phase; Humans; Leptin | 2000 |
Serum leptin in short children born small for gestational age: dose-dependent effect of growth hormone treatment.
To study the effects of different regimens of growth hormone (GH) treatment on serum leptin levels in 78 short prepubertal children born small for gestational age (SGA).. The children were originally included in two independent multicenter trials, one in Belgium and one in the Nordic countries. SGA children were randomized either to remain untreated or to be treated with GH at a daily dose of 0.1, 0.2 or 0.3 IU/kg for 2 years. Thereafter, treatment was continued for another 2 years in the Nordic children, whereas it was discontinued in the Belgian children.. In the GH treatment groups, a significant dose-dependent decrease in leptin levels was found during the first year of therapy, with a mean decrease of 13, 23 and 32% in the groups receiving GH at 0.1, 0.2 and 0.3 IU/kg, respectively. When high-dose treatment was interrupted, serum leptin increased within 1 year to pretreatment levels.. Serum leptin levels in short children born SGA are transiently reduced by GH treatment in a dose-dependent fashion. The most pronounced changes in serum leptin were documented within the first year after initiation and withdrawal of high-dose GH treatment. Topics: Belgium; Body Height; Body Weight; Child; Child, Preschool; Female; Human Growth Hormone; Humans; Infant, Newborn; Infant, Small for Gestational Age; Leptin; Male; Sweden | 2000 |
Serum leptin in children with asthma treated with inhaled budesonide.
Leptin, a 167-amino-acid peptide, is a recently discovered hormone which is believed to play a major role in the regulation of body weight. Systemic administration of exogenous glucocorticoids has been found to increase circulating leptin levels. In this study, we aimed to assess serum leptin in children with asthma treated with inhaled budesonide 800 micrograms day-1. Ten boys and three girls with asthma, all adolescents aged from 12.9 to 16.6 years, were studied in a randomized double-blind two-period cross-over trial with 4-week treatment periods and a 1-week wash out. Placebo was given during one period and 800 micrograms budesonide during the other via a 750 ml volume spacer (Nebuhaler, Astra Draco, Lund, Sweden). On the last day of the placebo and budesonide periods blood samples were taken and serum leptin was measured by a specific radioimmunoassay. The difference in mean (SEM) leptin concentration between the budesonide and placebo period was 0.2 (0.4) microgram l-1 (P = 0.71; t = -0.4; df = 12, 95% confidence interval -0.9-0.7 microgram l-1). Inhaled budesonide 800 micrograms per day from a Nebuhaler does not influence circulating leptin levels, suggesting that regulation of body weight is unaffected. Topics: Administration, Topical; Adolescent; Anti-Inflammatory Agents; Appetite; Asthma; Biomarkers; Body Weight; Budesonide; Child; Cross-Over Studies; Double-Blind Method; Female; Glucocorticoids; Humans; Leptin; Male; Proteins | 1999 |
Leptin levels in pregnant women and newborn infants: gender differences and reduction during the neonatal period.
Leptin is a highly hydrophilic protein that circulates in plasma as a 16-kDa protein. It is produced in adipose tissue and also recently described to be synthesized by placental tissue. Plasma concentration of leptin is positively correlated to body fat mass, and administration of recombinant leptin to mice indicates that leptin participates in the regulation of food intake and energy expenditure. Leptin may have a role during initiation of human pubertal development. Gender differences have been reported among adults as well as among children, even after correction for body fat content. Little is known about variation in leptin levels during pregnancy or the level or function of leptin in the growing fetus and infants. The aim of the present study was to examine plasma concentration of leptin in pregnant women and their newborn infants during the first 3 months of life, and to relate plasma leptin concentration to body weight and gender during this period.. Among 609 women recruited to study the effect of very long-chain n-3 fatty acids during pregnancy, 180 women were selected to study leptin as well. The women were all healthy and nulli- or primiparas, and 16% were smokers. The study was randomized and double-blinded, and the participants received either 10 mL of cod liver oil (Peter Moller, avd.av Orkla ASA, Oslo, Norway) daily or the same amount of corn oil. Blood samples were taken from the mothers during pregnancy in weeks 18 and 35, and from the umbilical cord and from 4- and 14-week-old infants. The mothers' body mass index (BMI) at 18 and 35 weeks of pregnancy was calculated by using body weight recorded within 1 week or, if this was missing, by using means from weights at the closest time points before and after the sampling. The infants were weighed and measured at local health care centers. Plasma leptin concentration was measured by radio immunoassay (Linco Research, St Charles, MO) using recombinant 125I-leptin as tracer.. We found no differences between the group receiving cod liver oil and the group receiving corn oil in any of the measured variables; thus, the groups are treated statistically as one. Leptin concentration in maternal plasma increased during pregnancy from 15.5 +/- 9.0 microg/L (n = 175) in week 18 to 17.7 +/- 10.7 microg/L (n = 166) in week 35. Mothers, pregnant with female fetuses (n = 77), had a significant increase in plasma leptin concentration, from 15.5 +/- 8.8 microg/L (n = 83) at 18 weeks to 18.5 +/- 10.9 microg/L (n = 80) at 35 weeks of pregnancy, whereas in mothers pregnant with male fetuses, the increase was insignificant (15.4 +/- 9.3 microg/L (n = 92) to 17.0 +/- 10.5 microg/L (n = 86). BMI increased during the same time period, from 24.2 +/- 3.3 kg/m to 27.8 +/- 3.8 kg/m (n = 174). There was a significant correlation between BMI and plasma leptin concentration at 18 weeks (r = 0.54, n = 169) and at 35 weeks (r = 0.45, n = 160), but we found no change in the relative leptin concentration (plasma leptin concentration/BMI) from week 18 to week 35. We found no significant difference between smokers and nonsmokers in plasma leptin concentration, neither at 18 nor 35 weeks of pregnancy. Gender differences in plasma leptin concentration was present already at birth in umbilical cord plasma (10.8 +/- 9.2 microg/L for girls [n = 65] vs 7.6 +/- 6.6 microg/L for boys [n = 74]). We also observed gender differences in plasma leptin concentration at 4 weeks (3.9 +/- 1.8 microg/L, n = 68 vs 3.2 +/- 1.8 microg/L, n = 71) and 14 weeks of age (4.9 +/- 2.1 microg/L, n = 61 vs 4.1 +/- 3.1 microg/L, n = 73). Plasma leptin levels at 4 and 14 weeks were lower than the level in umbilical cord plasma (n = 101). An increase in plasma leptin concentration was observed from 4 to 14 weeks of age, both for girls (n = 48) and for boys (n = 60). Leptin concentration in umbilical cord plasma correlated with birth weight (r = 0.44, n = 139), and there was significant corre Topics: Adipose Tissue; Adult; Body Mass Index; Body Weight; Cod Liver Oil; Corn Oil; Diet; Double-Blind Method; Female; Fetal Blood; Gestational Age; Humans; Infant; Infant, Newborn; Leptin; Male; Pregnancy; Proteins; Sex Characteristics | 1998 |
Prolonged inhibition of presynaptic catecholamine synthesis does not alter leptin secretion in normal-weight men and women.
Leptin has been called a hormone of reproduction, and seems to link fat and fertility. It has been speculated that the neurotransmitter norepinephrine (NE) (noradrenaline), possibly via the sympathetic nervous system, may represent the afferent signal which modulates leptin release from adipocytes. The purpose of this study was to produce a state of decreased sympathetic output by using the catecholamine synthesis inhibitor alpha-methyl-para-tyrosine (AMPT), in order to study the effect of this compound on the secretion of leptin from fat cells. Ten subjects (five women and five men) received a total of 5 x 1 g doses of AMPT or 5 x 50 mg promethazine (active placebo) over a 26 h period, separated by 4-6 weeks using a randomized, double-blind, placebo-controlled, cross-over design. Blood samples for hormone measurements were obtained over 24 h (18 time points) on day 2 of each experiment. Urinary measurement of the NE metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) on study day 2 served as a marker of the effectiveness of AMPT as an inhibitor of NE synthesis. The daily excretion of this metabolite decreased from 1.56 +/- 0.22 mg in the placebo experiment to 0.53 +/- 0.1 mg in the active experiment (P < 0.05). Plasma leptin concentrations measured in the control group in women and men were similar to those reported previously in lean subjects with a body mass index < 27.5 kg/m2. Leptin concentrations in women were 3-fold higher than in men. Leptin is secreted in a circadian rhythm in both sexes with an increase of nocturnal concentrations by approximately 50%. Two-way analysis of variance reveals no significant difference in leptin secretion between the control and active groups in women and men. In summary, preliminary results do not support the hypothesis that NE represents the afferent signal from the central nervous system which modulates leptin release from adipocytes in the human. Further studies are needed to define the role of the sympathetic nervous system as well as NE in the regulation of leptin secretion and its involvement in obesity and reproduction. Topics: Adult; alpha-Methyltyrosine; Body Weight; Catecholamines; Female; Humans; Leptin; Male; Methoxyhydroxyphenylglycol; Presynaptic Terminals; Proteins; Reference Values; Sex Characteristics; Time Factors | 1998 |
Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective beta3-adrenoceptor agonist in humans.
Stimulation of beta3-adrenoceptors by selective agonists improves insulin action and stimulates energy metabolism in various rodent models of obesity and type 2 diabetes. Whether selective beta3-adrenoceptor stimulation exerts metabolic actions in humans remains to be proven. The effects of a highly selective beta3-adrenoceptor agonist on insulin action, energy metabolism, and body composition were assessed in 14 healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat [mean +/- SD]) randomly assigned to 8 weeks of treatment with either 1,500 mg/day of CL 316,243 (n = 10) or placebo (n = 4). Insulin-mediated glucose disposal (IMGD), nonoxidative glucose disposal (NOGD), oxidative glucose disposal (OGD) (indirect calorimetry), and splanchnic glucose output (SGO; beta3-[H3]glucose) were determined during a 100-min hyperinsulinemic-euglycemic glucose clamp (40 mU x m(-2) x min(-1)) before and after 4 and 8 weeks of treatment. The 24-h energy expenditure (24-EE), 24-h respiratory quotient (24-RQ), and the oxidation rates of fat and carbohydrate were determined in a respiratory chamber before and after 8 weeks. After 4 weeks, treatment with CL 316,243 increased IMGD (+45%, P < 0.01) in a plasma concentration-dependent manner (r = 0.76, P < 0.02). This effect was due to an 82% increase in NOGD (P < 0.01), while OGD and SGO remained unchanged. The effects on insulin action were markedly diminished after 8 weeks; this was significantly related to an unexpected decline in the plasma concentrations of CL 316,243 (-36%, P = 0.08). At this time, 24-RQ was lowered (P < 0.001), corresponding to a 23% increase in fat oxidation (P < 0.01) and a 17% decrease in carbohydrate oxidation (P = 0.05). The 24-EE after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Plasma concentrations of glucose, insulin, and leptin were unaffected by treatment, while free fatty acid concentrations increased by 41% (P < 0.05), again linearly with the achieved plasma concentration of CL 316,243 (r = 0.67, P < 0.05). Treatment with CL 316,243 had no effect on heart rate or blood pressure and caused no cases of tremors. We conclude that treatment of lean male subjects with CL 316,243 increases insulin action and fat oxidation, both in a plasma concentration-dependent manner. This is the first study to demonstrate unequivocal metabolic effects of a highly selective beta3-adrenoceptor agonist in humans. Topics: Adrenergic beta-Agonists; Adult; Blood Glucose; Body Composition; Body Weight; Dioxoles; Double-Blind Method; Energy Metabolism; Fatty Acids, Nonesterified; Glucose Clamp Technique; Humans; Insulin; Leptin; Lipid Metabolism; Male; Oxidation-Reduction; Proteins | 1998 |
Change in body weight after hormone replacement therapy in postmenopausal women is dependent on basal circulating leptin.
To address the effect of leptin in the modulation of change in body weight after hormone replacement therapy (HRT), we prospectively examined the responses of body weight and serum leptin after estrogen-progestin replacement in postmenopausal women.. Subjects consisted of 63 postmenopausal women aged 54-82 years on HRT for osteoporosis.. Thirty three of the subjects received 0.3 mg of conjugated equine estrogen (CEE) (group 1) while 30 were on 0.625 mg of CEE daily (group 2). All subjects also took 5 mg of medrogestone acetate and 750 mg elemental calcium supplement daily.. Fasting serum leptin was measured by RIA at baseline, 1 and 3 months after treatment. Data were expressed as mean +/- S.E.M.. Serum leptin was highly related to body weight both at baseline (r = 0.40, P < 0.001) and after 3 months of HRT (r = 0.42, P < 0.001). When divided the subjects into three equal groups according to baseline leptin levels, it was found that serum leptin significantly decreased in subjects with high baseline leptin at 3 months (-9.4 +/- 5.7%, P < 0.05) while it increased in subjects whose baseline leptin levels were in the lowest tertile at 1 month (33.2 +/- 8.3%, P < 0.001) and 3 month (27.8 +/- 8.3%, P < 0.01). In regards to body weight, those with leptin in the highest tertile demonstrated a reduction of body weight at 3 (-1.9 +/- 0.6%, P < 0.05) and 12 months (-3.2 +/- 0.5%, P < 0.05) after HRT while those whose serum leptin levels were in the lowest and middle tertiles did not demonstrate change in body weight. By repeated measured analysis of variance, it was found that the decrease in body weight in subjects with high serum leptin was independent of the doses of estrogen.. Postmenopausal hormone replacement does not cause weight gain. However, it results in a small reduction in body weight particularly in subjects with higher basal leptin concentrations. Topics: Aged; Aged, 80 and over; Body Weight; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Humans; Leptin; Middle Aged; Postmenopause; Prospective Studies; Proteins | 1998 |
Diet-induced obese mice develop peripheral, but not central, resistance to leptin.
Leptin administration reduces obesity in leptin-deficient ob/ob mice; its effects in obese humans, who have high circulating leptin levels, remain to be determined. This longitudinal study was designed to determine whether diet-induced obesity in mice produces resistance to peripheral and/or central leptin treatment. Obesity was induced in two strains of mice by exposure to a 45% fat diet. Serum leptin increased in proportion to body weight (P < 0.00001). Whereas C57BL/6 mice initially responded to peripherally administered leptin with a marked decrease in food intake, leptin resistance developed after 16 d on high fat diet; mice on 10% fat diet retained leptin sensitivity. In AKR mice, peripheral leptin significantly decreased food intake in both 10 and 45% fat-fed mice after 16 d of dietary treatment. However, after 56 d, both groups became resistant to peripherally administered leptin. Central administration of leptin to peripherally leptin-resistant AKR mice on 45% fat diet resulted in a robust response to leptin, with a dose-dependent decrease in food intake (P < 0.00001) and body weight (P < 0.0001) after a single intracerebroventricular infusion. These data demonstrate that, in a diet-induced obesity model, mice exhibit resistance to peripherally administered leptin, while retaining sensitivity to centrally administered leptin. Topics: Animals; Appetite Regulation; Body Weight; Dietary Fats; Dose-Response Relationship, Drug; Drug Resistance; Eating; Feeding Behavior; Leptin; Longitudinal Studies; Male; Mice; Mice, Inbred AKR; Mice, Inbred C57BL; Obesity; Proteins; Time Factors | 1997 |
3155 other study(ies) available for leptin and Body-Weight
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Role of insulin resistance and leptin in the effect of intermittent feeding with a high-protein ketogenic diet on body composition in rats.
The prevalence of obesity and overweight in children has been increasing rapidly worldwide and threatens society with various chronic diseases that these children are born with. High-protein ketogenic diets and intermittent nutrition are thought to be protective against obesity and metabolic syndrome MetS. However, the exact effects and results, insulin resistance, and the role of leptin in the functioning mechanism of these diets have not been fully elucidated. The aim of this study was to investigate the roles of insulin resistance and leptin hormone on the effects of body composition with a high-protein ketogenic diet and intermittent nutrition combination.. Thirty-two young non-obese rats were randomly divided into four equal groups. Both the standard diet and the high-protein ketogenic diet were given ad libitum and intermittently to the rats for 6 wk. The body weight and fat mass of the rats were measured at the end of the experiment. The fasting glucose, leptin, insulin, high- and low-density lipoprotein, and triacylglycerols were measured with the blood samples.. The lowest body weight was observed in the intermittent and high-protein ketogenic diet group, followed by the free high-protein ketogenic diet and standard intermittent diet group, respectively. Also, the lowest body fat mass was observed in the intermittent and high-protein ketogenic diet group, followed by the standard intermittent diet group. Although there was no change in leptin, insulin, high- and low-density lipoprotein, and triacylglycerol levels in any group, the lowest blood glucose rate was observed in the intermittent and high-protein ketogenic diet group.. The results of the present study revealed that an intermittent high-protein ketogenic diet is more effective than others in weight loss without disrupting biochemical health parameters, and the applied diets do not prevent growth and development. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Child; Diet, Ketogenic; Humans; Insulin; Insulin Resistance; Leptin; Lipoproteins, LDL; Obesity; Rats | 2024 |
Association between
Single nucleotide polymorphisms are commonly associated with changes in quantitative traits, and have been considered useful markers for improving different traits in livestock. The current study aimed to explore the effect of three SNPs located in Topics: Animals; Body Weight; Leptin; Polymorphism, Single Nucleotide; PPAR gamma; Rabbits; Receptor, Insulin; Weight Gain | 2023 |
Nutritional and Anthropometric Indices in Children Receiving Haemodiafiltration vs Conventional Haemodialysis - The HDF, Heart and Height (3H) Study.
The "HDF-Heart-Height" study showed that haemodiafiltration (HDF) is associated with improved growth compared to conventional haemodialysis (HD). We report a post-hoc analysis of this study assessing the effect of extracorporeal dialysis therapies on nutritional indices.. 107 children were included in the baseline cross-sectional analysis, of whom 79 (43 HD, 36 HDF) completed the 12-month follow-up. Height (Ht), optimal 'dry' weight (Wt), and body mass index (BMI) standard deviations scores (SDS), waist-to-hip ratio, des-acyl ghrelin (DAG), adiponectin, leptin, insulin-like growth factor-1 (IGF-1)-SDS and insulin were measured.. The levels of nutritional indices were comparable between HDF and HD patients at baseline and 12-month. On univariable analyses Wt-SDS positively correlated with leptin and IGF-1-SDS, and negatively with DAG, while Ht-SDS of the overall cohort positively correlated with IGF1-SDS and inversely with DAG and adiponectin. On multivariable analyses, higher 12-month Ht-SDS was inversely associated with baseline DAG (beta = -0.13 per 500 higher; 95%CI -0.22, -0.04; P = .004). Higher Wt-SDS at 12-month was positively associated with HDF modality (beta = 0.47 vs HD; 95%CI 0.12-0.83; P = .01) and inversely with baseline DAG (beta = -0.18 per 500 higher; 95%CI -0.32, -0.05; P = .006). Growth Hormone (GH) treated patients receiving HDF had higher annualized increase in Ht SDS compared to those on HD.. In children on HD and HDF both Wt- and Ht-SDS independently correlated with lower baseline levels of the anorexygenic hormone DAG. HDF may attenuate the resistance to GH, but further studies are required to examine the mechanisms linking HDF to improved growth. Topics: Adiponectin; Body Weight; Child; Cross-Sectional Studies; Hemodiafiltration; Humans; Insulin-Like Growth Factor I; Kidney Failure, Chronic; Leptin; Renal Dialysis | 2023 |
Thermo-TRP channels are involved in BAT thermoregulation in cold-acclimated Brandt's voles.
Transient receptor potential (TRP) channels, which can sense temperature, pressure and mechanical stimuli, were involved in many physiological and biochemical reactions. Whether thermosensitive TRP channels (Thermo-TRPs) are involved in thermoregulation in small mammals is still not clear. We measured the changes of thermo-TRPs at 4 °C, 23 °C and 30 °C in Brandt's voles (Lasiopodomys brandtii) to test the hypothesis that Thermo-TRPs are involved in cold-induced thermogenesis of brown adipose tissue (BAT) in small mammals. Results showed that air temperatures had no effect on body mass and rectal temperature, but the food intake and basal metabolic rate (BMR) in the 4 °C group were significantly higher than in the 30 °C group. Compared with 30 °C group, the protein contents of uncoupling protein 1(UCP1), TRP vanilloid 2 (TRPV2), TRP ankyrin 1 (TRPA1), TRP melastatin 2 (TRPM2), silent Information Regulator T1 (SIRT1), AMP-activated protein kinase (AMPK) and Calcium/calmodulin-dependent protein kinase II (CaMKII) in BAT increased significantly in 4 °C group, but there was no significant difference in the protein content of Thermo-TRPs in the hypothalamus among groups. Further, the expression of PRDM16 (PR domain containing 16) in inguinal white adipose tissue (iWAT) at 4 °C was significantly higher than that at 30 °C, but no difference was observed in the expression of other browning-related genes or TRPV2. In conclusion, TRP channels may participate in BAT thermoregulation through the CaMKII, AMPK, SIRT1 and UCP1 pathway in cold-acclimated Brandt's voles. Topics: Adipose Tissue, Brown; AMP-Activated Protein Kinases; Animals; Arvicolinae; Body Temperature Regulation; Body Weight; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Leptin; Mammals; Sirtuin 1; Transient Receptor Potential Channels | 2023 |
Inhibition of Hypothalamic FTO Activates STAT3 Signal through ERK1/2 Associated with Reductions in Food Intake and Body Weight.
Fat mass and obesity-associated (FTO) gene is strongly associated with obesity which brings a major health threat. Altered expression of its encoded protein FTO in the hypothalamus has been identified to contribute to central control of appetite and body weight. However, its molecular mechanisms remain elusive.. Mouse hypothalamic POMC cell line N43/5 was treated with FTO inhibitor rhein, FTO shRNA, or extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor U0126 to inhibit FTO or ERK1/2. Rhein and U0126 were injected into lateral ventricle of the mice by intracerebroventricular cannulation. Western blotting and immunofluorescent assays were performed to monitor protein level.. This study identified that inhibition of FTO in N43/5 cells led to phosphorylation of signal transducer and activator of transcription 3 (STAT3) at S727 site and induced p-STAT3-S727 nuclear translocation. We further showed that FTO inhibition promoted phosphorylation of ERK1/2; specific inhibition of ERK1/2 signaling by U0126 could abolish the effect of FTO inhibition on STAT3-S727 phosphorylation and nuclear translocation. Furthermore, we found that inhibition of hypothalamic FTO promoted STAT3-S727 phosphorylation in the hypothalamic arcuate nucleus, and the mice showed reductions in food intake and body weight. In addition, inhibition of hypothalamic ERK1/2 could abolish the effects of FTO inhibition on STAT3-S727 phosphorylation, reductions of food intake and body weight.. Our in vitro and in vivo data suggest that the inhibition of hypothalamic FTO could activate STAT3 through ERK1/2, which is potentially associated with reductions in food intake and body weight. Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Body Weight; Eating; Hypothalamus; Leptin; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase 3; Obesity; Phosphorylation; STAT3 Transcription Factor | 2023 |
Sucrose solution, but not liquid sucrose diet, leads to leptin resistance irrespective of the time of day that sucrose is available.
Rats offered free access to sucrose solution in addition to a sucrose-free composite diet develop leptin resistance whereas those consuming a similar amount of sucrose from a dry diet remain leptin responsive. Here we tested whether rats consuming a complete high sucrose diet in liquid form also became leptin resistant. Female Sprague Dawley rats were offered a sucrose free diet (NS), a dry high sucrose diet (HS), NS diet plus 30% sucrose solution (LiqS), NS diet in liquid form (NSLiq) or HS diet in Liquid form (HSLiq). After 30 days LiqS rats were leptin resistant, but all other groups were leptin responsive even though HSLiq rats consumed as much sucrose as LiqS rats and NSLiq rats had the greatest amount of body fat. Therefore, development of leptin resistance is dependent upon the consumption of sucrose independent of any other nutrients. Because LiqS rats consume sucrose throughout the day and night we tested whether limiting sucrose solution access to either the light or dark period prevented development of leptin resistance. Leptin resistant LiqS rats were either given free access to sucrose, had access to sucrose only at night or had access only during the day. The intake of rats with limited access was supplemented to the level of those with free access by tube-feeding. The results of this study show that leptin resistance of LiqS rats is independent of when the sucrose is consumed and is unrelated to total energy intake, body fat mass or serum leptin concentration. Topics: Animals; Body Weight; Diet; Dietary Sucrose; Energy Intake; Female; Leptin; Rats; Rats, Sprague-Dawley | 2023 |
Diet containing stearic acid increased food intake in mice by reducing serum leptin compared with oleic acid.
In today's society, obesity is becoming increasingly serious, and controlling food intake and maintaining weight balance have become increasingly important. Here, we found that a stearic acid diet can increase food intake without causing obesity in mice compared with an oleic acid diet. Stearic acid increases food intake in mice by reducing serum leptin and increasing NPY neuronal excitability through the JAK2/STAT3 pathway. The impaired anorexic effect of leptin is probably due to repressive cholesterol-oxysterol-LXR-α/SREBP-1c-mediated leptin expression in mouse iWAT. At the same time, we found that stearic acid was not only poorly absorbed by itself in the small intestine but also reduced the entire absorption system of the small intestine. In conclusion, we have proven that a stearic acid diet can increase food intake in mice and avoid obesity, but whether a stearic acid diet could cause adverse reactions in the body remains to be studied. Topics: Animals; Body Weight; Diet; Eating; Leptin; Mice; Obesity; Oleic Acid | 2023 |
Maternal Protein Restriction in Rats Alters Postnatal Growth and Brain Lipid Sensing in Female Offspring.
Perinatal nutrition is a key player in the susceptibility to developing metabolic diseases in adulthood, leading to the concept of "metabolic programming". The aim of this study was to assess the impact of maternal protein restriction during gestation and lactation on glucose homeostasis and eating behaviour in female offspring. Pregnant rats were fed a normal or protein-restricted (PR) diet and followed throughout gestation and lactation. Body weight, glucose homeostasis, and eating behaviour were evaluated in offspring, especially in females. Body weight gain was lower in PR dams during lactation only, despite different food and water intakes throughout gestation and lactation. Plasma concentration of leptin, adiponectin and triglycerides increased drastically before delivery in PR dams in relation to fat deposits. Although all pups had identical birth body weight, PR offspring body weight differed from control offspring around postnatal day 10 and remained lower until adulthood. Offspring glucose homeostasis was mildly impacted by maternal PR, although insulin secretion was reduced for PR rats at adulthood. Food intake, satiety response, and cerebral activation were examined after a lipid preload and demonstrated some differences between the two groups of rats. Maternal PR during gestation and lactation does induce extrauterine growth restriction, accompanied by alterations in maternal plasma leptin and adiponectin levels, which may be involved in programming the alterations in eating behaviour observed in females at adulthood. Topics: Adiponectin; Animals; Body Weight; Brain; Diet, Protein-Restricted; Female; Glucose; Lactation; Leptin; Maternal Nutritional Physiological Phenomena; Pregnancy; Rats; Triglycerides; Weight Gain | 2023 |
Serum Adipocytokines Profile in Children Born Small and Appropriate for Gestational Age-A Comparative Study.
Adipose tissue is not only a storage place for fat, but also an endocrine organ, secreting bioactive molecules which influence body metabolism. Such molecules are known as adipocytokines. In the past years the coincidence between adipocytokines and fetal growth restriction disorders was found. The aim of the study was to estimate serum levels of adiponectin, leptin and resistin in children born small for gestational age, compared to children born at an appropriate size for gestational age.. The study consisted of 35 children aged seven to nine years, born SGA (small for gestational age) on term and 25 healthy children (14 girls, 11 boys), born with proper birthweight (AGA-appropriate for gestational age)-control group.. Adiponectin and leptin levels were significantly higher in the SGA group compared to the AGA group (. Children born SGA have abnormal adipose tissue biomarkers profiles. Topics: Adipokines; Adiponectin; Body Weight; Child; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Infant, Small for Gestational Age; Insulin Resistance; Leptin; Male; Resistin | 2023 |
Glucose-dependent insulinotropic polypeptide counteracts diet-induced obesity along with reduced feeding, elevated plasma leptin and activation of leptin-responsive and proopiomelanocortin neurons in the arcuate nucleus.
To clarify the effects of glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (GIPRAs) on feeding and body weight.. Acute and subchronic effects of subcutaneous GIPFA-085, a long-acting GIPRA, on blood glucose, food intake, body weight, respiratory exchange ratio and plasma leptin levels were measured in diet-induced obese (DIO) mice and/or functional leptin-deficient ob/ob mice. The effects of GIPFA-085 on the hypothalamic arcuate nucleus (ARC) neurons from lean and DIO mice were studied by measuring cytosolic Ca. Single bolus GIPFA-085 (30, 300 nmol/kg) dose-dependently reduced blood glucose in glucose tolerance tests, elevated plasma leptin levels at 0.5-6 hours and inhibited food intake at 2-24 hours after injection in DIO mice. Daily GIPFA-085 (300 nmol/kg) inhibited food intake and increased fat utilization on day 1, and reduced body weight gain on days 3-12 of treatment in DIO, but not ob/ob, mice. GIPFA-085 increased [Ca. GIPFA-085 acutely inhibits feeding and increases lipid utilization, and sustainedly lowers body weight in DIO mice via mechanisms involving rises in leptin and activation of ARC leptin-responsive and POMC neurons. This study highlights the therapeutic potential of GIPRAs for treating obesity and diabetes. Topics: Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Diet; Leptin; Mice; Mice, Inbred C57BL; Neurons; Obesity; Pro-Opiomelanocortin; Receptors, G-Protein-Coupled | 2023 |
Inter-organ insulin-leptin signal crosstalk from the liver enhances survival during food shortages.
Crosstalk among organs/tissues is important for regulating systemic metabolism. Here, we demonstrate inter-organ crosstalk between hepatic insulin and hypothalamic leptin actions, which maintains survival during food shortages. In inducible liver insulin receptor knockout mice, body weight is increased with hyperphagia and decreased energy expenditure, accompanied by increased circulating leptin receptor (LepR) and decreased hypothalamic leptin actions. Additional hepatic LepR deficiency reverses these metabolic phenotypes. Thus, decreased hepatic insulin action suppresses hypothalamic leptin action with increased liver-derived soluble LepR. Human hepatic and circulating LepR levels also correlate negatively with hepatic insulin action indices. In mice, food restriction decreases hepatic insulin action and energy expenditure with increased circulating LepR. Hepatic LepR deficiency increases mortality with enhanced energy expenditure during food restriction. The liver translates metabolic cues regarding energy-deficient status, which is reflected by decreased hepatic insulin action, into soluble LepR, thereby suppressing energy dissipation and assuring survival during food shortages. Topics: Animals; Body Weight; Energy Metabolism; Humans; Hypothalamus; Insulin; Leptin; Liver; Mice; Mice, Knockout; Receptors, Leptin | 2023 |
Relationship between leptin and white blood cells: a potential role in infection susceptibility and severity-the Olivetti Heart Study.
A number of evidence showed an emerging role of leptin on immune system, involving inflammation, and innate and adaptive immunity. Few observational studies have evaluated the relationship between leptin and immunity, albeit with low statistical power and methodological differences. Therefore, the aim of this study was to evaluate the potential role of leptin on the immunity, expressed as white blood cells (WBC)-and its subpopulations, by comprehensive multivariate models in a sample of adult men. A cross-sectional evaluation of a general population comprised 939 subjects participating in the Olivetti Heart Study, with available leptin levels and WBC-and its subpopulations. WBC were significantly and positively associated with leptin, C-reactive protein and HOMA index (p < 0.05), but not with age and anthropometric indices (p > 0.05). The multivariate analysis confirmed the association between leptin and WBC, after accounting for main confounders (p < 0.05). Additional analysis on WBC subpopulations showed a positive and significant correlation between leptin and lymphocytes, monocytes and eosinophils (p < 0.05), but not with neutrophils and basophils (p > 0.05). After stratification by body weight, the positive and significant association between leptin and WBC-and its subpopulations-was found in excess body weight participants. The results of this study indicate a direct relationship between leptin levels and WBC-and its subpopulations-in excess body weight participants. These results support the hypothesis that leptin has modulatory functions on immunity and role in the pathophysiology of immune-related diseases, in particular in those associated with excess body weight. Topics: Adult; Body Weight; Cross-Sectional Studies; Humans; Leptin; Leukocytes; Male; Neutrophils | 2023 |
Aging Changes the Efficacy of Central Urocortin 2 to Induce Weight Loss in Rats.
Middle-aged obesity and aging cachexia present healthcare challenges. Central responsiveness to body-weight-reducing mediators, e.g., to leptin, changes during aging in a way, which may promote middle-aged obesity and aging cachexia. Leptin is connected to urocortin 2 (Ucn2), an anorexigenic and hypermetabolic member of the corticotropin family. We aimed to study the role of Ucn2 in middle-aged obesity and aging cachexia. The food intake, body weight and hypermetabolic responses (oxygen consumption, core temperature) of male Wistar rats (3, 6, 12 and 18 months) were tested following intracerebroventricular injections of Ucn2. Following one central injection, Ucn2-induced anorexia lasted for 9 days in the 3-month, 14 days in the 6-month and 2 days in the 18-month group. Middle-aged 12-month rats failed to show anorexia or weight loss. Weight loss was transient (4 days) in the 3-month, 14 days in the 6-month and slight but long-lasting in the 18-month rats. Ucn2-induced hypermetabolism and hyperthermia increased with aging. The age-dependent changes in the mRNA expression of Ucn2 detected by RNAscope in the paraventricular nucleus correlated with the anorexigenic responsiveness. Our results show that age-dependent changes in Ucn2 may contribute to middle-aged obesity and aging cachexia. Ucn2 shows potential in the prevention of middle-aged obesity. Topics: Aging; Animals; Anorexia; Body Weight; Cachexia; Leptin; Male; Obesity; Rats; Rats, Wistar; Urocortins | 2023 |
The effects of Spirulina platensis on behavior in adolescent rats fed a high-fat diet.
In recent years, childhood overweight and obesity have become a universal public health problem. Obesity may lead to cognitive disorders, depression and anxiety by affecting neuronal processes. Spirulina platensis (SP), a species of microalgae from the Chlorophyceae green algae class, has neuroprotective effects and may reduce body weight. In this study, we aimed to investigate the effects of SP on behavior alongside the role of leptin and Sirtuin-1 in fed with high-fat diet (HFD) adolescent rats. Four-week-old Sprague Dawley male rats were divided into four groups: control, HFD, HFD + SP150 (150 mg/kg/day SP, orally), HFD + SP450 (450 mg/kg/day SP, orally). Rats except for the control group exposed to 60% HFD along 12 weeks. Last 6 weeks SP or vehicle administered. After the behavioral tests, leptin and Sirtuin-1 levels in prefrontal cortex and hippocampus regions were evaluated. SP150 significantly reduced body weight compared with HFD group. The time spent in the center of open field increased significantly in SP150-treated rats compared with HFD. SP150 and SP450 significantly decreased immobility time in forced swim test compared with HFD. Leptin levels in HFD group were significantly lower in prefrontal cortex compared to control group. Leptin levels of the HFD + SP450 group were significantly higher than HFD group in the hippocampus. There was no significant difference between groups in Sirtuin-1 levels. In conclusion, SP supplementation in adolescence period might positively affect chronic high fat-induced anxiety-like and depressive-like behavior by partially affecting brain leptin levels and without affecting Sirtuin-1 levels. Topics: Animals; Body Weight; Child; Diet, High-Fat; Humans; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Sirtuins | 2023 |
GDF15 enhances body weight and adiposity reduction in obese mice by leveraging the leptin pathway.
GDF15 regulates its anorexic effects through the hindbrain area postrema (AP) and nucleus of the solitary tract (NTS) neurons where its receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), is expressed. The actions of GDF15 may interact with other appetite regulators elevated in obesity, such as leptin. Here, we report that in mice with high-fat-diet-induced obesity (HFD), the combined infusion of GDF15 and leptin causes significantly greater weight and adiposity loss than either treatment alone, indicating potentiation between GDF15 and leptin. Furthermore, obese, leptin-deficient ob/ob mice are less responsive to GDF15, as are normal mice treated with a competitive leptin antagonist. GDF15 and leptin induce more hindbrain neuronal activation in HFD mice than either treatment alone does. We report extensive connections between GFRAL- and LepR-expressing neurons and find LepR knockdown in the NTS to reduce the GDF15-mediated activation of AP neurons. Overall, these findings suggest that leptin signaling pathways in the hindbrain increase GDF15's metabolic actions. Topics: Adiposity; Animals; Body Weight; Leptin; Mice; Mice, Obese; Obesity; Receptors, Leptin; Solitary Nucleus | 2023 |
Leptin, but not Estradiol, Signaling in PACAP Neurons Modulates Puberty Onset.
The adipose-derived hormone leptin critically modulates reproductive function, such that its absence results in hypothalamic hypogonadism. Pituitary adenylate cyclase-activating polypeptide (PACAP)-expressing neurons are potential mediators of leptin's action on the neuroendocrine reproductive axis because they are leptin-sensitive and involved in both feeding behavior and reproductive function. In the complete absence of PACAP, male and female mice exhibit metabolic and reproductive abnormalities, yet there is some sexual dimorphism in the reproductive impairments. We tested whether PACAP neurons play a critical and/or sufficient role in mediating leptin's effects on reproductive function by generating PACAP-specific leptin receptor (LepR) knockout and rescue mice, respectively. We also generated PACAP-specific estrogen receptor alpha knockout mice to determine whether estradiol-dependent regulation of PACAP was critically involved in the control of reproductive function and whether it contributed to the sexually dimorphic effects of PACAP. We showed that LepR signaling in PACAP neurons is critically involved in the timing of female, but not male, puberty onset, but not fertility. Rescuing LepR-PACAP signaling in otherwise LepR-deficient mice was unable to rescue the reproductive deficits observed in LepR null mice but led to a marginal improvement in body weight and adiposity in females. Finally, PACAP-specific estrogen receptor alpha knockout did not lead to any changes in body weight or puberty onset compared with control mice. These data highlight that PACAP is a critical mediator of some of leptin's, but not estradiol's, influence on puberty onset in females, but is not critically involved in relaying leptin's effects in males or in adult females. Topics: Animals; Body Weight; Estradiol; Estrogen Receptor alpha; Female; Leptin; Male; Mice; Mice, Knockout; Neurons; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Leptin; Sexual Maturation | 2023 |
Paternal developmental thyrotoxicosis disrupts neonatal leptin leading to increased adiposity and altered physiology of the melanocortin system.
The genetic code does not fully explain individual variability and inheritance of susceptibility to endocrine conditions, suggesting the contribution of epigenetic factors acting across generations.. We used a mouse model of developmental thyrotoxicosis (. Compared to controls, adult females with an exposed father (EF females) exhibited higher body weight and fat mass, but not lean mass, a phenotype that was much milder in EF males. After fasting, both EF females and males exhibited a more pronounced decrease in body weight than controls. EF females also showed markedly elevated serum leptin, increased white adipose tissue mRNA expression of leptin and mesoderm-specific transcript but decreased expression of type 2 deiodinase. EF females exhibited decreased serum ghrelin, which showed more pronounced post-fasting changes in EF females than in control females. EF female hypothalami also revealed significant decreases in the expression of pro-opiomelanocortin, agouti-related peptide, neuropeptide. A paternal excess of thyroid hormone during development modifies the endocrine programming and energy balance in the offspring in a sexually dimorphic manner, with baseline and dynamic range alterations in the leptin-melanocortin system and thyroid gland, and consequences for adiposity phenotypes. We conclude that thyroid hormone overexposure may have important implications for the non-genetic, inherited etiology of endocrine and metabolic pathologies. Topics: Adiposity; Animals; Body Weight; Fathers; Female; Humans; Leptin; Male; Melanocortins; Mice; Obesity; Thyroid Hormones; Thyrotoxicosis | 2023 |
WKYMVm ameliorates obesity by improving lipid metabolism and leptin signalling.
Obesity is a metabolic disorder that results from an imbalance of energy intake and consumption. As low-grade chronic inflammation caused by obesity can lead to various complications, it is important to develop effective treatments against obesity. In this study, we investigate the effects of WKYMVm, a strong anti-inflammatory agent, against obesity. Administration of WKYMVm into high fat diet (HFD)-induced obese mice significantly attenuated body weight gain, food intake and increased insulin sensitivity. HFD-induced hepatic steatosis and adipose tissue hypertrophy were also markedly ameliorated by WKYMVm. During the maturation of adipocytes, WKYMVm improves lipid metabolism by increasing lipolysis, adipogenesis, mitochondrial biogenesis and fat browning. WKYMVm administration also elicited a decrease in leptin levels, but an increase in leptin sensitivity via regulation of hypothalamic endoplasmic reticulum stress and the leptin receptor cascade. Taken together, our results show that WKYMVm ameliorates obesity by improving lipid metabolism and leptin signalling, suggesting that WKYMVm can be a useful molecule for the development of anti-obesity agents. Topics: Adipose Tissue; Animals; Body Weight; Leptin; Lipid Metabolism; Mice; Obesity | 2023 |
The effect of N-arachidonoylethanolamide administration on energy and fat metabolism of early lactating dairy cows.
The aim of the study was to investigate the effect of N-arachidonoylethanolamide (AEA), an endocannabinoid with orexigenic characteristics, on plasma endocannabinoid concentrations, feed intake, energy balance, lipomobilisation, and hepatic lipid metabolism of early-lactating dairy cows. The experiment involved 10 pairs of Holstein half-sibling cows (end of 2nd-3rd pregnancy). Half-sibs of each pair were randomly assigned to either AEA (n = 10) or control (CON) group (n = 10). From day 1 to 30 postpartum, the AEA group received 5 intraperitoneal injections per week of 3 µg/kg body weight AEA and the CON group 0.9% NaCl. In week 1-3 postpartum, AEA administration had no effect on dry matter intake, body weight, or lipomobilisation, but increased plasma triglyceride concentration on d 21 p.p. and mRNA abundances of genes related to hepatic triglyceride synthesis. In week 4 postpartum, the AEA group showed reduced feed intake and whole-body carbohydrate oxidation, but increased whole-body fat oxidation and hepatic lipid accumulation, likely as a result of a counter-regulatory leptin increase. In conclusion, the present study shows a tissue-specific AEA insensitivity and may point to a leptin-controlled regulation of the ECS in early-lactation. Topics: Animals; Body Weight; Cattle; Endocannabinoids; Female; Lactation; Leptin; Lipid Metabolism; Pregnancy | 2023 |
Effects of weight loss and feeding specially formulated diets on the body composition, blood metabolite profiles, voluntary physical activity, and fecal metabolites and microbiota of overweight cats.
Feline obesity is a common and preventable disease, posing a myriad of health risks and detriments. Specially formulated diets and restricted feeding may serve as an intervention strategy to promote weight loss and improve feline health. In this study, our objective was to determine the effects of restricted feeding and weight loss on body composition, voluntary physical activity, blood hormones and metabolites, and fecal microbiota of overweight cats. Twenty-two overweight adult spayed female and neutered male cats [body weight (BW) = 5.70 ± 1.0 kg; body condition score (BCS) = 7.68 ± 0.6; age = 4 ± 0.4 yr] were used in a weight loss study. A control diet (OR) was fed during a 4-wk baseline to identify intake needed to maintain BW. After baseline (week 0), cats were allotted to OR or a test diet (FT) and fed to lose ~1.0% BW/wk for 24 wk. At baseline and 6, 12, 18, and 24 wk after weight loss, dual-energy x-ray absorptiometry scans were performed and blood samples were collected. Voluntary physical activity was measured at weeks 0, 8, 16, and 24. Fecal samples were collected at weeks 0, 4, 8, 12, 16, 20, and 24. Change from baseline data were analyzed statistically using the Mixed Models procedure of SAS, with P < 0.05 considered significant. Restricted feeding of both diets led to weight and fat mass loss, lower BCS, and lower blood triglyceride and leptin concentrations. Cats fed the FT diet had a greater reduction in blood triglycerides and cholesterol than cats fed the OR diet. Restricted feeding and weight loss reduced fecal short-chain fatty acid, branched-chain fatty acid, phenol, and indole concentrations. Fecal valerate concentrations were affected by diet, with cats fed the OR diet having a greater reduction than those fed the FT diet. Fecal bacterial alpha diversity was not affected, but fecal bacterial beta diversity analysis showed clustering by diet. Restricted feeding and weight loss affected relative abundances of 7 fecal bacterial genera, while dietary intervention affected change from baseline relative abundances of 2 fecal bacterial phyla and 20 fecal bacterial genera. Our data demonstrate that restricted feeding promoted controlled and safe weight and fat loss, reduced blood lipids and leptin concentrations, and shifted fecal metabolites and microbiota. Some changes were also impacted by diet, highlighting the importance of ingredient and nutrient composition in weight loss diets.. The objective of this study was to determine the effects of diet, restricted feeding and weight loss on body composition, voluntary physical activity, blood hormones and metabolites, and fecal metabolites and microbiota of overweight cats. Overweight cats were allotted to a control diet (OR) or weight loss diet (FT) and fed to lose ~1.0% body weight/week for 24 wk. Body weight, body composition, and voluntary physical activity were measured, while fecal and blood samples were collected over time. Restricted feeding led to weight and fat mass loss, and lower blood triglyceride and leptin concentrations. Cats fed FT had a greater reduction in blood triglycerides and cholesterol than cats fed OR. Restricted feeding reduced fecal metabolite concentrations and affected relative abundances of 7 fecal bacterial genera. Fecal bacterial beta diversity analysis showed clustering by diet. Dietary intervention affected change from baseline relative abundances of 2 fecal bacterial phyla and 20 fecal bacterial genera. Our data demonstrate that restricted feeding promoted controlled and safe weight and fat loss, reduced blood lipids and leptin concentrations, and shifted fecal metabolites and microbiota. Some dietary differences were noted, highlighting the importance of ingredient and nutrient composition in weight loss diets. Topics: Animal Feed; Animals; Bacteria; Body Composition; Body Weight; Cat Diseases; Cats; Diet; Feces; Female; Leptin; Male; Microbiota; Overweight; Weight Loss | 2023 |
Impact of leptin deficiency on male tibia and vertebral body 3D bone architecture independent of changes in body weight.
Leptin an adipokine with potent effects on energy balance and body weight plays an important role in defining bone architecture in growing mammals. However, major changes in body weight can also influence morphology of trabecular and cortical bone. Therefore, we examined the impact of leptin deficiency on tibia and vertebral body 3D bone architecture independent of changes in body weight. Furthermore, advances in computational 3D image analysis suggest that average morphological values may mask regional specific differences in trabecular bone thickness. The study utilized leptin-deficient Ob/Ob mice (n = 8) weight-paired to C57BL/6 (C57) control mice (n = 8) which were split into either lean or obese groups for 24 ± 2 weeks. Whole tibias and L3 vertebrae were fixed before high resolution microcomputed tomography (μCT) scanning was performed. Leptin deficiency independent of body weight reduced tibia cortical bone volume, trabecular bone volume/tissue volume, number, and mineral density. Mean tibia trabecular thickness showed no significant differences between all groups; however, significant changes in trabecular thickness were found when analyzed by region. This study demonstrates that leptin deficiency significantly impacts tibia and vertebral body trabecular and cortical bone 3D architecture independent of changes in body weight. Topics: Animals; Body Weight; Bone Density; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Spine; Tibia; Vertebral Body; X-Ray Microtomography | 2023 |
Bo's abdominal acupuncture improves disordered metabolism in obese type 2 diabetic rats through regulating fibroblast growth factor 21 and its related adipokines.
To investigate the effect of Bo's abdominal acupuncture (BOAA) on fibroblast growth factor 21 (FGF21) and its related adipokines in type 2 diabetes mellitus (T2DM) rats.. This study established obese T2DM rat model by high-fat diet (HFD) with a dose of streptozotocin (STZ, 30 mg/kg). Obese T2DM rats were randomly subdivided into four groups (. Treatment with BOAA attenuated the histopathological changes in visceral fat and restored the alterations in the levels of body weight, fasting blood glucose (FBG), homeostasis model assessment for insulin resistance (HOMA-IR). BOAA treatment significantly decreased the levels of triglyceride, total cholesterol, low density lipoprotein cholesterol, leptin, and increased the serum levels of high-density lipoprotein cholesterol, fibroblast growth factor 21 (FGF21), adiponectin (ADP), peroxisome proliferator-activated receptor γ (PPAR-γ), C-peptide (C-P) in obese T2DM rats. Furthermore, BOAA treatment significantly increased the mRNA expressions of FGF21, ADP, leptin, PPAR-γ, PPAR-α and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Besides, BOAA treatment upregulated the protein expressions of fibroblast growth factor receptors3 (FGFR3), PPAR-. BOAA treatment reduced FBG and body weight, and improved insulin sensitivity through regulating FGF21 signaling pathway and its related adipokine in obese T2DM rats. Topics: Acupuncture Therapy; Adipokines; AMP-Activated Protein Kinases; Animals; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Fibroblast Growth Factors; Insulin Resistance; Leptin; Obesity; Peroxisome Proliferator-Activated Receptors; Rats | 2023 |
Correlation of serum levels of LH, IGF-1 and leptin in girls with the development of idiopathic central precocious puberty.
This paper aims to investigate the correlation between serum levels of luteinizing hormone (LH), insulin-like growth factor-1 (IGF-1) and leptin and the incidence of idiopathic central precocious puberty (ICPP) in girls, and to explore the clinical values in the diagnosis of ICPP.. A total of 48 girls with ICPP were selected in our hospital from March 2014 to March 2015 to serve as ICPP group. At the same time, 48 girls with the same age distribution were selected as control group. Bone age, body weight, Body Mass Index (BMI) and gender development index of girls in each group were recorded. Levels of LH, IGF-1 and leptin in serum were measured by chemiluminescence immunoassay. The correlations within levels of LH, IGF-1 and leptin, and the correlations between levels of LH, IGF-1 and leptin and body height, body weight and gender development index were analyzed.. Levels of LH, IGF-1 and leptin in ICPP group were significantly higher than those in control group (P<0.01). Body weight and BMI of ICPP group were significantly higher than those of control group (P<0.01), and were positively correlated with the expression level of leptin; ovarian volume and thickness of breast of ICPP group were significantly higher than those of control group (P<0.01), and were positively correlated with serum level of LH; serum level of IGF-1 was positively correlated with bone age. Levels of LH, IGF-1 and leptin in serum of ICPP girls were all increased compared with control group.. LH peak value and levels of IGF-1 and leptin in serum can be used as diagnostic indexes of ICPP. Topics: Body Weight; Female; Humans; Insulin-Like Growth Factor I; Leptin; Luteinizing Hormone; Puberty, Precocious | 2023 |
Androgen Excess Increases Food Intake in a Rat Polycystic Ovary Syndrome Model by Downregulating Hypothalamus Insulin and Leptin Signaling Pathways Preceding Weight Gain.
Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder characterized by high androgen levels. The aim of this study was to evaluate the effects of hyperandrogenism on the hypothalamus and subsequently on the food intake and obesity in females.. A dihydroxy testosterone (DHT)-induced rat model was established to recapitulate the hyperandrogenism features of PCOS patients. Body weight and food intake of the rats were recorded. The food intake of DHT-induced rats was restricted by pair feeding to exclude possible effects of weight gain on the hypothalamus. The expression levels of relevant proteins and mRNAs in the hypothalamus and primary hypothalamic neurons exposed to DHT were analyzed by Western blotting and RT-PCR, respectively. The leptin levels in the serum and cerebrospinal fluid (CSF) were measured, and leptin was injected via the intracerebroventricular (ICV) route to test the leptin sensitivity of the hypothalamus.. The excessive prepuberty androgen levels in the DHT-induced rats markedly elevated food intake prior to weight gain. Consistent with this, the expression of neuropeptide Y and agouti-related peptide mRNAs was upregulated, which occurred prior to obesity and even with restricted food intake. In addition, the hypothalamic sensitivity to insulin and leptin was also impaired in the DHT-induced rats before obesity and with restricted food intake. DHT significantly reduced the leptin levels in the CSF, and ICV injection of leptin inhibited the DHT-induced increase in food intake.. Androgen excess increased food intake in rats and promoted obesity by downregulating insulin and leptin signaling in the hypothalamus, most likely by suppressing leptin levels in the CSF. Topics: Androgens; Animals; Body Weight; Eating; Female; Humans; Hyperandrogenism; Hypothalamus; Insulin; Leptin; Neuropeptide Y; Obesity; Polycystic Ovary Syndrome; Rats; RNA, Messenger; Signal Transduction; Testosterone; Weight Gain | 2022 |
Methyl donor supplementation alters serum leptin levels and increases appetite but not body weight in cross-fostered male Syrian hamster offspring (Mesocricetus auratus).
A pregnant hamster's exposure to changes in environmental factors, such as light, temperature and nutrition, may influence behavioural and physiological changes in offspring. In this study, dietary methyl donor supplementation was employed to examine the role of maternal diet on appetite, body weight, serum leptin levels and locomotor activity in male Syrian hamster offspring. Dams were fed a standard control (SC) or methyl donor-supplemented (MDSD) diet through pregnancy and lactation. At birth, offspring were cross-fostered to dams fed an SC or MDSD diet (SC-MDSD and MDSD-SC) or remained with their birth mothers (SC-SC and MDSD-MDSD). At weaning, offspring were fed a SC or MDSD diet until 60 days of age. Food intake, serum leptin levels and locomotor activity were measured from 30-60 days of age. Offspring fed a MDSD diet post-weaning (MDSD-MDSD and SC-MDSD) consumed more than double the amount of food daily compared with offspring fed a SC diet post-weaning (SC-SC, MDSD-SC). Interestingly, there were no observed differences in body weight among all four groups. Serum leptin levels at 60 days of age were depressed in offspring fed a MDSD diet post-weaning (MDSD-MDSD and SC-MDSD). There were no observed differences in wheel running activity between the SC-SC and MDSC-SC groups. Wheel running activity was at least twice the amount in offspring fed a MDSD diet post-weaning (SC-MDSD and MDSD-MDSD). Taken together, these results indicate that the timing of methyl donor supplementation appears to be an important factor during the development of offspring. Topics: Animals; Appetite; Body Weight; Cricetinae; Dietary Supplements; Female; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Mesocricetus; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Rodent Diseases | 2022 |
Impaired leptin responsiveness in the nucleus accumbens of leptin-overexpressing transgenic mice with dysregulated sucrose and lipid preference independent of obesity.
While hypothalamic leptin resistance can occur prior to establishment of obesity, clarification is needed as to whether the impaired response to leptin in the reward-related nuclei occurs independently of obesity. To answer this question, we attempted to dissociate the normally coexisting leptin resistance from obesity. We investigated phenotypes of leptin-overexpressing transgenic mice fed for 1 week with 60 % high-fat diet (HFD) (LepTg-HFD1W mice). After 1 week, we observed that LepTg-HFD1W mice weighed as same as wild type (WT) mice fed standard chow diet (CD) for 1 week (WT-CD1W mice). However, compared to WT-CD1W mice, LepTg-HFD1W mice exhibited attenuated leptin-induced anorexia, decreased leptin-induced c-fos immunostaining in nucleus accumbens (NAc), one of important site of reward system, decreased leptin-stimulated pSTAT3 immunostaining in hypothalamus. Furthermore, neither sucrose nor lipid preference was suppressed by leptin in LepTg-HFD1W mice. On the contrary, leptin significantly suppressed both preferences in WT mice fed HFD (WT-HFD1 W mice). These results indicate that leptin responsiveness decreases in NAc independently of obesity. Additionally, in this situation, suppressive effect of leptin on the hedonic feeding results in impaired regulation. Such findings suggest the impaired leptin responsiveness in NAc partially contributes to dysregulated hedonic feeding behavior independently of obesity. Topics: Animals; Body Weight; Diet, High-Fat; Leptin; Lipids; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nucleus Accumbens; Obesity; Sucrose | 2022 |
The brain neuropeptides and STAT3 mediate the inhibitory effect of 17-β Estradiol on central leptin resistance in young but not aged female high-fat diet mice.
Aging and menopause effect on body composition and energy balance. Estrogen (E2) plays an important role in body's metabolism. The aim of the present study was to determine changes in leptin function in young intact and ovariectomized (OVX) animals in comparison to the aged animals treated with E2. Young (Intact and OVX 4 months) and aged (19-21 months) female mice were fed High-fat diet (HFD) for 12 weeks and, then they were divided into eight groups including: Intact + OIL, Intact + E2, Intact + Pair body weight (PBW), OVX + OIL, OVX + E2, OVX + PBW, Aged + OIL, and Aged + E2. E2 was administered subcutaneously every four days for four weeks. Responsiveness to leptin was assessed by measuring energy balance components. Results showed that eating HFD increased weight and calorie consumption in young mice, and chronic treatment with E2 decreased both these variables in young animals. E2 only improved the sensitivity to leptin in young animals. Treatment with E2 resulted in increased α-MSH neuropeptide, reduced NPY and AgRP neuropeptides in the brain, and decreased serum leptin in the young animals. Also, treatment with E2 increased the expression of p-STAT3 molecular level in the hypothalamic arcuate nucleus (ARC) in the young animals. Our results indicated that response to E2 depended on age and E2 protects young HFD fed mice from obesity and improves leptin sensitivity. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Diet, High-Fat; Estradiol; Female; Leptin; Mice; Mice, Inbred C57BL; Neuropeptides | 2022 |
Histone deacetylase 6 inhibition restores leptin sensitivity and reduces obesity.
The adipose tissue-derived hormone leptin can drive decreases in food intake while increasing energy expenditure. In diet-induced obesity, circulating leptin levels rise proportionally to adiposity. Despite this hyperleptinemia, rodents and humans with obesity maintain increased adiposity and are resistant to leptin's actions. Here we show that inhibitors of the cytosolic enzyme histone deacetylase 6 (HDAC6) act as potent leptin sensitizers and anti-obesity agents in diet-induced obese mice. Specifically, HDAC6 inhibitors, such as tubastatin A, reduce food intake, fat mass, hepatic steatosis and improve systemic glucose homeostasis in an HDAC6-dependent manner. Mechanistically, peripheral, but not central, inhibition of HDAC6 confers central leptin sensitivity. Additionally, the anti-obesity effect of tubastatin A is attenuated in animals with a defective central leptin-melanocortin circuitry, including db/db and MC4R knockout mice. Our results suggest the existence of an HDAC6-regulated adipokine that serves as a leptin-sensitizing agent and reveals HDAC6 as a potential target for the treatment of obesity. Topics: Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Dose-Response Relationship, Drug; Energy Metabolism; Enzyme Activation; Gene Expression Regulation; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Leptin; Liver; Male; Mice; Mice, Obese; Models, Biological; Obesity; Signal Transduction | 2022 |
Maternal exercise and high-fat diet affect hypothalamic neural projections in rat offspring in a sex-specific manner.
This study aimed to investigate the effect of maternal high-fat (HF) diet and exercise during gestation and lactation on hypothalamic neural projection development in the offspring. Pregnant Sprague-Dawley rats were fed a CHOW or HF diet during gestation and lactation, and further divided into two subgroups: voluntary exercised and sedentary. Offspring's brains and tissue were collected at weaning and 16 weeks of age. Maternal exercise downregulated dams' body weight and food intake during lactation, but failed to normalize increased fat weight, plasma and milk leptin levels of HF dams at weaning. Maternal HF diet significantly increased offspring's body weight, adipose depots, plasma insulin, and leptin at weaning and had long-term effect on body weight of male offspring, while maternal exercise decreased offspring's body weight from 3 to 5 weeks of age in both sexes. At weaning, maternal exercise decreased αMSH fiber density and maternal HF diet impaired agouti-related peptide fiber density in the paraventricular nucleus of hypothalamus of male pups, while maternal HF diet disrupted αMSH fiber density in the paraventricular nucleus of hypothalamus of female pups. The impaired αMSH fiber density was consistent with reduced STAT3 signaling in the arcuate nucleus of hypothalamus, while the reduced agouti-related peptide fiber density was consistent with reduced ERK1/2 signaling in the arcuate nucleus of hypothalamus. The impaired hypothalamic projections were compensated in adulthood in both sexes. Our findings suggest that maternal HF diet and exercise exerts different effects on hypothalamic neural projections development through distinct signaling pathways in a sex-specific manner. Topics: Adiposity; Adult; Animals; Body Weight; Diet, High-Fat; Female; Humans; Hypothalamus; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Weight Gain | 2022 |
Male Rat Offspring Are More Impacted by Maternal Obesity Induced by Cafeteria Diet than Females-Additive Effect of Postweaning Diet.
Topics: Acetyl-CoA Carboxylase; Animals; Body Weight; Diet, High-Fat; Fatty Acid Synthase, Type I; Female; Gene Expression Regulation; Glucose; Leptin; Male; Maternal Nutritional Physiological Phenomena; Obesity, Maternal; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Weaning | 2022 |
Intragastric safflower yellow and its main component HSYA improve leptin sensitivity before body weight change in diet-induced obese mice.
Our previous studies found that safflower yellow (SY) and its main component hydroxysafflor yellow A (HSYA) could alleviate obesity and improve leptin resistance in high-fat diet (HFD) induced obese mice. Therefore, our present study aimed to investigate whether the above effect of SY/HSYA was a direct effect or follow-up effect of weight loss and whether leptin was essential for the anti-obesity effect of SY/HSYA or not. HFD-induced obese mice were treated with SY or HSYA for 4 weeks, while ob/ob mice were treated with SY for 10 weeks. Body weight, food intake, fat mass, and serum leptin levels were measured. The leptin sensitivity experiment was conducted in HFD-induced obese mice. The expressions of leptin and its signaling-related genes were detected by RT-qPCR and Western blot methods. SY/HSYA treatment had no effect on food intake, energy expenditure, body weight, fat mass, and serum leptin levels in HFD-induced obese mice. However, the leptin sensitivity experiment showed that the food intake decreased by 18.4% in the HFD-SY group and the body weight gain decreased by 104.6% in the HFD-HSYA group, respectively (both P < 0.05). Furthermore, the expressions of leptin and leptin signaling inhibitory regulators were significantly decreased, while the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) were notably increased in WAT of HFD-induced obese mice, fully differentiated 3T3-L1 adipocytes after SY/HSYA intervention (all P < 0.05). Interestingly, SY treatment was ineffective on body weight, fat mass, and glucose metabolism in leptin-deficient ob/ob mice. SY/HSYA administration could firstly improve peripheral leptin resistance in adipose tissue of HFD-induced obese mice before their body weight was significantly changed, and leptin was essential for the anti-obesity effect of SY. Topics: Animals; Body Weight; Chalcone; Diet, High-Fat; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Quinones | 2022 |
Transient receptor potential cation channel 6 deficiency leads to increased body weight and metabolic dysfunction.
Topics: Animals; Anorexia; Blood Pressure; Body Weight; Eating; Female; Leptin; Male; Mice; Mice, Knockout; Obesity; TRPC6 Cation Channel; Weight Gain | 2022 |
An orally active plant Rubisco-derived peptide increases neuronal leptin responsiveness.
Nutrient excess, such as the intake of a high-fat diet, reduces hypothalamic responses to exogenously administered leptin and induces dietary obesity; however, orally active components that attenuate neural leptin dysregulation have yet to be identified. We herein demonstrated that YHIEPV, derived from the pepsin-pancreatin digestion of the green leaf protein Rubisco, increased the leptin-induced phosphorylation of STAT3 in ex vivo hypothalamic slice cultures. We also showed that YHIEPV mitigated palmitic acid-induced decreases in leptin responsiveness. Furthermore, orally administered YHIEPV promoted leptin-induced reductions in body weight and food intake in obese mice. In addition, dietary-induced body weight gain was significantly less in mice orally or centrally administered YHIEPV daily than in saline-control mice. Cellular leptin sensitivity and the levels of proinflammatory-related factors, such as IL1β and Socs-3, in the hypothalamus of obese mice were also restored by YHIEPV. YHIEPV blocked cellular leptin resistance induced by forskolin, which activates Epac-Rap1 signaling, and reduced the level of the GTP-bound active form of Rap1 in the brains of obese mice. Collectively, the present results demonstrated that the orally active peptide YHIEPV derived from a major green leaf protein increased neural leptin responsiveness and reduced body weight gain in mice with dietary obesity. Topics: Animals; Body Weight; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Ribulose-Bisphosphate Carboxylase; Weight Gain | 2022 |
Evaluation of antiobesity and hepatorenal protective activities of Salvia officinalis extracts pre-treatment in high-fat diet-induced obese rats.
The present study evaluated the effects of Hail Salvia officinalis total extract (SOTE) and its high flavonoid fraction (SOHFF) on the high-fat diet (HFD)-induced obesity and hepatorenal damage in rats. Salvia officinalis plants were collected from Hail region, Saudi Arabia. Rats were fed HFD and supplemented orally with SOTE (250 mg kg Topics: Animals; Antioxidants; Biomarkers; Body Weight; Creatinine; Diet, High-Fat; Flavonoids; Inflammation Mediators; Insulins; Interleukin-1beta; Leptin; Lipids; NF-E2-Related Factor 2; Nitric Oxide; Obesity; Oxidative Stress; Plant Extracts; PPAR gamma; Rats; Salvia officinalis; Simvastatin; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Urea | 2022 |
Perinatal Treatment with Leptin, but Not Celastrol, Protects from Metabolically Obese, Normal-Weight Phenotype in Rats.
Perinatal nutrition has a well-known influence on obesity susceptibility. We previously demonstrated the protective anti-obesity effects of perinatal leptin administration. Celastrol is a natural compound acting as a leptin sensitizer with anti-obesity effects when administered in adult animals. Here, we aimed to determine if perinatal treatment with leptin, celastrol, or their combination was able to improve metabolic health in animals fed an isocaloric high-fat (HF) diet. Leptin and/or celastrol or their vehicle were administered orally to rats during the suckling period. After weaning, animals were chronically pair-fed with an HF diet provided isocaloric to the intake of a normal-fat diet by control animals to avoid obesity. Isocaloric HF feeding in vehicle-treated animals resulted in metabolic features characteristic of the metabolically obese, normal-weight (MONW) phenotype, i.e., obesity-related disturbances without increased body weight. Leptin treatment prevented liver fat deposition and insulin resistance, induced greater insulin and leptin signaling capacity, decreased gene expression of orexigenic signals at the hypothalamic level, and induced browning in retroperitoneal adipose tissue. However, celastrol treatment did not provide any protective effect and resulted in greater size of the retroperitoneal adipose depot, higher circulating glucose and insulin levels, and decreased leptin sensitivity capacity in adipose tissue. The co-administration of leptin ameliorated the negative effects of celastrol on the retroperitoneal depot, inducing browning and decreasing its size. In conclusion, the perinatal administration of leptin, but not celastrol, provided protection against the consequences of dietary unbalances leading to an MONW phenotype in adulthood. Topics: Animals; Body Weight; Diet, High-Fat; Dietary Fats; Female; Insulin; Leptin; Obesity; Pentacyclic Triterpenes; Phenotype; Pregnancy; Rats | 2022 |
Intrauterine malnutrition disrupts leptin and ghrelin milk hormones, programming rats.
Herein, we assessed milk hormones, the biochemical composition of milk, and its association with neonatal body weight gain and metabolic homeostasis in weaned rats whose mothers were undernourished in the last third of pregnancy. From the 14th day of pregnancy until delivery, undernourished mothers had their food restricted by 50% (FR50), whereas control mothers were fed ad libitum. The litter size was adjusted to eight pups, and rats were weaned at 22 days old. Milk and blood from mothers, as well as blood and tissues from pups, were collected for further analyses. At birth, FR50 pups were smaller than control pups, and they exhibited hyperphagia and rapid catch-up growth during the suckling period. On day 12, the milk from FR50 mothers had higher energy content, glucose, total cholesterol, triglycerides, and acylated ghrelin but lower leptin and corticosterone levels. Interestingly, FR50 mothers were hypoglycemic and hyperleptinemic at the end of the nursing period. Weaned FR50 pups had an obese phenotype and exhibited insulin resistance, which was associated with hyperglycemia and hypertriglyceridemia; they also had high blood levels of total cholesterol, leptin, and acylated ghrelin. In addition, the protein expression of growth hormone secretagogue receptor (GHSR) in the hypothalamus was increased by almost 4-fold in FR50 pups. In summary, maternal calorie restriction during the last third of pregnancy disrupts energy and metabolic hormones in milk, induces pup hyperleptinemia and hyperghrelinemia, and upregulates their hypothalamic GHSR, thus suggesting that the hypothalamic neuroendocrine circuitry may be working to address the early onset of obesity. Topics: Animals; Body Weight; Cholesterol; Female; Ghrelin; Leptin; Malnutrition; Milk; Obesity; Pregnancy; Rats; Rats, Wistar | 2022 |
Water intake, thirst, and copeptin responses to two dehydrating stimuli in lean men and men with obesity.
Physiological systems responsible for water homeostasis and energy metabolism are interconnected. This study hypothesized altered responses to dehydration including thirst, ad libitum water intake, and copeptin in men with obesity.. Forty-two men (22 lean and 20 with obesity) were stimulated by a 2-hour hypertonic saline infusion and a 24-hour water deprivation. In each dehydrating condition, thirst, ad libitum water intake after dehydration, and urinary and hormonal responses including copeptin were assessed.. After each dehydration condition, ad libitum water intake was similar between both groups (p > 0.05); however, those with obesity reported feeling less thirsty (p < 0.05) and had decreased copeptin response and higher urinary sodium concentrations when stressed (p < 0.05). Angiotensin II, aldosterone, atrial and brain natriuretic peptides, and apelin concentrations did not differ by adiposity group and did not explain the different thirst or copeptin responses in men with obesity. However, leptin was associated with copeptin response in lean individuals during the hypertonic saline infusion (p < 0.05), but the relationship was diminished in those with obesity.. Diminished thirst and copeptin responses are part of the obesity phenotype and may be influenced by leptin. Adiposity may impact pathways regulating thirst and vasopressin release, warranting further investigation. Topics: Body Weight; Dehydration; Drinking; Glycopeptides; Humans; Leptin; Male; Obesity; Saline Solution, Hypertonic; Thirst | 2022 |
Linagliptin in Combination With Metformin Ameliorates Diabetic Osteoporosis Through Modulating BMP-2 and Sclerostin in the High-Fat Diet Fed C57BL/6 Mice.
Diabetic osteoporosis is a poorly managed serious skeletal complication, characterized by high fracture risk, increased bone resorption, reduced bone formation, and disrupted bone architecture. There is a need to investigate drugs that can improve bone health along with managing glycemic control. DPP-4 inhibitors and metformin have proven benefits in improving bone health. Here, we investigated the effects of linagliptin, a DPP inhibitor, and metformin alone and in combination to treat diabetic osteoporosis in high-fat-fed mice.. C57BL/6 mice were kept on the high-fat diet (HFD) for 22 weeks to induce diabetic osteoporosis. Linagliptin (10mg/Kg), metformin (150mg/Kg), and their combination were orally administered to the diabetic mice from the 18. HFD feeding resulted in impaired bone microarchitecture, reduced BMD, distorted bone histology, and altered bone turnover biomarkers as indicated by the significant reduction in bone ALP, BMP-2, osteocalcin, and an increase in sclerostin, TRAP, and serum calcium. Interestingly, treatment with linagliptin and its combination with metformin significantly reverted the impaired bone architecture, BMD, and positively modulated bone turnover biomarkers, while metformin alone did not exhibit any significant improvement. Further, HFD induced diabetes and metabolic abnormalities (including an increase in body weight, FBG, impaired glucose and insulin tolerance, leptin, triglycerides, cholesterol), and pro-inflammatory cytokines (TNF-alpha and IL-1β) were successfully reversed by treatment with linagliptin, metformin, and their combination.. Linagliptin and its combination with metformin successfully ameliorated diabetic osteoporosis in HFD-fed mice possibly through modulation of BMP-2 and sclerostin. The study provides the first evidence for the possible use of linagliptin and metformin combination for managing diabetic osteoporosis. Topics: Animals; Biomarkers; Body Weight; Calcium; Cytokines; Diabetes Mellitus, Experimental; Diet, High-Fat; Glucose; Insulin; Leptin; Linagliptin; Metformin; Mice; Mice, Inbred C57BL; Osteocalcin; Osteoporosis | 2022 |
Pharmacological FGF21 signals to glutamatergic neurons to enhance leptin action and lower body weight during obesity.
Fibroblast growth factor 21 (FGF21) is a peripherally-derived endocrine hormone that acts on the central nervous system (CNS) to regulate whole body energy homeostasis. Pharmacological administration of FGF21 promotes weight loss in obese animal models and human subjects with obesity. However, the central targets mediating these effects are incompletely defined.. To explore the mechanism for FGF21's effects to lower body weight, we pharmacologically administer FGF21 to genetic animal models lacking the obligate FGF21 co-receptor, β-klotho (KLB), in either glutamatergic (Vglut2-Cre) or GABAergic (Vgat-Cre) neurons. In addition, we abolish FGF21 signaling to leptin receptor (LepR-Cre) positive cells. Finally, we examine the synergistic effects of FGF21 and leptin to lower body weight and explore the importance of physiological leptin levels in FGF21-mediated regulation of body weight.. Here we show that FGF21 signaling to glutamatergic neurons is required for FGF21 to modulate energy expenditure and promote weight loss. In addition, we demonstrate that FGF21 signals to leptin receptor-expressing cells to regulate body weight, and that central leptin signaling is required for FGF21 to fully stimulate body weight loss during obesity. Interestingly, co-administration of FGF21 and leptin synergistically leads to robust weight loss.. These data reveal an important endocrine crosstalk between liver- and adipose-derived signals which integrate in the CNS to modulate energy homeostasis and body weight regulation. Topics: Animals; Body Weight; Fibroblast Growth Factors; Humans; Leptin; Neurons; Obesity; Receptors, Leptin; Weight Loss | 2022 |
Repetitive transcranial direct current stimulation modulates the brain-gut-microbiome axis in obese rodents.
Complex interactions between the brain, gut and adipose tissue allow to recognize obesity as a neurometabolic disorder. The recent data have shown that gut microbiota can play a potential role in obesity development. Transcranial direct current stimulation (tDCS) is a safe and non-invasive technique to modulate the activity of cerebral cortex and other connected brain areas also in context of appetite control. The objective of this study was to evaluate the effects of repetitive anodal tDCS (AtDCS) of prefrontal cortex on feeding behavior, metabolic status and selected phyla of gut microbiota in rats with obesity induced by high-calorie diet (HCD).. 32 female Wistar rats were equally divided into 4 subgroups depending on diet effect (lean versus obese) and type of stimulation (active versus sham tDCS versus no stimulation). Feed intake, body weight, blood lipoproteins and leptin levels as well as Firmicutes and Bacteroidetes in intestines and stool were examined.. HCD changed feeding behavior and metabolic parameters typically for obesity-related ranges and resulted in an abundance of Firmicutes at the expanse of Bacteroidetes in the large intestine and stool. AtDCS decreased appetite, body weight, and cholesterol levels. In addition, AtDCS reduced ratio of the average number of Firmicutes to average number of Bacteroidetes in all examined tissues.. Repetitive AtDCS is not only effective for appetite restriction but can also modulate gut microbiome composition which demonstrates the existence of the brain-gut-microbiome axis and points at this technique as a promising complementary treatment for obesity. However, the effects should be further replicated in human studies. Topics: Animals; Body Weight; Brain-Gut Axis; Cholesterol; Female; Humans; Leptin; Obesity; Rats; Rats, Wistar; Rodentia; Transcranial Direct Current Stimulation | 2022 |
Socs3 ablation in kisspeptin cells partially prevents lipopolysaccharide-induced body weight loss.
Many cytokines have been proposed to regulate reproduction due to their actions on hypothalamic kisspeptin cells, the main modulators of gonadotropin-releasing hormone (GnRH) neurons. Hormones such as leptin, prolactin and growth hormone are good examples of cytokines that lead to Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation, consequently exerting effects in kisspeptin neurons. Different studies have investigated how specific components of the JAK/STAT signaling pathway affect the functions of kisspeptin cells, but the role of the suppressor of cytokine signaling 3 (SOCS3) in mediating cytokine actions in kisspeptin cells remains unknown. Cre-Loxp technology was used in the present study to ablate Socs3 expression in kisspeptin cells (Kiss1/Socs3-KO). Then, male and female control and Kiss1/Socs3-KO mice were evaluated for sexual maturation, energy homeostasis features, and fertility. It was found that hypothalamic Kiss1 mRNA expression is significantly downregulated in Kiss1/Socs3-KO mice. Despite reduced hypothalamic Kiss1 mRNA content, these mice did not present any sexual maturation or fertility impairments. Additionally, body weight gain, leptin sensitivity and glucose homeostasis were similar to control mice. Interestingly, Kiss1/Socs3-KO mice were partially protected against lipopolysaccharide (LPS)-induced body weight loss. Our results suggest that Socs3 ablation in kisspeptin cells partially prevents the sickness behavior induced by LPS, suggesting that kisspeptin cells can modulate energy metabolism in mice in certain situations. Topics: Animals; Body Weight; Cytokines; Female; Kisspeptins; Leptin; Lipopolysaccharides; Male; Mice; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Weight Loss | 2022 |
PREMATURE MENOPAUSE AND OBESITY DUE TO OOCYTE LOSS IN FEMALE MICE CHRONICALLY EXPOSED TO LOW DOSE-RATE γ-RAYS.
In previous reports, the authors showed a significant overall increase in neoplasms originating from the ovaries (2007) and increased body weights (2007, 2010) in female B6C3F1 mice chronically exposed to low dose-rate γ-rays at 20 mGy/day (total doses = 8 (2007) or 6 Gy (2010)), as well as significant increases in serum leptin, total cholesterol, adipose tissue deposits and liver lipid content (2010). The present study chronicles the progression of ovarian failure in relation to obesity and dyslipidemia in female B6C3F1 mice chronically exposed to low dose-rate of γ-rays from 9 to 43 weeks of age (total dose = 4.8 Gy). We monitored changes in body weights, estrus cycles, ovarian follicle counts, serum cholesterol and serum leptin. The number of mice with irregular estrus cycles and increased body weights (with increased fat deposits) significantly increased from 30-36 weeks of age. Depletion of oocytes in ovaries from irradiated mice at 30 weeks of age (accumulated dose = 3 Gy) was also observed. Findings suggest that obesity in female B6C3F1 mice continuously irradiated with low dose-rate of γ-rays at 20 mGy/day is a consequence of premature menopause due to radiation-induced oocyte depletion. Topics: Body Weight; Cholesterol; Female; Humans; Leptin; Menopause, Premature; Obesity; Oocytes | 2022 |
Risk variants of obesity associated genes demonstrate BMI raising effect in a large cohort.
Obesity is highly polygenic disease where several genetic variants have been reportedly associated with obesity in different ethnicities of the world. In the current study, we identified the obesity risk or protective association and BMI raising effect of the minor allele of adiponectin, C1Q and collagen domain containing (ADIPOQ), cholesteryl ester transfer protein (CEPT), FTO alpha-ketoglutarate dependent dioxygenase (FTO), leptin (LEP), and leptin receptor (LEPR) genes in a large cohort stratified into four BMI-based body weight categories i.e., normal weight, lean, over-weight, and obese. Based on selected candidate genetic markers, the genotyping of all study subjects was performed by PCR assays, and genotypes and allele frequencies were calculated. The minor allele frequencies (MAFs) of all genetic markers were computed for total and BMI-based body weight categories and compared with MAFs of global and South Asian (SAS) populations. Genetic associations of variants with obesity risk were calculated and BMI raising effect per copy of the minor allele were estimated. The genetic variants with higher MAFs in obese BMI group were; rs2241766 (G = 0.43), rs17817449 (G = 0.54), rs9939609 (A = 0.51), rs1421085 (C = 0.53), rs1558902 (A = 0.63), and rs1137101 (G = 0.64) respectively. All these variants were significantly associated with obesity (OR = 1.03-4.42) and showed a high BMI raising effect (β = 0.239-0.31 Kg/m2) per copy of the risk allele. In contrast, the MAFs of three variants were higher in lean-normal BMI groups; rs3764261 A = 0.38, rs9941349 T = 0.43, and rs7799039 G = 0.40-0.43). These variants showed obesity protective associations (OR = 0.68-0.76), and a BMI lowering effect per copy of the protective allele (β = -0.103-0.155 Kg/m2). The rs3764261 variant also showed significant and positive association with lean body mass (OR = 2.38, CI = 1.30-4.34). Overall, we report six genetic variants of ADIPOQ, FTO and LEPR genes as obesity-risk markers and a CETP gene variant as lean mass/obesity protective marker in studied Pakistani cohort. Topics: Adiponectin; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Body Mass Index; Body Weight; Cholesterol Ester Transfer Proteins; Complement C1q; Dioxygenases; Genetic Markers; Humans; Ketoglutaric Acids; Leptin; Obesity; Polymorphism, Single Nucleotide; Receptors, Leptin | 2022 |
Galactose in the Post-Weaning Diet Programs Improved Circulating Adiponectin Concentrations and Skeletal Muscle Insulin Signaling.
Short-term post-weaning nutrition can result in long-lasting effects in later life. Partial replacement of glucose by galactose in the post-weaning diet showed direct effects on liver inflammation. Here, we examined this program on body weight, body composition, and insulin sensitivity at the adult age. Three-week-old female C57BL/6JRccHsd mice were fed a diet with glucose plus galactose (GAL; 16 energy% (en%) each) or a control diet with glucose (GLU; 32 en%) for three weeks, and afterward, both groups were given the same high-fat diet (HFD). After five weeks on a HFD, an oral glucose tolerance test was performed. After nine weeks on a HFD, energy metabolism was assessed by indirect calorimetry, and fasted mice were sacrificed fifteen minutes after a glucose bolus, followed by serum and tissue analyses. Body weight and body composition were not different between the post-weaning dietary groups, during the post-weaning period, or the HFD period. Glucose tolerance and energy metabolism in adulthood were not affected by the post-weaning diet. Serum adiponectin concentrations were significantly higher ( Topics: Adiponectin; Animals; Body Weight; Diet, High-Fat; Female; Galactose; Glucose; Inflammation; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Mice; Mice, Inbred C57BL; Muscle, Skeletal; RNA, Messenger; Weaning | 2022 |
Plant-based diets contribute to lower circulating leptin in healthy subjects independently of BMI.
Much research has shown how important role leptin - a hormone secreted by adipose tissue - plays in the regulation of human body weight, mainly due to its appetite-decreasing effects. Under the conditions of energy balance, leptin is an indicator of the amount of triglycerides stored in adipose tissue. In contrast, in a state of hunger or overeating, it acts as an energy balance sensor, and when its level is too high, it fails to reduce food intake, disturbing maintenance of the proper body mass. Recent studies indicate that there is a relationship between a vegetarian diet and the decreased incidence of cardiovascular diseases, certain types of cancer and obesity. It has been noted that people on plant-based diets have lower body weight and percentage of body fat than omnivores. The aim of the study was to analyze the relationship between serum leptin concentrations and the type of diet. The 143 female volunteers on a vegetarian, vegan or omnivore diet were enrolled in the study. All participants had normal body weight (BMI≥18.5<24.9kg/m2). There were statistically significant differences in the serum leptin concentrations of the studied women. Both in the group of vegetarians and vegans circulating leptin was significantly lower (p<0.001) than in the group of omnivores, with the lack of differences in neither BMI nor in body fat content. This suggests that leptin levels are affected not only by the amount of stored fat, but also by the consumed food. This observation indicates the health-promoting properties of plant diets, by influencing circulating leptin. Topics: Body Mass Index; Body Weight; Diet; Diet, Vegetarian; Female; Healthy Volunteers; Humans; Leptin | 2022 |
Oxytocin signaling in the posterior hypothalamus prevents hyperphagic obesity in mice.
Decades of studies have revealed molecular and neural circuit bases for body weight homeostasis. Neural hormone oxytocin (Oxt) has received attention in this context because it is produced by neurons in the paraventricular hypothalamic nucleus (PVH), a known output center of hypothalamic regulation of appetite. Oxt has an anorexigenic effect, as shown in human studies, and can mediate satiety signals in rodents. However, the function of Oxt signaling in the physiological regulation of appetite has remained in question, because whole-body knockout (KO) of Topics: Animals; Body Weight; Humans; Hyperphagia; Hypothalamus; Hypothalamus, Posterior; Leptin; Mice; Obesity; Oxytocin; Paraventricular Hypothalamic Nucleus; Triglycerides | 2022 |
Central Irisin Signaling Is Required for Normal Timing of Puberty in Female Mice.
Timing of puberty requires exquisite coordination of genes, hormones, and brain circuitry. An increasing level of body adiposity, signaled to the brain via the fat-derived hormone leptin, is recognized as a major factor controlling puberty onset. However, it is clear that leptin is not the only metabolic cue regulating puberty, and that developmental regulation of this process also involves tissues other than adipose, with muscle development potentially playing a role in the timing of puberty. The proteolytic processing of fibronectin type 3 domain-containing protein 5 (FNDC5) releases a hormone, irisin. Irisin is primarily produced by muscle and is released into circulation, where levels increase dramatically as puberty approaches. We investigated the effects of a global deletion of the Fndc5 gene on pubertal timing. The absence of irisin induced a delay in puberty onset in female knockout mice compared with controls, without affecting body weight or gonadotropin-releasing hormone (GnRH) neuronal density. We next treated pre-pubertal wild-type male and female mice with an irisin receptor antagonist, cilengitide, for 7 days and observed a delay in first estrus occurrence compared to vehicle-treated control mice. Male puberty timing was unaffected. Next, we deleted the irisin receptor (integrin subunit alpha V) in all forebrain neurons and found a delay in the occurrence of first estrus in knockout females compared to controls. Taken together, these data suggest irisin plays a role in the timing of puberty onset in female mice via a centrally mediated mechanism. Topics: Animals; Body Weight; Female; Fibronectins; Leptin; Male; Mice; Muscle, Skeletal; Obesity; Sexual Maturation; Transcription Factors | 2022 |
Hypolipidemic effect of ethanol extract from Chimonanthus nitens Oliv. leaves in hyperlipidemia rats via activation of the leptin/JAK2/STAT3 pathway.
This study aims to explore the protective role of ethanol extract from Chimonanthus nitens Oliv. leaf (COE) in hyperlipidemia via the leptin/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway.. Male Sprague‒Dawley rats were randomly divided into 6 groups (n = 8): normal-fat diet (NMD), high-fat diet (HFD), HFD treated with simvastatin (SIM, 5 mg/kg/day), and HFD treated with COE (40, 80, 160 mg/kg/day). Lipid parameters, oxidative stress factors, serum leptin, body weight, hepatic wet weight and liver index were measured. Proteins in the leptin/JAK2/STAT3 pathway in liver tissues were determined using western blotting. Additionally, the expression levels of cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) were quantified using western blotting and quantitative real-time polymerase chain reaction (qPCR).. COE decreased HFD-induced increases in body weight, hepatic wet weight and the liver index. HFD-induced hyperlipidemia and oxidative stress were observed in rat serum and livers. Additionally, COE repressed these two symptoms in rats fed a HFD. Moreover, COE caused CYP7A1 upregulation and HMGCR downregulation in HFD-fed rats. Mechanistically, COE induced the expression of leptin receptor (OB-Rb) and JAK2 and STAT3 phosphorylation in HFD-treated rats.. COE activates the leptin/JAK2/STAT3 pathway, leading to an improvement in liver function and lipid metabolism and ultimately alleviating hyperlipidemia in rats. Therefore, COE may be a potential hypolipidemic drug for the treatment of hyperlipidemia. Topics: Animals; Body Weight; Diet, High-Fat; Ethanol; Hyperlipidemias; Janus Kinase 2; Leptin; Liver; Male; Plant Leaves; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor | 2022 |
Reduced Visceral Fat Weight and Body Weight Due to Ingestion of Fermented Collagen Peptide in High-Fat Diet-Fed Obese Mice.
Oral ingestion of collagen hydrolysate has various benecial effects. We developed a novel fermented collagen peptide (FCP), different from the conventional collagen peptides, by fermenting gelatin with Aspergillus sojae. This study aimed to investigate the effect of FCP in inhibiting fat accumulation under high-fat loading. Male C57BL/6J mice were fed a low- or high-fat diet, or a high-fat diet including 5% FCP for 28 d. Body weight, visceral fat weight, adiponectin levels, leptin concentration, fatty acid synthase (FAS) activity, and carnitine palmitoyltransferase 1A (CPT) activity were determined. FCP supplementation was found to significantly decrease the body weight, visceral fat weight, leptin concentration, and FAS activity, and increase adiponectin levels and CPT activity compared to that in the high-fat diet-fed group. In conclusion, FCP intake reduced visceral fat weight and body weight in high-fat diet-fed mice. Topics: Adiponectin; Animals; Body Weight; Collagen; Diet, High-Fat; Eating; Intra-Abdominal Fat; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese | 2022 |
Anti-Obesity Effect of Chitoglucan in High-Fat-Induced Obesity Mice.
Chitoglucan (CG) is a bioactive component obtained from. The present study aimed to investigate the anti-obesity effects of chitoglucan and its hormonal mechanisms in high-fat diet (HFD)-induced mice.. The mice were fed either a normal diet (Normal group) or a high fat diet (HFD group) over 6 weeks. The HFD fed mice were administered with saline (HFD group), adipex (HFD + adipex group), chitoglucan 50, 150, or 300 mg/kg/day for 3 weeks (HFD + CG groups). The food consumption, body weight, fat contents, and the levels of serum leptin and resistin were assessed after treatment of chitoglucan.. the HFD produced a marked increase in body and fat weights after 6 weeks of feeding compared with the Normal group. Administration of chitoglucan for 3 weeks tended to reduce body weight and significantly decreased parametrical adipose tissues in HFD groups. The level of serum leptin in the HFD group was markedly higher than that in the Normal group, whereas the level of leptin in the chitoglucan treated groups was significantly decreased in comparison with the HFD group. In addition, the level of serum resistin in high-fat diet group tended to be more increased than Normal group. However, the serum resistin level was significantly reduced in HF diet groups after treatment with chitoglucan (50 mg/kg or 150 mg/kg).. Collectively, these data suggest that chitoglucan from the Topics: Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Leptin; Mice; Mice, Inbred C57BL; Obesity; Resistin; Vocalization, Animal | 2022 |
Sex- and Age-Dependent Changes in the Adiponectin/Leptin Ratio in Experimental Diet-Induced Obesity in Mice.
Biological sex and aging impact obesity development and type 2 diabetes, changing the secretion of leptin and adiponectin. The balance between these factors has been propounded as a reliable biomarker of adipose tissue dysfunction. Our proposal was to study sexual differences and aging on the adiponectin/leptin (Adpn/Lep) ratio in order to acquire a broader view of the impact of consuming an high-fat diet (HFD) on energy metabolism according to sex and age. Male and female C57BL/6J mice were fed a normal chow diet or an HFD for 12 or 32 weeks (n = 7−10 per group) and evolution of body weight, food intake and metabolic profile were registered. The HFD triggered an increase in body weight (p < 0.001), body weight gain (p < 0.01) and adiposity index (p < 0.01) in both sexes at 32 weeks of age, but female mice fed the HFD exhibited these changes to a significantly lower extent than males. Aged female mice showed an increase (p < 0.01) in the Adpn/Lep ratio, which was negatively correlated with body weight gain, changes in different fat depots and insulin resistance. Females were more metabolically protected from obesity development and its related comorbidities than males regardless of age, making the Adpn/Lep ratio a relevant factor for body composition and glucose metabolism. Topics: Adiponectin; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Female; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Weight Gain | 2022 |
Effects of TNF inhibitors and an IL12/23 inhibitor on changes in body weight and adipokine levels in psoriasis patients: a 48-week comparative study.
Psoriasis is a chronic inflammatory disease associated with obesity and metabolic syndrome. Adipokines are thought to be a link between psoriasis and obesity. Leptin, adiponectin, and omentin are bioactive adipokines thought to play a role in both metabolic comorbidities and inflammation. Anti-tumour necrosis factor alfa (anti-TNF-α) agents are effective for psoriasis treatment, although significant weight gain has been reported during anti-TNF-α therapy. The interleukin 12/23 (IL 12/23) inhibitor ustekinumab is also effective for psoriasis treatment. We compared the effects of three anti-TNF-α drugs and an IL-12/23 inhibitor on adipokines and weight gain during treatment.. This prospective study included 80 patients (37 women, 43 men) with moderate to severe plaque psoriasis whose age and weight were matched. The patients were divided into four equal groups: etanercept, infliximab, adalimumab, and ustekinumab treatment groups. Psoriasis Area Severity Index (PASI) score, body weight (muscle and fat compartments), and leptin, adiponectin, and omentin levels were evaluated at baseline and weeks 4, 12, 24, and 48 of treatment.. There were no differences between drug groups in terms of weight parameters or biochemical parameters at baseline. At the end of 48 weeks, there was significant weight gain in the adalimumab group. Patients who received infliximab showed significant weight gain by week 12, but in the following weeks they returned to their initial weight. Body weight reached a maximum level by week 12 in patients using etanercept, but they lost weight in the following weeks and finished the study below their initial weight. Patients using ustekinumab did not demonstrate significant weight change during the 48 weeks except at week 12. At the end of week 48, PASI75 (improvement in PASI ≥75%) response rates were approximately 85% for the ustekinumab group, 80% for the adalimumab group, 75% for the infliximab group, and 50% for the etanercept group. Leptin, adiponectin, and omentin levels were higher in the ustekinumab group at all weeks except baseline. The lowest levels were observed in the etanercept group. The treatment response rate was also lower in the etanercept group.. We did not evaluate visfatin and resistin levels, insulin sensitivity, and cardiovascular risk that may be associated with weight gain and adipokine levels.. Unlike TNF inhibitors, ustekinumab does not cause significant weight changes and it increases adipokine levels more than TNF inhibitors. Adipokine levels seem to be related to the treatment response. Topics: Adalimumab; Adipokines; Adiponectin; Body Weight; Etanercept; Female; Humans; Infliximab; Interleukin-12; Interleukin-23; Leptin; Male; Obesity; Prospective Studies; Psoriasis; Severity of Illness Index; Tumor Necrosis Factor Inhibitors; Ustekinumab; Weight Gain | 2022 |
Leptin sensitizing effect of 1,3-butanediol and its potential mechanism.
Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. ATP-deficient cells are vulnerable to ER stress and ATP treatment protects cells against ER stress. Thus, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma β-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. Co-administration experiment demonstrated that BD treatment sensitizes leptin action in both DIO and ob/ob mice. We also demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence suggesting that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration. Ketone bodies and hypothalamic ATP are the potential target for the treatment of obesity and its complications. Topics: 3-Hydroxybutyric Acid; Adenosine Triphosphate; Animals; Body Weight; Butylene Glycols; Endoplasmic Reticulum Stress; Energy Metabolism; Hypothalamus; Leptin; Male; Mice; Mice, Obese; Obesity | 2021 |
Energy homeostasis deregulation is attenuated by TUDCA treatment in streptozotocin-induced Alzheimer's disease mice model.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. While cognitive deficits remain the major manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown beneficial effects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin-induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the effects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz + TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz + TUDCA mice reduced fluorescence and gene expression of inflammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz + TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals. Topics: Adiposity; Alzheimer Disease; Animals; Biomarkers; Body Weight; Disease Management; Disease Models, Animal; Energy Metabolism; Gene Expression; Homeostasis; Immunohistochemistry; Inflammation Mediators; Leptin; Male; Mice; Organ Specificity; Signal Transduction; Streptozocin; Taurochenodeoxycholic Acid; Thermogenesis | 2021 |
PERK in POMC neurons connects celastrol with metabolism.
ER stress and activation of the unfolded protein response in the periphery as well as the central nervous system have been linked to various metabolic abnormalities. Chemically lowering protein kinase R-like ER kinase (PERK) activity within the hypothalamus leads to decreased food intake and body weight. However, the cell populations required in this response remain undefined. In the current study, we investigated the effects of proopiomelanocortin-specific (POMC-specific) PERK deficiency on energy balance and glucose metabolism. Male mice deficient for PERK in POMC neurons exhibited improvements in energy balance on a high-fat diet, showing decreased food intake and body weight, independent of changes in glucose and insulin tolerances. The plant-based inhibitor of PERK, celastrol, increases leptin sensitivity, resulting in decreased food intake and body weight in a murine model of diet-induced obesity (DIO). Our data extend these observations by demonstrating that celastrol-induced improvements in leptin sensitivity and energy balance were attenuated in mice with PERK deficiency in POMC neurons. Altogether, these data suggest that POMC-specific PERK deficiency in male mice confers protection against DIO, possibly providing a new therapeutic target for the treatment of diabetes and metabolic syndrome. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Diet, High-Fat; Eating; eIF-2 Kinase; Endoplasmic Reticulum Stress; Energy Metabolism; Glucose; Insulin Resistance; Leptin; Male; Mice; Mice, Knockout; Neurons; Obesity; Pentacyclic Triterpenes; Pro-Opiomelanocortin | 2021 |
Development of Visceral and Subcutaneous-Abdominal Adipose Tissue in Breastfed Infants during First Year of Lactation.
This study aimed to investigate relationships between infant abdominal visceral and subcutaneous adiposity and human milk (HM) components and maternal body composition (BC) during first year of lactation. Subcutaneous-abdominal depth (SAD), subcutaneous-abdominal fat area (SFA), visceral depth (VD) and preperitoneal fat area of 20 breastfed infants were assessed at 2, 5, 9 and 12 months using ultrasound. Maternal BC was determined with bioimpedance spectroscopy. HM macronutrients and bioactive components concentrations and infant 24-h milk intake were measured and calculated daily intakes (CDI) determined. Maternal adiposity associated with infant SFA (negatively at 2, 5, 12, positively at 9 months, all overall Topics: Adiponectin; Adiposity; Body Composition; Body Weight; Breast Feeding; Dietary Carbohydrates; Female; Humans; Infant; Intra-Abdominal Fat; Lactation; Leptin; Longitudinal Studies; Male; Milk, Human; Nutrients; Obesity; Subcutaneous Fat, Abdominal | 2021 |
Chronic Exposure to HIV-Derived Protein Tat Impairs Endothelial Function via Indirect Alteration in Fat Mass and Nox1-Mediated Mechanisms in Mice.
People living with human immunodeficiency virus (HIV) (PLWH) have increased risk for atherosclerosis-related cardiovascular disease (CVD), the main cause of death in this population. Notwithstanding, the mechanisms of HIV-associated vascular pathogenesis are not fully elucidated. Therefore, we sought to determine whether HIV-regulatory protein Tat mediates HIV-induced endothelial dysfunction via NADPH oxidase 1 (Nox1)-dependent mechanisms. Body weight, fat mass, leptin levels, expression of reactive oxygen species (ROS)-producing enzymes and vascular function were assessed in C57BL/6 male mice treated with Tat for 3 days and 4 weeks. Aortic rings and human endothelial cells were also treated with Tat for 2-24 h in ex vivo and in vitro settings. Chronic (4 weeks) but not acute (3 days and 2-24 h) treatment with Tat decreased body weight, fat mass, and leptin levels and increased the expression of Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue; Animals; Body Weight; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; NADPH Oxidase 1; Reactive Oxygen Species; Signal Transduction; tat Gene Products, Human Immunodeficiency Virus | 2021 |
Female Mice with Selenocysteine tRNA Deletion in Agrp Neurons Maintain Leptin Sensitivity and Resist Weight Gain While on a High-Fat Diet.
The role of the essential trace element selenium in hypothalamic physiology has begun to come to light over recent years. Selenium is used to synthesize a family of proteins participating in redox reactions called selenoproteins, which contain a selenocysteine residue in place of a cysteine. Past studies have shown that disrupted selenoprotein expression in the hypothalamus can adversely impact energy homeostasis. There is also evidence that selenium supports leptin signaling in the hypothalamus by maintaining proper redox balance. In this study, we generated mice with conditional knockout of the selenocysteine tRNA Topics: Adipose Tissue, Brown; Animals; Body Weight; Carbon Dioxide; Diet, High-Fat; Energy Metabolism; Female; Glucose Tolerance Test; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Obesity; RNA, Transfer, Amino Acid-Specific; Signal Transduction | 2021 |
Pregnancy Is Enough to Provoke Deleterious Effects in Descendants of Fructose-Fed Mothers and Their Fetuses.
The role of fructose in the global obesity and metabolic syndrome epidemic is widely recognized. However, its consumption is allowed during pregnancy. We have previously demonstrated that maternal fructose intake in rats induces detrimental effects in fetuses. However, these effects only appeared in adult descendants after a re-exposure to fructose. Pregnancy is a physiological state that leads to profound changes in metabolism and hormone response. Therefore, we wanted to establish if pregnancy in the progeny of fructose-fed mothers was also able to provoke an unhealthy situation. Pregnant rats from fructose-fed mothers (10% Topics: Animals; Body Weight; Feeding Behavior; Female; Fetus; Fructose; Gene Expression Regulation; Insulin; Leptin; Lipids; Liver; Oxidative Stress; Placenta; Pregnancy; Rats, Sprague-Dawley | 2021 |
The Effects of Separate and Combined Treatment of Male Rats with Type 2 Diabetes with Metformin and Orthosteric and Allosteric Agonists of Luteinizing Hormone Receptor on Steroidogenesis and Spermatogenesis.
Topics: Adenylate Kinase; Allosteric Regulation; Animals; Area Under Curve; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Therapy, Combination; Estradiol; Gene Expression Regulation; Glycated Hemoglobin; Insulin; Insulin Resistance; Leptin; Male; Metformin; Phosphorylation; Rats, Wistar; Receptors, LH; Seminiferous Tubules; Spermatogenesis; Steroids; Testosterone | 2021 |
Exposure to pollutants altered glucocorticoid signaling and clock gene expression in female mice. Evidence of tissue- and sex-specificity.
Environmental pollutants suspected of disrupting the endocrine system are considered etiologic factors in the epidemic of metabolic disorders. As regulation of energy metabolism relies on the integrated action of a large number of hormones, we hypothesized that certain chemicals could trigger changes in glucocorticoid signaling. To this end, we exposed C57Bl6/J female and male mice between 5 and 20 weeks of age to a mixture of 2,3,7,8- tetrachlorodibenzo-p-dioxin (20 pg/kg body weight/day [bw/d]), polychlorobiphenyl 153 (200 ng/kg bw/d), di-[2-ethylhexyl]-phthalate (500 μg/kg bw/d) and bisphenol A (40 μg/kg bw/d). In female mice fed a standard diet (ST), we observed a decrease in plasma levels of leptin as well as a reduced expression of corticoid receptors Nr3c1 and Nr3c2, of leptin and of various canonical genes related to the circadian clock machinery in visceral (VAT) but not subcutaneous (SAT) adipose tissue. However, Nr3c1 and Nr3c2 mRNA levels did not change in high-fat-fed females exposed to pollutants. In ST-fed males, pollutants caused the same decrease of Nr3c1 mRNA levels in VAT observed in ST-fed females but levels of Nr3c2 and other clock-related genes found to be down-regulated in female VAT were enhanced in male SAT and not affected in male VAT. The expression of corticoid receptors was not affected in the livers of both sexes in response to pollutants. In summary, exposure to a mixture of pollutants at doses lower than the no-observed adverse effect levels (NoAELs) resulted in sex-dependent glucocorticoid signaling disturbances and clock-related gene expression modifications in the adipose tissue of ST-fed mice. Topics: Adipose Tissue; Animals; Benzhydryl Compounds; Body Weight; Environmental Pollutants; Female; Gene Expression; Glucocorticoids; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Phenols; Polychlorinated Dibenzodioxins; RNA, Messenger; Sensitivity and Specificity | 2021 |
Leptin signaling in vagal afferent neurons supports the absorption and storage of nutrients from high-fat diet.
Activation of vagal afferent neurons (VAN) by postprandial gastrointestinal signals terminates feeding and facilitates nutrient digestion and absorption. Leptin modulates responsiveness of VAN to meal-related gastrointestinal signals. Rodents with high-fat diet (HF) feeding develop leptin resistance that impairs responsiveness of VAN. We hypothesized that lack of leptin signaling in VAN reduces responses to meal-related signals, which in turn decreases absorption of nutrients and energy storage from high-fat, calorically dense food.. Mice with conditional deletion of the leptin receptor from VAN (Nav1.8-Cre/LepR. After 4 weeks of HF feeding, KO mice gained less body weight and fat mass that WT controls, but this was not due to differences in food intake or energy expenditure. KO mice had reduced expression of carbohydrate transporters and absorption of carbohydrate in the jejunum. KO mice had fewer hepatic lipid droplets and decreased expression of de novo lipogenesis-associated enzymes and lipoproteins for endogenous lipoprotein pathway in liver, suggesting decreased long-term storage of carbohydrate in KO mice.. Impairment of leptin signaling in VAN reduces responsiveness to gastrointestinal signals, which reduces intestinal absorption of carbohydrates and de novo lipogenesis resulting in reduced long-term energy storage. This study reveals a novel role of vagal afferents to support digestion and energy storage that may contribute to the effectiveness of vagal blockade to induce weight loss. Topics: Animals; Body Weight; Carbohydrates; Diet, High-Fat; Energy Metabolism; Intestinal Absorption; Leptin; Lipogenesis; Liver; Male; Mice; Neurons, Afferent; Nutrients; Receptors, Leptin; Signal Transduction; Vagus Nerve | 2021 |
Associations of serum kisspeptin levels with metabolic and reproductive parameters in men.
Central kisspeptin action is well known in reproductive regulation; however, its peripheral action is not well understood. This study aimed to 1) compare serum or cerebrospinal fluid (CSF) kisspeptin levels between different body mass index (BMI) groups 2) compare the levels of kisspeptin between serum and CSF, and 3) determine correlations between serum or CSF kisspeptin levels with clinical, metabolic, and reproductive parameters. There were 40 male subjects undergoing operations with lumbar puncture anesthesia. Subgroup analysis was performed to compare between the normal (n = 12), overweight (n = 10), and obese groups (n = 17). One lean subject was recruited for correlation analysis. Serum kisspeptin levels were significantly higher in the obese group when compared to the normal weight and overweight groups even after adjusting for age or diastolic blood pressure (DBP) (p < 0.05 all). Serum leptin levels were significantly higher in the obese group when compared to the normal weight and overweight groups (p < 0.05 all). CSF kisspeptin levels were below the minimum detectable concentration for the assay (<0.06 ng/mL). Serum kisspeptin was positively correlated with body weight, BMI, plasma insulin, the homeostatic model assessment for insulin resistance (HOMA-IR), and serum leptin but was negatively correlated with plasma LH (p < 0.05 all). In conclusion, serum kisspeptin was related to obesity, leptin, insulin, and insulin resistance, while CSF kisspeptin was below the limits of detection. Thus, peripheral kisspeptin might have a role in metabolic regulation. Topics: Adult; Anesthesia; Body Mass Index; Body Weight; Female; Humans; Insulin Resistance; Kisspeptins; Leptin; Male; Obesity; Overweight; Reproduction; Spinal Puncture | 2021 |
CB1 and GLP-1 Receptors Cross Talk Provides New Therapies for Obesity.
Glucagon-like peptide 1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally restricted cannabinoid receptor type 1 (CB1R) inhibitors, which are devoid of the neuropsychiatric adverse effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the coadministration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies by promoting negative energy balance. This cotreatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the antiobesity and antidiabetic effects of currently available GLP-1R agonists. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Diet, High-Fat; Eating; Energy Metabolism; Glucagon-Like Peptide-1 Receptor; Insulin; Leptin; Male; Mice; Mice, Knockout; Obesity; Receptor, Cannabinoid, CB1 | 2021 |
Relationship of age at menarche and serum leptin with the metabolically unhealthy phenotype in adolescents.
Objective: to analyze the relationship of age at menarche and leptin with the metabolically healthy (MH) and metabolically unhealthy (MUH) phenotypes in adolescent girls in different body mass index (BMI) categories. Method: an observational and cross-sectional study consisting of 139 female adolescents attended to at the Adolescent Reference Center in Macaé, Rio de Janeiro. Menarche was classified as early (EM) when the first menstruation occurred at or before 11 years of age; normal menarche (NM) was categorized at ages 12 to 14; menarche was considered late (LM) when it occurred at age 15 or older. The factors required to ascertain the subjects' phenotype, as well as their leptin levels, weight, and height, were measured and their BMIs were calculated. The girls were classified as MH or MUH based on the NCEP-ATP III criteria as adapted for children and adolescents. Results: 82 % (n = 114) of the girls were classified as MH and 18 % (n = 25) as MUH. Mean age at menarche was 11.79 ± 1.39 years. There was a higher prevalence of MUH amongst the girls who had EM (p = 0.04). A higher inadequacy of serum leptin concentrations was found in girls who had EM (p = 0.05) and in those classified as MUH (p = 0.01). The adolescents who were severely obese exhibited inadequate leptin levels (p < 0.01) and had gone through EM (p = 0.02). A total of 8.1 % (n = 7) of the normal-weight girls were classified as MUH, and 29.4 % (n = 5) of those who were severely obese were classified as MH (p < 0.01). Conclusion: early menarche and high serum leptin concentrations are related with the MUH phenotype in adolescent girls in different BMI categories.. Objetivo: analizar la relación de la edad de la menarquia y los niveles de leptina con los fenotipos metabólicamente saludables (MS) y metabólicamente no saludables (MNS) en adolescentes de diferentes categorías de índice de masa corporal (IMC). Método: estudio observacional y transversal compuesto por 139 adolescentes de sexo feminino, atendidas en el Centro de Referencia para Adolescentes de Macaé, Río de Janeiro. La menarquia se clasificó como precoz (MP) cuando se produjo la primera menstruación a o antes de los 11 años de edad; la menarquia normal (MN) se clasificó como aquella sucedida a la edad de 12 a 14 años; la menarquia se consideró tardía (MT) cuando ocurrió a los 15 años o más. Se midieron los factores necesarios para determinar el fenotipo de los sujetos, y se midieron sus niveles de leptina, peso y altura, y se calculó su IMC. Las adolescentes se clasificaron como MS y MNS según los criterios de NCEP-ATP III, adaptados para niños y adolescentes. Resultados: el 82 % (n = 114) de las adolescentes se clasificaron como MH y el 18 % (n = 25) como MUH. La edad media de la menarquia fue de 11,79 ± 1,39 años. Hubo una mayor prevalencia de MUH entre las adolescentes que tenían MP (p = 0,04). Se encontró una mayor insuficiencia de las concentraciones séricas de leptina en las adolescentes que tenían MP (p = 0,05) y en aquellas clasificadas como MNS (p = 0,01). Las adolescentes que eran severamente obesas exhibieron niveles inadecuados de leptina (p < 0,01) y habían pasado por una MP (p = 0,02). El 8,1 % (n = 7) de las adolescentes de peso normal se clasificaron como MNS y el 29,4 % (n = 5) de las que eran severamente obesas se clasificaron como MS (p < 0,01). Conclusión: la menarquia temprana y las altas concentraciones séricas de leptina están relacionadas con el fenotipo MNS en las adolescentes de diferentes categorías de IMC. Topics: Adolescent; Age Factors; Body Height; Body Mass Index; Body Weight; Brazil; Child; Cross-Sectional Studies; Female; Humans; Leptin; Menarche; Pediatric Obesity; Phenotype; Puberty; Sexual Maturation | 2021 |
Antioxidation, anti-hyperlipidaemia and hepatoprotection of polysaccharides from Auricularia auricular residue.
Topics: Adiponectin; Animals; Antioxidants; Auricularia; Body Weight; Cytoprotection; Fungal Polysaccharides; Hyperlipidemias; Hypolipidemic Agents; Insulin; Leptin; Liver; Male; Mice | 2021 |
Metreleptin worked in a diabetic woman with a history of hematopoietic stem cell transplantation (HSCT) during infancy: further support for the concept of 'HSCT-associated lipodystrophy'.
A 17-year-old woman with a history of childhood leukemia and hematopoietic stem cell transplantation (HSCT), preceded by total body irradiation, developed diabetes, dyslipidemia, fatty liver, and marked insulin resistance. Based on Dunnigan phenotype, HSCT-associated lipodystrophy was suspected. Because of rapid deterioration of diabetes control, metreleptin was introduced at 23 years of age upon receipt of her caregiver's documented consent. This trial was initially planned as a prospective 18 month-long study, with regular assessments of the patient's physical activity, food intake, and body composition analysis. However, because an abrupt and transient attenuation of the metreleptin effect occurred 16 months after the treatment initiation, the entire course of 28 months is reported here. Over the period, her HbA1c decreased from 10.9% to 6.7% despite no significant increase of physical activity and with a stable food intake. Decreased levels of triglyceride and non-HDL cholesterol were found. Her liver function improved, indicating the amelioration of fatty liver. In addition, a 25% reduction in the subcutaneous fat area at umbilical level was found, accompanied by a decrease in fat percentage of both total-body and trunk. The formation of neutralizing antibodies to metreleptin may be responsible for the transient loss of efficacy, considering a sudden elevation in her serum leptin level. In conclusion, metreleptin is useful for the management of HSCT-associated lipodystrophy, supporting the concept that adipose tissue dysfunction is responsible for diverse post-HSCT metabolic aberrations. Topics: Adolescent; Body Composition; Body Weight; Carbohydrate Metabolism; Diabetes Mellitus; Female; Hematopoietic Stem Cell Transplantation; Humans; Leptin; Lipodystrophy; Treatment Outcome; Young Adult | 2021 |
Bifidobacterium longum counters the effects of obesity: Partial successful translation from rodent to human.
The human gut microbiota has emerged as a key factor in the development of obesity. Certain probiotic strains have shown anti-obesity effects. The objective of this study was to investigate whether Bifidobacterium longum APC1472 has anti-obesity effects in high-fat diet (HFD)-induced obese mice and whether B. longum APC1472 supplementation reduces body-mass index (BMI) in healthy overweight/obese individuals as the primary outcome. B. longum APC1472 effects on waist-to-hip ratio (W/H ratio) and on obesity-associated plasma biomarkers were analysed as secondary outcomes.. B. longum APC1472 was administered to HFD-fed C57BL/6 mice in drinking water for 16 weeks. In the human intervention trial, participants received B. longum APC1472 or placebo supplementation for 12 weeks, during which primary and secondary outcomes were measured at the beginning and end of the intervention.. B. longum APC1472 supplementation was associated with decreased bodyweight, fat depots accumulation and increased glucose tolerance in HFD-fed mice. While, in healthy overweight/obese adults, the supplementation of B. longum APC1472 strain did not change primary outcomes of BMI (0.03, 95% CI [-0.4, 0.3]) or W/H ratio (0.003, 95% CI [-0.01, 0.01]), a positive effect on the secondary outcome of fasting blood glucose levels was found (-0.299, 95% CI [-0.44, -0.09]).. This study shows a positive translational effect of B. longum APC1472 on fasting blood glucose from a preclinical mouse model of obesity to a human intervention study in otherwise healthy overweight and obese individuals. This highlights the promising potential of B. longum APC1472 to be developed as a valuable supplement in reducing specific markers of obesity.. This research was funded in part by Science Foundation Ireland in the form of a Research Centre grant (SFI/12/RC/2273) to APC Microbiome Ireland and by a research grant from Cremo S.A. Topics: Adiposity; Adrenal Cortex Hormones; Animals; Bifidobacterium longum; Biomarkers; Body Weight; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Disease Resistance; Energy Metabolism; Glucose; Host Microbial Interactions; Leptin; Male; Mice; Neuropeptides; Obesity; Probiotics; Rodentia; Translational Research, Biomedical | 2021 |
Maternal high-fat-diet exposure is associated with elevated blood pressure and sustained increased leptin levels through epigenetic memory in offspring.
Maternal metabolism dysregulation during pregnancy predisposes offspring to major diseases, including hypertension, in later life, but the mechanism involved remains to be fully elucidated. A high-fat-diet (HFD) pregnant rat model was used to investigate whether excessive intrauterine lipid exposure was associated with elevated blood pressure in offspring and increased levels of leptin, an important biomarker and mediator of vascular dysfunction and hypertension. We found that gestational hyperlipidemia predisposed offspring to blood pressure elevation and sustained increases in leptin levels with no difference in body weight in the rat model. Increased leptin expression and leptin promoter hypomethylation were found in adipose tissues of HFD-exposed offspring. The treatment of mesenchymal stem cells with free fatty acids during adipogenic differentiation resulted in increased leptin expression, accompanied by leptin promoter hypomethylation. In addition, we also followed up 121 children to evaluate the association between maternal triglyceride levels and offspring blood pressure. Consistent with the animal study results, we observed elevated serum leptin levels and blood pressure in the offspring born to women with gestational hypertriglyceridemia. Our findings provide new insights that maternal hyperlipidemia is associated with elevated blood pressure in offspring and is associated with increases in leptin levels through epigenetic memory. Topics: Adiponectin; Animals; Blood Glucose; Blood Pressure; Body Weight; Diet, High-Fat; Epigenesis, Genetic; Female; Insulin; Leptin; Male; Maternal Exposure; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Triglycerides | 2021 |
The Role of Mediobasal Hypothalamic PACAP in the Control of Body Weight and Metabolism.
Body energy homeostasis results from balancing energy intake and energy expenditure. Central nervous system administration of pituitary adenylate cyclase activating polypeptide (PACAP) dramatically alters metabolic function, but the physiologic mechanism of this neuropeptide remains poorly defined. PACAP is expressed in the mediobasal hypothalamus (MBH), a brain area essential for energy balance. Ventromedial hypothalamic nucleus (VMN) neurons contain, by far, the largest and most dense population of PACAP in the medial hypothalamus. This region is involved in coordinating the sympathetic nervous system in response to metabolic cues in order to re-establish energy homeostasis. Additionally, the metabolic cue of leptin signaling in the VMN regulates PACAP expression. We hypothesized that PACAP may play a role in the various effector systems of energy homeostasis, and tested its role by using VMN-directed, but MBH encompassing, adeno-associated virus (AAVCre) injections to ablate Adcyap1 (gene coding for PACAP) in mice (Adcyap1MBHKO mice). Adcyap1MBHKO mice rapidly gained body weight and adiposity, becoming hyperinsulinemic and hyperglycemic. Adcyap1MBHKO mice exhibited decreased oxygen consumption (VO2), without changes in activity. These effects appear to be due at least in part to brown adipose tissue (BAT) dysfunction, and we show that PACAP-expressing cells in the MBH can stimulate BAT thermogenesis. While we observed disruption of glucose clearance during hyperinsulinemic/euglycemic clamp studies in obese Adcyap1MBHKO mice, these parameters were normal prior to the onset of obesity. Thus, MBH PACAP plays important roles in the regulation of metabolic rate and energy balance through multiple effector systems on multiple time scales, which highlight the diverse set of functions for PACAP in overall energy homeostasis. Topics: Adipose Tissue, Brown; Animals; Body Weight; Energy Metabolism; Female; Humans; Hypothalamus; Leptin; Male; Mice; Mice, Knockout; Neurons; Obesity; Pituitary Adenylate Cyclase-Activating Polypeptide; Sympathetic Nervous System; Thermogenesis; Ventromedial Hypothalamic Nucleus | 2021 |
Association of serum adiponectin and myostatin levels with skeletal muscle in patients with obesity: A cross-sectional study.
Adiponectin has been reported to be associated with lower skeletal muscle mass and skeletal strength and may be involved in skeletal muscle regulation along with myostatin. This study aims to evaluate the association between serum adiponectin and myostatin levels and identify independent factors using body composition and metabolic parameters in patients with obesity.. Overall, 148 patients (age, 45.9 ± 14.3 years, body mass index, 37.2 ± 8.0 kg/m2) who initially visited the outpatient clinic of obesity between November 2013 and November 2019 were included. Body composition was measured using InBody 720 and dual energy X-ray absorptiometry. In addition, muscle strength, vascular function, and metabolic parameters were measured. Serum levels of adiponectin, leptin, myostatin, and irisin were measured from blood samples.. The serum adiponectin level was 2.9 μg/mL (1.7-4.1 μg/mL), and the serum myostatin level was 2398.4 pg/mL (1,777.1-2952.5 pg/mL). The stepwise regression analysis revealed less leg strength, homeostasis model assessment of insulin resistance, and C-reactive protein as an independent predictor of serum adiponectin levels based on the significance of the univariate analysis (R2 = 0.190, P < 0.001). A high appendicular lean mass/body weight, reactive hyperemia index, and irisin were independent factors for serum myostatin levels (R2 = 0.260, P < 0.001).. The serum adiponectin level was associated with less muscle strength. Although serum myostatin was associated with a high appendicular lean mass, it is possible that myostatin was regulated by the percentage of body weight from appendicular lean mass. Topics: Absorptiometry, Photon; Adiponectin; Adult; Body Composition; Body Mass Index; Body Weight; C-Reactive Protein; Correlation of Data; Cross-Sectional Studies; Female; Fibronectins; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Muscle Strength; Muscle, Skeletal; Myostatin; Obesity | 2021 |
Antiobesity effects of kimchi added with Jeju citrus concentrate on high-fat diet-induced obese mice.
Topics: Adipogenesis; Adiponectin; Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Citrus; Diet, High-Fat; Fermented Foods; Fruit; Gene Expression Regulation; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Obesity | 2021 |
Resveratrol Supplementation Attenuates Cognitive and Molecular Alterations under Maternal High-Fat Diet Intake: Epigenetic Inheritance over Generations.
Environmental factors such as maternal high-fat diet (HFD) intake can increase the risk of age-related cognitive decline in adult offspring. Epigenetic mechanisms are a possible link between diet effect and neurodegeneration across generations. Here, we found a significant decrease in triglyceride levels in a high-fat diet with resveratrol (RSV) HFD + RSV group and the offspring. Firstly, we obtained better cognitive performance in HFD+RSV groups and their offspring. Molecularly, a significant increase in DNA methylation (5-mC) levels, as well as increased gene expression of Topics: Adenosine; Animals; Body Weight; Brain; Cognition; Diet, High-Fat; Dietary Supplements; DNA Methylation; Epigenesis, Genetic; Epigenomics; Female; Inflammation; Leptin; Male; Maternal Exposure; Maze Learning; Methylation; Mice; Neurodegenerative Diseases; Neuronal Plasticity; Obesity; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Resveratrol; Triglycerides | 2021 |
Sex-Specific Effects of Myo-Inositol Ingested During Lactation in the Improvement of Metabolic Health in Adult Rats.
To examine the effects of myo-inositol supplementation during lactation in male and female rats on metabolic parameters and its potential to reverse metabolic alterations associated with a moderate gestational calorie restriction.. The offspring of control and 25% gestational calorie-restricted rats are supplemented with myo-inositol or vehicle throughout lactation and exposed to a Western diet (WD) from 5 to 7 months of age. Blood parameters are measured and gene expression and protein levels in retroperitoneal white adipose tissue (rWAT) and liver are analyzed. In male offspring, but not in females, myo-inositol supplementation resulted in lower fasting triglyceride and insulin levels and HOMA-IR at 7 months, and reversed the alterations in these parameters due to gestational calorie restriction. The expression pattern of key genes in metabolism in rWAT and liver support the beneficial effect of myo-inositol supplementation in reversing metabolic alterations programmed by gestational calorie restriction in male rats.. Myo-inositol supplementation at physiological doses during lactation improves metabolic health and prevents the programmed trend to develop insulin resistance and hypertriglyceridemia in male rats acquired by inadequate fetal nutrition and exacerbated by a diabetogenic diet in adulthood. The absence of clear effects in females deserves further investigation. Topics: Adipose Tissue, White; Animals; Body Weight; Caloric Restriction; Dietary Supplements; Eating; Energy Metabolism; Female; Gene Expression Regulation; Inositol; Insulin Resistance; Lactation; Leptin; Male; Obesity; Pregnancy; Rats, Wistar; Sex Factors; Triglycerides | 2021 |
Choline and Folic Acid in Diets Consumed during Pregnancy Interact to Program Food Intake and Metabolic Regulation of Male Wistar Rat Offspring.
North American women consume high folic acid (FA), but most are not meeting the adequate intakes for choline. High-FA gestational diets induce an obesogenic phenotype in rat offspring. It is unclear if imbalances between FA and other methyl-nutrients (i.e., choline) account for these effects.. This study investigated the interaction of choline and FA in gestational diets on food intake, body weight, one-carbon metabolism, and hypothalamic gene expression in male Wistar rat offspring.. Pregnant Wistar rats were fed an AIN-93G diet with recommended choline and FA [RCRF; 1-fold, control] or high (5-fold) FA with choline at 0.5-fold [low choline and high folic acid (LCHF)], 1-fold [recommended choline and high folic acid (RCHF)], or 2.5-fold [high choline and high folic acid (HCHF)]. Male offspring were weaned to an RCRF diet for 20 wk. Food intake, weight gain, plasma energy-regulatory hormones, brain and plasma one-carbon metabolites, and RNA sequencing (RNA-seq) in pup hypothalamuses were assessed.. Adult offspring from LCHF and RCHF, but not HCHF, gestational diets had 10% higher food intake and weight gain than controls (P < 0.01). HCHF newborn pups had lower plasma insulin and leptin compared with LCHF and RCHF pups (P < 0.05), respectively. Pup brain choline (P < 0.05) and betaine (P < 0.01) were 22-33% higher in HCHF pups compared with LCHF pups; methionine was ∼23% lower after all high FA diets compared with RCRF (P < 0.01). LCHF adult offspring had lower brain choline (P < 0.05) than all groups and lower plasma 5-methyltetrahydrofolate (P < 0.05) than RCRF and RCHF groups. HCHF adult offspring had lower plasma cystathionine (P < 0.05) than LCHF adult offspring and lower homocysteine (P < 0.01) than RCHF and RCRF adult offspring. RNA-seq identified 144 differentially expressed genes in the hypothalamus of HCHF newborns compared with controls.. Increased choline in gestational diets modified the programming effects of high FA on long-term food intake regulation, plasma energy-regulatory hormones, one-carbon metabolism, and hypothalamic gene expression in male Wistar rat offspring, emphasizing a need for more attention to the choline and FA balance in maternal diets. Topics: Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Appetite Regulation; Body Weight; Brain; Choline; Eating; Female; Folic Acid; Gene Expression; Hypothalamus; Insulin; Intra-Abdominal Fat; Leptin; Male; Maternal Nutritional Physiological Phenomena; Maternal-Fetal Exchange; Models, Animal; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Weaning | 2021 |
Cafeteria diet induces global and
Increased visceral adipose tissue (VAT) is associated with metabolic dysfunction, while subcutaneous adipose tissue (SAT) is considered protective. The mechanisms underlying these differences are not fully elucidated. This study aimed to investigate molecular differences in VAT and SAT of male Wistar rats fed a cafeteria diet (CD) or a standard rodent diet (STD) for three months. The expression of fatty acid metabolism genes was analysed by quantitative real-time PCR. Global and gene-specific DNA methylation was quantified using the Imprint® Methylated DNA Quantification Kit and pyrosequencing, respectively. Bodyweight, retroperitoneal fat mass, insulin resistance, leptin and triglyceride concentrations and adipocyte hypertrophy were higher in CD- compared to STD-fed rats. The expression of solute carrier family 27 member 3 (Slc27a3), a fatty acid transporter, was 9.6-fold higher in VAT and 6.3-fold lower in SAT of CD- versus STD-fed rats. Taqman probes confirmed increased Slc27a3 expression, while pyrosequencing showed Slc27a3 hypomethylation in VAT of CD- compared to STD-fed rats. The CD decreased global methylation in both VAT and SAT, although no depot differences were observed. Dysregulated fatty acid influx in VAT, in response to a CD, provides insight into the mechanisms underlying depot-differences in adipose tissue expansion during obesity and metabolic disease. Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet; Diet, High-Fat; DNA Methylation; Fatty Acid Transport Proteins; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Metabolic Diseases; Obesity; Rats; Rats, Wistar; Subcutaneous Fat | 2021 |
Hypothalamic Renin-Angiotensin System and Lipid Metabolism: Effects of Virgin Olive Oil versus Butter in the Diet.
The brain renin-angiotensin system (RAS) has been recently involved in the homeostatic regulation of energy. Our goal was to analyse the influence of a diet rich in saturated fatty acids (butter) against one enriched in monounsaturated fatty acids (olive oil) on hypothalamic RAS, and their relationship with the metabolism of fatty acids. Increases in body weight and visceral fat, together with an increase in aminopeptidase A expression and reductions in AngII and AngIV were observed in the hypothalamus of animals fed with the butter diet. In this group, a marked reduction in the expression of genes related to lipid metabolism (LPL, CD36, and CPT-1) was observed in liver and muscle. No changes were found in terms of body weight, total visceral fat and the expression of hepatic genes related to fatty acid metabolism in the olive oil diet. The expressions of LPL and CD36 were reduced in the muscles, although the decrease was lower than in the butter diet. At the same time, the fasting levels of leptin were reduced, no changes were observed in the hypothalamic expression of aminopeptidase A and decreases were noted in the levels of AngII, AngIV and AngIII. These results support that the type of dietary fat is able to modify the hypothalamic profile of RAS and the body energy balance, related to changes in lipid metabolism. Topics: Angiotensin II; Angiotensin III; Animals; Body Weight; Butter; CD36 Antigens; Diet, High-Fat; Energy Metabolism; Fasting; Gene Expression; Glutamyl Aminopeptidase; Hypothalamus; Intra-Abdominal Fat; Leptin; Lipid Metabolism; Lipoprotein Lipase; Liver; Male; Mice; Mice, Inbred ICR; Muscle, Skeletal; Olive Oil; Real-Time Polymerase Chain Reaction; Renin-Angiotensin System; RNA, Messenger; Weight Gain | 2021 |
Sex differences in markers of metabolic syndrome and adipose tissue inflammation in obesity-prone, Osborne-Mendel and obesity-resistant, S5B/Pl rats.
The current study examined the role of sex differences in the development of risk factors associated with obesity and its comorbidities using models that differ in their susceptibility to develop obesity, obesity-resistant S5B/Pl (S5B) and obesity-prone Osborne-Mendel (OM) rats. Male and female rats were fed a low fat or high fat diet (HFD) and markers of metabolic syndrome (MetSyn) and expression of inflammatory cytokines/chemokines in visceral and subcutaneous adipose depots were measured. We hypothesized that male and female OM and S5B rats would exhibit differential responses to the consumption of HFD and that females, regardless of susceptibility to develop obesity, would display decreased obesity-related risk factors. Results suggested that consumption of HFD increased adiposity and fasting glucose levels in male OM and S5B rats, decreased circulating adiponectin levels in male S5B rats, and increased body weight and triglyceride levels in male OM rats. The consumption of HFD increased body weight and adiposity in female OM rats, not female S5B rats. Overall, female rats did not meet criteria for MetSyn, while male rats consuming HFD met criteria for MetSyn. Visceral and subcutaneous adipose tissue inflammation was higher in male rats. In visceral adipose tissue, HFD consumption differentially altered expression of cytokines in male and female S5B and OM rats. These findings suggest that resistance to obesity in males may be overridden by chronic consumption of HFD and lead to increased risk for development of obesity-related comorbidities, while female rats appear to be protected from the adverse effects of HFD consumption. Topics: Adipose Tissue; Animals; Biomarkers; Body Weight; Diet, High-Fat; Female; Inflammation; Leptin; Male; Metabolic Syndrome; Obesity; Rats; Sex Factors; Weight Gain | 2021 |
Phenotypic characterization of Adig null mice suggests roles for adipogenin in the regulation of fat mass accrual and leptin secretion.
Topics: Adipocytes; Adipogenesis; Adiponectin; Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Female; Glucose Tolerance Test; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Nuclear Proteins; Phenotype; Uncoupling Protein 1 | 2021 |
Leptin deficiency affects glucose homeostasis and results in adiposity in zebrafish.
Leptin is a hormone which functions in the regulation of energy homeostasis via suppression of appetite. In zebrafish, there are two paralogous genes encoding leptin, called lepa and lepb. In a gene expression study, we found that the lepb gene, not the lepa gene, was significantly downregulated under the state of insulin-resistance in zebrafish larvae, suggesting that the lepb plays a role in glucose homeostasis. In the current study, we characterised lepb-deficient (lepb-/-) adult zebrafish generated via a CRISPR-CAS9 gene editing approach by investigating whether the disruption of the lepb gene would result in the development of type 2 diabetes mellitus (T2DM) and diabetic complications. We observed that lepb-/- adult zebrafish had an increase in body weight, length and visceral fat accumulation, compared to age-matched control zebrafish. In addition, lepb-/- zebrafish had significantly higher blood glucose levels compared to control zebrafish. These data collectively indicate that lepb-/- adult zebrafish display the features of T2DM. Furthermore, we showed that lepb-/- adult zebrafish had glomerular hypertrophy and thickening of the glomerular basement membrane, compared to control zebrafish, suggesting that lepb-/- adult zebrafish develop early signs of diabetic nephropathy. In conclusion, our results demonstrate that lepb regulates glucose homeostasis and adiposity in zebrafish, and suggest that lepb-/- mutant zebrafish are a promising model to investigate the role of leptin in the development of T2DM and are an attractive model to perform mechanistic and therapeutic research in T2DM and its complications. Topics: Adiposity; Animals; Blood Glucose; Body Weight; CRISPR-Cas Systems; Gene Deletion; Glucose; Homeostasis; Hypertrophy; Kidney Glomerulus; Leptin; Zebrafish | 2021 |
919 syrup inhibits ROS-mediated leptin-induced anorexia by activating PPARγ and improves gut flora abnormalities.
Women with postpartum psychiatric disorders are prone to severe anorexia. Clinical studies have revealed the efficacy of 919 syrup, a traditional Chinese medicine mixture against postpartum illnesses, such as in regulating maternal mood and improving postpartum anorexia.. This study investigated the mechanisms through which 919 syrup improved anorexia induced by postpartum stress, focussing on the combined peroxisome proliferator-activated receptor gamma (PPARγ) and leptin signalling pathway, and its effects on the structure of the gut flora.. Mice were randomly divided into five groups-control group, immobilisation stressed (IS) group (normal saline), pioglitazone (Piog; western medicine control) group, 919 syrup low-dose (TJD; 13.5 g/kg) group, and 919 syrup high-dose (TJG; 27.0 g/kg) group. The control group was housed normally. The other groups received IS for 3 h daily for 21 days. The treatments were initiated following the first postnatal day and were administered by gastric gavage. All mice were sacrificed under anaesthesia on postnatal day 22. Blood, hypothalamus, stomach, and faecal specimens were collected. Gene and protein expression levels of components of the PPARγ-leptin signalling pathway in the serum, hypothalamus, and stomach were determined. Immunofluorescence staining for proopiomelanocortin (POMC), phosphorylated signal transducer and activator of transcription 3 (pSTAT3), and leptin was performed to observe their spatial distributions in the hypothalamus and stomach. 16s rRNA gene sequencing and bioinformatics analysis of fecal specimens were performed.. After IS, postpartum mice showed significantly reduced appetite and body weight, accompanied by abnormalities in the structure of the gut flora. Treatment with 919 syrup (27.0 g/kg) downregulated malondialdehyde and upregulated catalase, glutathione peroxidase, and superoxide dismutase by activating PPARγ, thereby affecting the expression of leptin signalling pathway components (leptin, leptin receptor, pSTAT3, POMC, and cocaine and amphetamine-related transcript and neuropeptide Y), and modulated the gut flora in stressed mice.. 919 syrup improved appetite in mice with postnatal stress by activating PPARγ to induce crosstalk with the leptin signalling pathway, this mechanism was similar to that of PPARγ agonists. 919 syrup also improved gut flora structure, and the changes in the relative abundances of the gut flora strongly correlated with the expression levels of PPARγ and leptin pathway components. Topics: Actinidia; Animals; Anorexia; Appetite; Body Weight; Female; Gastrointestinal Microbiome; Leptin; Male; Mice; Plant Extracts; Postpartum Period; PPAR gamma; Pregnancy; Reactive Oxygen Species | 2021 |
Physiological and metabolic characteristics of novel double-mutant female mice with targeted disruption of both growth hormone-releasing hormone and growth hormone receptor.
Mice with disruptions of growth hormone-releasing hormone (GHRH) or growth hormone receptor (GHR) exhibit similar phenotypes of prolonged lifespan and delayed age-related diseases. However, these two models respond differently to calorie restriction indicating that they might carry different and/or independent mechanisms for improved longevity and healthspan. In order to elucidate these mechanisms, we generated GHRH and GHR double-knockout mice (D-KO). In the present study, we focused specifically on the characteristics of female D-KO mice. The D-KO mice have reduced body weight and enhanced insulin sensitivity compared to wild-type (WT) controls. Growth retardation in D-KO mice is accompanied by decreased GH expression in pituitary, decreased circulating IGF-1, increased high-molecular-weight (HMW) adiponectin, and leptin hormones compared to WT controls. Generalized linear model-based regression analysis, which controls for body weight differences between D-KO and WT groups, shows that D-KO mice have decreased lean mass, bone mineral density, and bone mineral content, but increased adiposity. Indirect calorimetry markers including oxygen consumption, carbon dioxide production, and energy expenditure were significantly lower in D-KO mice relative to the controls. In comparison with WT mice, the D-KO mice displayed reduced respiratory exchange ratio (RER) values only during the light cycle, suggesting a circadian-related metabolic shift toward fat utilization. Interestingly, to date survival data suggest extended lifespan in D-KO female mice. Topics: Adiposity; Aging; Animals; Body Weight; Caloric Restriction; Carbon Dioxide; Energy Metabolism; Female; Gene Editing; Gene Knockout Techniques; Growth Hormone; Growth Hormone-Releasing Hormone; Insulin-Like Growth Factor I; Leptin; Longevity; Mice; Mice, Knockout; Oxygen Consumption; Receptors, Somatotropin; Signal Transduction | 2021 |
Safflower seed oil improves steroidogenesis and spermatogenesis in rats with type II diabetes mellitus by modulating the genes expression involved in steroidogenesis, inflammation and oxidative stress.
Diabetes mellitus (DM), as a multiorgan syndrome, is an endocrine and metabolic disorder that is associated with male reproductive system dysfunction and infertility. Safflower (Carthamus tinctorius L.) as an herbal remedy improves DM and infertility-related disorders. The anti-hypercholesterolemic, anti-inflammatory, and antioxidative properties of this herb have been well documented, but its role in testosterone production, male reproductive system and zinc homeostasis has not been fully illustrated.. This study aimed to investigate the preventive and therapeutic properties of different doses of safflower seed oil against reproductive damage caused by type II DM by investigating zinc element homeostasis, inflammation and oxidative damage in testis tissue and their relationship with testosterone production and sperm parameters.. Eighty adult male Sprague-Dawley rats were randomly divided into eight groups and treated daily for 12 and 24 weeks in protective and therapeutic studies, respectively. Type II DM was induced by a High Fat Diet (HFD) in normoglycemic rats for three months. At the end of each study, serum level of glucose, testosterone, gonadotropins, TNF-α, insulin, and leptin were measured. Moreover, antioxidant enzymes activity, lipid peroxidation, zinc and testosterone along with the expression of Nrf-2, NF-κB, TNF-α, StAR, P450scc, and 17βHSD3 genes in the testis were detected.. After the intervention, the activity of antioxidant enzymes and the level of testosterone and gonadotropins significantly decreased in the rats with DM in comparison to the others. However, lipid peroxidation and serum level of insulin, leptin and TNF-α increased and the testicular level of zinc significantly changed in the rats with DM compared to the control groups (p < 0.05). The gene expression of NF-κB and TNF-α were also significantly increased and the gene expression of Nrf2, StAR, P450scc and 17βHSD3 were decreased in the testis of diabetic rats (p < 0.05). The results showed that pretreatment and treatment with safflower seed oil could improve these parameters in diabetic rats compared with untreated diabetic rats (p < 0.05).. HFD could impair the production of testosterone and sperm, and reduce gonadotropin by increasing the serum level of leptin and inducing insulin resistance, oxidative stress and inflammation. However, safflower oil in a dose-dependent manner could improve testosterone level and sperm parameters by improving the level of leptin, zinc and insulin resistance, and the genes expression involved in testosterone synthesis, inflammation and oxidative stress. Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Eating; Gene Expression Regulation; Gonadotropins; Inflammation; Insulin; Leptin; Lipid Peroxidation; Lipogenesis; Male; Oxidative Stress; Rats, Sprague-Dawley; Safflower Oil; Seeds; Spermatogenesis; Spermatozoa; Steroids; Testis; Testosterone; Tumor Necrosis Factor-alpha; Zinc | 2021 |
Asperuloside Enhances Taste Perception and Prevents Weight Gain in High-Fat Fed Mice.
Asperuloside is an iridoid glycoside found in many medicinal plants that has produced promising anti-obesity results in animal models. In previous studies, three months of asperuloside administration reduced food intake, body weight, and adipose masses in rats consuming a high fat diet (HFD). However, the mechanisms by which asperuloside exerts its anti-obesity properties were not clarified. Here, we investigated homeostatic and nutrient-sensing mechanisms regulating food intake in mice consuming HFD. We confirmed the anti-obesity properties of asperuloside and, importantly, we identified some mechanisms that could be responsible for its therapeutic effect. Asperuloside reduced body weight and food intake in mice consuming HFD by 10.5 and 12.8% respectively, with no effect on mice eating a standard chow diet. Fasting glucose and plasma insulin were also significantly reduced. Mechanistically, asperuloside significantly reduced hypothalamic mRNA ghrelin, leptin, and pro-opiomelanocortin in mice consuming HFD. The expression of fat lingual receptors (CD36, FFAR1-4), CB1R and sweet lingual receptors (TAS1R2-3) was increased almost 2-fold by the administration of asperuloside. Our findings suggest that asperuloside might exert its therapeutic effects by altering nutrient-sensing receptors in the oral cavity as well as hypothalamic receptors involved in food intake when mice are exposed to obesogenic diets. This signaling pathway is known to influence the subtle hypothalamic equilibrium between energy homeostasis and reward-induced overeating responses. The present pre-clinical study demonstrated that targeting the gustatory system through asperuloside administration could represent a promising and effective new anti-obesity strategy. Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cyclopentane Monoterpenes; Diet, High-Fat; Energy Intake; Ghrelin; Glucosides; Hypothalamus; Insulin; Leptin; Male; Mice; Pro-Opiomelanocortin; Pyrans; Taste Perception; Weight Gain | 2021 |
Retarding effect of dietary fibers from bamboo shoot (Phyllostachys edulis) in hyperlipidemic rats induced by a high-fat diet.
The effects of the administration of bamboo shoot (Phyllostachys edulis) dietary fiber (BSDF) on high-fat diet (HDF) induced hyperlipidemia were studied with SD rat models. The results indicated that the body weight of rats and the mass of their adipose tissue were significantly (P < 0.05) decreased after the combination treatment of soluble dietary fiber (SDF) and insoluble dietary fiber (IDF). The levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol were significantly (P < 0.05) decreased by 30.20%, 53.28% and 35.63%, respectively, compared to those of the model group. The levels of serum alanine aminotransferase, aspartate aminotransferase, leptin, and insulin-like growth factor-1 of the SDF + IDF group were also significantly lower than those of the HDF model group (P < 0.05). Additionally, the perirenal fat percentage and body fat percentage in the SDF + IDF group were reduced by 31.61% and 25.09%, respectively. IDF exhibited better hypolipidemic ability than SDF in HFD induced rats at the same dose, while SDF and IDF showed a synergistic hyperlipidemia prevention effect. The mRNA expression levels of lipid synthesis genes SREBP-1c and FAS were significantly down-regulated by SDF + IDF treatment (P < 0.05). These results suggested that BSDF composed of IDF and SDF, with potential hypolipidemic effects, could be used in the production of health-beneficial food. Topics: Adipose Tissue; Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; Dietary Fiber; Down-Regulation; Hyperlipidemias; Leptin; Lipoproteins, LDL; Liver; Male; Plant Shoots; Rats; Rats, Sprague-Dawley; Sasa; Triglycerides | 2021 |
Characterization of the onset of leptin effects on the regulation of energy balance.
Leptin is a hormone required for the regulation of body weight in adult animals. However, during the postnatal period, leptin is mostly involved in developmental processes. Because the precise moment at which leptin starts to exert its metabolic effects is not well characterized, our objective was to identify the approximate onset of leptin effects on the regulation of energy balance. We observed that male Lepob/ob mice started to exhibit increased body fat mass from postnatal day 13 (P13), whereas in females, the increase in adiposity began on P20. Daily leptin injections from P10 to P22 did not reduce the weight gain of WT mice. However, an acute leptin injection induced an anorexigenic response in 10-day-old C57BL/6 mice but not in 7-day-old mice. An age-dependent increase in the number of leptin receptor-expressing neurons and leptin-induced pSTAT3 cells was observed in the hypothalamus of P7, P10 and P16 mice. Leptin deficiency started to modulate the hypothalamic expression of transcripts involved in the regulation of metabolism between P7 and P12. Additionally, fasting-induced hypothalamic responses were prevented by leptin replacement in 10-day-old mice. Finally, 12-day-old males and females showed similar developmental timing of axonal projections of arcuate nucleus neurons in both WT and Lepob/ob mice. In summary, we provided a detailed characterization of the onset of leptin's effects on the regulation of energy balance. These findings contribute to the understanding of leptin functions during development. Topics: Aging; Animals; Animals, Suckling; Body Composition; Body Weight; Energy Metabolism; Female; Fetal Development; Food Deprivation; Gene Expression Regulation, Developmental; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Receptors, Leptin; STAT3 Transcription Factor | 2021 |
Diet Supplementation with Fish-Derived Extracts Suppresses Diabetes and Modulates Intestinal Microbiome in a Murine Model of Diet-Induced Obesity.
Metabolic syndrome-related diseases affect millions of people worldwide. It is well established that changes in nutritional habits and lifestyle can improve or prevent metabolic-related pathologies such as type-2 diabetes and obesity. Previous reports have shown that nutritional supplements have the capacity to limit glucose intolerance and suppress diabetes development. In this study, we investigated the effect of dietary supplementation with fish-derived extracts on obesity and type 2 diabetes and their impact on gut microbial composition. We showed that nutritional supplements containing Fish Complex (FC), Fish Complex combined with Cod Powder (FC + CP), or Cod Powder combined with Collagen (CP + C) improved glucose intolerance, independent of abdominal fat accumulation, in a mouse model of diet-induced obesity and type 2 diabetes. In addition, collagen-containing supplements distinctly modulate the gut microbiome in high-fat induced obesity in mice. Our results suggest that fish-derived supplements suppress diet-induced type 2 diabetes, which may be partly mediated through changes in the gut microbiome. Thus, fish-derived supplements and particularly the ones containing fish collagen have potential beneficial properties as dietary supplements in managing type 2 diabetes and metabolic syndrome via modulation of the gut microbiome. Topics: Abdominal Fat; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Female; Fishes; Gastrointestinal Microbiome; Glucose Intolerance; Hypoglycemic Agents; Insulin Resistance; Leptin; Mice, Inbred C57BL; Obesity; Tissue Extracts | 2021 |
Is LRP2 Involved in Leptin Transport over the Blood-Brain Barrier and Development of Obesity?
The mechanisms underlying the transport of leptin into the brain are still largely unclear. While the leptin receptor has been implicated in the transport process, recent evidence has suggested an additional role of LRP2 (megalin). To evaluate the function of LRP2 for leptin transport across the blood-brain barrier (BBB), we developed a novel leptin-luciferase fusion protein (pLG), which stimulated leptin signaling and was transported in an in vitro BBB model based on porcine endothelial cells. The LRP inhibitor RAP did not affect leptin transport, arguing against a role of LRP2. In line with this, the selective deletion of LRP2 in brain endothelial cells and epithelial cells of the choroid plexus did not influence bodyweight, body composition, food intake, or energy expenditure of mice. These findings suggest that LRP2 at the BBB is not involved in the transport of leptin into the brain, nor in the development of obesity as has previously been described. Topics: Animals; Binding Sites; Blood-Brain Barrier; Body Composition; Body Weight; CHO Cells; Choroid Plexus; Cricetulus; Endothelial Cells; Extracellular Signal-Regulated MAP Kinases; Female; Leptin; Low Density Lipoprotein Receptor-Related Protein-2; Luciferases; Male; Models, Biological; Obesity; Phosphorylation; Protein Transport; Receptors, Leptin; Recombinant Fusion Proteins; Swine | 2021 |
Reduction in Maternal Energy Intake during Lactation Decreased Maternal Body Weight and Concentrations of Leptin, Insulin and Adiponectin in Human Milk without Affecting Milk Production, Milk Macronutrient Composition or Infant Growth.
Maternal diet has the potential to affect human milk (HM) composition, but very few studies have directly assessed the effect of maternal diets on HM composition. The primary aim of this study was to assess the effect of improving dietary quality in lactating women over 2 weeks on the concentrations of macronutrients and metabolic hormones in HM. The secondary aims were to assess the impact of the dietary intervention on 24 h milk production, maternal body composition and infant growth. Fifteen women completed a 1-week baseline period followed by a 2-week dietary intervention phase targeted towards reducing fat and sugar intake. Maternal anthropometric and body composition and infant growth measurements were performed weekly. Total 24 h milk production was measured before and after the dietary intervention, and HM samples were collected daily. Maternal intakes of energy (-33%), carbohydrate (-22%), sugar (-29%), fat (-54%) and saturated fat (-63%) were significantly reduced during the dietary intervention. HM insulin, leptin and adiponectin concentrations were 10-25% lower at the end of the dietary intervention, but HM concentrations of macronutrients were unaffected. Maternal body weight (-1.8%) and fat mass (-6.3%) were significantly reduced at the end of the dietary intervention, but there were no effects on 24 h milk production or infant growth. These results suggest that reducing maternal energy, carbohydrate, fat and sugar intake over a 2-week period is associated with significant reductions in HM insulin, leptin and adiponectin concentrations. These changes may be secondary to decreases in maternal weight and fat mass. The limited studies to date that have investigated the association between metabolic hormone concentrations in HM and infant growth raise the possibility that the changes in HM composition observed in the current study could impact infant growth and adiposity, but further studies are required to confirm this hypothesis. Topics: Adipokines; Adiponectin; Adult; Body Weight; Breast Feeding; Child Development; Energy Intake; Female; Humans; Infant; Insulin; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Milk, Human; Mothers; Nutrients | 2021 |
Mucuna pruriens treatment shows anti-obesity and intestinal health effects in obese rats.
This study evaluated the anti-obesity effect and intestinal health of obese rats treated with Mucuna pruriens (MP), focusing on food consumption and somatic, biochemical, and histological parameters. A total of 32 adult male Wistar rats were initially randomized into a healthy group (HG, n = 16) which consumed a control diet and an obese group (OG, n = 16) which consumed a cafeteria diet for eight weeks. They were then subdivided into four groups: healthy (HG, n = 8); healthy treated with MP (HGMP, n = 8); obese (OG, n = 8); obese treated with MP (OGMP, n = 8), with consumption of their respective diets continuing for another eight weeks; the treated groups received 750 mg kg Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Diet, High-Fat; Feces; Insulin; Intestines; Leptin; Liver; Male; Mucuna; Obesity; Plant Extracts; Rats; Rats, Wistar; Triglycerides | 2021 |
Inhibition of the Renin-Angiotensin System Reduces Gene Expression of Inflammatory Mediators in Adipose Tissue Independent of Energy Balance.
Obesity is a growing health problem worldwide. The renin-angiotensin system (RAS) is present in adipose tissue, and evidence suggests that it is involved in both diet-induced obesity and the inflammation associated with obesity. The present experiments determined the effect of (1) different angiotensin-converting enzyme (ACE) inhibitors (captopril, perindopril, enalapril) and angiotensin receptor blockers (ARBs: telmisartan, losartan) on adiposity of mice fed a high-fat diet for 28 days (2); acute treatment with the ACE-inhibitor captopril on gene expression of inflammatory markers in mice fed a high-fat diet (HFD); and (3) short-term (2 days) and chronic (28 days) treatment of ACE-inhibition on energy expenditure (EE) and energy balance in mice fed HFD Topics: Adiponectin; Adipose Tissue; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Composition; Body Weight; Eating; Energy Metabolism; Gene Expression; Inflammation Mediators; Leptin; Male; Mice, Inbred C57BL; Obesity; Renin-Angiotensin System | 2021 |
Caloric Restriction and Hypothalamic Leptin Gene Therapy Have Differential Effects on Energy Partitioning in Adult Female Rats.
Dieting is a common but often ineffective long-term strategy for preventing weight gain. Similar to humans, adult rats exhibit progressive weight gain. The adipokine leptin regulates appetite and energy expenditure but hyperleptinemia is associated with leptin resistance. Here, we compared the effects of increasing leptin levels in the hypothalamus using gene therapy with conventional caloric restriction on weight gain, food consumption, serum leptin and adiponectin levels, white adipose tissue, marrow adipose tissue, and bone in nine-month-old female Sprague-Dawley rats. Rats ( Topics: Adipokines; Adiponectin; Adipose Tissue, White; Adiposity; Animals; Biomarkers; Body Weight; Bone Marrow; Caloric Restriction; Dependovirus; Energy Intake; Energy Metabolism; Female; Gene Expression; Genetic Therapy; Genetic Vectors; Hypothalamus; Leptin; Rats; Transgenes | 2021 |
HDAC inhibitor Trichostatin A suppresses adipogenesis in 3T3-L1 preadipocytes.
Obesity is becoming a major global health issue and is mainly induced by the accumulation of adipose tissues mediated by adipogenesis, which is reported to be regulated by peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer-binding protein α (C/EBPα). Trichostatin A (TSA) is a novel histone deacetylase inhibitor (HDACI) that was recently reported to exert multiple pharmacological functions. The present study will investigate the inhibitory effect of TSA on adipogenesis, as well as the underlying mechanism.. TSA inhibited adipogenesis in 3T3-L1 preadipocytes by activating the AMPK pathway. Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Fatty Acid-Binding Proteins; Glycerol; Histone Deacetylase Inhibitors; Hydroxamic Acids; Leptin; Lipolysis; Male; Mice; Mice, Obese; Obesity; Triglycerides | 2021 |
Di(2-ethylhexyl)phthalate exposure exacerbates metabolic disorders in diet-induced obese mice.
Both phthalate exposure and obesity are positively associated with metabolic disorders. The study aimed to investigate whether DEHP exposure caused metabolic disorders in an obesity-dependent manner. Both lean and diet-induced obese mice were subjected to environmentally relevant DEHP exposure. DEHP-treated obese mice exhibited higher glucose intolerance and insulin resistance than obese mice; the metabolic disorders were accompanied by increased blood levels of leptin, LDL cholesterol, and alanine transaminase. In obese mice, DEHP enhanced macrophage infiltration into epididymal white adipose tissue (eWAT) and hepatic tissue, and promoted hepatic steatosis/steatohepatitis. The DEHP effects were not observed in lean mice. Transcriptomic changes in eWAT and hepatic tissue were determined with microarray analysis. Results indicated that obesity and DEHP synergistically regulated carbohydrate uptake, lipolysis, and abnormality of adipose tissue, via the upstream regulators Pparg, Lipe, Cd44, and Irs1. Meanwhile, obesity and DEHP differentially modulated transcriptomic changes in hepatic tissue. Obesity was associated with lipid/cholesterol synthesis, lipid accumulation, and inflammation in hepatic tissue via the upstream regulators Zbtb20 and Nr1i2. In obese mice, DEHP exposure caused hepatic injury, cell migration, and changes in glycogen quantity mainly via Cd44. Microarray analysis suggested the potential mechanism underlying the early onset of metabolic disorders in DEHP-treated obese mice. Topics: Adipose Tissue, White; Animals; Body Weight; Cholesterol, LDL; Diet; Diethylhexyl Phthalate; Glucose; Glucose Tolerance Test; Leptin; Liver; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Obesity; Transcriptome | 2021 |
Metabolic benefits of novel histamine H
One of the therapeutic approaches in the treatment of obesity is the use of histamine H. Histamine ligands were selected based on the preliminary studies which included determination of intrinsic activity and selected pharmacokinetic parameters. Female Wistar rats were fed palatable feed for 28 days and simultaneously the tested compounds were administered intraperitoneally at a dose of 10 mg/kg b.w./day. Rats' weight was evaluated daily and calories intake was evaluated once per week. At the end of experiment insulin and glucose tolerance tests was performed. Plasma levels of cholesterol, triglycerides, leptin, insulin, glucose, C-peptide and CRP were also determined. In order to rule out false-positive results the influence of tested compounds on spontaneous activity of rats was monitored.. Animals fed palatable feed and treated with KSK-61 or KSK-63 compounds showed the slowest weight gain which was comparable to the one observed in control animals. Both compounds with the highest pharmacological activity have also similar pharmacokinetic properties with quite long half-life and high volume of distribution indicating that they can freely cross most biological barriers. Some compounds, especially KSK-63, compensated for metabolic disorders.. The presented study proves that search among the active histamine H Topics: Adipose Tissue; Animals; Body Weight; C-Peptide; Carrier Proteins; Cholesterol; Energy Intake; Feeding Behavior; Female; Glucose Tolerance Test; Histamine Agonists; Histamine Antagonists; Injections, Intraperitoneal; Insulin; Insulin Resistance; Leptin; Ligands; Metformin; Models, Animal; Obesity; Rats, Wistar; Receptors, Histamine H3; Triglycerides | 2021 |
Chronic Antidiabetic Actions of Leptin: Evidence From Parabiosis Studies for a CNS-Derived Circulating Antidiabetic Factor.
We used parabiosis to determine whether the central nervous system (CNS)-mediated antidiabetic effects of leptin are mediated by release of brain-derived circulating factors. Parabiosis was surgically induced at 4 weeks of age, and an intracerebroventricular (ICV) cannula was placed in the lateral cerebral ventricle at 12 weeks of age for ICV infusion of leptin or saline vehicle. Ten days after surgery, food intake, body weight, and blood glucose were measured for 5 consecutive days, and insulin-deficiency diabetes was induced in all rats by a single streptozotocin (STZ) injection (40 mg/kg). Five days after STZ injection, leptin or vehicle was infused ICV for 7 days, followed by 5-day recovery period. STZ increased blood glucose and food intake. Chronic ICV leptin infusion restored normoglycemia in leptin-infused rats while reducing blood glucose by ∼27% in conjoined vehicle-infused rats. This glucose reduction was caused mainly by decreased hepatic gluconeogenesis. Chronic ICV leptin infusion also reduced net cumulative food intake and increased GLUT4 expression in skeletal muscle in leptin/vehicle compared with vehicle/vehicle conjoined rats. These results indicate that leptin's CNS-mediated antidiabetic effects are mediated, in part, by release into the systemic circulation of leptin-stimulated factors that enhance glucose utilization and reduce liver gluconeogenesis. Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Central Nervous System; Diabetes Mellitus, Experimental; Drinking; Eating; Hypoglycemic Agents; Infusions, Intraventricular; Insulin; Leptin; Male; Parabiosis; Rats; Rats, Inbred Lew; Streptozocin | 2021 |
Effect of white tea consumption on serum leptin, TNF-α and UCP1 gene expression in ovariectomized rats.
Obesity and dyslipidemia due to estrogen deficiency are among the important health problems in menopausal women. Increasing evidence reports the anti-obesity and anti-hyperlipidemic properties of tea polyphenols. However, the effect of white tea (WT) with high polyphenol content on overweight and lipid profile is uncertain. Here, we aimed to examine the effects of long-term WT consumption on serum leptin, tumor necrosis factor- alpha (TNF-α) and uncoupling protein 1 (UCP1) mRNA gene expression in ovariectomized (OVX) rats.. Adult rats were divided into four groups (n = 8): (i) sham, (ii) OVX, (iii) WT and (iv) OVX + WT. WT was given at a dose of 0.5% w/v for 12 weeks. In the study, body weight, serum leptin, TNF, estradiol (E2) levels, lipid profile and UCP1 mRNA gene expression in brown adipose tissue (BAT) were evaluated.. There was a significant increase in body weight of OVX rats, which was decreased following WT consumption. While leptin and E2 levels decreased in the OVX group, TNF levels increased. There was no difference between the NF-kB levels of the groups. In addition, BAT UCP1 mRNA expression was significantly decreased in OVX groups, while WT treatment stimulated UCP1 activity.. We explain the stimulatory effect of WT on weight loss mainly by the induction of UCP1 gene-mediated thermogenesis and suppression of inflammation. Therefore, we suggest that prolonged WT consumption may have beneficial effects in limiting excess weight gain caused by estrogen deficiency. Topics: Animals; Biomarkers; Body Weight; Drinking Behavior; Female; Gene Expression; Health Impact Assessment; Leptin; Lipid Metabolism; Ovariectomy; Rats; Tea; Time Factors; Tumor Necrosis Factor-alpha; Uncoupling Protein 1 | 2021 |
The relationships between leptin levels in maternal serum and breast milk of mothers and term infants.
Leptin in breast milk play a significant role in metabolic programming.. The aim of this study to evaluate the relationship between leptin levels in maternal serum and breast milk, and certain anthropometric measurements of infants and mothers.. This study was conducted with 65 females and term infants. Anthropometric measurements of the mothers and the infants were obtained on the first, third, and sixth months, and leptin levels in maternal serum and breast milk were measured.. In this study, leptin levels in breast milk were positively correlated with leptin levels in maternal serum while the leptin levels in breast milk were lower than the serum leptin levels. It was also determined that mothers' body weights, BMI values, waist and hip circumferences were increased in a statistically significant way in terms of the months (. This study was determined that leptin levels in breast milk and maternal serum were related to anthropometric measurements of both mothers and infants. Future studies with larger populations are needed to understand the long-term consequences of leptin metabolism comprehensively.Key messagesThis study was determined that breast milk leptin level and maternal serum leptin level demonstrated a positive correlation, and breast milk leptin level was lower than maternal serum leptin level.Mothers' anthropometric measurements were positively correlated with leptin levels in breast milk and maternal serum in all the months.There was mostly a negative correlation between breast milk leptin level and infant body weight. Topics: Adult; Anthropometry; Body Weight; Female; Humans; Infant; Leptin; Male; Milk, Human; Mothers; Nutritional Status | 2021 |
Exploring the Mechanisms of Recovery in Anorexia Nervosa through a Translational Approach: From Original Ecological Measurements in Human to Brain Tissue Analyses in Mice.
Anorexia nervosa (AN) is a severe eating disorder where caloric restriction, excessive physical activity and metabolic alterations lead to life-threatening situations. Despite weight restoration after treatment, a significant part of patients experience relapses. In this translational study, we combined clinical and preclinical approaches. We describe preliminary data about the effect of weight gain on the symptomatology of patients suffering from acute AN ( Topics: Adolescent; Adult; Animals; Anorexia Nervosa; Body Mass Index; Body Weight; Exercise; Feeding Behavior; Female; Ghrelin; Heart Rate; Humans; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Models, Animal; Neuropeptides; Recurrence; RNA, Messenger; Weight Gain; Young Adult | 2021 |
Transgenic mice expressing human IL-32 develop adipokine profiles resembling those of obesity-induced metabolic changes.
Low-grade inflammation is associated with the development of insulin resistance in obese individuals. The present study aims to provide additional evidence strengthening the role of interleukin (IL)-32 in this key process. Using an IL-32 transgenic (IL-32tg) mouse model, we observed that IL-32tg fed a normal diet had greater body weight, due to greater accumulation of white adipose tissue (WAT) along with larger sized adipocytes. This led to metabolic consequences, with significant higher leptin levels and a trend towards hyperinsulinemia, indicating a phenotype resembling the metabolic syndrome. Adipocytes of IL-32tg mice were more prone to induce a pro-inflammatory response locally, which would be expected when predisposed to insulin resistance and type2 diabetes mellitus (T2D). In conclusion, our study provides novel evidence of a direct contribution of IL-32 to pathophysiological perturbations within the adipose tissue, possibly contributing to the metabolic syndrome that precedes frank insulin resistance and T2D. Future research should focus on the role of IL-32 in the obesity epidemic. Topics: Adipocytes; Adipokines; Adipose Tissue, White; Animals; Body Weight; Cytokines; Hyperinsulinism; Inflammation; Interleukins; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity | 2020 |
Adipocyte-specific gp130 signalling mediates exercise-induced weight reduction.
Repetitive physical activity is a well-established intervention to reduce obesity and to prevent weight regain. Besides increased energy expenditure, reduced caloric intake may contribute to exercise-induced weight loss in obesity. Using adipocyte-specific glycoprotein 130 knockout (gp130. gp130. Repetitive physical activity reduced food intake and HFD-induced weight gain in gp130. Adipocyte-specific IL-6 signalling is involved in exercise-mediated regulation of food intake and weight reduction in HFD-fed mice. Topics: Adipocytes; Animals; Body Weight; Cytokine Receptor gp130; Diet, High-Fat; Eating; Energy Metabolism; Insulin; Leptin; Male; Mice; Mice, Knockout; Obesity; Physical Conditioning, Animal; Signal Transduction; Weight Loss | 2020 |
Longitudinal changes in adipokines and free leptin index during and after pregnancy in women with obesity.
Detailed data on adipokines and body composition during and after pregnancy in women of different BMI categories are lacking. Furthermore, adipokine regulation during pregnancy and the factors contributing to gestational insulin resistance are not completely understood. The objective was to longitudinally determine adipokine levels, body composition, and insulin sensitivity during and after pregnancy in women of healthy weight (HW) and with obesity (OB), and identify factors associated with insulin resistance.. Women (30 HW, 19 OB) underwent blood sampling and body composition examination, by air-displacement plethysmography, longitudinally during pregnancy (trimesters 1, 2, 3) and after pregnancy (6, 12, 18 months postpartum). Serum leptin, soluble leptin receptor (sOB-R), and adiponectin levels were measured and free leptin index (FLI) and homeostatic model assessment of insulin resistance (HOMA-IR) determined.. Fat mass and leptin increased during pregnancy in the HW (p < 0.01) but not in the OB group. sOB-R increased during pregnancy in both groups (p < 0.001). Thus, FLI was unchanged in HW throughout pregnancy but reduced in OB (p = 0.001), although consistently higher in OB. Adiponectin decreased in both groups during pregnancy (p < 0.001 for HW, p = 0.01 for OB). After pregnancy, adiponectin increased in both groups, but more markedly in OB where it reached trimester 1 levels. Multivariable regression identified FLI as the variable most strongly associated with HOMA-IR in all trimesters, but not after pregnancy.. Leptin, sOB-R, adiponectin, and FLI undergo marked changes during and after pregnancy with differences in women of different BMI. We suggest that leptin activity is regulated by its soluble receptor and that this is an important factor for optimizing fat mass and insulin sensitivity during pregnancy. Topics: Adipokines; Adult; Body Composition; Body Weight; Female; Gestational Weight Gain; Humans; Insulin Resistance; Leptin; Obesity; Pregnancy; Pregnancy Complications | 2020 |
First evidence on the role of palmitoylethanolamide in energy homeostasis in fish.
The objective of this study was to investigate the role of palmitoylethanolamide (PEA) in the regulation of energy homeostasis in goldfish (Carassius auratus). We examined the effects of acute or chronic intraperitoneal treatment with PEA (20 μg·g Topics: Amides; Animals; Body Weight; CLOCK Proteins; Eating; Energy Metabolism; Ethanolamines; Gene Expression Regulation; Goldfish; Homeostasis; Hypothalamus; Injections, Intraperitoneal; Leptin; Lipid Metabolism; Liver; Locomotion; Palmitic Acids; Peroxisome Proliferator-Activated Receptors; Weight Gain | 2020 |
Leptin and insulin in young adulthood are associated with weight in infancy.
Low weight in early infancy is a known risk factor for cardio-metabolic syndrome in adult life. However, little is known either about developmental programming in subjects of normal birthweight or about events between the ages which separate early programming and the occurrence of disease at late adulthood. We tested the hypothesis that circulating concentrations of leptin, adiponectin and insulin in young, healthy adults, born with a birth size within the normal range, are influenced by early life growth patterns. In an observational study of 188 healthy volunteers aged 18-25 years (97 males, 91 females) we investigated the association of metabolic function with their birth size, their growth during childhood and their body composition. High plasma leptin in early adulthood, a risk factor for cardio-metabolic syndrome, was associated with low weight at age 2 years (correlation coefficient controlled for adult weight = -0.21, P < 0.01). It was also positively associated with pre-prandial insulin and with HOMA (Homeostasis Model Assessment) insulin resistance. Leptin, leptin-adiponectin ratio and insulin correlated with lean mass, fat mass and percent fat (P < 0.0001). In conclusion, high leptin in early adulthood was associated with both low weight at age 2 years and insulin resistance. We speculate that high leptin is developmentally programmed and can contribute to the association between low weight in early infancy and increased cardio-metabolic risk in adulthood in healthy subjects. Topics: Adiponectin; Adolescent; Adult; Birth Weight; Body Weight; Child Development; Child, Preschool; Female; Humans; Infant; Insulin; Insulin Resistance; Leptin; Male; Young Adult | 2020 |
Lack of NPY in neurotensin neurons leads to a lean phenotype.
Neuropeptide Y (NPY) producing neurons in the arcuate nucleus (Arc) of the hypothalamus are essential to the regulation of food intake and energy homeostasis. Whilst they have classically been thought to co-express agouti-related peptide (AgRP), it is now clear that there is a sub-population of NPY neurons in the Arc that do not. Here, we show that a subset of AgRP-negative, NPY-positive neurons in the Arc also express neurotensin (NTS) and we use an NTS-Cre line to investigate the function of this sub-population of NPY neurons. The lack of NPY in NTS-positive neurons led to a marked reduction in fat mass and bodyweight as well as a significant reduction in food intake in male NPY Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Energy Metabolism; Homeostasis; Hypothalamus; Leptin; Mice, Transgenic; Neurons; Neuropeptide Y; Neurotensin; Phenotype | 2020 |
Synergistic effect of leptin and lipidized PrRP on metabolic pathways in ob/ob mice.
Lack of leptin production in ob/ob mice results in obesity and prediabetes that could be partly reversed by leptin supplementation. In the hypothalamus, leptin supports the production of prolactin-releasing peptide (PrRP), an anorexigenic neuropeptide synthesized and active in the brain. In our recent studies, the palmitoylated PrRP analog palm11-PrRP31 showed a central anorexigenic effect after peripheral administration. This study investigates whether PrRP could compensate for the deficient leptin in ob/ob mice. In two separate experiments, palm11-PrRP31 (5 mg/kg) and leptin (5 or 10 μg/kg) were administered subcutaneously twice daily for 2 or 8 weeks to 8- (younger) or 16-(older) week-old ob/ob mice, respectively, either separately or in combination. The body weight decreasing effect of palm11-PrRP31 in both younger and older ob/ob mice was significantly powered by a subthreshold leptin dose, the combined effect could be then considered synergistic. Leptin and palm11-PrRP31 also synergistically lowered liver weight and blood glucose in younger ob/ob mice. Reduced liver weight was linked to decreased mRNA expression of lipogenic enzymes. In the hypothalamus of older ob/ob mice, two main leptin anorexigenic signaling pathways, namely, Janus kinase, signal transducer and activator of transcription-3 activation and AMP-activated protein kinase de-activation, were induced by leptin, palm11-PrRP31, and their combination. Thus, palm11-PrRP31 could partially compensate for leptin deficiency in ob/ob mice. In conclusion, the results demonstrate a synergistic effect of leptin and our lipidized palm11-PrRP31 analog. Topics: Animals; Body Temperature; Body Weight; Drug Synergism; Eating; Glucose Tolerance Test; Leptin; Lipid Metabolism; Liver; Male; Metabolic Networks and Pathways; Mice; Mice, Obese; Obesity; Prolactin-Releasing Hormone | 2020 |
Perinatal over- and underfeeding affect hypothalamic leptin and ghrelin neuroendocrine responses in adult rats.
Changes in the nutritional supply during the perinatal period can lead to metabolic disturbances and obesity in adulthood.. The divergent litter size model was used to investigate the hypothalamic sensitivity to leptin and ghrelin as well as the mechanisms involved in the disruption of food intake and energy expenditure.. On postnatal day 3 (P3), male Wistar rats were divided into 3 groups: small litter (SL - 3 pups), normal litter (NL - 10 pups), and large litter (LL - 16 pups). Animals at P60 were intraperitoneally treated with leptin (500 µg/Kg), ghrelin (40 µg/Kg), or vehicle (0.9% NaCl) at 5 pm and the following parameters were assessed: food intake and body weight; immunostaining of p-STAT-3 in the hypothalamus; Western Blotting analysis of p-AMPKα and UCP2 in the mediobasal hypothalamus (MBH), and UCP1 in the interscapular brown adipose tissue (BAT); or heat production, VO. SL rats had earlier leptin and ghrelin surges, while LL rats had no variations. At P60, after leptin treatment, LL rats showed hypophagia and increased p-STAT-3 expression in the arcuate nucleus, but SL rats had no response. After ghrelin treatment, LL rats did not have the orexigenic response or AMPKα phosphorylation in the MBH, while SL animals, unexpectedly, decreased body weight gain, without changes in food intake, and increased metabolic parameters and UCP1 expression in the BAT.. Changes in the nutritional supply at early stages of life modify leptin and ghrelin responsiveness in adulthood, programming metabolic and central mechanisms, which contribute to overweight and obesity in adulthood. Topics: Aging; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Energy Metabolism; Female; Ghrelin; Hyperphagia; Hypothalamus; Leptin; Litter Size; Male; Malnutrition; Obesity; Pregnancy; Rats; Rats, Wistar; STAT3 Transcription Factor | 2020 |
MetAP2 inhibition reduces food intake and body weight in a ciliopathy mouse model of obesity.
The ciliopathies Bardet-Biedl syndrome and Alström syndrome are genetically inherited pleiotropic disorders with hyperphagia and obesity as primary clinical features. Methionine aminopeptidase 2 inhibitors (MetAP2i) have been shown in preclinical and clinical studies to reduce food intake, body weight, and adiposity. Here, we investigated the effects of MetAP2i administration in a mouse model of ciliopathy produced by conditional deletion of the Thm1 gene in adulthood. Thm1 conditional knockout (cko) mice showed decreased hypothalamic proopiomelanocortin expression as well as hyperphagia, obesity, metabolic disease, and hepatic steatosis. In obese Thm1-cko mice, 2-week administration of MetAP2i reduced daily food intake and reduced body weight 17.1% from baseline (vs. 5% reduction for vehicle). This was accompanied by decreased levels of blood glucose, insulin, and leptin. Further, MetAP2i reduced gonadal adipose depots and adipocyte size and improved liver morphology. This is the first report to our knowledge of MetAP2i reducing hyperphagia and body weight and ameliorating metabolic indices in a mouse model of ciliopathy. These results support further investigation of MetAP2 inhibition as a potential therapeutic strategy for ciliary-mediated forms of obesity. Topics: Adaptor Proteins, Signal Transducing; Animals; Blood Glucose; Body Weight; Ciliopathies; Disease Models, Animal; Eating; Enzyme Inhibitors; Fatty Liver; Leptin; Liver; Male; Methionyl Aminopeptidases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Transcriptome | 2020 |
Physiological consequences of transient hyperleptinemia during discrete developmental periods on body weight in mice.
Leptin plays a role in central nervous system developmental programs and intercurrent physiological processes related to body fat regulation. The timing and neuromolecular mechanisms for these effects are relevant to the prevention and treatment of obesity. Factors implicated in a body weight "set point" including dietary fat, circulating leptin, and other adipokines tend to covary with adiposity and are difficult to disarticulate experimentally. To dissociate leptin effects from adiposity and diet, we created a transgenic mouse in which leptin expression is regulated by doxycycline exposure. Using this system, we investigated the physiological consequences of developmentally-timed transient hyperleptinemia on subsequent adiposity. We evaluated physiological effects of leptin elevation during adulthood (9 to 29 weeks old), "adolescence" (3 to 8 weeks old), and the immediate postnatal period [postnatal days 0 to 22 (P0 to P22)] on long-term adiposity and susceptibility to gain weight on high-fat diet (HFD) fed ad libitum. We found that inducing chronic hyperleptinemia in adult or "adolescent" mice did not alter body weight when excess leptin was discontinued, and upon later exposure to HFD, weight gain did not differ from controls. However, transient elevation of circulating leptin from P0 to P22 increased weight and fat gain in response to HFD, indicating greater susceptibility to obesity as adults. Thus, transient plasma leptin elevations-mimicking one aspect of transient adiposity-increased later susceptibility to diet-induced obesity, although these effects were restricted to a critical developmental (P0 to P22) time window. These findings may have clinical implications for weight management in infancy. Topics: Aging; Animals; Animals, Newborn; Body Weight; Chronic Disease; Doxycycline; Female; Leptin; Male; Mice, Inbred C57BL; Mice, Transgenic; Reproducibility of Results | 2020 |
Sexually Dimorphic Associations between Maternal Factors and Human Milk Hormonal Concentrations.
While human milk composition is characterised by marked dynamicity, we are far from having a clear picture of what factors drive this variation. Hormones in human milk are known to vary according to specific maternal phenotypes, but limited evidence shows the infant also has a role in determining milk composition. The present study aimed to investigate the interplay between maternal and infant characteristics in relation to human milk hormonal profile. In total, 501 human milk samples from mothers recruited in the Finnish STEPS cohort study (Steps to the healthy development) were analysed. Pre-pregnancy and pregnancy maternal data, socioeconomic status and infant characteristics at birth were collated. Leptin, adiponectin, insulin-like growth factor-1 and cyclic Glycine-Proline in milk were measured. Multivariate analysis of variance (MANOVA) and linear regression were utilised for statistical analysis. Sex-specific interactions with maternal factors were observed, as the infant sex mediated associations between gestational diabetes and milk adiponectin ( Topics: Adiponectin; Adult; Body Mass Index; Body Weight; Breast Feeding; Cesarean Section; Diabetes, Gestational; Female; Humans; Infant, Newborn; Insulin-Like Growth Factor I; Lactation; Leptin; Male; Milk, Human; Mothers; Obesity; Peptides, Cyclic; Pregnancy; Proteins; Sex Factors; Socioeconomic Factors | 2020 |
Serum concentrations of leptin in pregnant and non-pregnant bitches.
Leptin regulates body weight and several physiological processes including reproduction. We evaluated the circulating levels of leptin in pregnant and non-pregnant bitches as well as their correlation with body weight, food intake and number of foetuses. Nineteen healthy German shepherd bitches were used and divided in two groups (pregnant n = 12 and non-pregnant n = 7). Blood samples were collected every 15 days starting from ovulation (Day 0) throughout pregnancy (pregnant group, P) or throughout luteal phase (non-pregnant group, NP) In pregnant bitches, leptin concentrations increased from the day of ovulation (1.32 ± 0.06 ng/ml) up to day 45 (1.51 ± 0.06 ng/ml; p < .01) and returned to baseline values from day 60 post-ovulation. In non-pregnant bitches, leptin concentrations remained constant throughout the whole observation period (estimated marginal mean ± SE=1.33 ± 0.38 ng/ml). Pairwise comparisons showed significant differences between P and NP at day 45 post-ovulation (p < .05). Multivariable models indicated that, controlling for time and litter size, there was a positive relationship between leptin concentration and BW (p < .05) although Pearson coefficients showed that the correlation between BW and leptin was only significant in NP animals at day 45 (r = 0.76, p < .05). The multivariable approach also suggested that, holding BW and time constant, leptin concentrations tend to increase as the number of puppies increased (p = .06). Our study supports indirectly the contribution of the feto-placental unit to the circulating maternal leptin concentration. Topics: Animals; Body Weight; Dogs; Female; Leptin; Litter Size; Luteal Phase; Ovulation; Placenta; Pregnancy; Pregnancy, Animal | 2020 |
Molecular characterization of two leptin genes and their transcriptional changes in response to fasting and refeeding in Northern snakehead (Channa argus).
Leptin has been proved to play critical roles in energy metabolism, body weight regulation, food intake, reproduction and immunity in mammals. However, its roles are still largely unclear in fish. Here, we report two leptin genes (lepA and lepB) from the Northern snakehead (Channa argus) and their transcriptions in response to different feeding status. The snakehead lepA is 781 bp in length and contains a 480 bp open reading frame (ORF) encoding a 159-aa protein, while the snakehead lepB is 553 bp in length and contains a 477 bp ORF encoding a 158-aa protein. Multi-sequences alignment, three-dimensional (3D) model prediction, syntenic and genomic comparison, and phylogenetic analysis confirm two leptin genes are widely existing in teleost. Tissue distribution revealed that the two leptin genes exhibit different patterns. In a post-prandial experiment, the hepatic lepA and brain lepB showed a similar transcription pattern. In a long-term (2-week) fasting and refeeding experiment, the hepatic lepA and brain lepB showed a similar transcription change pattern induced by food deprivation stimulation but differential changes after refeeding. These findings suggest snakehead lepA and lepB are differential both in tissue distribution and molecular functions, and they might play as an important regulator in energy metabolism and food intake in fish, respectively. Topics: Amino Acid Sequence; Animals; Base Sequence; Body Weight; Fasting; Feeding Behavior; Fishes; Genomics; Leptin; Open Reading Frames; Phylogeny; Sequence Alignment; Tissue Distribution; Transcription, Genetic | 2020 |
Anagliptin suppresses diet-induced obesity through enhancing leptin sensitivity and ameliorating hyperphagia in high-fat high-sucrose diet fed mice.
Obesity is a major risk factors for type 2 diabetes, and weight loss is beneficial to diabetic patients who are obese or overweight. Dipeptidyl peptidase-4 (DPP-4) inhibitors are anti-diabetic drugs. Although it has been known that the effect of most of the DPP-4 inhibitors on body weight is neutral, several studies suggested that some DPP-4 inhibitors suppressed body weight. Nonetheless, the mechanisms underlying DPP-4 inhibitor-induced weight loss are not fully understood. In this study, the mice fed high-fat high sucrose diet (HFHSD) containing a DPP4 inhibitor, anagliptin, showed reduced food intake and body weight compared to the mice fed non-treated HFHSD, but oxygen consumption and respiratory exchange ratio (RER) were not altered. Sequential administration of leptin suppressed food intake and body weight more apparently in anagliptin treated HFHSD fed mice than non-treated HFHSD fed mice. Oxygen consumption and RER were comparable between anagliptin treated and non-treated mice after leptin administration. The number of phospho STAT3 expressed cells in the arcuate nucleus after leptin administration was increased in anagliptin treated mice compared to non-treated mice. These data suggested that anagliptin ameliorated leptin resistance induced by HFHSD and thereby decreased food intake and body weight. These effects of anagliptin could be beneficial to the treatment of obese diabetic patients. Topics: Animals; Body Weight; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Eating; Hyperphagia; Leptin; Mice; Motor Activity; Obesity; Oxygen Consumption; Pyrimidines | 2020 |
Ginsenosides reduce body weight and ameliorate hepatic steatosis in high fat diet‑induced obese mice via endoplasmic reticulum stress and p‑STAT3/STAT3 signaling.
Obesity has been increasing globally for over three decades. According to previous studies, dietary obesity is usually associated with endoplasmic reticulum stress (ERS) and STAT3 signaling, which result in interference with the homeostatic control of energy and lipid metabolism. Ginsenosides (GS) administered to mice will modulate adiposity and food intake; however, the mechanism of food inhibition is unknown. The aim of the present study was to investigate whether GS may inhibit ERS and regulate STAT3 phosphorylation in GT1‑7 cells (a mouse hypothalamus gonadotropin‑releasing hormone neuron cell line) and the hypothalamus in order to reduce the body weight and ameliorate hepatic steatosis in high fat diet (HFD)‑induced obese mice. In the present study, GS inhibited the appetite, reduced the body weight, visceral fat, body fat content and blood glucose, and ameliorated the glucose tolerance of the obese mice compared with HFD mice. In addition, the levels of aspartate aminotransferase and alanine aminotransferase, triglyceride (TG), leptin and insulin in the serum were reduced compared with HFD mice. There was less TG in the liver, but more in the feces compared with HFD mice. Using hematoxylin and eosin staining of HepG2 cells and liver tissues, GS were demonstrated to improve the non‑alcoholic fatty liver of the HFD‑induced obese mice and reduce the diameter of the fat cells compared with HFD mice. GS also increased oxygen consumption and carbon dioxide emissions in the metabolic cage data compared with HFD mice. In the GT1‑7 cells, GS alleviated the ERS induced by tunicamycin and enhanced the activation of the STAT3 phosphorylation pathway. Furthermore the ERS of the liver was relieved to achieve the aforementioned pharmacological effects. GS were used in the homeostatic control of the energy and lipid metabolism of a diet‑induced obesity model. In conclusion, present studies suggest that GS exert these effects by increasing STAT3 phosphorylation expression and reducing the ERS. Thus, GS reduce body weight and ameliorate hepatic steatosis in HFD‑induced obese mice. Topics: Adiposity; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Endoplasmic Reticulum Stress; Fatty Liver; Ginsenosides; Insulin; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Signal Transduction; STAT3 Transcription Factor | 2020 |
Expression of a hypomorphic Pomc allele alters leptin dynamics during late pregnancy.
Proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC) are essential for normal energy homeostasis. Maximal ARC Pomc transcription is dependent on neuronal Pomc enhancer 1 (nPE1), located 12 kb upstream from the promoter. Selective deletion of nPE1 in mice decreases ARC Pomc expression by 70%, sufficient to induce mild obesity. Because nPE1 is located exclusively in the genomes of placental mammals, we questioned whether its hypomorphic mutation would also alter placental Pomc expression and the metabolic adaptations associated with pregnancy and lactation. We assessed placental development, pup growth, circulating leptin and expression of Pomc, Agrp and alternatively spliced leptin receptor (LepR) isoforms in the ARC and placenta of Pomc∆1/∆1 and Pomc+/+ dams. Despite indistinguishable body weights, lean mass, food intake, placental histology and Pomc expression and overall pregnancy outcomes between the genotypes, Pomc ∆1/∆1 females had increased pre-pregnancy fat mass that paradoxically decreased to control levels by parturition. However, Pomc∆1/∆1 dams had exaggerated increases in circulating leptin, up to twice of that of the typically elevated levels in Pomc+/+ mice at the end of pregnancy, despite their equivalent fat mass. Pomc∆1/∆1dams also had increased placental expression of soluble leptin receptor (LepRe), although the protein levels of LEPRE in circulation were the same as Pomc+/+ controls. Together, these data suggest that the hypomorphic Pomc∆1/∆1 allele is responsible for the perinatal super hyperleptinemia of Pomc∆1/∆1 dams, possibly due to upregulated leptin secretion from individual adipocytes. Topics: Adiposity; Alleles; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Female; Gene Expression Regulation, Developmental; Leptin; Male; Mice, Inbred C57BL; Mice, Knockout; Neurons; Placenta; Pregnancy; Pro-Opiomelanocortin; Receptors, Leptin | 2020 |
Perinatal exposure of rats to a maternal diet with varying protein quantity and quality affects the risk of overweight in female adult offspring.
The maternal protein diet during the perinatal period can program the health of adult offspring. This study in rats evaluated the effects of protein quantity and quality in the maternal diet during gestation and lactation on weight and adiposity in female offspring. Six groups of dams were fed a high-protein (HP; 47% protein) or normal-protein (NP; 19% protein) isocaloric diet during gestation ( Topics: Adiposity; Animals; Animals, Newborn; Body Weight; Diet; Diet, High-Protein; Dietary Proteins; Female; Lactation; Leptin; Maternal Nutritional Physiological Phenomena; Milk; Overweight; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Risk Factors | 2020 |
Berberine attenuated olanzapine-induced metabolic alterations in mice: Targeting transient receptor potential vanilloid type 1 and 3 channels.
Transient receptor potential vanilloid type 1 (TRPV1) channels are emerging therapeutic targets for metabolic disorders. Berberine, which is a modulator of TRPV1, has proven antiobesity and antidiabetic potentials. The present study was aimed to investigate the protective effects of berberine in olanzapine-induced alterations in hypothalamic appetite control, inflammation and metabolic aberrations in mice targeting TRPV1 channels. Female BALB/c mice (18-23 g) were treated with olanzapine (6 mg/kg, p.o.) for six weeks to induce metabolic alterations, while berberine (100 and 200 mg/kg, p.o.) and metformin (100 mg/kg, p.o) were used as test and standard interventions respectively. Weekly assessment of feed-water intake, body temperature and body weight was done, while locomotion was measured at the end of week 1 and 6. Serum glucose and lipid profile were assessed by biochemical methods, while other serum biomarkers were assessed by ELISA. qPCR was used to quantify the mRNA expression in the hypothalamus. Olanzapine treatment significantly increased the feed intake, weight gain, adiposity index, while reduced body temperature and locomotor activity which were reversed by berberine treatment. Berberine treatment reduced serum ghrelin and leptin levels as well decrease in hypothalamic mRNA expression of orexigenic neuropeptides, inflammatory markers and ghrelin receptor in olanzapine-treated mice. Olanzapine treatment increased expression of TRPV1/TRPV3 in the hypothalamus which was significantly decreased by berberine treatment. Our results suggest that berberine, by TRPV1/TRPV3 modulation, attenuated the olanzapine-induced metabolic alterations in mice. Hence berberine supplementation in psychiatric patients could be a preventive approach to reduce the metabolic adverse effects of antipsychotics. Topics: Animals; Antipsychotic Agents; Berberine; Body Temperature; Body Weight; Cytokines; Drinking; Female; Gene Expression Regulation; Ghrelin; Hypothalamus; Leptin; Metabolic Diseases; Metformin; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy; Neuropeptides; Obesity; Olanzapine; RNA, Messenger; Signal Transduction; Treatment Outcome; TRPV Cation Channels | 2020 |
Methylation of the LEP gene promoter in blood at 12 months and BMI at 4 years of age-a population-based cohort study.
Increasing evidence links epigenetic variation to anthropometric and metabolic measures. Leptin signalling regulates appetite and energy expenditure, and in pregnancy is important for nutrient supply to the foetus. Maternal metabolic health and foetal growth are linked to infant blood leptin gene (LEP) methylation, which has been cross-sectionally associated with adolescent obesity. Despite this, few studies have explored the relationship between infant LEP methylation and childhood anthropometry, or the impact of genetic variation on these relationships. Using a prospective birth cohort, we investigated whether blood LEP promoter methylation at birth and 12 months predicts weight and adiposity at 4-years. Locus-specific methylation data was analysed by partial correlation tests and multivariable linear regression. There was weak evidence of an association of birth LEP methylation with anthropometry measures at 4 years. Methylation at a specific site (cg19594666) at 12 months was inversely associated with 4-year weight (r = -0.11, p = 0.02) and body-mass index (BMI) (r = -0.13, p = 0.007), which persisted following adjustment for weight at birth and at 12 months. Neither association was influenced by genotype. We report the first evidence of an association between LEP methylation in infancy and childhood weight. Replication in additional cohorts is required to determine if this relationship persists. Topics: Adiposity; Body Mass Index; Body Weight; Child, Preschool; Cohort Studies; DNA Methylation; Female; Humans; Infant; Leptin; Male; Pediatric Obesity; Promoter Regions, Genetic | 2020 |
Effects of gut microbiota on leptin expression and body weight are lessened by high-fat diet in mice.
Aberration in leptin expression is one of the most frequent features in the onset and progression of obesity, but the underlying mechanisms are still unclear and need to be clarified. This study investigated the effects of the absence of gut microbiota on body weight and the expression and promoter methylation of the leptin. Male C57 BL/6 J germ-free (GF) and conventional (CV) mice (aged 4-5 weeks) were fed either a normal-fat diet (NFD) or a high-fat diet (HFD) for 16 weeks. Six to eight mice from each group, at 15 weeks, were administered exogenous leptin for 7 d. Leptin expression and body weight gain in GF mice were increased by NFD with more CpG sites hypermethylated at the leptin promoter, whereas there was no change with HFD, compared with CV mice. Adipose or hepatic expression of genes associated with fat synthesis (Acc1, Fas and Srebp-1c), hydrolysis and oxidation (Atgl, Cpt1a, Cpt1c, Ppar-α and Pgc-1α) was lower, and hypothalamus expression of Pomc and Socs3 was higher in GF mice than levels in CV mice, particularly with NFD feeding. Exogenous leptin reduced body weight in both types of mice, with a greater effect on CV mice with NFD. Adipose Lep-R expression was up-regulated, and hepatic Fas and hypothalamic Socs3 were down-regulated in both types of mice. Expression of fat hydrolysis and oxidative genes (Atgl, Hsl, Cpt1a, Cpt1c, Ppar-α and Pgc-1α) was up-regulated in CV mice. Therefore, the effects of gut microbiota on the leptin expression and body weight were affected by dietary fat intake. Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Gastrointestinal Microbiome; Hypothalamus; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Pro-Opiomelanocortin; Receptors, Leptin | 2020 |
Loss of leptin receptor-expressing cells in the hindbrain decreases forebrain leptin sensitivity.
Previous studies indicate that inhibition of food intake by leptin is mediated by an integrated response to activation of hypothalamic and hindbrain receptors. This study tested whether loss of hindbrain leptin receptor signaling changed sensitivity to forebrain leptin. Injections of leptin-conjugated saporin (Lep-Sap) into the medial nucleus of the solitary tract (NTS) were used to destroy hindbrain leptin receptor-expressing neurons of male Sprague-Dawley rats. Controls were injected with saporin conjugated with a nonsense peptide (Blk-Sap). Lep-Sap had no effect on daily food intake or body weight, but expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in the NTS following a peripheral injection of leptin was abolished 26 days after Lep-Sap injections. To test forebrain leptin sensitivity, Lep-Sap and Blk-Sap rats received third-ventricle injections of 0, 0.05, 0.1, 0.25, or 0.5 μg leptin. Food intake was inhibited by 0.25 and 0.5 μg leptin in Blk-Sap rats, but there was no significant effect of leptin on food intake of Lep-Sap rats. There was no difference in hypothalamic pSTAT3 in unstimulated conditions, but pSTAT3 was lower in the dorsomedial region of the ventromedial nucleus of the hypothalamus (VMH) of Lep-Sap rats compared with Blk-Sap rats following a third-ventricle injection of 0.25 μg leptin. These results are consistent with previous data showing that loss of VMH leptin receptor-expressing cells prevents weight loss caused by fourth-ventricle leptin infusion and show that the integrated response between the hindbrain and forebrain is heavily dependent on leptin activity in the VMH. Topics: Animals; Body Weight; Eating; Leptin; Male; Neurons; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Rhombencephalon; Ventromedial Hypothalamic Nucleus | 2020 |
Effects of phosphorus and calcium to phosphorus consumption ratio on mineral metabolism and cardiometabolic health.
Phosphorus is a common additive used in food processing that is typically consumed in excess of the recommended daily allowance; however, our knowledge of its effects on health, in the context of normal renal function, is limited. Unlike phosphorus, calcium intake is generally less than recommended, and it has been hypothesized that the calcium to phosphorus ratio may be partly responsible for the proposed negative health consequences. Therefore, this study sought to determine the effects of increased phosphorus additive intake, in the context of high calcium consumption, on endocrine markers of mineral metabolism and cardiometabolic health. An outpatient feeding study was performed in which healthy adults were fed a run-in control diet for 2 weeks followed by a phosphorus additive enhanced diet with supplemental calcium to an approximate ratio of 1 (experimental diet) for 2 weeks. Blood and urine samples were collected, and participants had brachial flow-mediated dilatation measured, with analyses comparing follow-up measures to baseline. Two weeks of experimental diet increased serum fibroblast growth factor 23 concentrations but lowered body weight and serum leptin; however, other phosphorus responsive factors such as osteopontin and osteocalcin did not increase. A complementary study in male mice also demonstrated that the regulation of known dietary phosphorus responsive factors was mostly abrogated when dietary calcium was raised in parallel with phosphorus. In conclusion, the study identifies weight, leptin and insulin as responsive to dietary phosphorus and that certain aspects of the systemic phosphorus response are attenuated by a corresponding high calcium intake. Topics: Adult; Animals; Biomarkers; Body Weight; Calcium; Calcium, Dietary; Cardiovascular Diseases; Diet; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Food Additives; Humans; Insulin; Leptin; Male; Mice; Minerals; Osteocalcin; Osteopontin; Phosphorus; Phosphorus, Dietary | 2020 |
Sirt6 in pro-opiomelanocortin neurons controls energy metabolism by modulating leptin signaling.
Sirt6 is an essential regulator of energy metabolism in multiple peripheral tissues. However, the direct role of Sirt6 in the hypothalamus, specifically pro-opiomelanocortin (POMC) neurons, controlling energy balance has not been established. Here, we aimed to determine the role of Sirt6 in hypothalamic POMC neurons in the regulation of energy balance and the underlying mechanisms.. For overexpression studies, the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice was targeted bilaterally and adenovirus was delivered by using stereotaxic apparatus. For knockout studies, the POMC neuron-specific Sirt6 knockout mice (PKO mice) were generated. Mice were fed with chow diet or high-fat diet, and body weight and food intake were monitored. Whole-body energy expenditure was determined by metabolic cages. Parameters of body composition and glucose/lipid metabolism were evaluated.. Sirt6 overexpression in the ARC ameliorated diet-induced obesity. Conversely, selective Sirt6 ablation in POMC neurons predisposed mice to obesity and metabolic disturbances. PKO mice showed an increased fat mass and food intake, while the energy expenditure was decreased. Mechanistically, Sirt6 could modulate leptin signaling in hypothalamic POMC neurons, with Sirt6 deficiency impairing leptin-induced phosphorylation of signal transducer and activator of transcription 3. The effects of leptin on reducing food intake and body weight and leptin-stimulated lipolysis were also impaired. Moreover, Sirt6 inhibition diminished the leptin-induced depolarization of POMC neurons.. Our results reveal a key role of Sirt6 in POMC neurons against energy imbalance, suggesting that Sirt6 is an important molecular regulator for POMC neurons to promote negative energy balance. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Body Weight; Brain; Diet, High-Fat; Energy Metabolism; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Neurons; Obesity; Pro-Opiomelanocortin; Signal Transduction; Sirtuins | 2020 |
Partial leptin deficiency confers resistance to diet-induced obesity in mice.
Hyperleptinemia per se is sufficient to promote leptin resistance in the obese state. Leptin sensitivity can be restored by reducing circulating leptin levels within a physiologically healthy range and is a viable antiobesity and antidiabetic strategy. However, a previous study suggests that partial leptin deficiency favors diet-induced obesity and related metabolic disorders in mice, arguing that a lower leptin level may indeed promote diet-induced obesity and its associated metabolic disorders. Here, we aim to elucidate what the impact of partial leptin deficiency is on fat mass and insulin sensitivity.. We used two different mouse models of partial leptin deficiency: an adipocyte-specific congenital heterozygous leptin knockout mouse line (LepHZ) and the well-established whole body heterozygous leptin knockout mouse (OBHZ). The metabolic studies of OBHZ and LepHZ mice were performed both on normal carbohydrate-rich chow diet and on a high-fat diet (HFD). Male and female mice were included in the study to account for sex-specific differences. Body weight, food intake, glucose tolerance, and insulin tolerance were tested. Histology of adipose tissue and liver tissue allowed insights into adipose tissue inflammation and hepatic triglyceride content. Immunohistochemistry was paired with RT-PCR analysis for expression levels of inflammatory markers.. Both OBHZ and LepHZ mice displayed reduced circulating leptin levels on the chow diet and HFD. On chow diet, male OBHZ and LepHZ mice showed elevated fat mass and body weight, while their glucose tolerance and insulin sensitivity remained unchanged. However, the inability in partially leptin-deficient mice to fully induce circulating leptin during the development of diet-induced obesity results in reduced food intake and leaner mice with lower body weight compared to their littermate controls. Importantly, a strong reduction of adipose tissue inflammation is observed along with improvements in insulin sensitivity and enhanced glucose tolerance. Additionally, partial leptin deficiency protects the mice from fatty liver and liver fibrosis. Chronically HFD-fed OBHZ and LepHZ mice remain more sensitive to exogenous leptin injection, as reflected by their reduced food intake upon an acute leptin treatment.. In response to HFD feeding, the inability to upregulate leptin levels due to partial leptin deficiency protects mice from diet-induced obesity and metabolic dysregulation. Thus, in an obesogenic environment, maintaining lower leptin levels is highly beneficial for both obesity and diabetes management. Chronic leptin reduction represents a viable preventive strategy whose efficacy awaits clinical testing. Topics: Adipose Tissue; Adipose Tissue, White; Animals; Body Composition; Body Weight; Diet, High-Fat; Fatty Liver; Female; Insulin; Insulin Resistance; Leptin; Liver; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity | 2020 |
Hypothalamic Pomc expression restricted to GABAergic neurons suppresses Npy overexpression and restores food intake in obese mice.
Hypothalamic arcuate proopiomelanocortin (Arc-POMC) neurons are involved in different physiological processes such as the regulation of energy balance, glucose homeostasis, and stress-induced analgesia. Since these neurons heterogeneously express different biological markers and project to many hypothalamic and extrahypothalamic areas, it is proposed that Arc-POMC neurons could be classified into different subpopulations having diverse physiological roles. The aim of the present study was to characterize the contribution of the subpopulation of Arc-POMC neurons cosecreting gamma-aminobutyric acid (GABA) neurotransmitter in the control of energy balance.. Arc-Pomc expression restricted to GABAergic-POMC neurons was achieved by crossing a reversible Pomc-deficient mouse line (arcPomc. Tamoxifen treatment of arcPomc. In the present study, we show that the expression of Pomc in the subpopulation of Arc-GABAergic-POMC neurons is sufficient to maintain normal food intake. In addition, we found that DMH-NPY expression is negatively correlated with Pomc expression in GABAergic-POMC neurons, suggesting that food intake may be regulated by an Arc-GABAergic-POMC → DMH-NPY pathway. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Dorsomedial Hypothalamic Nucleus; Eating; Energy Metabolism; Female; GABAergic Neurons; Gene Expression; Gene Expression Regulation; Hypothalamus; Leptin; Male; Mice; Mice, Obese; Neuropeptide Y; Pro-Opiomelanocortin | 2020 |
The endoplasmic reticulum stress-autophagy pathway controls hypothalamic development and energy balance regulation in leptin-deficient neonates.
Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation. Topics: Adiposity; Animals; Antiviral Agents; Autophagy; Autophagy-Related Protein 7; Body Weight; Cholagogues and Choleretics; Disease Models, Animal; Eating; Endoplasmic Reticulum Stress; Energy Metabolism; Feeding Behavior; Homeostasis; Hyperphagia; Hypothalamus; Leptin; Male; Metabolic Diseases; Mice; Mice, Inbred Strains; Mice, Knockout; Neuroendocrinology; Neurogenesis; Obesity; Pro-Opiomelanocortin; Taurochenodeoxycholic Acid | 2020 |
Adiponectin and leptin levels in normal weight women with polycystic ovary syndrome.
Since polycystic ovarian syndrome (PCOS) is prevalent in reproductive women with obesity and insulin resistance, adipocytokines are often accused and investigated for pathophysiology. The aim of this study was to evaluate the adiponectin and leptin levels in normal-weight women with PCOS.. Forty women with PCOS and 40 age and body mass index (BMI) matched controls were included in the study. Adiponectin and leptin levels in addition to other biochemical parameters were measured.. Leptin levels were statistically significantly higher in the study group compared to the control group (6.53 ± 2.670 vs 3.37 ± 2.002 ng/mL, p < 0.001 respectively). Although Adiponectin levels were lower in the study group compared to the control group (28.89 ± 16.124 μg/mL vs 31.05 ± 20.507, p = 0.714 respectively) the difference did not reach statistical significance. Leptin levels were positively correlated with fasting glucose, fasting insulin, free testosterone levels and homeostatic model assessment of insulin resistance (HOMA-IR) values. Adiponectin levels were negatively correlated with BMI.. Adiponectin and leptin have been suggested to play a crucial role in the pathogenesis of PCOS. Different adipocytokine levels in the normal weight PCOS group compared to age and BMI matched controls support the idea that adipose tissue in this group of women has some distinctive features not only in high BMI subgroup but also in normal weight subgroup. Topics: Adiponectin; Adult; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; Case-Control Studies; Female; Humans; Insulin; Leptin; Polycystic Ovary Syndrome | 2020 |
Cooperative effects of galanin and leptin on alleviation of insulin resistance in adipose tissue of diabetic rats.
It was reported that either orexigenic neuropeptide galanin or anorexigenic hormone leptin caught benefit insulin sensitivity through increasing the translocation of glucose transporter 4 (GLUT4) in patients with diabetes. To date, it is unknown whether galanin can potentiate the effect of leptin on alleviation of insulin resistance. Therefore, in the current study we sought to assess the combined effect of central leptin and galanin on insulin resistance in the adipose tissues of type 2 diabetic rats. Galanin and leptin were injected into the intracerebroventricle of the diabetic rats, respectively, or cooperatively once a day for 2 weeks. Then, several indexes of insulin resistance were examined. The results showed that glucose infusion rates in the hyperinsulinaemic-euglycaemic clamp test, plasma adiponectin content and GLUT4 translocation, as well as Akt phosphorylation in fat cells, were higher, not GLUT4 protein and GLUT4 mRNA expression, but HOMA index was lower in the galanin + leptin group than either one of them. Furthermore, treatment with MK-2206, an Akt inhibitor, blocked the combined effects of galanin + leptin on alleviation of insulin resistance. These results suggest that galanin can improve the leptin-induced mitigative effects on insulin resistance in the fat cells, and those provided new insights into the potential tactics for prevention and remedy of insulin resistance. Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Body Weight; Deoxyglucose; Diabetes Mellitus, Experimental; Feeding Behavior; Galanin; Glucose Clamp Technique; Glucose Transporter Type 4; Hyperinsulinism; Insulin Resistance; Leptin; Male; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Wistar; RNA, Messenger | 2020 |
Discordant Dose-Dependent Metabolic Effects of Eicosapentanoic Acid in Diet-Induced Obese Mice.
Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Diet, High-Fat; Dietary Supplements; Eicosapentaenoic Acid; Energy Metabolism; Glucose; Insulin; Insulin Resistance; Leptin; Male; Mice, Inbred Strains; Motor Activity; Obesity; Oxygen Consumption; Triglycerides | 2020 |
In utero nutritional stress as a cause of obesity: Altered relationship between body fat, leptin levels and caloric intake in offspring into adulthood.
Emerging evidence suggests that during gestation the in utero environment programs metabolism and can increase risk of obesity in adult offspring. Our aim was to study how alterations in maternal diets during gestation might alter body weight evolution, circulating leptin levels and caloric intake in offspring, leading to changes in body composition.. We fed gestating rats either a control diet (CD), high fat diet (HFD) or an isocaloric low protein diet (LPD), and examined the repercussions in offspring fed similar diets post-weaning on birth weight, body weight evolution, body composition, insulin sensitivity, glucose tolerance and in the relationship between plasma leptin concentration and caloric intake in offspring during growth and development.. Offspring from dams fed LPD maintained reduced body weight with greater % lean mass and consumed fewer calories despite having leptin levels similar to controls. On the other hand, offspring from dams fed a HFD were insulin resistant and maintained increased body weight and % fat mass, while consuming more calories than controls despite elevated leptin concentrations. Therefore the uterine environment, modulated primarily through maternal nutrition, modified the relationship between circulating leptin levels, body fat, and caloric intake in the offspring, and dams fed a HFD produced offspring with excess adiposity, insulin resistance, and leptin resistance into adulthood.. Our data indicates that in utero environmental factors affected by maternal diet program alterations in the set point around which leptin regulates body weight in offspring into adulthood contributing to obesity. Topics: Adipose Tissue; Adiposity; Animals; Animals, Newborn; Birth Weight; Body Composition; Body Weight; Diet, High-Fat; Dietary Fats; Energy Intake; Female; Insulin Resistance; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Rats; Rats, Sprague-Dawley; Weaning | 2020 |
In utero exposure to arsenite contributes to metabolic and reproductive dysfunction in male offspring of CD-1 mice.
In utero exposure to arsenite (iAs) is known to increase disease risks later in life. We investigated the effect of in utero exposure to iAs in the drinking water on metabolic and reproductive parameters in male mouse offspring at postnatal and adult stages. Pregnant CD-1 mice were exposed to iAs (as sodium arsenite) in the drinking water at 0 (control), 10 ppb (EPA standard for drinking water), and 42.5 ppm (tumor-inducing dose in mice) from embryonic day (E) 10-18. At birth, pups were fostered to unexposed females. Male offspring exposed to 10 ppb in utero exhibited increase in body weight at birth when compared to controls. Male offspring exposed to 42.5 ppm in utero showed a tendency for increased body weight and a smaller anogenital distance. The body weight in iAs-exposed pups continued to increase significantly compared to control at 3 weeks and 11 weeks of age. At 5 months of age, iAs-exposed males exhibited greater body fat content and glucose intolerance. Male offspring exposed to 10 ppb in utero had higher circulating levels of leptin compared to control. In addition, males exposed to 42.5 ppm in utero exhibited decreased total number of pups born compared to controls and lower average number of litters sired over a six-month period. These results indicate that in utero exposure to iAs at either human relevant concentration or tumor-inducing concentration is a potential cause of developmental origin of metabolic and reproductive dysfunction in adult male mice. Topics: Animals; Arsenites; Body Weight; Female; Fertility; Glucose; Leptin; Male; Maternal-Fetal Exchange; Mice; Pregnancy; Prenatal Exposure Delayed Effects; Spermatozoa; Testis | 2020 |
Reward and psychopathological correlates of eating disorders: The explanatory role of leptin.
It has been hypothesized that leptin level alterations in Eating Disorders (EDs) represent a maintaining factor for pathological reward-related ED behaviors, given leptin role in the dopaminergic reward systems. The aim of the present study was to evaluate the role of leptin in EDs as a mediator for the relationship between Body Mass Index (BMI) and several pathological behaviors, such as dietary restraint, compensatory exercise, vomiting, binge eating and emotional eating. Sixty-two patients with EDs and 41 healthy controls (HC) had their blood drawn and completed psychometric tests for the evaluation of general psychopathology, ED psychopathology and emotional eating. Moderated linear regression models showed that, in the presence of high levels of ED psychopathology, leptin levels were negatively associated with dietary restraint and compensatory exercise, and positively with emotional eating and binge eating. Finally, leptin showed an indirect effect on the association between BMI and all these reward-related behaviors. These results suggest that a variation of BMI maintains these pathological ED behaviors through a variation in leptin levels. Considering the role of leptin in reward circuits, the results seem to confirm an aberrant food-related reward mechanism in ED patients. Topics: Adult; Anorexia Nervosa; Binge-Eating Disorder; Body Mass Index; Body Weight; Bulimia; Case-Control Studies; Emotions; Exercise; Feeding and Eating Disorders; Female; Food; Humans; Leptin; Male; Psychopathology; Reward | 2020 |
Human Milk Oligosaccharide Supplementation Affects Intestinal Barrier Function and Microbial Composition in the Gastrointestinal Tract of Young Sprague Dawley Rats.
Topics: Animals; Biomarkers; Body Weight; Cecum; Dietary Supplements; Feces; Female; Gastrointestinal Microbiome; Gastrointestinal Tract; Interleukin-18; Lactose; Leptin; Male; Milk, Human; Oligosaccharides; Organ Size; Rats; Rats, Sprague-Dawley; RNA, Ribosomal, 16S; Sequence Analysis, RNA; Sialic Acids; Trisaccharides | 2020 |
Blackcurrant (
Estrogen is involved in lipid metabolism. Menopausal women with low estrogen secretion usually gain weight and develop steatosis associated with abnormal lipid metabolism. A previous study showed that blackcurrant ( Topics: Adipocytes; Adiponectin; Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Dyslipidemias; Fatty Liver; Female; gamma-Glutamyltransferase; Intra-Abdominal Fat; Leptin; Lipid Metabolism; Liver; Menopause; Non-alcoholic Fatty Liver Disease; Ovariectomy; Phytoestrogens; Plant Extracts; Rats; Rats, Sprague-Dawley; Ribes; Triglycerides | 2020 |
Tocilizumab Increases Body Weight and Serum Adipokine Levels in Patients with Rheumatoid Arthritis Independently of Their Treatment Response: a Retrospective Cohort Study.
Causes of weight change after tocilizumab treatment are unclear. We aimed to investigate the effects of tocilizumab treatment on body weight and serum adipokine levels in patients with rheumatoid arthritis (RA).. In this retrospective cohort study, we evaluated weight changes in patients with RA who received methotrexate (Cohort I) or tocilizumab with methotrexate (Cohorts II and III) for 24 weeks. Adipokine concentrations at baseline and 24 weeks were analyzed in Cohorts I and III. Cohorts I and II received tocilizumab therapy for an additional 48 weeks, during which weight changes were monitored (24-72 weeks).. No significant weight change occurred after 24 weeks of methotrexate treatment (mean difference, -0.2 kg;. Weight and the leptin-adiponectin ratio increased after tocilizumab treatment. Given that cardiovascular (CV) risk factors may deteriorate in patients with RA who receive tocilizumab, further studies are required to determine the effects of weight gain on CV outcomes in these patients. Topics: Adiponectin; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Body Weight; Drug Therapy, Combination; Female; Heart Disease Risk Factors; Humans; Leptin; Male; Methotrexate; Middle Aged; Receptors, Interleukin-6; Resistin; Retrospective Studies; Tumor Necrosis Factor-alpha | 2020 |
Altered Gene Expression Profiles in Peripheral Blood Mononuclear Cells in Obese Subjects.
Gene expression profiles in human peripheral blood mononuclear cells (PBMCs) may act as a useful tool to better understand obesity. We investigated gene expression levels in PMBCs for possible differences between obese and non-obese subjects (19-55 years) and evaluated correlations between gene expression in PBMCs and clinical obesity indices.. Body weight, BMI, fat amount, fat percentage, waist/hip ratio, leptin, and adiponectin levels were determined in 30 obese and 20 non-obese subjects. Expression levels of 19 genes, which were differentially expressed by clinical obesity indices in the PBMCs of high fat-fed rats, were determined in their PBMCs using real-time PCR.. The expression of 9 of 19 previously selected genes was significantly correlated with one or more clinical obesity indices. Both TFEC and CCL2 expression were negatively correlated with BMI, fat amount, fat percentage, waist/hip ratio, and leptin concentration. Similarly, TNFAIP2, VCAN, ASSI, IRF1, and HK3 expression negatively correlated with some clinical obesity indices, such as TNFAIP2 for BMI, fat amount, fat percentage, and waist/hip ratio, VCAN for fat amount, fat percentage, and waist/hip ratio, ASS1 for BMI and fat amount, IRF1 for BMI, fat amount, and fat percentage, and HK3 for fat amount. In contrast, both TNF-α and LPL expression were positively correlated with waist/hip ratio.. We identified 9 of 19 genes in human PBMCs that significantly correlated with one or more clinical obesity indices. Because these genes have a mechanistic basis for the development or progression of obesity and its metabolic derangements, they may help to determine possible underlying mechanisms for obesity. Topics: Adiponectin; Adult; Animals; Body Mass Index; Body Weight; Female; Humans; Leptin; Leukocytes, Mononuclear; Male; Middle Aged; Obesity; Rats; Transcriptome; Waist-Hip Ratio; Young Adult | 2020 |
Changes in Expression of the Genes for the Leptin Signaling in Hypothalamic-Pituitary Selected Areas and Endocrine Responses to Long-Term Manipulation in Body Weight and Resistin in Ewes.
Both long-term undernutrition and overnutrition disturb metabolic balance, which is mediated partially by the action of two adipokines, leptin and resistin (RSTN). In this study, we manipulated the diet of ewes to produce either a thin (lean) or fat (fat) body condition and investigated how RSTN affects endocrine and metabolic status under different leptin concentrations. Twenty ewes were distributed into four groups ( Topics: Animal Feed; Animals; Blood Glucose; Body Weight; Cholesterol; Female; Gene Expression Regulation; Hypothalamus; Leptin; Lipoproteins, HDL; Lipoproteins, LDL; Pituitary Gland; Receptors, Leptin; Resistin; Sheep; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein | 2020 |
Intermittent fasting, adipokines, insulin sensitivity, and hypothalamic neuropeptides in a dietary overload with high-fat or high-fructose diet in mice.
The intermittent fasting (IF) might have benefits on metabolism and food intake. Twelve-week old C57BL/6 J mice were fed a control diet (C, 10% kcal fat), a high-fat diet (HF, 50% kcal fat) or a high-fructose diet (HFru, 50% kcal fructose) for 8 weeks, then half of the animals in each group underwent IF (24 h fed, 24 h fasting) for an additional 4 weeks. Although food intake on the fed day remained the same for all groups, all fasting groups showed a reduction in body mass compared to their counterparts. IF reduced total cholesterol, triacylglycerol, fasting glucose, fasting insulin resistance index, and plasma leptin, but increased plasma adiponectin. IF reduced Leptin gene expression in the HF-IF group, but increased proinflammatory markers in the hypothalamus, also in the C-IF group. Both groups HFru-IF and C-IF, showed alterations in the leptin signaling pathway (Leptin, OBRb, and SOCS3), mainly in the HFru-IF group, suggesting leptin resistance. NPY and POMC neuropeptides labeled the neurons of the hypothalamus by immunofluorescence, corroborating qualitatively other quantitative findings of the study. In conclusion, current results are convincing in demonstrating the IF effect on central regulation of food intake control, as shown by NPY and POMC neuropeptide expressions, resulting in a lower weight gain. Besides, IF improves glycemia, lipid metabolism, and consequently insulin and leptin resistance. However, there is increased expression of inflammatory markers in mouse hypothalamus challenged by the HF and HFru diets, which in the long term may induce adverse effects. Topics: Adipokines; Adiponectin; Animals; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; Dietary Fats; Fasting; Fructose; Humans; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptides; Triglycerides | 2020 |
DHA reduces hypothalamic inflammation and improves central leptin signaling in mice.
Anti-obesity effects and improved leptin sensitivity from n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported in diet-induced obese animals. This study sought to determine the beneficial central effects and mechanism of docosahexaenoic acid (DHA, 22:6 n-3) in high-fat (HF) diet fed mice.. Male C57BL/6J mice were given HF diet with or without intracerebroventricular (icv) injection of docosahexaenoic acid (DHA, 22:6 n-3) for two days. Central leptin sensitivity, hypothalamic inflammation, leptin signaling molecules and tyrosine hydroxylase (TH) were examined by central leptin sensitivity test and Western blot. Furthermore, the expression of hepatic genes involved in lipid metabolism was examined by RT-PCR.. We found that icv administration of DHA not only reduced energy intake and body weight gain but also corrected the HF diet-induced hypothalamic inflammation. DHA decreased leptin signaling inhibitor SOCS3 and improved the leptin JAK2-Akt signaling pathways in the hypothalamus. Furthermore, icv administration of DHA improved the effects of leptin in the regulation of mRNA expression of enzymes related to lipogenesis, fatty acid β-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus.. Therefore, increasing central DHA concentration may prevent the deficit of hypothalamic regulation, which is associated with disorders of energy homeostasis in the liver as a result of a high-fat diet. Topics: Animals; Body Weight; Diet, High-Fat; Docosahexaenoic Acids; Energy Intake; Energy Metabolism; Hypothalamus; Inflammation; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Signal Transduction | 2020 |
High-refined carbohydrate diet leads to polycystic ovary syndrome-like features and reduced ovarian reserve in female rats.
Obesity is associated with several female reproductive complications, such as polycystic ovary syndrome (PCOS). The exact mechanism of this relationship remains unclear. Few previous studies using diet containing refined carbohydrate (HCD) leading to obesity have been performed and it is unclear if HCD is linked with reproductive dysfunctions. In this investigation, we assessed whether subchronic HCD exposure results in reproductive and other irregularities. Female rats were fed with HCD for 15 days and metabolic outcomes and reproductive tract morphophysiology were assessed. We further assessed reproductive tract inflammation, oxidative stress (OS) and fibrosis. HCD rats displayed metabolic impairments, such as an increase in body weight/adiposity, adipocyte hypertrophic, abnormal lipid profile, glucose tolerance and insulin resistance (IR) and hyperleptinemia. Improper functioning of the HCD reproductive tract was observed. Specifically, irregular estrous cyclicity, high LH levels and abnormal ovarian morphology coupled with reduction in primordial and primary follicle numbers was observed, suggesting ovarian reserve depletion. Improper follicular development and a reduction in antral follicles, corpora lutea and granulosa layer area together with an increase in cystic follicles were apparent. Uterine atrophy and reduction in endometrial gland (GE) number was observed in HCD rats. Reproductive tract inflammation, OS and fibrosis were seen in HCD rats. Further, strong positive correlations were observed between body weight/adiposity and IR with estrous cycle length, cystic follicles, ovarian reserve, GE and other abnormalities. Thus, these data suggest that the subchronic HCD exposure led to PCOS-like features, impaired ovarian reserve, GE number, and other reproductive abnormalities in female rats. Topics: Adiposity; Animals; Body Weight; Diet; Dietary Carbohydrates; Estrous Cycle; Female; Fibrosis; Glucose Intolerance; Insulin Resistance; Leptin; Lipid Metabolism; Ovarian Follicle; Ovarian Reserve; Ovary; Oxidative Stress; Polycystic Ovary Syndrome; Rats; Rats, Wistar | 2020 |
Inhalation of Patchouli (
Topics: Acyclic Monoterpenes; Administration, Inhalation; Animals; Anti-Obesity Agents; Blood Preservation; Blood Pressure; Body Weight; Disease Models, Animal; Eating; Leptin; Lipoproteins, HDL; Lipoproteins, LDL; Male; Obesity; Oils, Volatile; Phytotherapy; Pogostemon; Rats, Sprague-Dawley | 2020 |
The energy budget and fat accumulation in striped hamsters (Cricetulus barabensis) during post-lactation.
Adaptive adjustments of energy intake and body fat play an important role in allowing animals' to meet the energy demands of thermoregulation during cold conditions and reproduction. Body fat is usually metabolized during lactation, which is one of the most energetically demanding activities of female mammals, however the effect of this on the energy budget and body fat regulation after lactation remains unclear. We compared the energy intake and body fat of female striped hamsters (Cricetulus barabensis) fed either a high-fat or low-fat diet for 21 days after the end of lactation (post-lactation, PL) to those of virgin controls. Serum leptin levels and the expression of hypothalamic orexigenic and anorexigenic neuropeptide genes were also measured and compared. Although lactating females consumed significantly more food, they had significantly lower body fat than virgin controls. The energy intake and body fat levels of the PL females were, however, significantly higher than those of virgin females. This was particularly true for the PL females that were fed high-fat diet. These females had significantly higher serum leptin concentrations, but lower hypothalamic leptin receptor gene expression, than virgin females. Neither orexigenic nor anorexigenic neuropeptide levels in the hypothalamus differed significantly between the PL and virgin females. This suggests that a negative energy balance during lactation drives fat accumulation after lactation. Furthermore, leptin resistance may occur after the end of lactation, causing females to consume more food, and accumulate more fat, than virgin females. Topics: Adipose Tissue; Animal Feed; Animals; Blood; Body Composition; Body Weight; Cricetinae; Cricetulus; Eating; Energy Intake; Energy Metabolism; Female; Hypothalamus; Lactation; Leptin; Neuropeptides; Receptors, Leptin | 2020 |
Metabolic Activity of Anthocyanin Extracts Loaded into Non-ionic Niosomes in Diet-Induced Obese Mice.
Anthocyanins (ACNs) are polyphenols that might reduce pathological processes associated with type 2 diabetes mellitus and other chronic diseases, but their bioavailability is still controversial. In this study, the metabolic activity of oral delivery of ACN-loaded niosomes was investigated and evaluated in a diet-induced obesity (DIO) mice model.. ACNs extracted from Vaccinium Meridionale by the supercritical fluid extraction method were loaded in niosomes. The niosomal formulation was physically characterized and further administrated in drinking water to obese, insulin resistant mouse. We evaluated the effect of ACN loaded niosomes on hyperglycemia, glucose and insulin intolerance and insulin blood levels in C57BL/6 J mice fed with a high-fat diet.. The ACN-loaded particles were moderately monodisperse, showed a negative surface charge and 57% encapsulation efficiency. The ACN-loaded niosomes ameliorated the insulin resistance and glucose intolerance in the DIO mice model. Additionally, they reduced animal weight and plasma insulin, glucose, leptin and total cholesterol levels in obese mice.. ACN-loaded niosomes administration, as a functional drink, had a beneficial effect on the reversal of metabolic abnormalities associated with obesity. Topics: Animals; Anthocyanins; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Compounding; Drug Liberation; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Liposomes; Male; Mice, Inbred C57BL; Mice, Obese; Nanocapsules; Obesity; Plant Extracts; Streptophyta | 2020 |
Chronic G
Maintaining energy homeostasis requires coordinating physiology and behavior both on an acute timescale to adapt to rapid fluctuations in caloric intake and on a chronic timescale to regulate body composition. Hypothalamic agouti-related peptide (AgRP)-expressing neurons are acutely activated by caloric need, and this acute activation promotes increased food intake and decreased energy expenditure. On a longer timescale, AgRP neurons exhibit chronic hyperactivity under conditions of obesity and high dietary fat consumption, likely due to leptin resistance; however, the behavioral and metabolic effects of chronic AgRP neuronal hyperactivity remain unexplored. Here, we use chemogenetics to manipulate G Topics: Adiposity; Agouti-Related Protein; Animals; Body Weight; Caloric Restriction; Eating; Energy Intake; Energy Metabolism; Female; GTP-Binding Protein alpha Subunits, Gq-G11; Homeostasis; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Neurons; Obesity; Signal Transduction; Weight Gain | 2020 |
Cholinergic neurons in the hypothalamus and dorsal motor nucleus of the vagus are directly responsive to growth hormone.
Cholinergic neurons are distributed in brain areas containing growth hormone (GH)-responsive cells. We determined if cholinergic neurons are directly responsive to GH and the metabolic consequences of deleting the GH receptor (GHR) specifically in choline acetyltransferase (ChAT)-expressing cells.. Mice received an acute injection of GH to detect neurons co-expressing ChAT and phosphorylated STAT5 (pSTAT5), a well-established marker of GH-responsive cells. For the physiological studies, mice carrying ablation of GHR exclusively in ChAT-expressing cells were produced and possible changes in energy and glucose homeostasis were determined when consuming regular chow or high-fat diet (HFD).. The majority of cholinergic neurons in the arcuate nucleus (60%) and dorsomedial nucleus (84%) of the hypothalamus are directly responsive to GH. Approximately 34% of pre-ganglionic parasympathetic neurons in the dorsal motor nucleus of the vagus also exhibited GH-induced pSTAT5. GH-induced pSTAT5 in these ChAT neurons was absent in GHR ChAT knockout mice. Mice carrying ChAT-specific GHR deletion, either in chow or HFD, did not exhibit significant changes in body weight, body adiposity, lean body mass, food intake, energy expenditure, respiratory quotient, ambulatory activity, serum leptin levels, glucose tolerance, insulin sensitivity and metabolic responses to 2-deoxy-d-glucose. However, GHR deletion in ChAT neurons caused decreased hypothalamic Pomc mRNA levels in HFD mice.. Cholinergic neurons that regulate the metabolism are directly responsive to GH, although GHR signaling in these cells is not required for energy and glucose homeostasis. Thus, the physiological importance of GH action on cholinergic neurons still needs to be identified. Topics: Acetylcholine; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Choline O-Acetyltransferase; Cholinergic Neurons; Diet, High-Fat; Energy Metabolism; Glucose; Growth Hormone; Hypothalamus; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Somatotropin; STAT5 Transcription Factor; Vagus Nerve | 2020 |
High-fat diet from parental generation exaggerates body and adipose tissue weights in pregnant offspring.
Parental high-fat diet (HFD) programs for obesity and hypertension in female offspring in rats, but it is unknown how the pregnancies of these offspring are impacted. Therefore, the hypothesis was tested that parental HFD exaggerates obesity and hypertension during pregnancy of the offspring. Wistar Hannover rat dams (the parental, P generation) were maintained on normal-fat diet (NFD) or HFD from weaning and were kept on respective diets through pregnancy and lactation. Their offspring (the first filial, F1 generation) were weaned onto the same diet as the P generation, or they were changed to the other diet to determine if combined HFD in the P and F1 generations exaggerates body weight and blood pressure levels during pregnancy in these offspring. This diet paradigm resulted in the following groups of pregnant F1 offspring: P-NFD/F1-NFD, P-HFD/F1-NFD, P-NFD/F1-HFD, and P-HFD/F1-HFD. Maternal body and adipose tissue weights were greatest in the P-HFD/F1-HFD group compared to the other 3 groups by the end of pregnancy. Plasma leptin and conscious mean arterial blood pressure were not significantly different between any group, although there was a main effect for increased blood pressure in the F1-HFD groups. Circulating levels of the antihypertensive pregnancy factor, placental growth factor (PlGF), were assessed. Although average PlGF levels were similar among all groups, correlative studies revealed that lower levels of PlGF were associated with higher blood pressure only in the P-HFD/F1-HFD group. In summary, HFD feeding from the P generation exaggerated HFD-induced body and adipose tissue weights in the pregnant offspring. Topics: Adiposity; Animals; Blood Pressure; Body Weight; Diet, High-Fat; Disease Models, Animal; Female; Humans; Hypertension; Leptin; Male; Maternal Inheritance; Obesity; Placenta Growth Factor; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Weaning | 2020 |
Pregabalin induced reproductive toxicity and body weight changes by affecting caspase3 and leptin expression: Protective role of wheat germ oil.
Pregabalin (PGB) drug abuse is common among the youth. It substituted tramadol before its recent schedule as a controlled drug since April 2019. PGB is an antiepileptic drug acting on the central nervous system. It blocks calcium channels regulating the action of neurotransmitters and causing prolonged depolarization. The present study aimed to investigate the toxic effect of long term pregabalin abuse on the reproductive function and body weight in both male and female albino rats and to evaluate the ameliorative effect of wheat germ oil (WGO). Forty-eight rats were randomly divided into eight groups. The first four groups were males and they were treated as follows: control group (1.5 mL saline), WGO group (1.5 mL L/kg), PGB group (300 mg/kg), and protective group (PGB + WGO). All doses were administrated once per day for 60 days by gastric gavage. The second four groups were females. They were divided and treated the same as the male groups. Pregabalin caused significant weight loss, decreased serum triglyceride level, and increased leptin gene expression in all rats. PGB affected male rats reproduction by decreasing total testosterone serum level and inhibiting spermatogenesis. Reproductive toxicity in females was caused by decreasing pituitary steroids, increasing gonadal hormones, and increasing the number of atretic ovarian follicles. Mechanism of toxicity may be attributed to the PGB oxidative stress effect that induced apoptosis and caused diffuse gonadal atrophy. WGO showed a protective effect on PGB induced toxicity as all measured parameters were relatively improved. Topics: Animals; Body Weight; Caspase 3; Female; Leptin; Oxidative Stress; Plant Oils; Pregabalin; Protective Agents; Rats; Reproduction | 2020 |
Short-term metreleptin treatment of patients with anorexia nervosa: rapid on-set of beneficial cognitive, emotional, and behavioral effects.
To examine the hypothesis that normalization of low circulating leptin levels in patients with anorexia nervosa ameliorates hyperactivity, three seriously ill females with hyperactivity were treated off-label with metreleptin (recombinant human leptin) for up to 14 days. Drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased in two patients. Surprisingly, depression improved rapidly in all patients. No serious adverse events occurred. Due to obvious limitations of uncontrolled case series, placebo-controlled clinical trials are mandatory to confirm the observed rapid onset of beneficial effects. Our findings suggest an important role of hypoleptinemia in the mental and behavioral phenotype of anorexia nervosa. Topics: Anorexia Nervosa; Body Weight; Cognition; Female; Humans; Leptin | 2020 |
Anti-obesity potentiality of Tapra fish (Opisthopterus tardoore) oil.
In this present investigation, we have extracted and characterized the Tapra fish oil as well as applied it to evaluate anti-obesity potentiality. The Tapra fish oil had 1.14 ± 0.10 mg KOH/g of acid value, 129.8 ± 5.09 mg KOH/g of saponification number, 2.67 ± 0.67 mEq/kg of peroxide value, 121.9 ± 2.14 mg of iodine value, and 17.67 ± 1.45 totox value. Gas Chromatography-Mass Spectrometric analysis clearly revealed the presence of nine different fatty acids. When the fish oil was applied to high-fat diet-induced obese mice, it showed significant reduction of body weight, Body Mass Index, and serum lipid profiles compared to the high-fat diet-induced obese mice. The levels of leptin and TNF-α were moderately reduced in fish oil treated high-fat diet-induced obese mice than control obese mice. In conclusion, the Tapra fish oil was enriched with essential fatty acids and it could be used as an antiobese food supplement. PRACTICAL APPLICATIONS: Considering the adverse effects of drugs used for the treatment of obesity, there is always a need to find out the alternatives. While the anti-obesity potentialities of different sea fish oil have been documented, the same for the Tapra fish (Opisthopterus tardoore) oil has not been studied at all. The extracted Tapra fish oil was found good in quality. Administration of fish oil in the mice exhibited anti-obesity effect in terms of lowering body weight, Body Mass Index, and serum lipid profiles, leptin, and TNF-α in mice model. These findings are fostering new therapeutic approaches to obesity treatment. Topics: Animals; Body Weight; Diet, High-Fat; Fish Oils; Fishes; Leptin; Mice; Obesity | 2020 |
"Behavior" of the Hormonal Ensemble through the Prism of Cluster Analysis.
The serum hormone concentrations were studied in a group of male F1 (C57BL/6×DBA/2) mice in different states of food activity (satiety, 24-h food deprivation, and cognitive load against the background of food deprivation). The hormonal response depended on food activity: the content of leptin, triiodothyronine, and testosterone decreased in hungry animals, while during cognitive load (learning), we observed a decrease in the concentrations of ghrelin, leptin, thyroxine, and testosterone. The exceptions were neuropeptide Y (its concentration increased in hungry animals) and corticosterone (its level remained unchanged). The use of hierarchical cluster analysis allowed identifying functional organization of the relationships within the hormonal ensemble that underwent plastic changes depending on the state of the organism. It was shown that the hormonal ensemble was system-organized in the form of a "core" that determines stability of the system and the "field", within which functional interactions of the hormones are preserved. Topics: Animals; Body Weight; Cluster Analysis; Corticosterone; Crosses, Genetic; Food Deprivation; Ghrelin; Hunger; Leptin; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neuropeptide Y; Satiation; Testosterone; Thyroxine; Triiodothyronine | 2020 |
Adiponectin is Increased in Pediatric Patients With Autoimmune Hepatitis Independent of Body Weight.
A high prevalence of obesity is reported in children and adolescents with autoimmune hepatitis (AIH). Adipokines participate in inflammatory processes. The objective of this study was to examine the relationship between excess weight and systemic inflammation, adipokines, and ghrelin in adolescents with AIH.. This case-controlled study included 27 adolescents with AIH (13 with excess weight and 14 with normal weight) and a control group. Excess weight was defined by a body mass index/age Z score >+1 standard deviation. Adipokines (adiponectin, leptin, tumor necrosis factor alpha, interleukin 6 [IL-6], and IL-10) and ghrelin were measured with Luminex technology.. Adiponectin (μg/mL) was higher (P < 0.001) in AIH adolescents with and without excess weight (median: 35.0 and 42.1, respectively) than in normal-weight (17.5) and excess-weight (17.0) controls. Leptin was higher (P < 0.001) in excess-weight AIH patients (18.0 ng/mL) and controls (19.8 ng/mL) than in normal-weight AIH (7.7 ng/mL) and control (7.0 ng/mL) adolescents. IL-6 levels were higher in excess-weight (3.8 pg/mL) and normal-weight (3.8 pg/mL) AIH patients than in excess-weight (1.1 pg/mL) and normal-weight (0.5 pg/mL) controls. IL-10 levels were higher (5.2 pg/mL) in normal-weight AIH patients than in excess-weight (1.8 pg/mL) and normal-weight (2.1 pg/mL) controls. Ferritin levels were lower in patients with AIH than in controls.. Independent of body weight, AIH patients had higher levels of adipokines, especially adiponectin and IL-6. Leptin levels were associated with body weight and were not influenced by AIH. IL-10 levels were associated with lean tissue in AIH. Topics: Adipokines; Adiponectin; Adolescent; Body Weight; Child; Hepatitis, Autoimmune; Humans; Leptin | 2020 |
Maternal High-Fat-High-Carbohydrate Diet-Induced Obesity Is Associated with Increased Appetite in Peripubertal Male but Not Female C57Bl/6J Mice.
Diet-induced maternal obesity might play a critical role in altering hypothalamic development, predisposing the offspring to obesity and metabolic disease later in life. The objective of this study was to describe both phenotypic and molecular sex differences in peripubertal offspring energy homeostasis, using a mouse model of maternal obesity induced by a high-fat-high-carbohydrate (HFHC) diet. We report that males, not females, exposed to a maternal HFHC diet had increased energy intake. Males exposed to a maternal HFHC diet had a 15% increased meal size and a 46% increased frequency, compared to the control (CON) males, without a change in energy expenditure. CON and HFHC offspring did not differ in body weight, composition, or plasma metabolic profile. HFHC diet caused decreased hypothalamic glucocorticoid expression, which was further decreased in males compared to females. Maternal weight, maternal caloric intake, and male offspring meal frequency were inversely correlated with offspring hypothalamic insulin receptor (IR) expression. There was a significant interaction between maternal-diet exposure and sex in hypothalamic IR. Based on our preclinical data, we suggest that interventions focusing on normalizing maternal nutrition might be considered to attenuate nutritional influences on obesity programming and curb the continuing rise in obesity rates. Topics: Adrenocorticotropic Hormone; Animals; Appetite; Body Weight; Cholesterol; Corticosterone; Diet, Carbohydrate Loading; Diet, High-Fat; Energy Metabolism; Female; Hypothalamus; Insulin; Leptin; Male; Maternal Nutritional Physiological Phenomena; Mice; Mice, Inbred C57BL; Obesity, Maternal; Pregnancy; Prenatal Exposure Delayed Effects; Receptor, Insulin; Sex Characteristics; Triglycerides | 2020 |
Early life overnutrition impairs plasticity of non-neuronal brainstem cells and drives obesity in offspring across development in rats.
The prevalence of adolescent obesity has increased dramatically, becoming a serious public health concern. While previous evidence suggests that in utero- and early postnatal overnutrition increases adult-onset obesity risk, the neurobiological mechanisms underlying this outcome are not well understood. Non-neuronal cells play an underestimated role in the physiological responses to metabolic/nutrient signals. Hypothalamic glial-mediated inflammation is now considered a contributing factor in the development and perpetuation of obesity; however, attention on the role of gliosis and microglia activation in other nuclei is still needed.. Here, we demonstrate that early life consumption of high-fat/sucrose diet (HFSD) is sufficient to increase offspring body weight, hyperleptinemia and potentially maladaptive cytoarchitectural changes in the brainstem dorsal-vagal-complex (DVC), an essential energy balance processing hub, across postnatal development. Our data demonstrate that pre- and postnatal consumption of HFSD result in increased body weight, hyperleptinemia and dramatically affects the non-neuronal landscape, and therefore the plasticity of the DVC in the developing offspring.. Current findings are very provocative, considering the importance of the DVC in appetite regulation, suggesting that HFSD-consumption during early life may contribute to subsequent obesity risk via DVC cytoarchitectural changes. Topics: Animals; Body Weight; Brain Stem; Diet, High-Fat; Dietary Sucrose; Female; Glucagon-Like Peptide 1; Insulin; Leptin; Male; Maternal Nutritional Physiological Phenomena; Neuronal Plasticity; Obesity; Overnutrition; Rats; Rats, Sprague-Dawley; Weight Gain | 2020 |
HIV Protease Inhibitor Ritonavir Impairs Endothelial Function Via Reduction in Adipose Mass and Endothelial Leptin Receptor-Dependent Increases in NADPH Oxidase 1 (Nox1), C-C Chemokine Receptor Type 5 (CCR5), and Inflammation.
Topics: Adipose Tissue; Animals; Body Weight; Cardiovascular Diseases; Endothelial Cells; HIV Protease Inhibitors; Inflammation; Leptin; Mice; NADPH Oxidase 1; Oxidative Stress; Receptors, CCR5; Receptors, Leptin; Ritonavir; Signal Transduction | 2020 |
Skeletal glucocorticoid signalling determines leptin resistance and obesity in aging mice.
Aging and chronic glucocorticoid excess share a number of critical features, including the development of central obesity, insulin resistance and osteoporosis. Previous studies have shown that skeletal glucocorticoid signalling increases with aging and that osteoblasts mediate the detrimental skeletal and metabolic effects of chronic glucocorticoid excess. Here, we investigated whether endogenous glucocorticoid action in the skeleton contributes to metabolic dysfunction during normal aging.. As they aged, wild-type mice became obese and insulin-resistant. In contrast, HSD2. Skeletal glucocorticoid signalling is critical for the development of leptin resistance, obesity and insulin resistance during aging. These findings underscore the skeleton's importance in the regulation of body weight and implicate osteoblastic/osteocytic glucocorticoid signalling in the aetiology of aging-related obesity and metabolic disease. Topics: Adipose Tissue; Age Factors; Aging; Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Body Weight; Bone and Bones; Brain; Female; Glucocorticoids; Glucose; Hypothalamus; Insulin; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Obesity; Signal Transduction; Thermogenesis | 2020 |
Leptin alters energy intake and fat mass but not energy expenditure in lean subjects.
Based on studies in mice, leptin was expected to decrease body weight in obese individuals. However, the majority of the obese are hyperleptinemic and do not respond to leptin treatment, suggesting the presence of leptin tolerance and questioning the role of leptin as regulator of energy balance in humans. We thus performed detailed novel measurements and analyses of samples and data from our clinical trials biobank to investigate leptin effects on mechanisms of weight regulation in lean normo- and mildly hypo-leptinemic individuals without genetic disorders. We demonstrate that short-term leptin administration alters food intake during refeeding after fasting, whereas long-term leptin treatment reduces fat mass and body weight, and transiently alters circulating free fatty acids in lean mildly hypoleptinemic individuals. Leptin levels before treatment initiation and leptin dose do not predict the observed weight loss in lean individuals suggesting a saturable effect of leptin. In contrast to data from animal studies, leptin treatment does not affect energy expenditure, lipid utilization, SNS activity, heart rate, blood pressure or lean body mass. Topics: Adipose Tissue; Adult; Body Weight; Eating; Energy Intake; Energy Metabolism; Fats; Female; Humans; Leptin; Male; Obesity; Randomized Controlled Trials as Topic; Thinness; Young Adult | 2020 |
PGC-1β-expressing POMC neurons mediate the effect of leptin on thermoregulation in the mouse.
The arcuate nucleus (ARC) of the hypothalamus is a key regulator of food intake, brown adipose tissue (BAT) thermogenesis, and locomotor activity. Whole-body deficiency of the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1β (PGC-1β) disrupts mouse circadian locomotor activity and BAT-regulated thermogenesis, in association with altered gene expression at the central level. We examined whether PGC-1β expression in the ARC is required for proper energy balance and locomotor behavior by generating mice lacking the PGC-1β gene specifically in pro-opiomelanocortin (POMC) neurons. POMC neuron-specific deletion of PGC-1β did not impact locomotor behavior, food intake, body composition, energy fuel utilization and metabolic rate in fed, 24-h fasted and 24-h refed conditions. In contrast, in the fed state, deletion of PGC-1β in POMC cells elevated core body temperature during the nighttime period. Importantly, this higher body temperature is not associated with changes in BAT function and gene expression. Conversely, we provide evidence that mice lacking PGC-1β in POMC neurons are more sensitive to the effect of leptin on heat dissipation. Our data indicate that PGC-1β-expressing POMC neurons are part of a circuit controlling body temperature homeostasis and that PGC-1β function in these neurons is involved in the thermoregulatory effect of leptin. Topics: Adipose Tissue, Brown; Animals; Arcuate Nucleus of Hypothalamus; Body Temperature Regulation; Body Weight; Energy Metabolism; Gene Expression Regulation; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Neurons; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pro-Opiomelanocortin; Thermogenesis; Transcription Factors | 2020 |
Early metformin treatment improves pancreatic function and prevents metabolic dysfunction in early overfeeding male rats at adulthood.
What is the central question of this study? Studies reported the efficacy of metformin as a promising drug for preventing or treating of metabolic diseases. Nutrient stresses during neonatal life increase long-term risk for cardiometabolic diseases. Can early metformin treatment prevent the malprogramming effects of early overfeeding? What is the main finding and its importance? Neonatal metformin treatment prevented early overfeeding-induced metabolic dysfunction in adult rats. Inhibition of early hyperinsulinaemia and adult hyperphagia might be associated with decreased metabolic disease risk in these animals. Therefore, interventions during infant development offer a key area for future research to identify potential strategies to prevent the long-term metabolic diseases. We suggest that metformin is a potential tool for intervention.. Given the need for studies investigating the possible long-term effects of metformin use at crucial stages of development, and taking into account the concept of metabolic programming, the present work aimed to evaluate whether early metformin treatment might program rats to resist the development of adult metabolic dysfunctions caused by overnutrition during the neonatal suckling phase. Wistar rats raised in small litters (SLs, three pups per dam) and normal litters (NLs, nine pups per dam) were used as models of early overfeeding and normal feeding, respectively. During the first 12 days of suckling, animals from SL and NL groups received metformin, whereas the controls received saline injections. Food intake and body weight were monitored from weaning until 90 days of age, when biometric and biochemical parameters were assessed. The metformin treatment decreased insulin concentrations in pups from SL groups, and as adults, these animals showed improvements in glucose tolerance, insulin sensitivity, body weight gain, white fat pad stores and food intake. Low-glucose insulinotrophic effects were observed in pancreatic islets from both NL and SL groups. These results indicate that early postnatal treatment with metformin inhibits early overfeeding-induced metabolic dysfunctions in adult rats. Topics: Adipose Tissue, White; Animals; Animals, Newborn; Blood Glucose; Body Composition; Body Weight; Female; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Male; Metabolic Diseases; Metformin; Obesity; Overnutrition; Rats; Rats, Wistar; Weight Gain | 2020 |
Association of adipocytokines with lipid and glycemic profiles in women with normal weight obesity.
Individuals with normal weight obesity (NWO) are predisposed to having cardiometabolic disorders. This study aims to investigate the circulating levels of vaspin, leptin and their association with glycemic and lipid profiles in women with NWO.. Forty women with body mass index (BMI) = 18.5-24.9 kg/m. The mean ± standard deviation (SD) age of participants was 28.76 ± 4.76 years in the NWO group and 29.23 ± 4.50 years in the control group. The NWO group had the higher mean serum levels of insulin (9.02 ± 4.75 vs. 6.24 ± 2.51, P = 0.009), leptin (17.31 ± 8.10 vs. 9.94 ± 4.30, P < 0.001) and homeostatic model assessment of insulin resistance (HOMA-IR) (33.77 ± 20.71 vs. 23.48 ± 10.03, P = 0.009) compared to the NWNO group. The serum level of vaspin was higher in the NWO group compared to the control group (34.82 pg/ml vs. 27.72 pg/ml, respectively, P = 0.12). In NWO group, the serum levels of leptin had positive correlation with FBS (r = 0.45, P = 0.02), insulin (r = 0.51, P = 0.008), and HOMA-IR (r = 0.46, P = 0.02) and vaspin concentration was associated with insulin (r = 0.36, P = 0.02) and HOMA-IR (r = 0.30, P = 0.06), positively.. It is concluded that the concentration of insulin and HOMA-IR index were significantly higher in women with NWO compared to NWNO. Higher concentrations of leptin and vaspin in the NWO group were associated with glycemic profile. Topics: Adipokines; Adult; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; Case-Control Studies; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Iran; Leptin; Lipids; Middle Aged; Obesity; Prognosis; Young Adult | 2020 |
Decreased sensitivity to the anorectic effects of leptin in mice that lack a Pomc-specific neural enhancer.
Enhancer redundancy has been postulated to provide a buffer for gene expression against genetic and environmental perturbations. While work in Drosophila has identified functionally overlapping enhancers, work in mammalian models has been limited. Recently, we have identified two partially redundant enhancers, nPE1 and nPE2, that drive proopiomelanocortin gene expression in the hypothalamus. Here we demonstrate that deletion of nPE1 produces mild obesity while knockout of nPE2 has no discernible metabolic phenotypes. Additionally, we show that acute leptin administration has significant effects on nPE1 knockout mice, with food intake and body weight change significantly impacted by peripheral leptin treatment. nPE1 knockout mice became less responsive to leptin treatment over time as percent body weight change increased over 2 week exposure to peripheral leptin. Both Pomc and Agrp mRNA were not differentially affected by chronic leptin treatment however we did see a decrease in Pomc and Agrp mRNA in both nPE1 and nPE2 knockout calorie restricted mice as compared to calorie restricted PBS-treated WT mice. Collectively, these data suggest dynamic regulation of Pomc by nPE1 such that mice with nPE1 knockout become less responsive to the anorectic effects of leptin treatment over time. Our results also support our earlier findings in which nPE2 may only be critical in adult mice that lack nPE1, indicating that these neural enhancers work synergistically to influence metabolism. Topics: Animals; Appetite Depressants; Body Weight; Eating; Enhancer Elements, Genetic; Hypothalamus; Leptin; Male; Mice; Mice, Knockout; Neurons; Pro-Opiomelanocortin | 2020 |
High Maternal Omega-3 Supplementation Dysregulates Body Weight and Leptin in Newborn Male and Female Rats: Implications for Hypothalamic Developmental Programming.
Maternal diet is critical for offspring development and long-term health. Here we investigated the effects of a poor maternal diet pre-conception and during pregnancy on metabolic outcomes and the developing hypothalamus in male and female offspring at birth. We hypothesised that offspring born to dams fed a diet high in fat and sugar (HFSD) peri-pregnancy will have disrupted metabolic outcomes. We also determined if these HFSD-related effects could be reversed by a shift to a healthier diet post-conception, in particular to a diet high in omega-3 polyunsaturated fatty acids (ω3 PUFAs), since ω3 PUFAs are considered essential for normal neurodevelopment. Unexpectedly, our data show that there are minimal negative effects of maternal HFSD on newborn pups. On the other hand, consumption of an ω3-replete diet during pregnancy altered several developmental parameters. As such, pups born to high-ω3-fed dams weighed less for their length, had reduced circulating leptin, and also displayed sex-specific disruption in the expression of hypothalamic neuropeptides. Collectively, our study shows that maternal intake of a diet rich in ω3 PUFAs during pregnancy may be detrimental for some metabolic developmental outcomes in the offspring. These data indicate the importance of a balanced dietary intake in pregnancy and highlight the need for further research into the impact of maternal ω3 intake on offspring development and long-term health. Topics: Animals; Animals, Newborn; Body Weight; Dietary Supplements; Fatty Acids, Omega-3; Female; Hypothalamus; Leptin; Male; Maternal Exposure; Neurogenesis; Rats | 2020 |
Berberine for Appetite Suppressant and Prevention of Obesity.
Berberine (BBR), a natural plant product, has been shown to have antidiabetic, cholesterol-reducing effects. To investigate the action of BBR as appetite suppressants, two experimental protocols were performed. In the first experiment, the mice were fed either a normal-chow diet or a high-fat diet (HF). The mice received daily intraperitoneal injections of BBR (10 mg/kg or saline at 1 ml/kg) for 3 weeks. To determine the antiobesity effects of BBR, the food consumption, body weight, fat contents, serum leptin, and glucose level were investigated. In the second experiment, we set out to validate the effect of BBR on central neuropeptide Y (NPY) stimulated rats. Experiments were carried out in 24-hour fasted rats, and then food intake and glucose level were subsequently recorded for 1 hour. The experimental groups were subdivided into the intra-3rd ventricular microinjections of ACSF (artificial cerebrospinal fluid), neuropeptide Y (NPY; 100 nM), NPY+BBR (10 nM), and NPY+BBR (100 nM) group. And then the blood glucose level was examined. In the first experiment, treatment with BBR in the HF diet mice reduced food intake, body weight, fat contents, serum leptin, and glucose level. In the second experiment, the NPY-injected group increased food intake by 39.3%, and food intake was reduced in the BBR group by 47.5%, compared with the ACSF-injected group. Also, the serum glucose level in the NPY+BBR (100 nM) group was significantly lower than that in the NPY (100 nM) group. The results suggest that BBR improved lipid dysregulation in obesity by controlling the central obesity related pathway. Topics: Animals; Appetite Depressants; Berberine; Blood Glucose; Body Weight; Feeding Behavior; Leptin; Lipid Metabolism; Male; Mice, Inbred C57BL; Obesity | 2020 |
[Leptin sexual dimorphism, insulin resistance, and body composition in normal weight prepubescent].
The prepubertal stage is a critical period of body fat development, in which leptin and insulin re sistance has been associated, however, there are few studies in normal-weight prepubescents. Ob jective: To assess the relationship between leptin and body composition and insulin resistance in a group of normal-weight prepubescents.. Analytical cross-sectional study with 128 healthy prepubescents of normal weight, aged between 6 and 10 years. Height, weight, body mass index (BMI), body fat percentage (BFP), waist circumference (WC), and hip circumference (HC) were measured. Plasma leptin (ng/mL) and insulin (mU/L) were evaluated by immunoassay and glycemia (mmol/L) by enzymatic method. HOMA-IR was calculated. A comparison study and correlation analysis by sex were performed.. Females presented higher values than males of leptin (6.8 ± 5 vs 3.3 ± 3.7; p = 0.000), insulin (7.1 ± 4.5 vs 5.2 ± 2.5; p = 0.016), BFP (22.4 ± 4.3 vs 18.6 ± 3.9; p = 0.000), and HC (67 ± 5.7 vs 65.0 ± 4.5; p = 0.019), and a lower waist/hip ratio (0.84 ± 0.04 vs 0.88 ± 0.04; p = 0.000). Leptin correlations with anthropometric variables were significant in both sexes, with greater association in females. The association of HOMA-IR with leptin was similar in both sexes.. in normal-weight prepubescents aged between 6-10 years, there are sex differences in adiposity and leptin levels not associated with differences in BMI or insulin resistance. The greater association of leptin with adiposity in girls could be related to a high rate of adipogenesis induced by this hormone. Topics: Adiposity; Blood Glucose; Body Composition; Body Height; Body Mass Index; Body Weight; Child; Cross-Sectional Studies; Female; Humans; Ideal Body Weight; Insulin; Insulin Resistance; Leptin; Male; Sex Characteristics; Sex Factors | 2020 |
Sex differences in the peripubertal response to a short-term, high-fat diet intake.
Obesity is one of the most important health problems facing developed countries because being overweight is associated with a higher incidence of type 2 diabetes, cardiovascular disease and cancer, as well as other comorbidities. Although increased weight gain results from a combination of poor dietary habits and decreased energy expenditure, not all individuals have equal propensities to gain weight or to develop secondary complications of obesity. This is partially a result not only of genetics, including sex, but also the time during which an individual is exposed to an obesogenic environment. In the present study, we have compared the response of male and female mice to short-term exposure to a high-fat diet (HFD) or a low-fat diet during the peripubertal period (starting at 42 days of age) because this is a stage of dramatic hormonal and metabolic modifications. After 1 week on a HFD, there was no significant increase in body weight, although females significantly increased their energy intake. Serum leptin levels increased in both sexes, even though no change in fat mass was detected. Glyceamia and homeostasis model assessment increased in males, suggesting a rapid change in glucose metabolism. Hypothalamic pro-opiomelanocortin mRNA levels were significantly higher in females on a HFD compared to all other groups, which may be an attempt to reduce their increased energy intake. Hypothalamic inflammation and gliosis have been implicated in the development of secondary complications of obesity; however, no indication of activation of inflammatory processes or gliosis was found in response to 1 week of HFD in the hypothalamus, hippocampus or cerebellum of these young mice. These results indicate that there are both sex and age effects in the response to poor dietary intake because peripubertal male and female mice respond differently to short-term dietary changes and this response is different from that reported in adult rodents. Topics: Adiposity; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Energy Intake; Female; Hypothalamus; Insulin; Leptin; Male; Mice; Pro-Opiomelanocortin; Sex Factors; Sexual Maturation | 2020 |
(-)-Epicatechin reduces adiposity in male offspring of obese rats.
To determine whether (-)-epicatechin (Epi) could decrease visceral adipose tissue and improve the metabolic profile of male offspring rats, after maternal obesity was induced by a high-fat diet (HFD).. Maternal obesity in albino Wistar rats was induced with a HFD, whereas male offspring were fed with chow diet throughout the study. Eight male offspring per group, from different litters, were randomly assigned to the experimental or to the control groups. In the experimental group, Epi was administered at a dose of 1 mg/kg of body weight to the male offspring twice daily for two weeks, beginning at postnatal day (PND).. Weight of visceral adipose tissue, adipocyte size, and several metabolic parameters.. Epi administration in the male offspring induced a significant decrease in the amount of visceral fat (11.61 g less, P < 0.05) and in the size of adipose cells (28% smaller, P < 0.01). Besides, Epi was able to decrease insulin, leptin, and Homeostasis Model Assessment -Insulin Resistance (HOMA-IR) (P < 0.05), as well as triglycerides, when the experimental group was compared to the untreated male offspring of obese rats (P < 0.01).. Epi administration can reverse the negative effects that maternal obesity has on the male offspring. This could be because Epi reduces the amount of visceral fat and improves metabolic profile. Topics: Adiposity; Animals; Body Weight; Catechin; Diet, High-Fat; Disease Models, Animal; Female; Humans; Insulin Resistance; Leptin; Male; Obesity, Maternal; Pregnancy; Prenatal Exposure Delayed Effects; Rats | 2020 |
Leptin and adiponectin dynamics at patients with rectal neoplasm - Gender differences.
Numerous studies associate adipokines with colorectal malignancy, but few data deal with patients suffering exclusively of rectal carcinoma (RC).. We evaluated leptin and adiponectin levels in RC patients compared to healthy population and their dynamics after surgery.. Serum leptin and adiponectin were evaluated before surgery in 59 RC consecutive patients (38 males and 21 females), and in age and weight matched healthy controls. Measurements were repeated at 24, 72 hours and 7 days after surgery.. Adipokine levels were higher in women. Controls had higher leptin (32.±4.34 vs 9.51±1.73 ng/ml in women and 11±2.66 vs 2.54±0.39 ng/ml in men, p = 0.00048 and 0.0032) and lower adiponectin (9±0.64 vs 11.85±1.02 μg/ml in women and 7.39±0.51 vs 8.5±0.62 μg/ml in men, p = 0.017 and 0.019) than RC patients. Surgery caused an increase of leptin from 5.11±0.8 to 18.7±2.42 ng/ml, p = 6.85 x 10¨8, and a decrease of adiponectin from 9.71±0.58 to 7.87±0.47 μg/ml, p = 1.4 x 10¨10 for all RC patients and returned thereafter to the initial range at 7 days. Adipokines were correlated with body weight (BW). The significance of correlation persisted after surgery only in males, but disappeared in females. Adipokines were not modified by tumor position, presurgical chemoradiotherapy or surgical technique. Women with RC experiencing weight loss had higher adiponectin than women without weight modifications (p<0.05 at all time points).. Adipokine levels of patients with RC differ from the healthy population, possibly reflecting an adaptation to disease. Adipokine modifications after surgery may be related to acute surgical stress. Whether leptin and adiponectin directly interact is not clear. Women have higher adipokine levels, more so after significant weight loss, but the strength of their correlation with BW decreases after surgery. These data suggest gender differences in the adipokine profile of RC patients which may find clinical applications. Topics: Adiponectin; Aged; Biomarkers, Tumor; Body Weight; Case-Control Studies; Female; Humans; Leptin; Male; Middle Aged; Rectal Neoplasms; Sex Factors; Stress, Physiological; Weight Loss | 2019 |
Impaired metabolic and hepatic functions following subcutaneous lipectomy in adult obese rats.
What is the central question of this study? What is the impact and drawbacks of subcutaneous lipectomy on body metabolism? What is the main finding and its importance? Subcutaneous lipectomy resulted in deterioration of hepatic functions, atherosclerotic lipid profile and disturbed redox state. While the results support lipectomy as an effective treatment for obesity, lipectomy induces unfavourable changes in health.. The number of obese older adults is on the rise, but data about proper treatment of obesity in the elderly is controversial. The present study was designed to investigate the effectiveness and consequences of partial subcutaneous lipectomy, as a rapid medical intervention against increased accumulation of body fat, in adult obese rats. The study was conducted on adult (9-12 months) female rats, in which obesity was induced by bilateral surgical ovariectomy. They were randomized into two main groups: short term (5 weeks) and long term (10 weeks). Both groups were subdivided into control, ovariectomized (OVX) and ovariectomized lipectomized groups. Body weight (BW) was measured and body mass index (BMI) calculated. Fasting blood glucose, lipid profile and plasma levels of total proteins, albumin, liver enzymes, malondialdehyde (MDA), leptin and adiponectin were determined. The content of both blood and hepatic tissue of reduced glutathione was estimated. In addition, histological study of the liver, aorta and peri-renal fat was performed. Compared to controls, OVX rats showed significant increase in BW, BMI and plasma levels of liver enzymes, MDA and leptin. Histological study revealed vacuolated ballooned hepatocytes and enlarged irregular visceral adipocytes with atherosclerotic changes in the wall of aorta. Following subcutaneous lipectomy, rats exhibited significant fasting hyperglycaemia, dyslipidaemia, lowered plasma albumin and disturbed redox state with aggravation of the histological changes. The findings indicate that although subcutaneous lipectomy appears to be effective in combating obesity in older females, it has unfavourable effects on both metabolic and hepatic functions. Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Mass Index; Body Weight; Disease Models, Animal; Fasting; Female; Insulin; Insulin Resistance; Leptin; Lipectomy; Liver; Malondialdehyde; Obesity; Rats | 2019 |
Postnatal administration of leptin antagonist mitigates susceptibility to obesity under high-fat diet in male αMUPA mice.
Perturbations in postnatal leptin signaling have been associated with altered susceptibility to diet-induced obesity (DIO) under high-fat-diet (HFD), albeit with contradicting evidence. Previous studies have shown that alpha murine urokinase-type plasminogen activator (αMUPA) mice have a higher and longer postnatal leptin surge compared with their wild types (WTs) as well as lower body weight and food intake under regular diet (RD). Here we explored αMUPA's propensity for DIO and the effect of attenuating postnatal leptin signaling with leptin antagonist (LA) on energy homeostasis under both RD and HFD. Four-day-old αMUPA pups were treated on alternate days until postnatal day 18 with either vehicle or LA (10 or 20 mg·day Topics: Animals; Animals, Newborn; Body Weight; Diet, High-Fat; Disease Susceptibility; Eating; Energy Metabolism; Female; Hyperinsulinism; Leptin; Mice; Obesity; Pregnancy; Receptors, Urokinase Plasminogen Activator; Signal Transduction; Species Specificity; Weight Gain | 2019 |
Anti-obesity effect of Yangkyuksanwha-tang in high-fat diet-induced obese mice.
Yangkyuksanwha-tang (YST) is an herbal medicine based on Sasang constitutional medicine (SCM) and is widely used in Korean traditional medicine. The aim of the study was to evaluate the effect of YST on obesity in high-fat diet (HFD)-induced obese mice.. We induced obesity in C57bl/6 J mice using a HFD, and then orally administered 300 mg/kg YST for 6 weeks. We measured body weight, food efficiency, organ and fat weight, serum biochemical parameters, and obesity-related gene expression, and carried out histological analysis at the end of the experimental period.. YST significantly reduced the absolute body weight and food efficiency ratio. The serum, aminotransferase, glucose, total cholesterol, triglyceride, and low-density lipoprotein-cholesterol levels were significantly lower in the YST-treated group than in the control group, whereas the high-density lipoprotein-cholesterol level in the YST-treated group was significantly higher. The YST-treated group also showed a significant reduction in regional fatty tissues and the absolute weight of various organs. We also observed a significantly reduced expression of AP2/FABP4, C/EBP-β, leptin, and SREBP1c/ADD1 mRNA, and significantly increased expression of UCP-2 and adiponectin mRNA in adipose tissue in the YST-treated group. YST also decreased the lipid droplet size and lipid accumulation in the liver, as well as adipocyte size in epididymal adipose tissue. At the dose tested, YST was non-toxic to the liver and kidneys of the mice.. The results imply that YST has anti-obesity effects in obesity-induced mice. Although the number of experimental animals was limited and the drug effects concern mice, rather than humans, which have different constitutions, the study has valuable implications with respect to the general effects of YST. Topics: Animals; Anti-Obesity Agents; Body Weight; CCAAT-Enhancer-Binding Protein-beta; Cholesterol, HDL; Diet, High-Fat; Humans; Leptin; Male; Medicine, Korean Traditional; Mice; Mice, Inbred C57BL; Obesity; Plant Extracts; Plants, Medicinal; Sterol Regulatory Element Binding Protein 1 | 2019 |
Genomic and epigenomic mapping of leptin-responsive neuronal populations involved in body weight regulation.
Genome wide association studies (GWAS) in obesity have identified a large number of noncoding loci located near genes expressed in the central nervous system. However, due to the difficulties in isolating and characterizing specific neuronal subpopulations, few obesity-associated SNPs have been functionally characterized. Leptin responsive neurons in the hypothalamus are essential in controlling energy homeostasis and body weight. Here, we combine FACS-sorting of leptin-responsive hypothalamic neuron nuclei with genomic and epigenomic approaches (RNA-seq, ChIP-seq, ATAC-seq) to generate a comprehensive map of leptin-response specific regulatory elements, several of which overlap obesity-associated GWAS variants. We demonstrate the usefulness of our leptin-response neuron regulome, by functionally characterizing a novel enhancer near Socs3, a leptin response-associated transcription factor. We envision our data to serve as a useful resource and a blueprint for functionally characterizing obesity-associated SNPs in the hypothalamus. Topics: Animals; Body Weight; Epigenomics; Genome-Wide Association Study; Genomics; Humans; Hypothalamus; Leptin; Mice; Neurons; Obesity; Polymorphism, Single Nucleotide; Transcriptome | 2019 |
Effect of GLP-1 Receptor Agonists in the Cardiometabolic Complications in a Rat Model of Postmenopausal PCOS.
Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have an elevated prevalence of cardiometabolic risk factors that worsen after menopause. Liraglutide (Lira), a glucagon-like peptide-1 receptor agonist, has shown beneficial metabolic effects in small clinic trials in reproductive-age women with PCOS. We have shown that chronic hyperandrogenemia in an experimental model of postmenopausal PCOS is associated with an adverse cardiometabolic profile and upregulation of the intrarenal renin-angiotensin system (RAS). We analyzed the effect of Lira in the cardiometabolic profile, intrarenal RAS, and blood pressure (BP) in postmenopausal PCOS. Four-week-old female Sprague Dawley rats were treated with DHT or placebo for 17 months. Lira administration during the last 3 weeks caused a bigger reduction in food intake, body weight, fat mass, and homeostasis model assessment of insulin resistance index in PCOS than in control rats. Moreover, Lira improved dyslipidemia and elevated leptin levels in PCOS. In contrast, Lira decreased intrarenal expression of RAS components only in the control group. Lira transiently increased heart rate and decreased BP in control rats. However, Lira did not modify BP but increased heart rate in PCOS. The angiotensin-converting-enzyme inhibitor enalapril abolished the BP differences between PCOS and control rats. However, Lira coadministration with enalapril further reduced BP only in control rats. In summary, Lira has beneficial effects for several cardiometabolic risk factors in postmenopausal PCOS. However, hyperandrogenemia blunted the BP-lowering effect of Lira in postmenopausal PCOS. Androgen-induced activation of intrarenal RAS may play a major role mediating increases in BP in postmenopausal PCOS. Topics: Animals; Blood Pressure; Body Composition; Body Weight; Disease Models, Animal; Drug Evaluation, Preclinical; Eating; Female; Glucagon-Like Peptide-1 Receptor; Heart Rate; Hyperandrogenism; Insulin Resistance; Leptin; Lipids; Liraglutide; Metabolic Syndrome; Polycystic Ovary Syndrome; Postmenopause; Random Allocation; Rats, Sprague-Dawley; Renin-Angiotensin System | 2019 |
High Maternal and Low Cord Blood Leptin Are Associated with BMI-SDS Gain in the First Year of Life.
Early infant weight development influences metabolic regulation later in life. For the prevention of obesity and metabolic diseases, it is important to understand the underlying mechanisms in detail.. This study aims to examine the effects of maternal anthropometric, sociodemographic, and lifestyle factors on maternal and cord blood leptin levels at birth and on the development of body mass index (BMI) standard deviation scores (SDS) in offspring up to 1 year of age.. Seventy-six mother-child pairs were enrolled in this follow-up analysis in a cross-sectional design. Standardized questionnaires were used to collect information regarding maternal anthropometrics, lifestyle habits, and sociodemographic conditions, and newborn weight, or, rather, BMI-SDS, development during the first year of life.. Cord blood leptin (β = -0.222, p = 0.074), maternal leptin (β = 0.414, p = 0.001), and female sex of the offspring (β = 0.385, p = 0.003) explained 29.0% of the variance in BMI-SDS changes in the first year of life. Cord blood leptin was influenced by newborn sex (male; β = -0.220, p = 0.025) and maternal moderate-intensity physical activity in the third trimester (β = 0.265, p = 0.007, corr. R2 = 9.2%); maternal leptin was influenced by maternal prepregnancy BMI (β = 0.602, p < 0.001) and weight gain during pregnancy (β = 0.247, p = 0.004, corr. R2 = 35.5%).. Higher maternal and lower cord blood leptin levels are associated with a higher BMI-SDS increase during the first year of life. Maternal leptin is influenced by maternal BMI and weight gain during pregnancy, and cord blood leptin is influenced by maternal physical activity; therefore, it can be suggested that an active and healthy maternal lifestyle may play a pivotal and beneficial role in the offspring's weight development. Topics: Adult; Birth Weight; Blood Glucose; Body Mass Index; Body Weight; Child Development; Cross-Sectional Studies; Female; Fetal Blood; Follow-Up Studies; Humans; Infant; Infant, Newborn; Leptin; Life Style; Male; Mothers; Obesity; Pregnancy; Reference Standards; Research Design; Weight Gain | 2019 |
Altered metabolic gene expression in the brain of a triprolyl-human amylin transgenic mouse model of type 2 diabetes.
Type 2 diabetes mellitus is a major health concern worldwide; however, the molecular mechanism underlying its development is poorly understood. The hormone amylin is postulated to be involved, as human amylin forms amyloid in the pancreases of diabetic patients, and oligomers have been shown to be cytotoxic to β-cells. As rodent amylin is non-amyloidogenic, mice expressing human amylin have been developed to investigate this hypothesis. However, it is not possible to differentiate the effects of amylin overexpression from β-cell loss in these models. We have developed transgenic mice that overexpress [ Topics: Animals; Blood Glucose; Body Weight; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Humans; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Phenotype; Phosphorylation; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-fos; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein | 2019 |
Differences in neurocognitive performance and metabolic and inflammatory indices in male adults with obesity as a function of regular exercise.
What is the central question of this study? Does regular exercise have benefits with regard to the neurocognitive problems related to obesity and are regular-exercise-induced neurocognitive changes associated with changes in the levels of metabolic/inflammatory biomarkers? What is the main finding and its importance? Although obese individuals with regular exercise showed higher C-reactive protein levels as compared to the healthy-weight individuals, only the obese individuals with a sedentary lifestyle showed deviant neurocognitive performance and higher metabolic and tumour necrosis factor-α levels. The P3 amplitude was correlated with the levels of leptin in the obese individuals with regular activity, implicating that the potential mechanism of neurocognitive facilitation as a result of regular exercise could be reduced serum leptin levels.. Obesity has been shown to be highly associated with deterioration in executive functions, elevated energy metabolic indices and low-grade systemic inflammation. Exercise has the capacity to reduce these negative phenomena. This work examined the effect of regular exercise on neurocognitive deficits and metabolic/inflammatory markers in obesity. Fifty-four participants were divided into three groups: healthy-weight (HW), obesity with regular exercise (ORE) and obesity with sedentary lifestyle (OSL), according to their BMI and frequency of exercise. Dual-energy X-ray absorptiometry was applied to assess the whole-body composition of the participants. The assessment included neurocognitive measures during the Posner paradigm test and fasting blood measurements. Relative to the HW group, only the OSL group showed significantly longer reaction times and smaller P3 amplitudes, even when controlling for the cardiorespiratory fitness co-variable. Although the OSL group exhibited a greater N2 amplitude than the HW group, when controlling for cardiorespiratory fitness the difference between the two groups disappeared. The OSL group showed greater levels of metabolic indices (i.e. leptin, insulin and glucose) than the HW group. The three groups had comparable interleukin (IL)-1β and IL-6 levels. However, the ORE and OSL groups showed higher levels of C-reactive protein than the HW group. The OSL group exhibited higher tumour necrosis factor-α levels than the HW and ORE groups. P3 amplitude was negatively correlated with the levels of leptin in the ORE group. Individuals with obesity can still obtain advantages with regard to neurocognitive and metabolic/inflammatory indices through engaging in regular exercise, possibly due to reduced serum leptin levels. Topics: Absorptiometry, Photon; Adult; Body Composition; Body Mass Index; Body Weight; C-Reactive Protein; Cardiorespiratory Fitness; Exercise; Humans; Inflammation; Leptin; Male; Mental Status and Dementia Tests; Obesity; Sedentary Behavior; Tumor Necrosis Factor-alpha; Young Adult | 2019 |
Beyond the metabolic syndrome: Visceral and marrow adipose tissues impair bone quantity and quality in Cushing's disease.
The present study was designed to evaluate the relationship between bone traits [bone mineral density (BMD) and trabecular bone score (TBS)] and the accumulation of fat in adipose tissues [abdominal subcutaneous (SAT), visceral (VAT), marrow (MAT) and intrahepatic lipids (IHL)], as well as insulin resistance, in subjects with Cushing's disease (CD). The study included control (C = 27), paired (P = 16) and Cushing's disease (CD = 10) groups, which underwent biochemical assessment, dual X-ray absorptiometry, TBS, and magnetic resonance imaging to determine fat deposits. The CD group showed higher serum levels of glucose and insulin, as well as HOMA-IR values, but lower circulatory levels of osteocalcin, in comparison to C and P. The CD group exhibited lower L1-L4 BMD than P (P = 1.059 ± 0.141 vs CD = 0.935 ± 0.093 g/cm2, p < 0.05) (Fig 1A). The lumbar spine BMD from the C group was similar to the other groups. TBS was lower in CD than in P and C (C = 1.512±0.077 vs P = 1.405±0.150 vs CD = 1.135±0.136; p<0.05); there was also significant difference between C and P (p<0.05). MAT, VAT, and IHL were higher in CD than in C and P (p<0.05). Considering all subjects, there was a positive association between TBS with both lumbar spine BMD (R2 = 0.45; p<0.0001) and osteocalcin (R2 = 0.44; p = 0.05). TBS was negatively associated with MAT (R2 = 0.49; p = 0.01), VAT (R2 = 0.55; p<0.05), and HOMA-IR (R2 = 0.44; p<0.01). MAT was positively related with VAT (R2 = 0.44; p<0.01) and IHL (R2 = 0.41; p<0.05). In CD, insulin resistance and adipose tissue dysfunction, including high MAT, are active players in bone deterioration, as confirmed by lower lumbar spine BMD and lower TBS. Thus, our findings point to an additional component of the already well-known complex mechanisms of osteoporosis associated with hypercortisolism. Topics: Adiponectin; Adipose Tissue; Adult; Body Weight; Bone and Bones; Bone Density; Bone Marrow; Cancellous Bone; Humans; Insulin Resistance; Leptin; Linear Models; Lipids; Metabolic Syndrome; Pituitary ACTH Hypersecretion | 2019 |
Roles of leptin in the recovery of muscle and bone by reloading after mechanical unloading in high fat diet-fed obese mice.
Muscle and bone masses are elevated by the increased mechanical stress associated with body weight gain in obesity. However, the mechanisms by which obesity affects muscle and bone remain unclear. We herein investigated the roles of obesity and humoral factors from adipose tissue in the recovery phase after reloading from disuse-induced muscle wasting and bone loss using normal diet (ND)- or high fat diet (HFD)-fed mice with hindlimb unloading (HU) and subsequent reloading. Obesity did not affect decreases in trabecular bone mineral density (BMD), muscle mass in the lower leg, or grip strength in HU mice. Obesity significantly increased trabecular BMD, muscle mass in the lower leg, and grip strength in reloading mice over those in reloading mice fed ND. Among the humoral factors in epididymal and subcutaneous adipose tissue, leptin mRNA levels were significantly higher in reloading mice fed HFD than in mice fed ND. Moreover, circulating leptin levels were significantly higher in reloading mice fed HFD than in mice fed ND. Leptin mRNA levels in epididymal adipose tissue or serum leptin levels positively correlated with the increases in trabecular BMD, total muscle mass, and grip strength in reloading mice fed ND and HFD. The present study is the first to demonstrate that obesity enhances the recovery of bone and muscle masses as well as strength decreased by disuse after reloading in mice. Leptin may contribute to the recovery of muscle and bone enhanced by obesity in mice. Topics: Adipose Tissue, White; Animals; Biomechanical Phenomena; Body Weight; Bone and Bones; Bone Density; Cancellous Bone; Diet, High-Fat; Hand Strength; Leptin; Male; Mice; Mice, Inbred C57BL; Muscles; Obesity; Organ Size; Tibia; Weight-Bearing | 2019 |
Altered temporal sensitivity in obesity is linked to pro-inflammatory state.
Temporal sensitivity to multisensory stimuli has been shown to be reduced in obesity. We sought to investigate the possible role of the pro-inflammatory state on such alteration, considering the effect of the expression of markers, such as leptin and IL6, which are notably high in obesity. The performance of 15 male individuals affected by obesity and 15 normal-weight males was compared using two audiovisual temporal tasks, namely simultaneity judgment and temporal order judgment. Analyses of serum levels of inflammatory markers of leptin and IL6, and of neurotrophic factors of BDNF and S100SB were quantified. At the behavioral level we confirmed previous evidence showing poorer temporal sensitivity in obesity compared to normal-weight participants. Furthermore, leptin, that is a cytokine overexpressed in obesity, represented the best predictor of behavioral differences between groups in both tasks. The hypothesis we put forward is that the immune system, rather than overall cerebral dysfunction, might contribute to explain the altered temporal sensitivity in obesity. The present finding is discussed within the context of the role of cytokines on the brain mechanisms supporting temporal sensitivity. Topics: Adult; Body Weight; Brain-Derived Neurotrophic Factor; Case-Control Studies; Humans; Hydrocortisone; Inflammation; Interleukin-6; Leptin; Male; Obesity; S100 Calcium Binding Protein beta Subunit; Task Performance and Analysis | 2019 |
Orexin A-induced inhibition of leptin expression and secretion in adipocytes reducing plasma leptin levels and hypothalamic leptin resistance.
Orexin A (OXA) is a neuropeptide associated with plasma insulin and leptin levels involved in body weight and appetite regulation. However, little is known about the effect of OXA on leptin secretion in adipocytes and its physiological roles. Leptin secretion and expression were analysed in 3T3-L1 adipocytes. Plasma leptin, adiponectin and insulin levels were measured by ELISA assay. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) levels in the hypothalamus were evaluated by western blotting. OXA dose-dependently suppressed leptin secretion from 3T3-L1 adipocytes by inhibiting its gene expression while facilitating adiponectin secretion. The leptin inhibition by OXA was mediated via orexin receptors (OXR1 and OXR2). In addition to the pathway via extracellular signal-regulated kinases, OXA triggered adenylyl cyclase-induced cAMP elevation, which results in protein kinase A-mediated activation of cAMP response element-binding proteins (CREB). Accordingly, CREB inhibition restored the OXA-induced downregulation of leptin gene expression and secretion. Exogenous OXA for 4 weeks decreased fasting plasma leptin levels and increased hypothalamic pSTAT3 levels in high-fat diet-fed mice, regardless of increase in body weight and food intake. These results suggest that high dose of OXA directly inhibits leptin mRNA expression and thus secretion in adipocytes, which may be a peripheral mechanism of OXA for its role in appetite drive during fasting. It may be also critical for lowering basal plasma leptin levels and thus maintaining postprandial hypothalamic leptin sensitivity. Topics: 3T3-L1 Cells; Adipocytes; Animals; Appetite; Body Weight; Cell Line; Diet, High-Fat; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptides; Orexin Receptors; Orexins | 2019 |
Collaborative effects of chlorogenic acid and caffeine on lipid metabolism via the AMPKα-LXRα/SREBP-1c pathway in high-fat diet-induced obese mice.
To investigate the mechanism of the combined effects of chlorogenic acid (CGA) and caffeine on lipid metabolism in high-fat diet-induced obese mice, eighty female ICR mice were randomly divided into eight groups and fed with a high-fat diet with/without CGA and/or caffeine for 14 weeks. The combination of CGA and caffeine effectively decreased body weight gain, intraperitoneal adipose tissue weight, serum LDL-c, FFA, TC, TG, leptin, IL-6 concentrations, and hepatic TG and TC levels and increased the serum adiponectin level. The CGA and caffeine combination also promoted the phosphorylation of AMPKα, inhibited the expressions of transcriptional regulators (SREBP-1c and LXRα), and decreased the expressions of FAS and HMGR. Besides, the expressions of ACO, ATGL and HSL were increased by the CGA and caffeine combinations. The results indicated that the combination of CGA and caffeine had anti-obesity effects and regulated lipid metabolism in high-fat diet-induced obese mice via the AMPKα-LXRα/SREBP-1c signaling pathway. Thus, chronic CGA and caffeine intakes may be potent for preventing obesity. Topics: Adipose Tissue; AMP-Activated Protein Kinases; Animals; Body Weight; Caffeine; Chlorogenic Acid; Diet, High-Fat; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Energy Intake; Female; Gene Expression Regulation; Interleukin-6; Leptin; Lipids; Liver; Liver X Receptors; Mice; Mice, Inbred ICR; Obesity; Sterol Regulatory Element Binding Protein 1 | 2019 |
Cortisol, leptin and free leptin index (FLI) in newborns in the first days of life and their importance for body weight programming.
Birth weight and leptin seem to be the factors responsible for early programming of body weight in later life. A marker for leptin action is free leptin index (FLI), which depends on soluble leptin receptor (Ob-Re) (FLI = leptin/Ob-Re). In the present article, we suggest that FLI is modulated partly by cortisol variations observed in newborns in the first days of life and is connected with their postnatal weight loss.. The study group consisted of 44 full-term newborns. Leptin, cortisol and Ob-Re concentrations were determined in the umbilical cord blood (UCB) and in the newborns' blood (NB) on the fourth day of life, free leptin index (FLI = leptin/Ob-Re) was calculated. Correlations between the assessed parameters and the somatic features of the newborns were examined.. Birth weight, length and chest circumference of newborns were positively correlated with leptin concentration in the UCB but not with FLI in the UCB. Cortisol and leptin concentrations, as well as FLI values declined concomitantly with body weight, and were lower on the fourth day of life than on the first one; however, Ob-Re concentration increased (p < 0.0001). There was a positive correlation between the newborns' birth weight loss percentage evaluated on the fourth day of life and FLI in newborns (R = 0.39; p < 0.01). Positive correlations between cortisol and Ob-Re in UCB (R = 0.35; p < 0.02) and in NB (R = 0.36; p < 0.01), as well as a negative correlation between cortisol and FLI (R = -0.32; p < 0.03) in NB were noted.. Our data suggest a possible relationship between cortisol and a soluble leptin receptor (Ob-Re), which changes free leptin index (FLI) and is connected with birth weight loss in newborns. Whether these observations are important for programming of future body weight of children requires further research. Topics: Age Factors; Body Weight; Female; Fetal Blood; Humans; Infant, Newborn; Leptin; Male; Receptors, Leptin; Weight Loss | 2019 |
Leptin and Adiponectin Signaling Pathways Are Involved in the Antiobesity Effects of Peanut Skin Extract.
Excessive food intake and metabolic disorder promote obesity and diabetes. In China, peanut skin is used as a herbal medicine to treat hemophilia, thrombocytopenic purpura, and hepatic hemorrhage. In the present study, we demonstrated that peanut skin extract (PSE) safely reduced appetite, body weight, fat tissue, plasma TG and TC, and blood glucose level in mice with diet-induced obesity (DIO). Moreover, the leptin/leptin receptor/neuropeptide Y (NPY) and adiponectin signaling pathways involved in the antiobesity effects of PSE are confirmed through leptin and adiponectin overexpression and leptin receptor silencing in mice. PSE consisted of oligosaccharide and polyphenol in a mass ratio of 45 : 55, and both parts were important for the antiobesity function of PSE. Our results suggested that PSE can be developed as functional medical food to treat metabolic disorders and obesity. Topics: Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Arachis; Body Weight; China; Diet, High-Fat; Disease Models, Animal; Humans; Leptin; Mice; Mice, Inbred ICR; Neuropeptide Y; Obesity; Plant Extracts; Receptors, Leptin; Signal Transduction | 2019 |
Adipose PTEN regulates adult adipose tissue homeostasis and redistribution via a PTEN-leptin-sympathetic loop.
Despite the large body of work describing the tumor suppressor functions of Phosphatase and tensin homologue deleted on chromosome ten (PTEN), its roles in adipose homeostasis of adult animals are not yet fully understood. Here, we sought to determine the role of PTEN in whole-body adipose homeostasis.. We genetically manipulated PTEN in specific fat depots through recombinant adeno-associated viral vector (rAAV)-based gene transfer of Cre recombinase to adult PTEN. Knockdown PTEN in individual fat depot resulted in massive expansion of the affected fat depot through activation of AKT signaling associated with suppression of lipolysis and induction of leptin. This hypertrophic expansion of the affected fat depot led to upregulation of PTEN level, higher lipolysis, and induction of white fat browning in other fat depots, and the compensatory reduced fat mass to maintain a set point of whole-body adiposity. Administration of AKT inhibitor MK-2206 prevented the adipose PTEN knockdown-associated effects. 6OHDA-mediated denervation demonstrated that sympathetic innervation was required for the PTEN knockdown-induced adipose redistribution. Knockdown hypothalamic leptin receptor attenuated the adipose redistribution induced by PTEN deficiency in individual fat depot.. Our results demonstrate the essential role of PTEN in adipose homeostasis, including mass and distribution in adulthood, and reveal an "adipose PTEN-leptin-sympathetic nervous system" feedback loop to maintain a set point of adipose PTEN and whole-body adiposity. Topics: Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Adiposity; Animals; Body Weight; Energy Metabolism; Female; Heterocyclic Compounds, 3-Ring; Hypothalamus; Leptin; Lipolysis; Male; Mice; Mice, Inbred C57BL; Obesity; Proteostasis; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Receptors, Leptin; Signal Transduction; Sympathetic Nervous System | 2019 |
A Rat Model of Maternal Polycystic Ovary Syndrome Shows that Exposure to Androgens In Utero Results in Dysbiosis of the Intestinal Microbiota and Metabolic Disorders of the Newborn Rat.
BACKGROUND Intestinal dysbiosis, or dysbacteriosis, is an abnormal interaction between the intestinal microbiota and the host cells due to altered microbial diversity. This study aimed to investigate the metabolic effects and changes in the intestinal microbiota in newborn rats following exposure to increased levels of maternal androgens in a rat model of maternal polycystic ovary syndrome (PCOS). MATERIAL AND METHODS The administration of androgen developed the rat maternal PCOS model during pregnancy. Maternal rat ovarian follicles were counting and assessed by histology. The metabolic phenotype of newborn rats was evaluated and included an insulin tolerance test, a glucose tolerance test, and measurement of serum levels of triglyceride, insulin, cholesterol, adiponectin, and leptin. Expression of pro-inflammatory cytokines was detected using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), serum levels were measured by enzyme-linked immunosorbent assay (ELISA), and proteins associated with adipose tissue remodeling and adipocyte differentiation were measured by Western blot. RESULTS Markers of systemic inflammation were significantly increased in the female offspring but not in the male offspring born to rat in the PCOS model. Following birth, newborn rats that received antibiotics showed an improved metabolic phenotype, with reduced serum lipid levels, insulin resistance, body weight, inflammation of adipose tissue, and serum levels of inflammatory cytokines compared with controls. Probiotics had no significant effects on these parameters in newborn rats. CONCLUSIONS In a rat model of maternal PCOS, exposure to androgens in utero resulted in dysbiosis of the intestinal microbiota and metabolic disorders of the newborn female rats. Topics: Adipose Tissue; Androgens; Animals; Animals, Newborn; Body Weight; China; Disease Models, Animal; Dysbiosis; Female; Gastrointestinal Microbiome; Glucose; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Male; Metabolic Diseases; Obesity; Ovarian Follicle; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley | 2019 |
Weight estimation and hormone concentrations related to body condition in Icelandic and Warmblood horses: a field study.
The main objectives of this study were to evaluate the accuracy of different body weight formulas for estimating body weight of Icelandic and Warmblood horses, as well as to assess the associations between the variables cresty neck score, body condition score, and plasma concentrations of leptin, insulin and cortisol. A total of 81 adult (≥ 4 years of age) horses (43 Icelandic and 38 Warmblood horses) was included in this study. The following morphological measurements were collected by two examiners simultaneously; body weight; height at withers; neck length; 0.5 neck length; neck circumference; umbilical circumference, two different heart girths, as well as two different body length measurements. The horse's body weights were measured on a weight scale, and cresty neck scores were rated along with body condition scores using both the 0 to 5 and the 1 to 9 systems.. In general, the concordance correlation coefficient was high for most formulas, but the mean bias and slope bias deviations varied between formulas. Some simple formulas using only heart girth, or heart girth and length can be used to estimate body weight of Icelandic and Warmblood horses as good as more complex formulas using four morphometric measurements. Plasma concentrations of leptin and insulin were higher (P < 0.001) for the Icelandic than the Warmblood horses, probably reflecting higher body fat content as suggested by the differences in body condition score.. Body weight formulas only give an estimate of body weight and not a completely correct determination. Some simple and more complex formulas can be used for Icelandic horses even though they are not developed for this breed. Complex formulas using four morphometric measurements were accurate, but simple formulas using only heart girth, or heart girth and length can be used to estimate body weight and thereby be applied to weight tapes and used to estimate the body weight of both Icelandic and Warmblood horses. Topics: Animals; Body Composition; Body Weight; Denmark; Female; Horses; Hydrocortisone; Insulin; Leptin; Male; Physical Examination; Species Specificity | 2019 |
Xiaoyaosan decoction regulates food intake and body weight via the leptin-leptin receptor-proopiomelanocortin pathway in rats with chronic immobilization stress.
To evaluate the effects of the Xiaoyaosan (XYS) decoction on the food intake and body weight of rats with chronic immobilization stress (CIS), as well as the concentration of serum leptin and the expression of feeding-related neuropeptides [leptin receptor (Ob-R), proopiomelanocortin (POMC), and α-melanocyte-stimulating hormone (α-MSH)] in the hypothalamic arcuate nucleus (ARC).. We subjected rats to CIS for 3 h a day. The rats were randomly divided into the following groups: control group, 7-day stress group, 21-day stress group and XYS-treated group. The rats in the two stress groups were exposed to CIS for 7 or 21 d. The rats in the XYS-treated group were also exposed to CIS for 21 d and were intragastrically administered the XYS decoction before stress. The body weight and food intake of the rats were measured every day. The content of leptin in serum and α-MSH in the ARC were detected by ELISA, and the expression of neuropeptides in the ARC was assayed by immunofluorescence, Western blot and qRT-PCR.. The food intake and body weight of rats exposed to CIS were lower than those of control rats. The serum leptin, and expression levels of Ob-R, POMC and α-MSH in the ARC were significantly higher than those in the control rats. Treatment with the XYS decoction improved the appetite and the body weight, and down-regulated serum leptin and Ob-R, POMC and α-MSH in hypothalamus ARC.. The leptin-Ob-R-POMC pathway might be the part of the mechanism underlying XYS's improvement of somatic symptoms such as reduction in food intake and body weight related to CIS. Topics: Animals; Blotting, Western; Body Weight; Drugs, Chinese Herbal; Eating; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Leptin; Male; Pro-Opiomelanocortin; Rats; Receptors, Leptin; Restraint, Physical; Signal Transduction; Stress, Physiological | 2019 |
Inter-relationship of serum leptin levels with selected anthropometric parameters among a non-diabetic population: a cross-sectional study.
Association between serum leptin levels and anthropometric parameter is well established in western countries according to the specific WHO cut-off values assigned for those populations, whereas it is not clearly defined for Asians especially with respect to gender. Thus, the objectives of this study were to determine the relationship of serum leptin levels with body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR) to identify the variations of serum leptin levels with gender and to evaluate the serum leptin levels in risk and non-risk groups based on their anthropometric values.. A cross-sectional study was carried out among 226 apparently healthy subjects (non-diabetics, age 20-70 years). Height, weight, WC, hip circumference (HC) and mid arm circumference (MAC) were measured. BMI, WHR, waist to height ratio (WHtR) were calculated. Fasting blood samples were collected. Serum leptin levels were measured using human leptin ELISA kits.. Majority of the participants were females (59.3%). Serum leptin levels were significantly higher in females (24.8 ± 17.1 ng/mL) compared to males (9.3 ± 7.9 ng/mL). Significant positive correlations (P < 0.05) were observed between serum leptin levels and all anthropometric parameters except height in both genders. The risk groups according to BMI, WC and WHR in females were hyperleptinaemic and had significantly (P < 0.05) higher serum leptin levels than the non-risk groups.. Linear trend was observed for serum leptin levels with weight, BMI, WC, HC, WHR, MAC and WHtR in both genders. Though the serum leptin levels were higher among risk groups, according to WHR, WC and BMI, the hyperleptinaemia was observed only among females.. A descriptive cross-sectional study, Level V. Topics: Adult; Aged; Anthropometry; Body Mass Index; Body Weight; Cross-Sectional Studies; Female; Humans; Leptin; Male; Middle Aged; Risk Factors; Sex Characteristics; Waist Circumference; Waist-Hip Ratio; Young Adult | 2019 |
Inhibition of hormonal and behavioral effects of stress by tryptophan in rats.
Stress in known to alter hormonal systems. Pharmacological doses of tryptophan, the essential amino acid precursor of serotonin, increase circulating leptin and decrease ghrelin in normal healthy adults. Because systemically injected leptin inhibits stress-induced behavioral deficits and systemically injected serotonin modulates leptin release from the adipocytes, we used tryptophan as a pharmacological tool to modulate hormonal and behavioral responses in unstressed and stressed rats.. Leptin, ghrelin, serotonin, tryptophan, and behavior were studied in unstressed and stressed rats following oral administration of 0, 100, 200, and 300 mg/kg of tryptophan.. Following oral administration of tryptophan at a dose of 300 mg/kg, circulating levels of serotonin and leptin increased and those of ghrelin decreased in unstressed animals. No effect occurred on 24-hours cumulative food intake and elevated plus maze performance. Exposure to 2 hours immobilization stress decreased 24 hours cumulative food intake and impaired performance in elevated plus maze monitored next day. Serum serotonin decreased, leptin increased, and no effect occurred on ghrelin. Stress effects on serotonin, leptin, food intake, and elevated plus maze performance did not occur in tryptophan-pretreated animals. Tryptophan-induced decreases of ghrelin also did not occur in stressed animals.. The findings show an important role of serum serotonin, leptin, and ghrelin in responses to stress and suggest that the essential amino acid tryptophan can improve therapeutics in stress-induced hormonal and behavioral disorders. Topics: Animals; Behavior, Animal; Body Weight; Eating; Ghrelin; Leptin; Male; Rats, Wistar; Restraint, Physical; Serotonin; Stress, Psychological; Tryptophan | 2019 |
Postpartum maternal adipokines and infant weight for length at 1 year in women with gestational diabetes.
Maternal, cord blood and childhood adipokines have been associated with childhood obesity. We investigated whether postpartum maternal adipokines are associated with increased weight at 1 year of age in children of women with gestational diabetes (GDM).. Plasma leptin and adiponectin concentrations were measured in 160 women at approximately 12 weeks following pregnancy with GDM and compared with infant weight for length z-score at 1 year of age after adjustment for maternal and infant demographic variables.. No association was demonstrated between maternal postpartum leptin and adiponectin concentrations and infant weight for length z-score at 1 year of age. Topics: Adiponectin; Adult; Birth Weight; Body Weight; Diabetes, Gestational; Female; Humans; Infant; Infant, Newborn; Leptin; Pediatric Obesity; Postpartum Period; Pregnancy | 2019 |
Camellia oleifera seed extract attenuated abdominal and hepatic fat accumulation in rats fed a high-fat diet.
The objective of this study was to evaluate the effects of the hot-water extract of defatted Camellia oleifera seeds (CSE) on body and liver fat accumulation in rats. Forty rats were divided into 5 groups and each group was fed either an isocaloric control diet or a high-fat liquid diet with 0% (H), 0.12% (H1), 0.24% (H2), or 0.48% CSE (H3) for 8 weeks. Ingestion of the high-fat liquid diet increased abdominal and liver fat accumulation, although no difference was found in body weights compared with rats fed the control diet. We found that rats fed the H2 and H3 diets had lower plasma alanine aminotransferase activities than the H group in the fourth and eighth weeks. At the end of the study, the H2 and H3 groups also had lower epididymal and retroperitoneal fat masses, and all CSE groups had lower circulatory leptin levels than the H group. CSE consumption decreased hepatic fat accumulation in terms of liver triglycerides and a histopathology analysis, and ameliorated high-fat diet-induced elevation of hepatic tumor necrosis factor-α levels. We also found that CSE groups had lower malondialdehyde and hydroxyproline levels in the liver. Our results suggested that CSE may exert beneficial effects through decreasing body fat accumulation and hepatic steatosis and regulating adipokine levels in diet-induced nonalcoholic fatty liver disease. Topics: Alanine Transaminase; Animals; Body Weight; Camellia; Diet, High-Fat; Hydroxyproline; Intra-Abdominal Fat; Leptin; Liver; Malondialdehyde; Non-alcoholic Fatty Liver Disease; Plant Extracts; Rats; Rats, Wistar; Seeds; Taiwan; Triglycerides; Tumor Necrosis Factor-alpha | 2019 |
Do the adiponectin and leptin levels in preterm and term breast milk samples relate to infants' short-term growth?
Adiponectin and leptin are involved in appetite control and body weight regulation. We aimed to evaluate the relationship between breast milk adipokine levels and short-term growth of preterm and term infants. Thirty-one preterm (median=35.3 weeks) and 34 term (median=38.7 weeks) infants were enrolled. Enzyme-linked immunosorbent assay was used to detect adipokines in mature milk. Infant growth was followed during the first 3 months. Although weight gain in the first month was insufficient, positive linear growth was observed in the following months for preterm infants, while term infants had positive steady linear growth. The median level of adipokines was found to be higher in preterm infants (P>0.05). Adiponectin showed significant negative correlations with some anthropometric measurements of term infants. However, in preterm infants, adiponectin was negatively correlated with length increment and positively correlated with body mass index (BMI) increment in the second-third month. In addition, leptin was negatively associated with the head circumference at birth in preterm infants and the triceps skinfold thickness increment in the first-second month term infants (P<0.05). In linear regression models, while gestational age, adiponectin and leptin were not related, maternal age and pre-pregnancy BMI had effects on body weight increment in 0-1 months (P<0.05). In conclusion, adiponectin may affect short-term growth, while leptin has no important effect. It would be beneficial to carry out longitudinal studies to evaluate the effects of these adipokines on the growth of infants. Topics: Adiponectin; Adolescent; Adult; Body Mass Index; Body Weight; Breast Feeding; Female; Follow-Up Studies; Gestational Age; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Infant, Premature; Leptin; Linear Models; Maternal Age; Milk, Human; Models, Biological; Pregnancy; Weight Gain; Young Adult | 2019 |
Acute physical exercise increases leptin-induced hypothalamic extracellular signal-regulated kinase1/2 phosphorylation and thermogenesis of obese mice.
Topics: Adipose Tissue, Brown; Animals; Body Weight; Diet, High-Fat; Energy Metabolism; Hypothalamus; Injections, Intraperitoneal; Leptin; MAP Kinase Signaling System; Mice; Mice, Obese; Obesity; Oxygen Consumption; Phosphorylation; Physical Conditioning, Animal; Thermogenesis; Uncoupling Protein 1 | 2019 |
The effects of leptin on F-actin remodelling in type 1 diabetes.
The aim of the current study is to investigate the effect of leptin on cytoskeleton structures in both in vivo and in vitro model of diabetes.. For in vivo studies, leptin in different doses (240, and 480 mg/kg) was injected to the diabetic rats after 1-week of streptozotocin (STZ, 55 mg/kg) treatment. Leptin levels were analysed in serum, liver, and pancreas samples. Hepatic and pancreatic F- and G-actin expressions were determined by Western blotting. For in vitro studies, hepatic and pancreatic primary cell lines were obtained from the control rats. To these cultures, STZ (15 and 30 mM), leptin (50, 60 and 100 ng/mL), and their combinations were applied for 1, 3, and 4 weeks. After the treatment period, F-actin was visualised by the Alexa-fluor fluorescent dye.. Streptozotocin decreased the G-actin in both tissues in vivo. However, leptin caused a dose-dependent increase in G-actin levels while F-actin decreased in both tissues. Moreover, leptin caused the perimembranous condensation of actin filaments and amelioration of F-actin structures in vivo. A dose-dependent corruption of F-actin filament structures was observed in leptin-treated primary cells in vitro, while STZ also caused corruption of these filaments. Co-exposure of STZ and leptin caused the amelioration of F-actin filaments, while the peri- membranous condensation was also observed as was in vivo study.. Leptin therapy could be a candidate for diabetes, but it should not be ruled out as being important the severity of diabetes and leptin doses. Topics: Actins; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Leptin; Liver; Male; Pancreas; Rats, Wistar | 2019 |
Anti-obesity effects of Diospyros lotus leaf extract in mice with high-fat diet-induced obesity.
Diospyros (D.) lotus has been demonstrated to have antioxidant and anti‑inflammatory properties. The purpose of the present study was to evaluate the effect of D. lotus leaf water extract (DLE) on high‑fat diet (HFD)‑induced obesity in C57BL/6 mice. The present study first investigated the effect of DLE on the lipid accumulation and triglyceride (TG) contents in 3T3‑L1 cells, and the results revealed that treatment with DLE suppressed the lipid accumulation and TG level. Subsequently, the anti‑obesity effects of DLE were investigated in vivo. Oral administration of DLE reduced the body weight gain, food efficiency ratio, and liver and visceral fat weight in mice fed with a HFD. DLE administration in these mice also reduced TG, total cholesterol, low‑density lipoprotein cholesterol, glucose, insulin and leptin levels, as well as the atherogenic index. Furthermore, DLE administration decreased hepatic steatosis, as well as serum aspartate transaminase, alanine transaminase and alkaline phosphatase levels in mice fed with HFD. It was further observed that treatment of the HFD‑fed mice with DLE prevented lipid peroxidation, while it recovered glutathione depletion and the activities of superoxide dismutase, catalase and glutathione peroxidase. In conclusion, the current study suggests that the anti‑obesity effect of DLE may provide positive insights as a potential functional food ingredient for the prevention of obesity. Topics: 3T3-L1 Cells; Animals; Anti-Obesity Agents; Atherosclerosis; Blood Glucose; Body Weight; Diet, High-Fat; Diospyros; Feeding Behavior; Insulin; Intra-Abdominal Fat; Leptin; Lipid Metabolism; Lipid Peroxidation; Lipids; Liver; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Obesity; Oxidative Stress; Phytochemicals; Plant Extracts; Plant Leaves | 2019 |
Leptin trajectories from birth to mid-childhood and cardio-metabolic health in early adolescence.
Leptin is a hormone produced by adipose tissue that promotes satiety, and some evidence suggests that greater early life leptin exposure prevents excessive adiposity gain in later life. However, few studies have analyzed dynamic changes in leptin throughout childhood in relation to later cardio-metabolic health. Our study aims to identify distinct leptin trajectories in childhood, and to examine their associations with cardio-metabolic outcomes in adolescence.. Among children in the Project Viva cohort born 1999-2002 in Massachusetts, we used latent class growth models to identify leptin trajectories independent of maternal BMI, child sex, race/ethnicity, size at birth and current age and size among 1360 children with leptin measured at least once at birth, early childhood (mean 3.3 ± SD 0.3 years), or mid-childhood (7.9 ± 0.8 years). At research visits in early adolescence (13.2 ± 0.9 years), we assessed cardio-metabolic outcomes including adiposity measures, fasting biomarkers, and blood pressure among 855 children. We then applied multiple regression models to examine associations of the leptin trajectories with these cardio-metabolic outcomes in early adolescence, adjusting for child age at outcome, maternal age, education, prenatal smoking and glucose, total gestational weight gain and paternal BMI.. The latent class growth model identified 3 distinct leptin trajectories: "low stable" (n = 1031, 75.8%), "high-decreasing" (n = 219, 16.1%) and "intermediate-increasing" (n = 110, 8.1%). In adjusted models, the intermediate-increasing leptin trajectory was associated with higher early adolescence adiposity measures (e.g. BMI z-score: 0.62 units; 95% confidence interval: 0.28, 0.96 and odds of obesity: 2.84: 1.17, 6.94), but lower systolic blood pressure (-0.46 z-score units; -0.74, -0.18), compared to the low-stable group.. Our findings on leptin trajectories in childhood suggest important differences and associations with later metabolic outcomes. Topics: Adiposity; Adolescent; Biomarkers; Birth Weight; Blood Pressure; Body Mass Index; Body Weight; Child; Child, Preschool; Cohort Studies; Female; Health Status; Heart; Humans; Infant; Infant, Newborn; Leptin; Male; Massachusetts; Metabolism; Pediatric Obesity; Pregnancy; Prospective Studies | 2019 |
Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade.
The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity. Topics: Adult; Animals; Body Weight; Cell Line, Tumor; Cell Proliferation; Diet; Disease Progression; Female; Humans; Immunotherapy; Leptin; Male; Mice, Inbred C57BL; Mice, Obese; Middle Aged; Neoplasms; Obesity; Programmed Cell Death 1 Receptor; Signal Transduction; Species Specificity; T-Lymphocytes; Tumor Burden | 2019 |
CPT1C in the ventromedial nucleus of the hypothalamus is necessary for brown fat thermogenesis activation in obesity.
Carnitine palmitoyltransferase 1C (CPT1C) is implicated in central regulation of energy homeostasis. Our aim was to investigate whether CPT1C in the ventromedial nucleus of the hypothalamus (VMH) is involved in the activation of brown adipose tissue (BAT) thermogenesis in the early stages of diet-induced obesity.. CPT1C KO and wild type (WT) mice were exposed to short-term high-fat (HF) diet feeding or to intracerebroventricular leptin administration and BAT thermogenesis activation was evaluated. Body weight, adiposity, food intake, and leptinemia were also assayed.. Under 7 days of HF diet, WT mice showed a maximum activation peak of BAT thermogenesis that counteracted obesity development, whereas this activation was impaired in CPT1C KO mice. KO animals evidenced higher body weight, adiposity, hyperleptinemia, ER stress, and disrupted hypothalamic leptin signaling. Leptin-induced BAT thermogenesis was abolished in KO mice. These results indicate an earlier onset leptin resistance in CPT1C KO mice. Since AMPK in the VMH is crucial in the regulation of BAT thermogenesis, we analyzed if CPT1C was a downstream factor of this pathway. Genetic inactivation of AMPK within the VMH was unable to induce BAT thermogenesis and body weight loss in KO mice, indicating that CPT1C is likely downstream AMPK in the central mechanism modulating thermogenesis within the VMH. Quite opposite, the expression of CPT1C in the VMH restored the phenotype.. CPT1C is necessary for the activation of BAT thermogenesis driven by leptin, HF diet exposure, and AMPK inhibition within the VMH. This study underscores the importance of CPT1C in the activation of BAT thermogenesis to counteract diet-induced obesity. Topics: Adipose Tissue, Brown; Adiposity; Animals; Body Weight; Carnitine O-Palmitoyltransferase; Diet, High-Fat; Eating; Energy Metabolism; Homeostasis; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Thermogenesis; Ventromedial Hypothalamic Nucleus | 2019 |
Role of melanocortin 4 receptor in hypertension induced by chronic intermittent hypoxia.
We previously demonstrated that central nervous system (CNS) melanocortin 4 receptors (MC4R) play a key role in regulating blood pressure (BP) in some conditions associated with increased SNS activity, including obesity. In this study, we examined whether activation of CNS MC4R contributes to chronic intermittent hypoxia (CIH)-induced hypertension and ventilatory responses to hypercapnia.. Rats were instrumented with an intracerebroventricular (ICV) cannula in the lateral cerebral ventricle for continuous infusion of MC4R antagonist (SHU-9119) and telemetry probes for measuring mean arterial pressure (MAP) and heart rate (HR). Untreated and SHU-9119-treated rats as well as obese and lean MC4R-deficient rats were exposed to CIH for 7-18 consecutive days.. Chronic intermittent hypoxia reduced cumulative food intake by 18 ± 5 g while MAP and HR increased by 10 ± 3 mm Hg and 9 ± 5 bpm in untreated rats. SHU-9119 increased food intake (from 15 ± 1 to 46 ± 3 g) and prevented CIH-induced reduction in food intake. CIH-induced hypertension was not attenuated by MC4R antagonism (average increase of 10 ± 1 vs 9 ± 1 mm Hg for untreated and SHU-9119 treated rats). In obese MC4R-deficient rats, CIH for 7 days raised BP by 11 ± 4 mm Hg. However, when MC4R-deficient rats were food restricted to prevent obesity, CIH-induced hypertension was attenuated by 32%. We also found that MC4R deficiency was associated with impaired ventilatory responses to hypercapnia independently of obesity.. These results show that obesity and the CNS melanocortin system interact in complex ways to elevate BP during CIH and that MC4R may be important in the ventilatory responses to hypercapnia. Topics: Animals; Baroreflex; Blood Glucose; Blood Pressure; Body Weight; Eating; Heart Rate; Hematocrit; Hypercapnia; Hypoxia; Insulin; Leptin; Male; Obesity; Pulmonary Ventilation; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Melanocortin, Type 4; Sympathetic Nervous System | 2019 |
Dietary supplementation with L-lysine affects body weight and blood hematological and biochemical parameters in rats.
L-Lysine (Lys) is a popular additive in foods, but the physiological effects of excess Lys supplementation are poorly understood and upper limits of safe intake have not been established. The objectives of this study were to examine the effects of dietary supplementation with increasing amounts of Lys on body weight (BW), food intake, and various blood hematological and biochemical parameters in rats. Male Sprague-Dawley rats at 10 weeks of age were assigned to ten diet groups (eight rats/group) and fed diets containing either 7% or 20% casein and supplemented with either 0% (Control), 1.5%, 3%, 6% Lys, or 6% Lys + 3% arginine for 1 week. Rats fed 7% casein with ≥ 1.5% Lys supplementation had lower serum albumin and leptin and higher LDL cholesterol (LDLC), ratios of total cholesterol (TC):HDL cholesterol (HDLC) and LDLC:HDLC than those fed 7% casein Control diet (P < 0.05). Rats fed 7% casein diet supplemented with 3% Lys diet had lower BW gain, food intake, serum alkaline phosphatase activity, and increased mean corpuscular hemoglobin concentration, blood urea nitrogen and serum pancreatic polypeptide compared to rats fed the Control diet (P < 0.05). Addition of 6% Lys in 7% casein caused significant BW loss (P < 0.001) and altered additional parameters. Addition of 6% Lys in a 20% casein diet reduced BW gain and food intake and altered numerous parameters. Arg supplementation normalized many of the endpoints changed by Lys. Collectively, these results show that Lys supplementation affects BW, food intake and a number of hematological and biochemical parameters. These effects of Lys supplementation were confined primarily in diets with lower levels of dietary protein. In the context of a low protein diet (7% casein), levels of Lys supplementation ≥ 1.5% may exert adverse health effects in rats. Topics: Animal Feed; Animals; Body Composition; Body Weight; Caseins; Cholesterol, HDL; Cholesterol, LDL; Diet; Dietary Supplements; Eating; Leptin; Lysine; Male; Rats; Rats, Sprague-Dawley; Serum Albumin; Weight Gain | 2019 |
The effect of di-2-ethylhexyl phthalate on inflammation and lipid metabolic disorder in rats.
Plasticizer di-2-ethylhexyl phthalate (DEHP) can induce lipid metabolic disorder. There was a chronic low level inflammatory response in adipose tissue of patients with lipid metabolic disorder. But the effect of inflammation on lipid metabolic disorder induced by DEHP is unclear. The present study was undertaken to explore the effect of di-2-ethylhexyl phthalate on inflammation and lipid metabolic disorder in rats.. Eighty healthy 21-day-old Wistar rats were randomly divided into 4 groups and administered DEHP by gavage at 0, 5, 50, and 500 mg/kg/ d for 8 weeks. Morphological changes of adipose tissue, the levels of IL-1β, TNF-α, LEP, and ADP in rat serum and adipose tissue, the serum TC, TG, HDL-C and LDL-C, the mRNA and protein expression levels of lipid metabolism-related gene CEBP/β and inflammation-related gene CD68 were measured.. After exposure to DEHP, the weight of rats in the high dose group was significantly higher than that in the control group (p < 0.05). And the number of adipose tissue cells in the medium-dose and high-dose DEHP groups increased, with much more macrophage infiltrated. The levels of LDL-C, HDL-C, TC in serum and LEP in adipose tissue of rats exposed to 500 mg/kg DEHP were significantly higher than those in the control group (p < 0.05); while the level of ADP in adipose tissue in rats exposed to DEHP was significantly lower (p < 0.05). The levels of IL-1β and TNF-α in surum and adipose tissue of rats exposed to DEHP were significantly higher than those in the control group (p < 0.05). The mRNA and protein expression levels of CEBP/β and CD68 in adipose tissue of rats exposed to DEHP were significantly higher than those in the control group. The TC, LEP and ADP Levels of rats were significantly different among different subgroup of IL-1β and TNF-α, and in high level subgroup, the TC, LEP and ADP Levels were increased. The levels of TC and LEP was increased in high level subgroup of CD68.. DEHP induced more macrophage infiltrated in adipose tissue of rats, promoted the secretion of IL-1β, TNF-α and the formation of inflammation, and disturbed the normal lipid metabolism and lead to lipid metabolic disorders. What is more, the levels of inflammation were associated with the lipid levels. Topics: Adipocytes; Adiponectin; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Body Weight; CCAAT-Enhancer-Binding Protein-beta; Cholesterol; Diethylhexyl Phthalate; Disease Models, Animal; Female; Inflammation; Interleukin-1beta; Leptin; Lipid Metabolism; Male; Metabolic Diseases; Rats; Rats, Wistar; Triglycerides; Tumor Necrosis Factor-alpha | 2019 |
Anti-diabetic effect of S-adenosylmethionine and α-glycerophosphocholine in KK-A
Six-week-old male KK-A Topics: Administration, Oral; Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Disease Models, Animal; Drinking Water; Drug Combinations; Eating; Glycerylphosphorylcholine; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Hypoglycemic Agents; Leptin; Male; Mice; Mice, Transgenic; Obesity; S-Adenosylmethionine; Triglycerides | 2019 |
Protein tyrosine phosphatase alpha inhibits hypothalamic leptin receptor signaling and regulates body weight in vivo.
Understanding how body weight is regulated at the molecular level is essential for treating obesity. We show that female mice genetically lacking protein tyrosine phosphatase (PTP) receptor type α (PTPRA) exhibit reduced weight and adiposity and increased energy expenditure, and are more resistant to diet-induced obesity than matched wild-type control mice. These mice also exhibit reduced levels of circulating leptin and are leptin hypersensitive, suggesting that PTPRA inhibits leptin signaling in the hypothalamus. Male and female PTPRA-deficient mice fed a high-fat diet were leaner and displayed increased metabolic rates and lower circulating leptin levels, indicating that the effects of loss of PTPRA persist in the obese state. Molecularly, PTPRA down-regulates leptin receptor signaling by dephosphorylating the receptor-associated kinase JAK2, with which the phosphatase associates constitutively. In contrast to the closely related tyrosine phosphatase ε, leptin induces only weak phosphorylation of PTPRA at its C-terminal regulatory site Y789, and this does not affect the activity of PTPRA toward JAK2. PTPRA is therefore an inhibitor of hypothalamic leptin signaling in vivo and may prevent premature activation of leptin signaling, as well as return signaling to baseline after exposure to leptin.-Cohen-Sharir, Y., Kuperman, Y., Apelblat, D., den Hertog, J., Spiegel, I., Knobler, H., Elson, A. Protein tyrosine phosphatase alpha inhibits hypothalamic leptin receptor signaling and regulates body weight in vivo. Topics: Adiposity; Animals; Body Weight; Female; Hypothalamus; Janus Kinase 2; Leptin; Male; Mice, Knockout; Obesity; Phosphorylation; Physical Conditioning, Animal; Receptor-Like Protein Tyrosine Phosphatases, Class 4; Receptors, Leptin; Signal Transduction | 2019 |
Maternal High-Protein Diet during Pregnancy Modifies Rat Offspring Body Weight and Insulin Signalling but Not Macronutrient Preference in Adulthood.
Diet of mothers during gestation may impact offspring phenotype. This study evaluated the consequences of a maternal High-Protein (HP) diet during gestation on food preferences and phenotypic characteristics in adult rat offspring. Dams were fed a HP or a Normal-Protein (NP) isocaloric diet during gestation only. Weaned female pups were divided into 3 diet groups: NP control or one of two dietary self-selection (DSS) conditions. In DSS1, offspring had a free choice between proteins (100%) or a mix of carbohydrates (88%) and lipids (12%). In DSS2, the choice was between proteins (100%), carbohydrate (100%) or lipids (100%). DSS2 groups consumed more of their energy from protein and lipids, with a decreased carbohydrate intake ( Topics: Adiposity; Animals; Body Composition; Body Weight; Diet, High-Protein; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; Female; Food Preferences; Insulin; Leptin; Liver; Maternal Nutritional Physiological Phenomena; Nutrients; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Signal Transduction | 2019 |
Dietary Inflammatory Index Score and Its Association with Body Weight, Blood Pressure, Lipid Profile, and Leptin in Indonesian Adults.
It was previously reported that dietary intake is an important trigger for systemic inflammation and one of the lifestyle factors for the development of cardiovascular diseases. The aim of this study was to evaluate the association between Dietary Inflammatory Index (DII) score and body weight, blood pressure, lipid profile and leptin in an Indonesian population. This was a cross-sectional study conducted in 503 Indonesian adults. The DII score was calculated based on data of 30 nutrients and food components. Anthropometric profile, blood pressure, lipid profile, and leptin were measured. The association of these variables with the DII score was analyzed. The DII score was not associated with body weight, body mass index (BMI), body fat, waist circumference, hip circumference, systolic and diastolic blood pressure, triglycerides, and high-density lipoprotein (HDL) (both unadjusted and after adjustment for covariates). However, plasma leptin concentration was significantly associated with the DII score (B = 0.096, Topics: Adult; Biomarkers; Blood Pressure; Body Mass Index; Body Weight; Cholesterol; Cross-Sectional Studies; Diet; Exercise; Female; Humans; Indonesia; Inflammation; Leptin; Life Style; Male; Middle Aged; Triglycerides; Waist Circumference | 2019 |
Insulin modulates the strong reinforcing effects of nicotine and changes in insulin biomarkers in a rodent model of diabetes.
This study examined whether the strong reinforcing effects of nicotine and changes in insulin biomarkers observed in diabetic rats are modulated via insulin. A model of diabetes was employed involving administration of streptozotocin (STZ), which produces hypoinsulinemia in rats. The present study included vehicle- or STZ-treated rats that received sham surgery or insulin pellets. Two weeks later, the rats were given extended access to intravenous self-administration (IVSA) of saline or nicotine. Concomitant changes in food intake, water responses, and body weight were assessed during 12 days of IVSA. After the last session, plasma levels of insulin, leptin, amylin, and glucagon-like peptide-1 (GLP-1) were assessed using Luminex Topics: Animals; Behavior, Animal; Biomarkers; Body Weight; Diabetes Mellitus, Experimental; Drinking Behavior; Feeding Behavior; Glucagon-Like Peptide 1; Insulin; Insulin Receptor Substrate Proteins; Islet Amyloid Polypeptide; Leptin; Male; Nicotine; Nicotinic Agonists; Nucleus Accumbens; Rats; Rats, Wistar; Receptor, IGF Type 1; Reinforcement, Psychology; Self Administration; Ventral Tegmental Area; Water | 2019 |
Obesity programmed by prenatal dexamethasone and postnatal high-fat diet leads to distinct alterations in nutrition sensory signals and circadian-clock genes in visceral adipose tissue.
Prenatal dexamethasone treatment has been shown to enhance the susceptibility of offspring to postnatal high-fat (HF) diet-induced programmed obesity. We investigated the metabolic phenotypes, nutrient-sensing signal and circadian-clock genes in adipose tissue that are programmed by prenatal dexamethasone exposure and postnatal HF diet.. Male offspring of Sprague-Dawley rats were divided into four experimental groups: normal diet, prenatal dexamethasone exposure, postnatal HF diet, and prenatal dexamethasone plus postnatal HF diet. Postnatal HF diet was prescribed from weaning to 6 months of age.. Prenatal dexamethasone and postnatal HF diet exerted synergistic effects on body weight and visceral adiposity, whereas prenatal dexamethasone and postnatal HF diet altered the metabolic profile and caused leptin dysregulation. Prenatal dexamethasone and postnatal HF diet distinctly influenced nutrient-sensing molecules and circadian-clock genes in adipose tissue. The mRNA expression of mTOR, AMPK-α2, PPAR-α, and PPAR-γ was suppressed by prenatal dexamethasone but enhanced by postnatal HF diet.. Prenatal dexamethasone and postnatal HF treatment cause dysregulation of nutrient-sensing molecules and circadian-clock genes in visceral adipose tissue. Characterizing altered nutrient-sensing molecules and circadian-clock genes has potential therapeutic relevance with respect to the pathogenesis and treatment of prenatal stress and postnatal HF diet-related metabolic disorders. Topics: Animal Nutritional Physiological Phenomena; Animals; Biomarkers; Blood Glucose; Body Weight; Circadian Clocks; Dexamethasone; Diet, High-Fat; Female; Inflammation; Intra-Abdominal Fat; Leptin; Obesity; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Sprague-Dawley; Sirtuin 1 | 2019 |
In utero exposure to di(2-ethylhexyl)phthalate suppresses blood glucose and leptin levels in the offspring of wild-type mice.
Exposure of pregnant mice to di(2-ethylhexyl)phthalate (DEHP) induces maternal lipid malnutrition and decreases the number of live fetuses/pups. In this study, we aimed to clarify the relationship between maternal lipid malnutrition and the nutritional status of the neonatal, lactational, and adult offspring, as well as the role of peroxisome proliferator-activated receptor α (PPARα) in these relationships. Sv/129 wild-type (mPPARA), Ppara-null, and PPARα-humanized (hPPARA) mice were fed diets containing 0, 0.01, 0.05, or 0.1% DEHP in utero and/or during the lactational stage. The male offspring were killed on postnatal day 2 or 21, or after 11 weeks. Exposure to either 0.05% or 0.1% DEHP during both the in utero and lactational periods decreased serum glucose concentrations in 2-day-old mPPARA offspring. These dosages also decreased both serum and plasma leptin levels in both 2- and 21-day-old mPPARA offspring. In contrast, exposure to DEHP only during the lactational period did not decrease leptin levels, suggesting the importance of in utero exposure to DEHP. Exposure to 0.05% DEHP during the in utero and lactational periods also increased food consumption after weaning in both mPPARA and hPPARA mice; this was not observed in Ppara-null offspring. In conclusion, in utero exposure to DEHP induces neonatal serum glucose malnutrition via PPARα. DEHP also decreases serum and plasma leptin concentrations in offspring during the neonatal and weaning periods, in association with PPARα, which presumably results in increased of food consumption after weaning. Topics: Animals; Blood Glucose; Body Weight; Cytochrome P450 Family 4; Diethylhexyl Phthalate; Dose-Response Relationship, Drug; Female; Leptin; Male; Maternal Exposure; Mice; Mice, Knockout; Organ Size; PPAR alpha; Pregnancy; Prenatal Exposure Delayed Effects; RNA, Messenger | 2019 |
Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.
Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis. Topics: Adolescent; Adult; Animals; Body Weight; Cell Line; Child; Child, Preschool; Disease Models, Animal; Eating; Energy Metabolism; Female; Genetic Variation; Homeostasis; Humans; Hypothalamus; Leptin; Male; Melanocortins; Mice; Mice, Inbred C57BL; Middle Aged; Nerve Tissue Proteins; Neurons; Obesity; Receptors, Cell Surface; Semaphorins; Young Adult; Zebrafish | 2019 |
Effects of ipragliflozin on glycemic control, appetite and its related hormones: A prospective, multicenter, open-label study (SOAR-KOBE Study).
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve blood glucose control, as well as reducing bodyweight by promoting urinary glucose excretion. The weight loss is less than expected from urinary glucose loss, however, likely because of an increase in food intake. To investigate whether SGLT-2 inhibitors might increase appetite by affecting related hormones, we examined the effects of the SGLT-2 inhibitor, ipragliflozin, including those on appetite-regulating hormones, in individuals with suboptimally controlled type 2 diabetes.. Both glycated hemoglobin level (from 7.9 ± 0.8 to 7.1 ± 0.7%) and bodyweight (from 75.2 ± 12.6 to 72.6 ± 12.4 kg) were significantly decreased after treatment for 16 weeks. The fasting serum leptin level was significantly decreased after 2 weeks (from 19.5 ± 13.1 to 18.1 ± 12.4 ng/mL) and remained decreased up to 16 weeks, even after adjustment for bodyweight, whereas the plasma active ghrelin level showed no significant change. The visual analog scale score for hunger was significantly increased at 2 and 8 weeks.. The present results suggest that ipragliflozin improved glycemic control and reduced bodyweight, but also reduced serum leptin levels and might thereby have increased appetite. Topics: Appetite; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Eating; Female; Follow-Up Studies; Ghrelin; Glucosides; Glycated Hemoglobin; Glycemic Index; Humans; Leptin; Male; Middle Aged; Prognosis; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Weight Loss | 2019 |
Toward a treatment of diabesity: In vitro and in vivo evaluation of uncharged bromophenol derivatives as a new series of PTP1B inhibitors.
Protein tyrosine phosphatase 1B (PTP1B) has been considered as a validated biological target for type 2 diabetes treatment, but past endeavors to develop inhibitors of PTP1B into drugs have been unsuccessful. Two challenging aspects are selective inhibition and cell permeability. A structure-based strategy was employed to develop uncharged bromophenols as a new series of PTP1B inhibitors. The most potent compound 22 (LXQ46) inhibited PTP1B with an IC Topics: Animals; Body Weight; Cell Line; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Enzyme Inhibitors; Insulin; Insulin Resistance; Leptin; Mice; Molecular Docking Simulation; Obesity; Phenols; Phosphorylation; Protein Conformation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Proto-Oncogene Proteins c-akt; Safety; Signal Transduction | 2019 |
Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons.
Weight loss triggers important metabolic responses to conserve energy, especially via the fall in leptin levels. Consequently, weight loss becomes increasingly difficult with weight regain commonly occurring in most dieters. Here we show that central growth hormone (GH) signaling also promotes neuroendocrine adaptations during food deprivation. GH activates agouti-related protein (AgRP) neurons and GH receptor (GHR) ablation in AgRP cells mitigates highly characteristic hypothalamic and metabolic adaptations induced by weight loss. Thus, the capacity of mice carrying an AgRP-specific GHR ablation to save energy during food deprivation is impaired, leading to increased fat loss. Additionally, administration of a clinically available GHR antagonist (pegvisomant) attenuates the fall of whole-body energy expenditure of food-deprived mice, similarly as seen by leptin treatment. Our findings indicate GH as a starvation signal that alerts the brain about energy deficiency, triggering key adaptive responses to conserve limited fuel stores. Topics: Agouti-Related Protein; Animals; Body Weight; Brain; Energy Metabolism; Female; Growth Hormone; Human Growth Hormone; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Somatotropin; Weight Loss | 2019 |
Enhancement of immune maturation in suckling rats by leptin and adiponectin supplementation.
Leptin and adiponectin, adipokines present in breast milk, have shown immunomodulatory properties. The current study aimed to ascertain whether a nutritional supplementation with leptin or adiponectin in neonatal rats was able to influence the maturation of the systemic immune response in early life. To achieve this, suckling Wistar rats were supplemented with either leptin (0.7 μg/kg/day) or adiponectin (35 μg/kg/day) during the whole suckling period. Plasmatic immunoglobulins were quantified, and spleen lymphocyte composition and their ability to proliferate and release cytokines were evaluated during (day 14) and at the end (day 21) of the suckling period. Rats fed with either adipokine showed higher plasma IgM and IgG1 concentrations and adiponectin supplementation also increased IgG2a at both studied days (P < 0.05). With regard to the lymphocyte composition, both adipokine supplementations increased T cell proportion and both CD4 Topics: Adiponectin; Animals; Animals, Suckling; Body Weight; Cytokines; Dietary Supplements; Immunoglobulins; Leptin; Organ Size; Rats; Rats, Wistar; Spleen; T-Lymphocyte Subsets; Thymus Gland | 2019 |
Metabolic Abnormalities of Chronic High-Dose Glucocorticoids Are Not Mediated by Hypothalamic AgRP in Male Mice.
Glucocorticoids are potent and widely used medicines but often cause metabolic side effects. A murine model of corticosterone treatment resulted in increased hypothalamic expression of the melanocortin antagonist AgRP in parallel with obesity and hyperglycemia. We investigated how these adverse effects develop over time, with particular emphasis on hypothalamic involvement. Wild-type and Agrp-/- male mice were treated with corticosterone for 3 weeks. Phenotypic, biochemical, protein, and mRNA analyses were undertaken on central and peripheral tissues, including white and brown adipose tissue, liver, and muscle, to determine the metabolic consequences. Corticosterone treatment induced hyperphagia within 1 day in wild-type mice, which persisted for 3 weeks. Despite this early increase in food intake, the body weight only started to increase after 10 days. Hyperinsulinemia occurred at day 1. Also, although after 2 days, alterations were present in the genes often associated with insulin resistance in several peripheral tissues, hyperglycemia only developed at 3 weeks. Throughout, sustained elevation in hypothalamic Agrp expression was present. Mice with Agrp deleted [using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, Agrp-/-] were partially protected against corticosterone-induced hyperphagia. However, Agrp-/- mice still had corticosterone-induced increases in body weight and adiposity similar to those of the Agrp+/+ mice. Loss of Agrp did not diminish corticosterone-induced hyperinsulinemia or correct changes in hepatic gluconeogenic genes. Chronic glucocorticoid treatment in mice mimics many of the metabolic side effects seen in patients and leads to a robust increase in Agrp. However, AgRP does not appear to be responsible for most of the glucocorticoid-induced adverse metabolic effects. Topics: Adipose Tissue; Agouti-Related Protein; Animals; Body Weight; Corticosterone; Eating; Gene Expression Regulation; Glucocorticoids; Hypothalamus; Leptin; Male; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Mice, Transgenic; Obesity | 2019 |
The effect of therapy on plasma ghrelin and leptin levels, and appetite in children with iron deficiency anemia.
Background It is known that iron deficiency anemia effects appetite and growth negatively. The aim of this study was to investigate the effect of iron therapy on appetite, growth and plasma ghrelin and leptin levels in children aged between 12 and 24 months with isolated nutritional iron deficiency anemia. Methods Iron deficiency anemia was diagnosed by clinic and laboratory findings. All 19 cases were given 5 mg/kg/day iron therapy for 3 months. Results The mean plasma ghrelin level was 936.7±428.8 pg/mL before therapy and it increased to 1284.7±533.3 pg/mL (p<0.001) while the mean plasma leptin level decreased from 3.4±1.6 ng/mL to 1.9±1.0 ng/mL (p<0.01) after therapy. The amount of daily caloric intake, carbohydrate and protein intake were significantly increased after therapy (p<0.001). Δ body weight was correlated with plasma ghrelin levels before and after therapy significantly. Conclusions In conclusion, the findings of this study indicate that plasma ghrelin level increases and leptin level decreases and growth accelerates because of an increase in appetite and daily calories, carbohydrate and protein amount in children with nutritional iron deficiency anemia after iron therapy. The increase in appetite and acceleration on growth in iron deficiency anemia might result from decreased leptin and increased plasma ghrelin levels. The most important finding of this study is significantly increased plasma ghrelin levels after iron therapy, and this finding might be related to both the improved appetite and catch-up growth. Topics: Anemia, Iron-Deficiency; Appetite; Body Weight; Female; Ghrelin; Humans; Infant; Iron; Leptin; Male; Treatment Outcome | 2019 |
Leptin Receptor Signaling in Sim1-Expressing Neurons Regulates Body Temperature and Adaptive Thermogenesis.
Leptin signals to regulate food intake and energy expenditure under conditions of normative energy homeostasis. The central expression and function of leptin receptor B (LepRb) have been extensively studied during the past two decades; however, the mechanisms by which LepRb signaling dysregulation contributes to the pathophysiology of obesity remains unclear. The paraventricular nucleus of the hypothalamus (PVN) plays a crucial role in regulating energy balance as well as the neuroendocrine axes. The role of LepRb expression in the PVN in regard to the regulation of physiological function of leptin has been controversial. The single-minded homolog 1 gene (Sim1) is densely expressed in the PVN and in parts of the amygdala, making Sim1-Cre mice a useful model for examining molecular mechanisms regulating PVN function. In this study, we characterized the physiological role of LepRb in Sim1-expressing neurons using LepRb-floxed × Sim1-Cre mice. Sim1-specific LepRb-deficient mice were surprisingly hypophagic on regular chow but gained more weight upon exposure to a high-fat diet than did their control littermates. We show that Sim1-specific deletion of a single LepRb gene copy caused decreased surface and core body temperatures as well as decreased energy expenditure in ambient room temperatures in both female and male mice. Furthermore, cold-induced adaptive (nonshivering) thermogenesis is disrupted in homozygous knockout mice. A defective thermoregulatory response was associated with defective cold-induced upregulation of uncoupling protein 1 in brown adipose tissue and reduced serum T4. Our study provides novel functional evidence supporting LepRb signaling in Sim1 neurons in the regulation of body weight, core body temperature, and cold-induced adaptive thermogenesis. Topics: Adipose Tissue, Brown; Animals; Basic Helix-Loop-Helix Transcription Factors; Body Temperature; Body Weight; Calorimetry, Indirect; Energy Metabolism; Hypothalamus; Leptin; Mice; Mice, Knockout; Mice, Transgenic; Motor Activity; Neurons; Receptors, Leptin; Repressor Proteins; Signal Transduction; Thermogenesis; Uncoupling Protein 1 | 2019 |
Pegylated Human Leptin D23L Mutant-Preparation and Biological Activity In Vitro and In Vivo in Male ob/ob Mice.
Recombinant monomeric human leptin (hLEP) and its D23L mutant were prepared in Escherichia coli and pegylated at their N-terminus using 20-kDa methoxy pegylated (PEG)-propionylaldehyde. As determined by both SDS-PAGE and size-exclusion chromatography, the pegylated proteins consisted of >90% monopegylated and <10% double-pegylated species. Circular dichroism spectra showed that their secondary structure, characteristic of all four α-helix bundle cytokines, was not affected by either the D23L mutation or pegylation. Because of the D23L mutation, affinity for hLEP receptor increased 25- and 40-fold for the pegylated and nonpegylated mutant, respectively. However, whereas the proliferation-promoting activity in vitro of nonmutated and mutated nonpegylated hLEP was identical, that of the respective pegylated mutant was approximately sixfold higher compared with the pegylated nonmutated hLEP. This difference was also seen in vivo. Both pegylated hLEPs at all doses significantly decreased body weight and food consumption, as compared with the vehicle-treated control. Once-daily administration of pegylated hLEP D23L at doses of 0.1, 0.3, and 1 mg/kg for 14 consecutive days in ob/ob mice resulted in significantly decreased body weight and food consumption as compared with respective pegylated hLEP-treated animals, with the biggest difference observed at 0.1 mg/kg. Repeated administration of either pegylated hLEP D23L or pegylated hLEP significantly decreased blood glucose levels compared with the control before glucose challenge and after oral glucose tolerance test, but with no difference between the two treatments. The pegylated hLEP D23L mutant seems to be a more potent reagent suitable for in vivo studies than the pegylated nonmutated hLEP. Topics: Animals; Blood Glucose; Body Weight; Eating; Glucose Tolerance Test; Leptin; Male; Mice; Mice, Obese; Mutation; Polyethylene Glycols; Receptors, Leptin | 2019 |
Maternal feeding associated to post-weaning diet affects metabolic and behavioral parameters in female offspring.
Genetic and environmental factors related to maternal diet may predispose offspring to serious diseases. However, consequences of a maternal diet intervention during gestation and lactation, and its association with caloric restriction after weaning on the progeny are not completely known. In this context, the goal of the present study was to investigate how different maternal diets, control (CONT), hypercaloric (HD) or restrictive (RD) diets during gestation and lactation, may affect the metabolism and behavior of the offspring that was also submitted to RD. Experimental groups were abbreviated accordingly maternal/offspring diets: CONT/CONT, CONT/RD, RD/CONT, RD/RD, HD/CONT, HD/RD. Our results showed that glucose serum concentration is increased in mice from dams fed a HD. However, offspring from RD-fed dams showed lower insulin and leptin levels than the other groups, indicating a maternal diet effect. Moreover, animals from RD/CONT group showed a higher adipocyte area in comparison to both HD/CONT and CON/CONT. Offspring from RD-fed dams exhibited a decrease in lateral area locomotion in the open field test. Evaluation of anxiety-like behavior and recognition memory showed no significant difference among groups. Thus, maternal RD provides a beneficial response in metabolic parameters, but its effects on behavior is not completely clarified. Topics: Adipocytes; Animals; Behavior, Animal; Body Weight; Caloric Restriction; Diet, High-Fat; Female; Insulin; Lactation; Leptin; Maternal Nutritional Physiological Phenomena; Mice; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Weaning | 2019 |
The leptin sensitizer celastrol reduces age-associated obesity and modulates behavioral rhythms.
The prevalence of obesity increases with age in humans and in rodents. Age-related obesity is characterized by leptin resistance and associated with heightened risk of metabolic disorders. However, the effect of leptin resistance per se has been difficult to disentangle from other effects of aging. Here we demonstrate that celastrol, a natural phytochemical that was previously shown to act as a leptin sensitizer, induces weight loss in aged animals, but not in young controls. Celastrol reduces food intake and lowers fasting glucose without affecting energy expenditure. Unexpectedly, administration of celastrol just before the dark period disrupted circadian rhythms of sleep and activity. This regimen was also associated with loss of lean mass an outcome that would not be desirable in elderly patients. Adjusting the timing of celastrol administration by 12 hr, to the beginning of the light period, avoided interference with circadian rhythms while retaining the reductions in body weight and adiposity. Thus, targeting leptin signaling is an effective strategy to ameliorate age-associated weight gain, and can profoundly impact circadian rhythms. Topics: Aging; Animals; Behavior, Animal; Body Weight; Circadian Rhythm; Eating; Energy Metabolism; Glucose Tolerance Test; Injections, Intraperitoneal; Leptin; Male; Mice; Obesity; Pentacyclic Triterpenes; Triterpenes; Weight Loss | 2019 |
Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity.
Quantitative changes in leptin concentration lead to alterations in food intake and body weight, but the regulatory mechanisms that control leptin gene expression are poorly understood. Here we report that fat-specific and quantitative leptin expression is controlled by redundant cis elements and trans factors interacting with the proximal promoter together with a long noncoding RNA (lncOb). Diet-induced obese mice lacking lncOb show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment, whereas control mice do not. Consistent with this finding, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms (SNPs) in the region of human lncOb with lower plasma leptin levels and obesity. These results show that reduced leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity and provide a framework for elucidating the pathogenic mechanism in the subset of obese patients with low endogenous leptin levels. Topics: Animals; Body Weight; Diet, High-Fat; Eating; Enhancer Elements, Genetic; Female; Gene Expression Regulation; Humans; Leptin; Male; Mice; Mice, Knockout; Mice, Transgenic; Obesity; Polymorphism, Single Nucleotide; RNA, Long Noncoding | 2019 |
Maternal resistin predisposes offspring to hypothalamic inflammation and body weight gain.
Resistin promotes hypothalamic neuroinflammation and insulin resistance through Toll like receptor 4 (TLR4), this hormone is thought to be a link between obesity and insulin-resistance. Indeed, resistin plasma levels are higher in obese and insulin resistant subjects. However, the impact of maternal resistin on the predisposition of offspring to hypothalamic neuroinflammation is unknown. Here, female mice were treated with resistin during gestation/lactation periods, then hypothalamic neuroinflammation was investigated in male offspring at p28 and p90. At p28, resistin increased the expression of inflammation markers (IL6, TNFα and NFκB) and TLR4 in the hypothalamus and decreased both hypothalamic insulin and leptin receptors' expression. The hypothalamic up-regulation IL6, TNFα and TLR4 was sustained until p90 promoting most likely hypothalamic inflammation. Maternal resistin also increased IL6 and TNFα in the adipose tissue of offspring at p90 associated with a higher body weight gain. In contrast, liver and muscle were not affected. These findings reveal that the augmentation of maternal resistin during gestation and lactation promotes hypothalamic and adipose tissue inflammation of offspring as evidenced by sustained increase of inflammation markers from weaning to adulthood. Thus, maternal resistin programs offspring hypothalamic and adipose tissue inflammation predisposing then offspring to body weight gain. Topics: Animals; Animals, Newborn; Body Weight; Female; Glucose Intolerance; Hypothalamus; Inflammation; Inflammation Mediators; Insulin Resistance; Insulinoma; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Mice; Pregnancy; Resistin; Weaning; Weight Gain | 2019 |
Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism.
Chronic low-grade inflammation and increased serum levels of the cytokine IL-6 accompany obesity. For brain-produced IL-6, the mechanisms by which it controls energy balance and its role in obesity remain unclear. Here, we show that brain-produced IL-6 is decreased in obese mice and rats in a neuroanatomically and sex-specific manner. Reduced IL-6 mRNA localized to lateral parabrachial nucleus (lPBN) astrocytes, microglia, and neurons, including paraventricular hypothalamus-innervating lPBN neurons. IL-6 microinjection into lPBN reduced food intake and increased brown adipose tissue (BAT) thermogenesis in male lean and obese rats by increasing thyroid and sympathetic outflow to BAT. Parabrachial IL-6 interacted with leptin to reduce feeding. siRNA-mediated reduction of lPBN IL-6 leads to increased weight gain and adiposity, reduced BAT thermogenesis, and increased food intake. Ambient cold exposure partly normalizes the obesity-induced suppression of lPBN IL-6. These results indicate that lPBN-produced IL-6 regulates feeding and metabolism and pinpoints (patho)physiological contexts interacting with lPBN IL-6. Topics: Adipose Tissue, Brown; Animals; Astrocytes; Body Weight; Eating; Energy Metabolism; Female; Interleukin-6; Leptin; Male; Mice; Mice, Inbred C57BL; Neurons; Parabrachial Nucleus; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System; Thermogenesis; Thyroid Hormones | 2019 |
The evidence of metabolic-improving effect of metformin in Ay/a mice with genetically-induced melanocortin obesity and the contribution of hypothalamic mechanisms to this effect.
In diet-induced obesity, metformin (MF) has weight-lowering effect and improves glucose homeostasis and insulin sensitivity. However, there is no information on the efficiency of MF and the mechanisms of its action in melanocortin-type obesity. We studied the effect of the 10-day treatment with MF at the doses of 200, 400 and 600 mg/kg/day on the food intake and the metabolic and hormonal parameters in female C57Bl/6J (genotype Ay/a) agouti-mice with melanocortin-type obesity, and the influence of MF on the hypothalamic signaling in obese animals at the most effective metabolic dose (600 mg/kg/day). MF treatment led to a decrease in food intake, the body and fat weights, the plasma levels of glucose, insulin and leptin, all increased in agouti-mice, to an improvement of the lipid profile and glucose sensitivity, and to a reduced fatty liver degeneration. In the hypothalamus of obese agouti-mice, the leptin and insulin content was reduced and the expression of the genes encoding leptin receptor (LepR), MC3- and MC4-melanocortin receptors and pro-opiomelanocortin (POMC), the precursor of anorexigenic melanocortin peptides, was increased. The activities of AMP-activated kinase (AMPK) and the transcriptional factor STAT3 were increased, while Akt-kinase activity did not change from control C57Bl/6J (a/a) mice. In the hypothalamus of MF-treated agouti-mice (10 days, 600 mg/kg/day), the leptin and insulin content was restored, Akt-kinase activity was increased, and the activities of AMPK and STAT3 were reduced and did not differ from control mice. In the hypothalamus of MF-treated agouti-mice, the Pomc gene expression was six times higher than in control, while the gene expression for orexigenic neuropeptide Y was decreased by 39%. Thus, we first showed that MF treatment leads to an improvement of metabolic parameters and a decrease of hyperleptinemia and hyperinsulinaemia in genetically-induced melanocortin obesity, and the specific changes in the hypothalamic signaling makes a significant contribution to this effect of MF. Topics: Agouti-Related Protein; Animals; Body Weight; Female; Gene Expression Regulation; Hypoglycemic Agents; Hypothalamus; Leptin; Melanocortins; Metformin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Receptors, Leptin | 2019 |
Resveratrol, lunularin and dihydroresveratrol do not act as caloric restriction mimetics when administered intraperitoneally in mice.
Resveratrol as well as caloric restriction were shown to extend lifespan in some model organisms and may possibly delay onset of ageing-related diseases in humans. Yet, resveratrol supplementation does not always extend lifespan of animal models or improve health status of humans. Because of interindividual differences in human microbiota, resveratrol metabolite production in the gut differs. While some individuals produce lunularin and dihydroresveratrol in their gut, others produce dihydroresveratrol only. Therefore, we addressed the question whether these metabolites differ in their biological impact on ageing and intraperitoneally injected 13-month-old C57BL/6JRj mice on an ad-libitum (AL) HFD with resveratrol, dihydroresveratrol or lunularin (24 mg/kg bodyweight; 3 times/week). Compared to mice injected with vehicle (AL-control), resveratrol and dihydroresveratrol did not change bodyweight and had no impact on insulin or glucose levels while lunularin slightly reduced feed intake and bodyweight gain. CR-mice showed lowered cholesterol, insulin and leptin levels, elevated adiponectin and phosphorylated AMPK levels in liver as well as increased transcription of Pck1 and Pgc1α when compared to the AL-control. In contrast, injections with the test substances did not change these parameters. We therefore conclude that in our model, resveratrol, lunularin and dihydroresveratrol did not act as CR mimetics. Topics: Animals; Bibenzyls; Blood Glucose; Body Weight; Caloric Restriction; Diet, High-Fat; Eating; Gene Expression Regulation; Heme Oxygenase-1; Injections, Intraperitoneal; Insulin; Leptin; Liver; Membrane Proteins; Mice, Inbred C57BL; Phenols; Resveratrol; Sirtuin 1; Stilbenes | 2019 |
Absence of the proteoglycan decorin reduces glucose tolerance in overfed male mice.
Studies have implicated the extracellular matrix (ECM) of adipose tissue in insulin resistance. The proteoglycan decorin, a component of ECM, has been associated with glucose tolerance, but possible causal effects on metabolism remain to be explored. We here sought to determine metabolic consequences of loss of decorin in mice (DcnKO). DcnKO mice were fed a low-fat (LF) or high-fat (HF) diet for 10 weeks and body weight and food intake was recorded. An intraperitoneal glucose tolerance test was performed after eight weeks. Blood samples and adipose, liver and muscle tissues were collected at sacrifice. Global gene expression was measured in adipose tissue, and expression of decorin was also analyzed in human adipose samples. DcnKO mice showed increased feed efficiency during overfeeding and impaired glucose tolerance. Adipose leptin mRNA and circulating leptin levels were elevated in DcnKO mice, along with a downregulation of genes involved in ECM organization and triglyceride biosynthesis, and an upregulation of adipose genes involved in complement and coagulation cascades. Consistent with a protective metabolic role for decorin, in obese patients we found increased adipose decorin expression after profound fat loss, particularly in the stromal vascular fraction. Loss of decorin in mice caused impaired glucose tolerance in association with increased feed efficiency and altered gene expression in adipose tissue. Our data provide evidence that decorin is an important factor for maintaining glucose tolerance. Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Decorin; Diet, High-Fat; Glucose; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Overnutrition; Proteoglycans | 2019 |
Kisspeptin and RFRP3 modulate body mass in Phodopus sungorus via two different neuroendocrine pathways.
Many animals exhibit remarkable metabolic and reproductive adaptations to seasonal changes in their environment. When day length shortens, Djungarian hamsters (Phodopus sungorus) reduce their body weight and inhibit their reproductive activity, whereas the opposite occurs in springtime. These physiological adaptations are considered to depend on photoperiodic changes in hypothalamic genes encoding the peptides kisspeptin (Kp) and RFamide-related peptide 3 (RFRP3) for the control of reproduction, as well as pro-opiomelanocortin and somatostatin for metabolic regulation. The present study investigates the effect of Kp and RFRP3 on long-term body weight regulation, aiming to establish whether metabolic and reproductive hypothalamic networks may interact during adaptation to seasonal physiology. We found that chronic central administration of both Kp and RFRP3 in short photoperiod-adapted male Djungarian hamsters increased body weight, although via different pathways. The effect of Kp was dependent on testicular activity because castration prevented the body weight increase and was associated with an increase in pro-opiomelanocortin and neuropeptide Y expression. On the other hand, the orexigenic effect of RFRP3 was associated with an increase in circulating insulin and leptin levels, although it had no effect on any of the hypothalamic metabolic genes investigated, and did not change circulating levels of sex steroids. Notably, neither Kp, nor RFRP3 altered female hamster metabolic parameters. Thus, using a rodent model exhibiting seasonal changes in reproduction and metabolism, the present study demonstrates that, in addition to its role in the central control of reproduction, Kp also participates in body weight control in a sex-dependent manner via an anabolic action of testosterone. Conversely, RFRP3 affects body weight control in males mostly by acting on adiposity, with no overt effect on the reproductive system in both sexes. Topics: Animals; Body Weight; Eating; Female; Gene Expression; Insulin; Kisspeptins; Leptin; Male; Neuropeptide Y; Neuropeptides; Neurosecretory Systems; Phodopus; Photoperiod; Pro-Opiomelanocortin; Reproduction; Seasons; Sex Factors; Testis | 2019 |
Interactions Between the Gravitostat and the Fibroblast Growth Factor System for the Regulation of Body Weight.
Both fibroblast growth factors (FGFs), by binding to FGF receptors (FGFRs), and activation of the gravitostat, by artificial loading, decrease the body weight (BW). Previous studies demonstrate that both the FGF system and loading have the capacity to regulate BW independently of leptin. The aim of the current study was to determine the possible interactions between the effect of increased loading and the FGF system for the regulation of BW. We observed that the BW-reducing effect of increased loading was abolished in mice treated with a monoclonal antibody directed against FGFR1c, suggesting interactions between the two systems. As serum levels of endocrine FGF21 and hepatic FGF21 mRNA were increased in the loaded mice compared with the control mice, we first evaluated the loading response in FGF21 over expressing mice with constant high FGF21 levels. Leptin treatment, but not increased loading, decreased the BW in the FGF21-overexpressing mice, demonstrating that specifically the loading effect is attenuated in the presence of high activity in the FGF system. However, as FGF21 knockout mice displayed a normal loading response on BW, FGF21 is neither mediating nor essential for the loading response. In conclusion, the BW-reducing effect of increased loading but not of leptin treatment is blocked by high activity in the FGF system. We propose that both the gravitostat and the FGF system regulate BW independently of leptin and that pharmacologically enhanced activity in the FGF system reduces the sensitivity of the gravitostat. Topics: Adipose Tissue; Animals; Antibodies, Monoclonal; Body Weight; Fibroblast Growth Factors; Gene Expression; Leptin; Liver; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Obesity; Receptor, Fibroblast Growth Factor, Type 1 | 2019 |
Relationship of Maternal Weight Status Before, During, and After Pregnancy with Breast Milk Hormone Concentrations.
The aim of this study was to test associations of prepregnancy BMI, gestational weight gain, oral glucose challenge test results, and postpartum weight loss as predictors of breast milk leptin, insulin, and adiponectin concentrations and whether these relationships vary over time.. Milk was collected at 1 and 3 months from 135 exclusively breastfeeding women from the longitudinal Mothers and Infants Linked for Healthy Growth (MILk) study. Hormones were assayed in skimmed samples using ELISA. Mixed-effects linear regression models were employed to assess main effects and effect-by-time interactions on hormone concentrations.. In adjusted models, BMI was positively associated with milk leptin (P < 0.001) and insulin (P = 0.03) and negatively associated with milk adiponectin (P = 0.02); however, the association was stronger with insulin and weaker with adiponectin at 3 months than at 1 month (time interaction P = 0.017 for insulin and P = 0.045 for adiponectin). Gestational weight gain was positively associated and postpartum weight loss was negatively associated with milk leptin (both P < 0.001), independent of BMI. Oral glucose challenge test results were not associated with these milk hormone concentrations.. Maternal weight status before, during, and after pregnancy contributes to interindividual variation in human milk composition. Continuing work will assess the role of these and other milk bioactive factors in altering infant metabolic outcomes. Topics: Adiponectin; Adult; Body Weight; Breast Feeding; Female; Glucose Tolerance Test; Humans; Infant, Newborn; Insulin; Leptin; Longitudinal Studies; Male; Middle Aged; Milk, Human; Mothers; Postpartum Period; Pregnancy; Young Adult | 2019 |
Differential regulation of thyrotropin-releasing hormone mRNA expression in the paraventricular nucleus and dorsomedial hypothalamus in OLETF rats.
Thyrotropin-releasing hormone (TRH) plays an important role in the regulation of energy balance. While the regulation of TRH in the paraventricular nucleus (PVN) in response to changes of energy balance has been well studied, how TRH is regulated in the dorsomedial hypothalamus (DMH) in maintaining energy homeostasis remains unclear. Here, we assessed the effects of food restriction and exercise on hypothalamic Trh expression using Otsuka Long-Evens Tokushima Fatty (OLETF) rats. Sedentary ad lib fed OLETF rats (OLETF-SED) became hyperphagic and obese. These alterations were prevented in OLETF rats with running wheel access (OLETF-RW) or food restriction in which their food was pair-fed (OLETF-PF) to the intake of lean control rats (LETO-SED). Evaluation of hypothalamic gene expression revealed that Trh mRNA expression was increased in the PVN of OLETF-SED rats and normalized in OLETF-RW and OLETF-PF rats compared to LETO-SED rats. In contrast, the expression of Trh in the DMH was decreased in OLETF-SED rats relative to LETO-SED rats. This alteration was reversed in OLETF-RW rats as seen in LETO-SED rats, but food restriction resulted in a significant increase in DMH Trh expression in OLETF-PF rats compared to LETO-SED rats. Strikingly, while Trh mRNA expression was decreased in the PVN of intact rats in response to acute food deprivation, food deprivation resulted in increased expression of Trh in the DMH. Together, these results demonstrate the differential regulation of Trh expression in the PVN and DMH in OLETF rats and suggest that DMH TRH also contributes to hypothalamic regulation of energy balance. Topics: Animals; Blood Glucose; Body Weight; Diet, Reducing; Dorsomedial Hypothalamic Nucleus; Eating; Leptin; Male; Obesity; Paraventricular Hypothalamic Nucleus; Physical Conditioning, Animal; Rats; RNA, Messenger; Thyrotropin-Releasing Hormone | 2019 |
Congenital Hypothyroidism is Associated With Impairment of the Leptin Signaling Pathway in the Hypothalamus in Male Wistar Animals in Adult Life.
The goal of this study is to investigate whether congenital hypothyroidism induced by MMI during gestation (G) or gestation plus lactation (GL) would affect the leptin action upon body weight control on hypothalamus. Six to eight pups per group were killed at 90 days of age. For statistical analysis one-way ANOVA followed by the Holm-Sìdak post hoc test was used. Hypothyroidism resulted in a significant increase in leptin serum levels in G 20% and GL 25% (p<0.04). There was a significant expression decrease of OBR in G 45% and GL 63%; pSTAT3 in G 56% and GL 51%; pERK in G 50% and GL 48%; POMC in G 41% and GL 46% (p<0.04), while a significant increase was assigned to SOCS3 in G 52% and GL 170% (p<0.04) protein expression. We can conclude that hypothyroxinemia condition in rats on adulthood results in impairment of the leptin signaling pathway via ObRb-STAT3 in the hypothalamus, which is likely to be involved in the leptin resistance. Topics: Aging; Animals; Body Weight; Congenital Hypothyroidism; Feeding Behavior; Female; Hormones; Hypothalamus; Leptin; Male; Rats, Wistar; Signal Transduction | 2019 |
Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis.
Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1 Topics: Alleles; Animals; Body Weight; Cell Line, Tumor; Crosses, Genetic; Gene Deletion; Gene Knock-In Techniques; Genetic Variation; HEK293 Cells; Heterozygote; Homeostasis; Humans; Hypothalamus; Leptin; Male; Membrane Potentials; Mice; Mice, Transgenic; Mutation, Missense; Neurons; Nuclear Receptor Coactivator 1; Obesity; Phenotype | 2019 |
GLP-1 induces alpha cell proliferation and overrides leptin suppression induced by negative energy balance in vagotomized rats.
Glucagon-like peptide-1 (GLP-1) influences energy balance by exerting effects on food intake and glucose metabolism, through mechanisms that are partially dependent on the vagal pathway. The aim of this study was to characterize the effects of chronic GLP-1 stimulation on energy homeostasis and glucose metabolism in the absence of vagal innervation Truncal vagotomized (VGX) and sham operated rats (SHAM) received an intraperitoneal GLP-1 infusion (3.5 pmol/kg/min) trough mini-osmotic pumps. To dissect the effects derived from vagal denervation on food intake, an additional group was included consisting of sham operated rats that were PAIR FED to VGX. Food intake and body weight were recorded throughout the experimental period, while the percentage of white and brown adipose tissue, fasting glucose, insulin, gastro-intestinal hormonal profile, hypothalamic, and BAT gene expression were assessed at endpoint. VGX rats had significantly lower food intake, body weight gain, and leptin levels when compared with SHAM rats. Despite having similar body weight, PAIR-FED rats had lower fasting leptin, insulin and insulin resistance, while having higher ghrelin levels than VGX. GLP-1 infusion did not influence food intake or body weight, but was associated with lower leptin levels in VGX and lower pancreatic α-cells ki-67 staining in SHAM. Concluding, this study corroborates that the vagus nerve may modulate whole body energy homeostasis by acting in peripheral signals. Our data suggest that in the absence of vagal or parasympathetic tonus, GLP-1 mediated inhibition of cell proliferation markers in α-cells is prevented, meanwhile leptin suppression, associated with a negative energy balance, is partially overridden. Topics: Animals; Body Weight; Cell Proliferation; Eating; Energy Metabolism; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Homeostasis; Leptin; Male; Rats; Vagotomy | 2019 |
ΔFosB Requires Galanin, but not Leptin, to Increase Bone Mass via the Hypothalamus, but both are needed to increase Energy expenditure.
Energy metabolism and bone homeostasis share several regulatory pathways. The AP1 transcription factor ΔFosB and leptin both regulate energy metabolism and bone, yet whether their pathways intersect is not known. Transgenic mice overexpressing ΔFosB under the control of the Enolase 2 (ENO2) promoter exhibit high bone mass, high energy expenditure, low fat mass, and low circulating leptin levels. Because leptin is a regulator of bone and ΔFosB acts on leptin-responsive ventral hypothalamic (VHT) neurons to induce bone anabolism, we hypothesized that regulation of leptin may contribute to the central actions of ΔFosB in the VHT. To address this question, we used adeno-associated virus (AAV) expression of ΔFosB in the VHT of leptin-deficient ob/ob mice and genetic crossing of ENO2-ΔFosB with ob/ob mice. In both models, leptin deficiency prevented ΔFosB-triggered reduction in body weight, increase in energy expenditure, increase in glucose utilization, and reduction in pancreatic islet size. In contrast, leptin deficiency failed to prevent ΔFosB-triggered increase in bone mass. Unlike leptin deficiency, galanin deficiency blocked both the metabolic and the bone ΔFosB-induced effects. Overall, our data demonstrate that, while the catabolic energy metabolism effects of ΔFosB require intact leptin and galanin signaling, the bone mass-accruing effects of ΔFosB require galanin but are independent of leptin. © 2019 American Society for Bone and Mineral Research. Topics: Animals; Body Weight; Bone and Bones; Energy Metabolism; Galanin; Gene Deletion; Glucose; Hypothalamus; Leptin; Mice, Inbred C57BL; Mice, Knockout; Organ Size; Phosphopyruvate Hydratase; Proto-Oncogene Proteins c-fos | 2019 |
Behavioral profile of intermittent vs continuous access to a high fat diet during adolescence.
Over the past few years, the effects of a high-fat diet (HFD) on cognitive functions have been broadly studied as a model of obesity, although no studies have evaluated whether these effects are maintained after the cessation of this diet. In addition, the behavioral effects of having a limited access to an HFD (binge-eating pattern) are mostly unknown, although they dramatically increase the vulnerability to drug use in contrast to having continuous access. Thus, the aim of the present study was to compare the effects of an intermittent versus a continuous exposure to an HFD during adolescence on cognition and anxiety-like behaviors, as well as to study the changes observed after the interruption of this diet. Adolescent male mice received for 40 days a standard diet, an HFD with continuous access or an HFD with sporadic limited access (2 h, three days a week). Two additional groups were fed with intermittent or continuous access to the HFD and withdrawn from this diet 15 days before the behavioral tests. Only the animals with a continuous access to the HFD showed higher circulating leptin levels, increased bodyweight, marked memory and spatial learning deficits, symptoms that disappeared after 15 days of HFD abstinence. Mice that binged on fat only showed hyperlocomotion, which normalized after 15 days of HFD cessation. However, discontinuation of fat, either in a binge or a continuous pattern, led to an increase in anxiety-like behavior. These results highlight that exposure to a high-fat diet during adolescence induces alterations in brain functions, although the way in which this diet is ingested determines the extent of these behavioral changes. Topics: Age Factors; Animals; Anxiety; Behavior, Animal; Body Weight; Bulimia; Cognition; Diet, High-Fat; Feeding Behavior; Learning; Leptin; Male; Memory; Mice; Obesity; Weight Gain | 2019 |
Antiobesity Effects of
The gut microbiota is the most important environmental factor that plays a role in inducing obesity. The gram-negative bacteria, Topics: Animals; Anti-Obesity Agents; Antibiosis; Body Weight; Diet, High-Fat; Enterobacter cloacae; Gastrointestinal Microbiome; Humans; Intestines; Lactobacillus plantarum; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Probiotics; Triglycerides | 2019 |
Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21.
Cardiac metabolism affects systemic energetic balance. Previously, we showed that Krüppel-like factor (KLF)-5 regulates cardiomyocyte PPARα and fatty acid oxidation-related gene expression in diabetes. We surprisingly found that cardiomyocyte-specific KLF5 knockout mice (αMHC-KLF5 Topics: Adipose Tissue, White; Animals; Body Weight; Diet, High-Fat; Female; Fibroblast Growth Factors; Humans; Kruppel-Like Transcription Factors; Leptin; Male; Mediator Complex; Mice; Mice, Knockout; MicroRNAs; Myocardium; Myocytes, Cardiac; Obesity; Signal Transduction | 2019 |
Chronic heart failure course prognosis depending on body weight and endogenous intoxication syndrome.
Introduction: Over the years, heart failure remains one of the most common and prognostically unfavorable conditions. The aim of our study was to determine the frequency of complications in patients with CHF depending on the body weight and intoxication syndrome of varying degrees of severity.. Materials and methods: A complete clinical examination was performed in 58 patients (41 (70.6%) men and 17 (29.4%) women) with CHF. In addition to the standard examination in accordance with the protocol, the level of endogenous intoxication was determined by the level of medium-weight molecules (MWM254) and leptin. The patients were randomized into 4 groups depending on their body mass index and the degree of endogenous intoxication. Statistical processing of the results was carried out using the methods of variation statistics "Statistica 6.0".. Results: It was revealed that the worst survival rate is observed in patients with normal body mass against the background of the expressed endogenous intoxication syndrome, the best survival rate is observed provided that there are a normal body mass and endogenous intoxication of a minimum degree. An inverse correlation between the body mass index and the endogenous intoxication indicator (blood MWM) was detected. Patients with CHF should have their leptin level evaluated. An increase in its level was associated with arterial hypertension, an increase in blood glucose levels and lipid metabolism disorders.. Conclusions: Increased level of blood MWM worsens the forecast of CHF. The unfavorable outcome was observed in patients with the combination of hypoleptinemia with severe endogenous intoxication. Topics: Body Mass Index; Body Weight; Chronic Disease; Female; Heart Failure; Humans; Leptin; Male; Prognosis | 2019 |
New Insights into the Regulation of Leptin Gene Expression.
Leptin is a key hormone in the homeostatic regulation of body weight. While past research focused mainly on overall leptin actions, a recent study by Dallner et al. (2019) takes a fresh look at the regulatory elements of the leptin gene locus, providing new insights into processes that modulate leptin levels. Topics: Body Weight; Gene Expression; Humans; Leptin; Obesity; RNA, Long Noncoding | 2019 |
Elevated maternal linoleic acid reduces circulating leptin concentrations, cholesterol levels and male fetal survival in a rat model.
Linoleic acid consumption is increasing in Western populations. We investigated whether elevated linoleic acid in pregnancy was deleterious to mothers or offspring. Maternal and fetal body and organ weights were not affected by elevated linoleic acid consumption. Maternal lipids and leptin were altered following elevated linoleic acid consumption. Male offspring numbers were reduced following elevated linoleic acid consumption.. Dietary intakes of linoleic acid (LA) have increased dramatically in Western populations, including in women of reproductive age. Pro-inflammatory effects of LA may have detrimental effects on maternal and offspring outcomes. We aimed to investigate whether consumption of a maternal diet with elevated LA altered maternal inflammatory or metabolic markers during pregnancy, fetal growth and/or the sex ratio of the offspring. Female Wistar Kyoto rats consumed a diet high in LA (HLA) (6.21% of energy) or a diet low in LA (LLA) (1.44% of energy) for 10 weeks prior to mating and during pregnancy. Pregnant rats were killed at embryonic day 20 (E20). There were no differences in maternal or fetal body weights or organ weights in the HLA group compared to the LLA group. There was no difference in maternal circulating cytokine concentrations between dietary groups. In the maternal liver, IL-1α concentrations were significantly lower, and TNF-α and IL-7 significantly higher in the HLA group. Total plasma cholesterol, LDL-cholesterol, HDL cholesterol and the total:HDL cholesterol ratio were lower in dams fed the HLA diet. mRNA expression of sterol regulatory element binding transcription factor 1 (SREBF-1) and leptin in maternal adipose tissue was lower in the HLA group, as were circulating leptin concentrations. The proportion of male fetuses was lower and circulating prostaglandin E metabolite concentrations were increased in the HLA group. In conclusion, consumption of a maternal diet high in linoleic acid alters cholesterol metabolism and prostaglandin E metabolite concentrations, which may contribute to the reduced proportion of male offspring. Topics: Adipose Tissue; Animals; Biomarkers; Body Weight; Cholesterol; Diet; Female; Fetus; Leptin; Linoleic Acid; Lipid Metabolism; Male; Models, Animal; Organ Size; Pregnancy; Rats; Rats, Inbred WKY | 2019 |
The effect of high fructose corn syrup on the plasma insulin and leptin concentration, body weight gain and fat accumulation in rat.
Studies on the effects of high fructose corn syrup (HFCS) on the metabolism are scarce and their results are inconsistent.. The aim of this research was to examine in an animal model the effect of replacing sucrose with HFCS-55 on the levels of glucose, insulin and leptin, and on the consumption of feed, body weight gain and fat storage.. The experiment was carried out on 30 Wistar male rats aged 5 months, fed 3 different diets, containing whole grains (group I), 10% sucrose (group II) and 10% HFCS (group III).. It was found that the amount of daily energy intake was similar for all the groups of animals. There was no difference in fasting glucose and insulin level and homeostatic model assessment for insulin resistance (HOMA-IR) index. The higher leptin level was determined in blood plasma of the animal fed a feed with sucrose (group 2) compared to group 1 and group 3 (360 ng/mL vs 263 and 230 ng/mL, respectively). Despite the similar amounts of consumed energy, the animals fed with modified feeds achieved higher weight gain and the effect of HFCS-55 was similar to the effect of sucrose.. The obtained results indicate similar metabolic effects of HFCS-55 and sucrose in feed, at the level of 11% dietary energy value, on the energy intake, body weight gain and periorgan adipose tissue accumulation in rats. The results suggest that accusations against HFCS as the major dietary contributor to overweight and obesity are unfounded, and the total elimination of HFCS from the diet seems to be unnecessary. The modified feeds (containing both sucrose and HFCS) produced greater absolute weight gain and weight gain per kilojoule consumed compared to standard feeds. This may indicate not just a basic thermodynamic consequence of consuming more energy, but a change in the metabolic efficiency when consuming a diet with simple sugars and refined carbohydrates. Topics: Animals; Body Weight; Energy Metabolism; High Fructose Corn Syrup; Insulin; Leptin; Male; Obesity; Rats; Rats, Wistar; Weight Gain | 2019 |
Modeling of antipsychotic-induced metabolic alterations in mice: An experimental approach precluding psychosis as a predisposing factor.
Despite benefits, atypical antipsychotics produce troublesome metabolic adverse effects particularly hyperphagia, weight gain, dyslipidemia, hyperglycemia and insulin resistance which further develop metabolic and cardiac complications. The animal models studied for antipsychotic-induced weight gain only focused on metabolic alteration in antipsychotics treated animals but none has considered psychosis as a predisposing factor which mimics the clinical condition. The present study was aimed to rule out the impact of pharmacologically induced psychosis-like phenotype on metabolic alterations induced by antipsychotics. Female BALB/c mice (weighing 18-23 g) exhibiting schizophrenia-like behavior after 5 days of MK-801 treatment (0.1 mg/kg, i.p.) were administered olanzapine (3 and 6 mg/kg, per oral) and risperidone (2 and 4 mg/kg, per oral) for six weeks. Acute as well as chronic treatment with olanzapine and risperidone treatment significantly reduced locomotion, increased feed intake and body weight in a time-dependent manner, which confirms the face validity of the animal model. Olanzapine (6 mg/kg) treatment significantly altered glucose and lipid homeostasis which was further accompanied by elevated levels of proinflammatory cytokines, ghrelin and leptin. These metabolic and biochemical alterations have demonstrated construct validity. Further, no significant difference was observed in the metabolic parameters in control and schizophrenic mice treated with olanzapine which confers that antipsychotic-induced metabolic alterations are independent of psychosis. Our study concluded that six-week olanzapine (6 mg/kg) treatment in control mice induced most of the clinically relevant physiological, biochemical and metabolic alterations (clinically relevant), that is independent of pharmacologically-induced psychosis. Topics: Animals; Antipsychotic Agents; Body Weight; Female; Ghrelin; Hyperglycemia; Leptin; Mice; Mice, Inbred BALB C; Olanzapine; Psychotic Disorders; Risperidone; Schizophrenia; Weight Gain | 2019 |
Adjustable feedings plus accurate serial length measurements decrease discharge weight-length disproportion in very preterm infants: quality improvement project.
Preterm very-low-birth-weight (≤1500 g) infants exhibit disproportionate weight-for-length growth in the Neonatal Intensive Care Unit.. High frequency of body mass index (BMI) > 90th centile at discharge and 1-year postnatal age associated with elevated blood pressure and serum leptin in infancy and adolescence.. Single-institution quality improvement project in appropriately grown infants born at 23. Adjustable feeding protocol based on valid serial length measurements (board or caliper).. The average monthly percentage of weight-for-length disproportion at discharge decreased from 13% in Epoch 1 to 0% in Epoch 2 (P < 0.05). Although the average Z-score for BMI at discharge was lower in Epoch 2 versus Epoch 1 (P < 0.01), this was absent by 1 year follow-up (P = 0.91).. Adjustable feedings plus use of accurate serial length measurements decreases weight-for-length disproportion at hospital discharge but not at 1 year. Topics: Body Height; Body Mass Index; Body Weight; Feeding Methods; Female; Humans; Infant; Infant, Extremely Premature; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Leptin; Male; Quality Improvement | 2019 |
Chronic Light Cycle Disruption Alters Central Insulin and Leptin Signaling as well as Metabolic Markers in Male Mice.
Recent evidence suggests that the circadian timing system plays a role in energy and glucose homeostasis, and disruptions to this system are a risk factor for the development of metabolic disorders. We exposed animals to a constantly shifting lighting environment comprised of a 6-hour advance, occurring every 6 days, to chronically disrupt their circadian timing system. This treatment caused a gradual increase in body weight of 12 ± 2% after 12 phase shifts, compared with a 6 ± 1% increase in mice under control lighting conditions. Additionally, after the fifth phase shift, light cycle-disrupted (CD) animals showed a reversal in their diurnal pattern of energy homeostasis and locomotor activity, followed by a subsequent loss of this rhythm. To investigate potential molecular mechanisms mediating these metabolic alterations, we assessed central leptin and insulin sensitivity. We discovered that CD mice had a decrease in central leptin signaling, as indicated by a reduction in the number of phosphorylated signal transducer and activator of transcription 3 immunoreactive cells in the arcuate nucleus of the hypothalamus. Furthermore, CD animals exhibited a marked increase in fasting blood glucose (269.4 ± 21.1 mg/dL) compared with controls (108.8 ± 21.3 mg/dL). This dramatic increase in fasting glucose levels was not associated with an increase in insulin levels, suggesting impairments in pancreatic insulin release. Peripheral hyperglycemia was accompanied by central alterations in insulin signaling at the level of phospho Akt and insulin receptor substrate 1, suggesting that light cycle disruption alters central insulin signaling. These results provide mechanistic insights into the association between light cycle disruption and metabolic disease. Topics: Animals; Biomarkers; Body Weight; Insulin; Leptin; Light; Male; Mice; Mice, Inbred C57BL; Photoperiod; Signal Transduction | 2019 |
Metabolic and behavioral parameters of mice with reduced expression of Syndecan-1.
Energy balance is essential for all species. Ligand-receptor interactions mediate processes that regulate body activities like reproduction and metabolism based on the energy status. Such receptors are the heparan sulfate proteoglycans and specifically the family of syndecans. Therefore we investigated the differences of metabolic parameters of heterozygous Syndecan 1 mice (Sdc1+/-) with reduced expression of Sdc1 and the corresponding wild type mice. Sdc1+/- mice have a reduced body weight although they show increased leptin and decreased corticosterone levels. Furthermore, their food and water intake is increased. This is accompanied with less adipose tissue, smaller adipocytes and thus an increased density of adipocytes. For the detailed analysis of the metabolism the automated PhenoMaster system has been used, which allowed continuous and undisturbed recording of food and water intake, energy expenditure and movement. The reason for the lower body weight was the higher energy expenditure of these animals compared to controls. Additionally, female Sdc1+/- mice showed an increased locomotor activity. Referring to organs, the intestine in Sdc1+/- mice was heavier and longer, but no differences at the cellular level could be observed. These findings were independent of normal mating or vice versa embryo transfers of Sdc1+/- and wild type embryos in recipient females of the other genotype. Herein we showed that the reduced expression of Sdc1 led to an altered metabolism on fetal as well as on maternal side, which may play a role in the growth restriction observed in human pregnancy pathologies and in mice lacking Sdc1. Topics: Adipocytes; Adipose Tissue; Animals; Biometry; Blood Glucose; Body Weight; Circadian Rhythm; Corticosterone; Feeding Behavior; Female; Gene Expression Regulation; Genotype; Intestinal Mucosa; Leptin; Ligands; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Syndecan-1 | 2019 |
Effects of multiple cycles of weight loss and regain on the body weight regulatory system in rats.
We studied the effects of multiple cycles of weight loss and regain on the defended body weight in rats. Thirty-six male Wistar rats were divided into three weight-matched groups: weight cyclers ( Topics: Adiposity; Animals; Body Composition; Body Weight; Caloric Restriction; Diet, Reducing; Ghrelin; Glucose Tolerance Test; Insulin; Leptin; Male; Rats; Rats, Wistar; Weight Loss | 2019 |
Irreversible metabolic abnormalities following chronic upper airway loading.
Treatment of obstructive sleep apnea increases obesity risk by an unclear mechanism. Here, we explored the effects of upper airway obstruction and its removal on respiratory homeostasis, energy expenditure, and feeding hormones during the sleep/wake cycle from weaning to adulthood.. The tracheas of 22-day-old rats were narrowed, and obstruction removal was performed on post-surgery day 14. Energy expenditure, ventilation, and hormone-regulated feeding were analyzed during 49 days before and after obstruction.. Energy expenditure increased and body temperature decreased in upper airway obstruction and was only partially recovered in obstruction removal despite normalization of airway resistance. Increased energy expenditure was associated with upregulation of ventilation. Decreased body temperature was associated with decreased brown adipose tissue uncoupling protein 1 level, suppressed energy expenditure response to norepinephrine, and decreased leptin level. Upper airway obstructed animals added less body weight, in spite of an increase in food intake, due to elevated hypothalamic orexin and neuropeptide Y and plasma ghrelin. Animals who underwent obstruction removal fed more due to an increase in hypothalamic neuropeptide Y and plasma ghrelin.. The need to maintain respiratory homeostasis is associated with persistent abnormal energy metabolism and hormonal regulation of feeding. Surgical treatment per se may not be sufficient to correct energy homeostasis, and endocrine regulation of feeding may have a larger effect on weight change. Topics: Animals; Body Weight; Eating; Energy Metabolism; Ghrelin; Homeostasis; Hypothalamus; Leptin; Male; Rats; Rats, Sprague-Dawley; Trachea; Uncoupling Protein 1 | 2019 |
Low-Protein Diets with Fixed Carbohydrate Content Promote Hyperphagia and Sympathetically Mediated Increase in Energy Expenditure.
Dietary protein restriction elicits hyperphagia and increases energy expenditure; however, less is known of whether these responses are a consequence of increasing carbohydrate content. The effects of protein-diluted diets with fixed carbohydrate content on energy balance, hormones, and key markers of protein sensing and thermogenesis in tissues are determined.. Obesity-prone rats (n = 13-16 per group) are randomized to diets containing fixed carbohydrate (52% calories) and varying protein concentrations: 15% (control), 10% (mild protein restriction), 5% (moderate protein restriction) or 1% (severe protein restriction) protein calories, or protein-matched to 5% protein, for 21 days. Propranolol and ondansetron are administered to interrogate the roles of sympathetic and serotonergic systems, respectively, in diet-induced changes in energy expenditure. It is found that mild-to-moderate protein restriction promotes transient hyperphagia, whereas severe protein restriction induces hypophagia, with alterations in meal patterns. Protein restriction enhances energy expenditure that is partly attenuated by propranolol, but not ondansetron. Moderate to severe protein restriction decreases gains in body weight, lean and fat mass, decreased postprandial glucose and leptin, but increased fibroblast growth factor-21 concentrations. Protein-matching retains lean mass suggesting that intake of dietary protein, but not calories, is important for preserving lean mass. Notably, protein restriction increases the protein and/or transcript abundance of key amino acid sensing molecules in liver and intestine (PERK, eIF2α, ATF2, CHOP, 4EBP1, FGF21), and upregulated thermogenic markers (β2AR, Klotho, HADH, UCP-1) in brown adipose tissue.. Low-protein diets promote hyperphagia and sympathetically mediated increase in energy expenditure, prevent gains in tissue reserves, and concurrently upregulate hepatic and intestinal amino acid sensing intermediaries and thermogenic markers in brown adipose tissue. Topics: Adipose Tissue, Brown; Animals; Body Composition; Body Weight; Diet, Protein-Restricted; Dietary Carbohydrates; Energy Intake; Energy Metabolism; Fibroblast Growth Factors; Hyperphagia; Leptin; Liver; Male; Rats, Sprague-Dawley; Thermogenesis | 2019 |
Adding α-tocopherol-selenium and ascorbic acid to periparturient sow diets influences hemogram, lipid profile, leptin, oxidant/antioxidant imbalance, performance and neonatal piglet mortality.
Alpha-tocopherol-selenium (ATS) and ascorbic acid (AA) are the potent antioxidants. The present study investigated whether supplementation of ATS and AA in periparturient sows has positive effects on amelioration of oxidative stress, serum immunoglobulin G (IgG), lipid profile and sows performance. For this, twenty-four pregnant multiparous sows (landrace×indigenous) were randomly distributed into four groups (6 sows per group) 20 days before expected date of farrowing as Control (basal diet); ATS (basal diet + ATS); AA (basal diet + AA) and ATS-AA (basal diet + ATS plus AA). The results of the study revealed that the concentrations of triglyceride and cholesterol significantly reduced from day -7 to day 7 of farrowing irrespective of supplementations to sows, but the leptin concentration significantly reduced on day 7 of farrowing in ATS-AA supplemented sows (p<0.05). Moreover, sows of supplemented groups experienced decreased oxidative stress and cortisol level than control sows. The serum IgG concentration was significantly increased on day 7 post-farrowing in ATS group but it was much earlier on day 2 of farrowing in ATS-AA group (p<0.001). Supplementing sows with ATS and/or AA did not influence significantly the birth weight, weaning weight and litter size at weaning (p>0.05). Although piglet survival rate was not affected significantly by supplementation, however, piglet mortality rate was lowest in ATS-AA than any other groups. It was concluded that supplementation of ATS and/or AA to sows during late gestating and early lactating period ameliorated oxidative stress, improved lipid profile and serum IgG level without influencing reproductive performance. Topics: alpha-Tocopherol; Animal Feed; Animals; Animals, Newborn; Ascorbic Acid; Blood Cell Count; Body Weight; Diet; Dietary Supplements; Female; Lactation; Leptin; Lipid Metabolism; Litter Size; Longevity; Oxidative Stress; Pregnancy; Selenium; Sus scrofa | 2019 |
Increased intake of energy-dense diet and negative energy balance in a mouse model of chronic psychosocial defeat.
Chronic exposure to stress may represent a risk factor for developing metabolic and eating disorders, mostly driven by the overconsumption of easily accessible energy-dense palatable food, although the mechanisms involved remain still unclear. In this study, we used an ethologically oriented murine model of chronic stress caused by chronic psychosocial defeat (CPD) to investigate the effects of unrestricted access to a palatable high fat diet (HFD) on food intake, body weight, energy homeostasis, and expression of different brain neuropeptides. Our aim was to shed light on the mechanisms responsible for body weight and body composition changes due to chronic social stress.. In our model of subordinate (defeated), mice (CPD) cohabitated in constant sensory contact with dominants, being forced to interact on daily basis, and were offered ad libitum access either to an HFD or to a control diet (CD). Control mice (of the same strain as CPD mice) were housed in pairs and left unstressed in their home cage (UN). In all these mice, we evaluated body weight, different adipose depots, energy metabolism, caloric intake, and neuropeptide expression.. CPD mice increased the intake of HFD and reduced body weight in the presence of enhanced lipid oxidation. Resting energy expenditure and interscapular brown adipose tissue (iBAT) were increased in CPD mice, whereas epididymal adipose tissue increased only in HFD-fed unstressed mice. Propiomelanocortin mRNA levels in hypothalamic arcuate nucleus increased only in HFD-fed unstressed mice. Oxytocin mRNA levels in the paraventricular nucleus and neuropeptide Y mRNA levels within the arcuate were increased only in CD-fed CPD mice. In the arcuate, CART was increased in HFD-fed UN mice and in CD-fed CPD mice, while HFD intake suppressed CART increase in defeated animals. In the basolateral amygdala, CART expression was increased only in CPD animals on HFD.. CPD appears to uncouple the intake of HFD from energy homeostasis causing higher HFD intake, larger iBAT accumulation, increased energy expenditure and lipid oxidation, and lower body weight. Overall, the present study confirms the notion that the chronic activation of the stress response can be associated with metabolic disorders, altered energy homeostasis, and changes of orexigenic and anorexigenic signaling. These changes might be relevant to better understand the etiology of stress-induced obesity and eating disorders and might represent a valid therapeutic approach for the development of new therapies in this field. Topics: Animals; Body Weight; Diet, High-Fat; Energy Intake; Energy Metabolism; Italy; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity | 2018 |
Interaction of 17β-estradiol and dietary fatty acids on energy and glucose homeostasis in female mice.
Fatty acid-induced hypothalamic inflammation (HI) is a potential cause of the obesity epidemic. It is unclear whether saturated or n-6 polyunsaturated fat is the primary driver of these effects. Premenopausal women are protected, in part, from obesity and associated comorbidities by circulating 17β-estradiol (E2). It is unknown how HI interacts with E2, because most studies of HI do not examine females despite the involvement of E2 in hypothalamic energy homeostasis. Our objective is to determine the effects of high-fat diets with varying levels of linoleic acid (LA) and saturated fat on the energy and glucose homeostasis in female mice with and without E2. Female C57BL/6J mice were fed either a control diet or a 45% kilocalories from fat diet with varying levels of LA (1, 15, or 22.5% kilocalories from LA) with or without E2 (300 μg/kg/day orally). After 8 weeks, the oil-treated high-fat groups gained more weight than control groups regardless of fat type. E2 reduced body fat accumulation in all high-fat groups. Glucose clearance from glucose challenge was impaired by LA. Nighttime O Topics: Adiposity; Animals; Blood Glucose; Body Composition; Body Weight; Diet; Diet, High-Fat; Dietary Fats; Estradiol; Fatty Acids; Female; Homeostasis; Hypothalamus; Interleukin-6; Leptin; Linoleic Acid; Mice; Mice, Inbred C57BL; Obesity; Oxygen Consumption; Weight Gain | 2018 |
GTRAP3-18 regulates food intake and body weight by interacting with pro-opiomelanocortin.
Topics: Adipose Tissue; alpha-MSH; AMP-Activated Protein Kinases; Animals; Appetite; Blood Glucose; Body Weight; Brain; Carrier Proteins; Eating; Heat-Shock Proteins; Hypothalamus; Insulin; Leptin; Male; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Pro-Opiomelanocortin; Weight Loss | 2018 |
Melatonin Prevents the Harmful Effects of Obesity on the Brain, Including at the Behavioral Level.
Obesity is a health problem caused by a diet rich in energy and the sedentary lifestyle of modern societies. A leptin deficiency is one of the worst causes of obesity, since it results in morbid obesity, a chronic disease without a cure. Leptin is an adipokine secreted in a manner dependent on the circadian rhythm that ultimately reduces food intake. We studied cellular alterations in brain of leptin-deficient obese animals and tested whether these alterations are reflected in abnormal behaviors. Obesity induced increases in oxidative stress and the unfolded protein response caused by endoplasmic reticulum stress. However, the subsequent signaling cascade was disrupted, blocking possible systemic improvements and increasing the production of misfolded proteins that trigger autophagy. Up-regulated autophagy was not indefinitely maintained and misfolded proteins accumulated in obese animals, which led to aggresome formation. Finally, neurodegenerative markers together with anxiety and stress-induced behaviors were observed in leptin-deficient mice. As oxidative stress has an essential role in the development of these harmful effects of obesity, melatonin, a powerful antioxidant, might counteract these effects on the brain. Following treatment with melatonin, the animals' antioxidant defenses were improved and misfolded protein, proteasome activity, and autophagy decreased. Aggresome formation was reduced due to the reduction in the levels of misfolded proteins and the reduction in tubulin expression, a key element in aggresome development. The levels of neurodegenerative markers were reduced and the behaviors recovered. The data support the use of melatonin in therapeutic interventions to reduce brain damage induced by leptin deficiency-dependent obesity. Topics: Animals; Autophagy; Behavior, Animal; Biomarkers; Body Weight; Brain; Cytokines; Endoplasmic Reticulum Stress; Inflammation Mediators; Leptin; Male; Melatonin; Mice, Inbred C57BL; Nerve Degeneration; Obesity; Organ Size; Oxidative Stress; Proteasome Endopeptidase Complex; Ubiquitin | 2018 |
iBAT sympathetic innervation is not required for body weight loss induced by central leptin delivery.
We evaluated the contribution of brown adipose tissue (BAT) sympathetic innervation on central leptin-mediated weight loss. In a short- and long-term study, F344BN rats were submitted to either a denervation of interscapular BAT (Denervated) or a sham operation (Sham). Animals from each group received the Ob (Leptin) or green fluorescent protein (GFP; Control) gene through a single injection of recombinant adeno-associated virus delivered centrally. Changes in body weight were recorded for 14 or 35 days, after which adipose tissues and skeletal muscles were weighed. In both studies, hypothalamic phosphorylated STAT3 (P-STAT3) was significantly higher in Sham-Leptin and Denervated-Leptin groups compared with their respective Control groups ( P < 0.01), indicating that leptin signaling was enhanced at the end point. We measured uncoupling protein 1 (UCP1), a marker of BAT thermogenic activity, and found a significant induction in Leptin in Sham animals ( P < 0.001) but not in Denervated animals, demonstrating that BAT UCP1 protein was only induced in Sham rats. Both Sham-Leptin and Denervated-Leptin rats lost ~15% of their initial body weight ( P < 0.001) by day 14 and reached a maximum of 18% body weight loss that stabilized over week 3 of treatment, indicating that sympathetic outflow to BAT is not required for leptin-mediated weight loss. In summary, interscapular BAT (iBAT) denervation did not prevent body weight loss following central leptin gene delivery. The present data show that sympathetic innervation of iBAT is not essential for leptin-induced body weight loss. Topics: Adipose Tissue, Brown; Animals; Body Weight; Denervation; Dependovirus; Gene Expression Regulation; Gene Transfer Techniques; Infusions, Intraventricular; Leptin; Male; Rats; Rats, Inbred F344; Rats, Transgenic; Sympathetic Nervous System; Thermogenesis; Uncoupling Protein 1; Weight Loss | 2018 |
Long-Term Intake of Green Tea Extract Causes Mal-Conformation of Trabecular Bone Microarchitecture in Growing Rats.
The purpose of this study was to examine the effects of green tea extract (GTE) intake on bone structural and physiological properties, such as bone mass, trabecular bone microarchitecture, cortical bone geometry, and bone mechanical strength, in growing rats. Four-week-old male Wistar rats were divided into the following four groups: standard diet feeding for 85 days (S-CON) or 170 days (L-CON), and GTE diet feeding for 85 days (S-GTE) or 170 days (L-GTE). At the end of the experiment, in addition to measurement of circulating bone formation/resorption markers, bone mass, trabecular bone microarchitecture, and cortical bone geometry were analyzed in the left femur, and bone mechanical strength of the right femur was measured. There was no difference in all bone parameters between the S-CON and S-GTE groups. On the other hand, the L-GTE group showed the decrease in some trabecular bone mass/microarchitecture parameters and no change in cortical bone mass/geometry parameters compared with the L-CON group, and consequently the reduction in bone weight corrected by body weight. There was no difference in bone formation/resorption markers and bone mechanical strength between the S-CON and S-GTE groups and also between the L-CON and L-GTE groups. However, serum leptin levels were significantly lower in the L-GTE group than in the L-CON group. Thus, the long-term GTE intake had negative effects on bone, especially trabecular bone loss and microarchitecture mal-conformation, in growing rats. Topics: Animals; Body Weight; Bone and Bones; Bone Density; Cortical Bone; Femur; Leptin; Male; Rats; Rats, Wistar; Tea | 2018 |
Gender Differences in Cardiometabolic Risk Factors in Metabolically Healthy Normal Weight Adults with Central Obesity.
We investigated whether metabolically healthy normal weight adults with central obesity display worse cardiometabolic profile compared with their centrally lean counterparts. This retrospective, cross-sectional study, comprised 1 135 subjects (64% females) aged 18-to-81 years, presenting ≤2 components of metabolic syndrome. They were classified as centrally lean (waist-to-height ratio (WHtR)<0.5 and waist circumference<80 cm in females and<94 cm in males) or presenting central obesity (WHtR ≥0.5, regardless of waist circumference). Data on blood pressure, glucose homeostasis, lipid profile, renal function, high-sensitive C-reactive protein (hsCRP), uric acid, adiponectin, leptin, and soluble receptor for advanced glycation end products were compared between the groups, separately in males and females. 5.7% of males and 6.9% of females presented WHtR ≥0.5. Compared with centrally lean subjects, those with central obesity had higher BMI-adjusted fasting plasma glucose (p<0.001), and leptin levels (p<0.05); females also presented higher blood pressure (p<0.001), while males had higher hsCRP concentrations (p=0.021). These changes associated with significantly higher BMI-adjusted odds to present fasting plasma glucose >5.6 mmol/l in both genders, higher odds to present hsCRP >3 mg/l in males, and those to present elevated blood pressure in females. Our analysis suggests that in metabolically healthy normal weight subjects WHtR ≥0.5 might indicate "early increased health risk". Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; C-Reactive Protein; Cross-Sectional Studies; Female; Humans; Leptin; Male; Middle Aged; Obesity, Abdominal; Retrospective Studies; Risk Factors; Sex Factors; Waist-Height Ratio; Young Adult | 2018 |
Aging affects the response of female rats to a hypercaloric diet.
Metabolic syndrome is a major risk factor for the development of cardiovascular diseases and diabetes, among other conditions. Studies have shown that aging and metabolic syndrome share several metabolic alterations, and that aged individuals, in particular females, are at an increased risk of developing metabolic disorders. Although several studies have investigated the effects of hypercaloric diets in the development of obesity and metabolic syndrome in young animals, few studies have investigated these parameters in aged animals, especially in females. Therefore, the aim of this study was to investigate the effects of a hypercaloric diet in metabolic parameters of young and aged female rats, including its effects on lipid and glycemic profile and on liver lipid content. When compared to young animals, the aged rats presented increased serum levels of triglycerides and decreased serum levels of HDL cholesterol and glycemia, as well as increased hepatic levels of triglycerides and total cholesterol. The hypercaloric diet increased food intake, body weight gain and adiposity index, leading both young and aged animals to a dyslipidemia, represented by increased serum levels of triglycerides. The hypercaloric diet increased the glycemia and the HOMA index only in the young animals. On the other hand, the diet increased the frequency of hepatocellular microvacuolar degeneration only in the aged animals. In summary, it was observed that the females from different ages respond differently to hypercaloric diet intake: while the aged animals were more resistant to the changes in the glycemic profile, they were more susceptible to the hepatic damage caused by this diet. Topics: Adiposity; Aging; Animals; Blood Glucose; Body Weight; Dyslipidemias; Energy Intake; Female; Hyperglycemia; Leptin; Lipid Metabolism; Liver; Metabolic Syndrome; Rats; Rats, Wistar; Triglycerides | 2018 |
Neuronal Cell Adhesion Molecule 1 Regulates Leptin Sensitivity and Bone Mass.
The central nervous system is widely known to exert control over our systemic physiology via several mechanisms including the regulation of skeletal metabolism. Neuronal circuits within the hypothalamus have been shown to impact bone mass via leptin-dependent and independent mechanisms; however, the full extent to which the brain controls bone homeostasis is not known. We previously identified cell adhesion molecule1 (Cadm1) as a regulator of body weight and energy homeostasis via its expression in multiple regions of the brain. Here, we show that loss of Cadm1 expression in excitatory neurons results in increased leptin sensitivity in addition to a concomitant reduction in bone mass. Femoral length, bone mineral content, diaphyseal cross-sectional area, and bone strength were all lower in Cadm1-deficient animals. Conversely, inducing expression of Cadm1 in excitatory neurons decreased leptin sensitivity and increased femoral length, bone mineral content, and diaphyseal cross-sectional area. Together, these results illustrate an essential role for this synaptic protein in the neuronal regulation of skeletal bone metabolism. Topics: Animals; Body Weight; Bone and Bones; Bone Density; Cell Adhesion Molecule-1; Cell Adhesion Molecules, Neuronal; Energy Metabolism; Homeostasis; Leptin; Mice; Neurons; Obesity | 2018 |
Central and peripheral leptin and agouti-related protein during and after pregnancy in relation to weight change.
To study changes of neuropeptides and adipokines in cerebrospinal fluid (CSF) and serum from pregnancy to postpregnancy in relation to weight changes, fat mass and glucose metabolism.. With high postpartum weight retention being a risk factor in future pregnancies and of lifelong obesity, we evaluated neuropeptide and adipokine changes in women who either gained weight or were weight stable.. Women were followed for 5 ± 1 years after pregnancy and divided into two groups, weight stable and weight gain, by weight change from start of pregnancy.. Twenty-five women (BMI 27 ± 5 kg/m. CSF and serum levels of agouti-related protein (AgRP), leptin and insulin, and serum levels of adiponectin and soluble leptin receptor were measured during and after pregnancy. These measurements were further related to fat mass and insulin sensitivity (HOMA-IR).. S-AgRP levels during pregnancy were lower in the weight stable group and a 1 unit increase in s-AgRP was associated with 24% higher odds of pertaining to the weight gain group. After pregnancy, s-AgRP increased in the weight stable group but decreased in the weight gain group. Decreased transport of leptin into CSF during pregnancy was reversed by an increased CSF:serum leptin ratio after pregnancy. In women who returned to their prepregnancy weight, serum adiponectin increased after pregnancy and correlated negatively with HOMA-IR.. S-AgRP concentration in late pregnancy may be one factor predicting weight change after pregnancy, and circulating AgRP may be physiologically important in the long-term regulation of body weight. Topics: Adiponectin; Adult; Agouti-Related Protein; Body Weight; Female; Humans; Insulin; Leptin; Pregnancy; Receptors, Leptin | 2018 |
Perinatal nicotine exposure increases obesity susceptibility by peripheral leptin resistance in adult female rat offspring.
Maternal nicotine (NIC) exposure causes overweight, hyperleptinemia and metabolic disorders in adult offspring. Our study aims to explore the underlying mechanism of perinatal NIC exposure increases obesity susceptibility in adult female rat offspring. In our model, we found that adult NIC-exposed females presented higher body weight and subcutaneous and visceral fat mass, as well as larger adipocytes, while no change was found in food intake. Serum profile showed a higher serum glucose, insulin and leptin levels in NIC-exposed females. In adipose tissue and liver, the leptin signaling pathway was blocked at 26 weeks, presented lower Janus tyrosine kinase 2 and signal transducer and activator of transcription 3 gene expression, higher suppressor of cytokine signaling 3 gene expression (in adipose tissue) and lower leptin receptors gene expression (in liver), indicating that peripheral leptin resistance occurred in NIC-exposed adult females. In female rats, the expression of lipolysis genes was affected dominantly in adipose tissue, but lipogenesis genes was affected in liver. Furthermore, the glucose and insulin tolerance tests showed a delayed glucose clearance and a higher area under the curve in NIC-exposed females. Therefore, perinatal NIC exposure programed female rats for adipocyte hypertrophy and obesity in adult life, through the leptin resistance in peripheral tissue. Topics: Adipocytes; Animals; Animals, Newborn; Body Weight; Cell Size; Female; Gene Expression; Intra-Abdominal Fat; Leptin; Lipolysis; Liver; Male; Nicotine; Nicotinic Agonists; Obesity; Pregnancy; Rats; Rats, Wistar | 2018 |
The effect of weight change over a 2-year period on inflammatory status in postmenopausal women.
Body fat distribution has been shown to be a predictor of adhesion molecule and inflammatory marker expression albeit the effect of modest weight change on concentrations of adhesion molecules and inflammatory markers in postmenopausal women are not fully understood. The primary aim was to investigate the effects of weight change on adhesion molecules and inflammatory markers over 24 months in postmenopausal women.. Body composition was assessed in 254 healthy postmenopausal women using dual-energy X-ray absorptiometry (DXA). Adhesion molecules and inflammatory markers were analysed by multiplex ELISA. Participants weight gain/loss at 24 months was defined as any value that was either above/below the weight value recorded at baseline.. Postmenopausal women with an average weight loss of 3% had significantly decreased leptin concentrations by 18% at 24 months (P < 0.01). A 4% increase in body weight or a 9% increase in FMI significantly increased intercellular adhesion molecule-1 (ICAM-1), tumour necrosis factor-α (TNF-α) and leptin concentrations in postmenopausal women at 24 months (P < 0.01).. Modest weight loss in postmenopausal women has a lowering effect on leptin concentrations over 24 months which may improve inflammatory status whilst modest weight gain increases ICAM-1, leptin and TNF-α, markers which are associated with a pro-inflammatory state and vascular complications. Topics: Aged; Biomarkers; Body Weight; Cohort Studies; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Leptin; Middle Aged; Postmenopause; Tumor Necrosis Factor-alpha; Weight Gain; Weight Loss | 2018 |
Body weight homeostat that regulates fat mass independently of leptin in rats and mice.
Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat ("gravitostat") that regulates fat mass. Topics: Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Energy Intake; Energy Metabolism; Gene Expression Regulation; Homeostasis; Leptin; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Osteocytes; Rats, Sprague-Dawley; Weight Loss | 2018 |
Gender-Associated Impact of Early Leucine Supplementation on Adult Predisposition to Obesity in Rats.
Early nutrition plays an important role in development and may constitute a relevant contributor to the onset of obesity in adulthood. The aim of this study was to evaluate the long-term impact of maternal leucine (Leu) supplementation during lactation on progeny in rats. A chow diet, supplemented with 2% Leu, was supplied during lactation (21 days) and, from weaning onwards, was replaced by a standard chow diet. Then, at adulthood (6 months of age), this was replaced with hypercaloric diets (either with high-fat (HF) or high-carbohydrate (HC) content), for two months, to induce obesity. Female offspring from Leu-supplemented dams showed higher increases in body weight and in body fat (62%) than their respective controls; whereas males were somehow protected (15% less fat than the corresponding controls). This profile in Leu-females was associated with altered neuronal architecture at the paraventricular nucleus (PVN), involving neuropeptide Y (NPY) fibers and impaired expression of neuropeptides and factors of the mTOR signaling pathway in the hypothalamus. Interestingly, leptin and adiponectin expression in adipose tissue at weaning and at the time before the onset of obesity could be defined as early biomarkers of metabolic disturbance, predisposing towards adult obesity under the appropriate environment. Topics: Adiponectin; Adiposity; Animal Nutritional Physiological Phenomena; Animals; Biomarkers; Blood Glucose; Body Weight; Dietary Supplements; Disease Susceptibility; Female; Hypothalamus; Insulin; Lactation; Leptin; Leucine; Male; Maternal Nutritional Physiological Phenomena; Obesity; Rats; Rats, Wistar; Sex Factors; Weaning | 2018 |
Leptin resistance was involved in susceptibility to overweight in the striped hamster re-fed with high fat diet.
Food restriction (FR) is the most commonly used intervention to prevent the overweight. However, the lost weight is usually followed by "compensatory growth" when FR ends, resulting in overweight. The present study was aimed to examining the behavior patterns and hormones mechanisms underpinning the over-weight. Energy budget and body fat content, and several endocrine markers related to leptin signals were examined in the striped hamsters under 20% FR refed by either low-fat diet (LF group) or high-fat diet (HF group). Body mass and fat content significantly regained when FR ended, and the hamsters in HF group showed 49.1% more body fat than in LF group (P < 0.01). Digestive energy intake was higher by 20.1% in HF than LF group, while metabolic thermogenesis and behavior patterns did not differed between the two groups. Gene expression of leptin receptor and anorexigenic peptides of pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript in hypothalamus were significantly up-regulated in LF group, but down-regulated in HF group. It suggests that effective leptin signals to the brain were involved in attenuation of hyperphagia in hamsters refed with LF. However, "leptin resistance" probably occurred in hamsters refed with HF, which impaired the control of hyperphagia, resulting in development of over-weight. Topics: Adipose Tissue; Animals; Body Weight; Cricetinae; Diet, High-Fat; Dietary Fats; Down-Regulation; Eating; Energy Intake; Hyperphagia; Hypothalamus; Leptin; Male; Overweight; Pro-Opiomelanocortin; Receptors, Leptin; Thermogenesis; Up-Regulation; Weight Loss | 2018 |
Omentectomy Prevents Metabolic Syndrome By Reducing Appetite and Body Weight In A Diet-Induced Obesity Rat Model.
Visceral fat deposition is associated with impairment of glucose and lipid metabolism while leptin levels are frequently related to subcutaneous fat area. At present, there is considerable controversy regarding the role of visceral adipose tissue accumulation in the development of metabolic syndrome (MS). Here we show the effects of omentectomy on the liver and MS in a diet induced obesity rat model. Our results reveal that undergoing omentectomy previously the establishment of the diet-induced-obesity reduced significantly body weight gain and avoid the development of MS, including non-alcoholic fatty liver disease. Intriguingly, the significantly lower body weight gain was due to decreased food intake. Omentum drives obesity progression through leptin resistance mediated by C-reactive protein, Interleucin (IL)-6 and high lipolysis activity. Omentum removal reversed immediately the increased plasma levels of CRP and IL-6 and gradually food intake, weight gain, and features of MS in diet-induced-obesity. Omentectomy caused no changes in normal-weigh-rats. This report displays causal mechanism by which omentum promotes obesity and propose omentectomy as a promising procedure in MS prevention. Topics: Adipogenesis; Animals; Appetite; Body Weight; C-Reactive Protein; Disease Models, Animal; Interleukin-6; Leptin; Metabolic Syndrome; Obesity; Omentum; Rats; Surgical Procedures, Operative; Treatment Outcome | 2018 |
Central and peripheral effects of physical exercise without weight reduction in obese and lean mice.
To investigate the central (hypothalamic) and peripheral effects of exercise without body weight change in diet-induced obesity (DIO). Twelve-week-old male C57Bl/6 mice received a control (C) or a high-fat diet (H). Half of them had free access to running wheels for 5 days/week for 10 weeks (CE) and HE, respectively). Hypothalamic expression of genes related to energy homeostasis, and leptin (Stat3 and p-Stat3) and insulin (Akt and p-Akt) signaling were evaluated. Glucose and leptin tolerance, peripheral insulin sensitivity, and plasma insulin, leptin and adiponectin were determined. Perigonadal and retroperitoneal fat depots were increased by diet but reduced by exercise despite lack of effect of exercise on body weight. Blood glucose during intraperitoneal glucose tolerance test (ipGTT) was higher and glucose decay during intraperitoneal insulin tolerance test (ipITT) was lower in H and HE compared with C and CE. Exercise increased liver p-Akt expression and reduced fast glycemia. High-fat diet increased plasma insulin and leptin. Exercise had no effect on insulin but decreased leptin and increased adiponectin. Leptin inhibited food intake in all groups. Hypothalamic total and p-Stat3 and Akt were similar amongst the groups despite higher plasma levels of leptin and insulin in H and HE mice. High-fat diet modulated gene expression favoring a positive energy balance. Exercise only marginally changed the gene expression. Exercise induced positive changes (decreased fast glycemia and fat depots; increased liver insulin signaling and adiponectin concentration) without weight loss. Thus, despite reducing body weight could bring additional benefits, the effects of exercise must not be overlooked when weight reduction is not achieved. Topics: Animals; Body Weight; Dietary Fats; Gene Expression Regulation; Hypothalamus; Insulin; Leptin; Male; Mice; Obesity; Physical Conditioning, Animal; Proto-Oncogene Proteins c-akt; STAT3 Transcription Factor | 2018 |
The antidepressant fluoxetine acts on energy balance and leptin sensitivity via BDNF.
Topics: Adipose Tissue, White; Animals; Antidepressive Agents; Body Weight; Brain-Derived Neurotrophic Factor; Energy Metabolism; Fluoxetine; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Receptor, trkB; Weight Gain | 2018 |
Fat feeding facilitates hot bodies, but is resistance futile?
Topics: Body Weight; Carotid Body; Diet, High-Fat; Dietary Fats; Humans; Leptin | 2018 |
Apelin-13 increased food intake with serum ghrelin and leptin levels in male rats.
In this study, we aimed to explain the role of apelin-13 on body weight, food and water intake with serum leptin, ghrelin, neuropeptid Y (NPY) and peptid YY (PYY) levels in male rat. Thirty-two Sprague-Dawley male rats were used for the study. The rats were injected SP (0.9 %) intraperitoneally (i.p) in the control group and 30 (AP30), 100 (AP100) and 300 (AP300) µg/kg apelin-13 in the study groups, respectively, 10 min before the transition to dark period, for 10 days. During the experimental period, with light and dark periods of food and water intake, body weights were recorded in rats. Rats were euthanized and serum samples were obtained. In serum samples leptin, ghrelin, NPY and PYY levels were measured with specific ELISA kit. Apelin-13 was increased body weights in all three (AP30, AP100 and AP300) groups compared with the control group. AP100 and AP300 groups had increased food intake in the dark and the cumulative period, but in the light period food intake values were not significantly increased (p > 0.05). As for the value of water intake, compared with the control group, all dose of apelin-13 increased water intake during the dark and the cumulative period. There was no significant change in water intake in the light period. On the other hand, compared with the control group, serum leptin levels were found to increase in the groups administered 100 and 300 µg/kg of apelin-13 (p < 0.05). Ghrelin levels were found high in all groups treated with apelin-13. Serum levels of NPY decreased only in the 300 µg/kg apelin-13 treated group (p 0.05). Apelin-13 increases body weight in rats as well as food and water intake (dark and cumulative period). Additionally, ghrelin can mediate the orexigenic effect of apelin-13 in the regulation of food intake (Fig. 4, Ref. 37). Topics: Animals; Apelin; Body Weight; Eating; Ghrelin; Leptin; Male; Rats; Rats, Sprague-Dawley | 2018 |
Regulation of compensatory growth by molecular mechanism in Labeo rohita juveniles under different feeding regimes.
A study was carried out to assess the regulation of compensatory growth under different restriction feeding regimes in Labeo rohita juveniles by the interaction of various feed intake and growth regulating genes. A 60 day feeding trial was conducted with five treatment groups, Control (3% body weight, bw), T1 (alternate days), T2 (0.5% bw), T3 (1% bw) and T4 (2% bw) and feeding was done for first 30 days of the trial. For next 30 days, all the treatment groups were fed at a rate of 3% bw as in the control group. There was significant (p < 0.05) difference in the weight gain among the treatment groups with lowest FCR and highest PER was found in T2 group. Ghrelin gene mRNA levels were upregulated during first 30th days of the trial with highest expression levels in the T2 group. The expression levels of leptin gene mRNA were found significantly different (p < 0.05) among the treatments, which was down-regulated during initial 30 days and upregulated as the experiment progress towards 60th day. The IGF-1 mRNA expression levels were upregulated more in liver compared to the muscle tissue. The results of the study suggest that increased ghrelin levels and decreased leptin levels lead to hyperphagia during the onset of refeeding, which further triggers the compensatory growth in L. rohita. The present study describes the molecular mechanism behind the compensatory growth following a different feed restriction regime in L. rohita which is regulated due to the interaction of different energy homeostasis and growth regulating genes. Topics: Animals; Body Weight; Cyprinidae; Feeding Behavior; Gene Expression Regulation; Ghrelin; Insulin-Like Growth Factor I; Leptin; Liver; Receptors, Ghrelin; RNA, Messenger | 2018 |
Acute anti-obesity effects of intracerebroventricular 11β-HSD1 inhibitor administration in diet-induced obese mice.
The hypothalamus is the regulatory centre of both appetite and energy balance and endoplasmic reticulum (ER) stress in the hypothalamus is involved in the pathogenesis of obesity. Recently, inhibition of 11 β hydroxysteroid dehydrogenase type1 (11β-HSD1) was reported to have an anti-obesity effect by reducing fat mass. However, the link between the role of 11β-HSD1 in the hypothalamus and obesity has yet to be determined. In the present study, embryonal primary hypothalamic neurones and high-fat diet (HFD) fed mice were used to investigate the anorexigenic effects of 11β-HSD1 inhibitors both in vitro and in vivo. In hypothalamic neurones, carbenoxolone (a non selecitve 11β-HSD inhibitor) alleviated ER stress and ER stress-induced neuropeptide alterations. In HFD mice, i.c.v. administration of carbenoxolone or KR67500 (nonselective and selective 11β-HSD1 inhibitors, respectively) was associated with less weight gain compared to control mice for 24 hours after treatment, presumably by reducing food intake. Furthermore, glucose regulated protein (Grp78), spliced X-box binding protein (Xbp-1s), c/EBP homologous protein (chop) and ER DnaJ homologue protein (Erdj4) expression was decreased in the hypothalami of mice administrated 11β-HSD1 inhibitors compared to controls. Conversely, the phosphorylation of protein kinase B (PKB/Akt), signal transducer and activator of transcription 3 (Stat3), mitogen-activated protein kinase (MAPK/ERK) and S6 kinase1 (S6K1) in the hypothalamus was induced more in mice treated using the same regimes. In conclusion, acute 11β-HSD1 inhibition in the hypothalamus could reduce food intake by decreasing ER stress and increasing insulin, leptin, and mammalian target of rapamycin complex 1 (mTORC1) signalling. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Anti-Obesity Agents; Body Weight; Carbenoxolone; Diet, High-Fat; Eating; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Hypothalamus; Injections, Intraventricular; Insulin; Leptin; Male; Mechanistic Target of Rapamycin Complex 1; Membrane Glycoproteins; Mice; Neurons; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; X-Box Binding Protein 1 | 2018 |
Physical exercise mitigates high-fat diet-induced adiposopathy and related endocrine alterations in an animal model of obesity.
The dysregulation of adipokine secretion owing to adiposopathy can contribute to the pathogenesis of obesity-related disorders. Being that exercise is an advised strategy against obesity-induced adiposopathy, we aimed to analyze the role of physical exercise as a preventive and therapeutic strategy against high-fat diet (HFD)-induced adipokine and ghrelin alterations. Rats were pair-fed the Lieber De Carli standard diet (S, 35 Kcal% fat) or HFD (71 Kcal% fat) over 17 weeks. Animals were assigned into four groups as follows: standard diet sedentary (SS), standard diet voluntary physical activity (SVPA), high-fat diet sedentary (HS), and high-fat diet voluntary physical activity (HVPA). After 9 weeks of dietary treatment, half of the SS and HS animals were submitted to an 8-week endurance training program, standard diet endurance training (SET), and high-fat-diet endurance training (HET) groups, maintaining the respective diets. Although there were no changes in body weight, HFD increased visceral adiposity, percentage of large adipocytes, hypoxia inducible factor (HIF)-1α, and leptin contents in epididymal adipose tissue (eWAT) and decreased plasma content of adiponectin (AdipQ). Both VPA and ET decreased visceral adiposity and percentage of large adipocytes in HFD-fed animals, but ET also increased the percentage of small- to medium-sized adipocytes. VPA increased plasma growth hormone secretagogue receptor (GHS-R) and decreased leptin protein in HVPA group. ET decreased plasma insulin and leptin levels and eWAT HIF-1α and leptin expression in HET group. Moreover, ET improved insulin sensitivity, plasma high molecular weight, and AdipQ and ghrelin levels and increased eWAT and GHS-R expression. Our data suggest that exercise, particularly ET, reverted adiposopathy and related endocrine alterations induced by an isocaloric HFD pair-fed diet. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Endocrine System; Ghrelin; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Insulin Resistance; Leptin; Male; Obesity; Physical Conditioning, Animal; Rats, Sprague-Dawley; Receptors, Ghrelin; Vascular Endothelial Growth Factor A | 2018 |
Differential effect of dietary vitamin D supplementation on natural killer cell activity in lean and obese mice.
Vitamin D has an immunoregulatory effect on both innate and adaptive immunity. Contradictory results regarding vitamin D and natural killer (NK) cell functions have been reported with in vitro studies, but little is known about this in vivo. We investigated whether vitamin D levels (50, 1000 or 10,000 IU/kg of diet: DD, DC or DS) affect NK cell functions in mice fed a control or high-fat diet (10% or 45% kcal fat: CD or HFD) for 12 weeks. The splenic NK cell activity was significantly higher in the CD-DS group than the HFD-DS group, and the CD-DS group showed significantly higher NK cell activity compared with the CD-DD and CD-DC groups. However, no difference in NK cell activity was observed among the HFD groups fed different levels of vitamin D. The splenic population of NK cells was significantly higher in the CD-DS group than the HFD-DS group. There was no difference in the intracellular expression of IFN-γ and the surface expression of NKG2D and CD107a in NK cells by both dietary fat and vitamin D content. The splenic mRNA expression of Ifng and Ccl5 was significantly lower in the HFD groups compared with the CD groups, but there was no difference in the mRNA levels of Vdup1 and Vdr among the groups. Taken together, these results suggest that dietary vitamin D supplementation can modulate innate immunity by increasing NK activity in control mice but not in obese mice. This effect might be mediated through alternation of the splenic NK cell population. Topics: Adipose Tissue; Animals; Body Weight; Cytokines; Diet, High-Fat; Dietary Supplements; Gene Expression Regulation; Interferon-gamma; Killer Cells, Natural; Leptin; Lysosomal Membrane Proteins; Male; Mice, Inbred C57BL; NK Cell Lectin-Like Receptor Subfamily K; Obesity; Spleen; Vitamin D | 2018 |
SRT1720 attenuates obesity and insulin resistance but not liver damage in the offspring due to maternal and postnatal high-fat diet consumption.
Recent studies indicate that sirtuin-1 (SIRT1), an important metabolic sensor and regulator of life span, plays a mechanistic role in maternal obesity-induced programming of metabolic disorders in the offspring. In this study we investigate whether SIRT1 activation in early childhood can mitigate metabolic disorders due to maternal and postnatal high-fat feeding in mice. Male offspring born to chow-fed (MC) or high fat diet-fed dams (MHF) were weaned onto postnatal chow or high-fat diet and treated with SRT1720 (25 mg/kg ip every 2 days) or vehicle control for 6 wk and examined for metabolic disorders. MHF exacerbated offspring body weight and insulin resistance in the offspring exposed to postnatal HFD (OHF). These metabolic changes were associated with reduced hepatic lipid droplet accumulation but increased plasma levels of alanine aminotransferase (ALT), a marker of liver damage. SRT1720 significantly decreased offspring body weight, adiposity, glucose intolerance, and hyperleptinemia due to OHF and reversed hyperinsulinemia and adipocyte hypertrophy due to the additive effects of MHF. Although SRT1720 suppresses liver lipogenesis, inflammation, and oxidative stress markers, it also reduces antioxidants and increased liver collagen deposition in OHF offspring independent of MHF. Hepatic steatosis was attenuated only in MC/OHF offspring in association with elevated plasma ALT levels. The study suggests that postnatal SRT1720 administration can mitigate obesity and insulin resistance in the offspring due to maternal and postnatal HFD exposure. However, the possibility of liver toxicity needs to be further examined. Topics: Alanine Transaminase; Animals; Animals, Newborn; Anti-Obesity Agents; Body Weight; Cell Size; Chemical and Drug Induced Liver Injury; Diet; Diet, High-Fat; Female; Hepatocytes; Heterocyclic Compounds, 4 or More Rings; Insulin Resistance; Leptin; Lipid Metabolism; Male; Mice; Obesity; Pregnancy; Prenatal Exposure Delayed Effects | 2018 |
Effects of chronic testosterone administration on the degree of preference for a high-fat diet and body weight in gonadal-intact and ovariectomized female rats.
Energy balance and reproductive functions are closely linked in some species. The sex hormones (estrogens and androgens) are involved in the regulation of appetite, metabolism, body weight (BW), and body composition in mammals. Previously, we showed that the effects of testosterone on BW, appetite, and fat weight were markedly affected by alterations to the gonadal hormonal milieu. In this study, we examined whether testosterone administration changes food preferences and whether these effects of testosterone depend on gonadal status in female rats. We also evaluated the underlying mechanisms responsible for these effects, focusing on hypothalamic inflammation and endoplasmic reticulum (ER) stress. In gonadal-intact (sham) female rats, chronic testosterone administration promoted a preference for a high-fat diet (HFD) and increased BW gain, fat weight, and adipocyte size, whereas no such effects were observed in ovariectomized (OVX) rats. Testosterone administration increased hypothalamic interleukin-1 mRNA expression in the sham rats, but not the OVX rats. On the contrary, testosterone administration decreased the hypothalamic mRNA levels of ER stress-response genes in the OVX rats, but not the sham rats. These testosterone-induced alterations in OVX rats might represent a regulatory mechanism for preventing hypothalamic inflammation and the overconsumption of a HFD. In conclusion, testosterone's effects on food preferences and the subsequent changes were affected by gonadal status. Testosterone-induced changes in hypothalamic inflammatory cytokine production and ER stress might be related to these findings. Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Feeding Behavior; Female; Hypothalamus; Interleukin-1; Leptin; Ovariectomy; Random Allocation; Rats, Sprague-Dawley; RNA, Messenger; Testosterone | 2018 |
mTORC1 pathway disruption abrogates the effects of the ciliary neurotrophic factor on energy balance and hypothalamic neuroinflammation.
Ciliary neurotrophic factor (CNTF) potently decreases food intake and body weight in diet-induced obese mice by acting through neuronal circuits and pathways located in the arcuate nucleus (ARC) of the hypothalamus. CNTF also exerts pro-inflammatory actions within the brain. Here we tested whether CNTF modifies energy balance by inducing inflammatory responses in the ARC and whether these effects depend upon the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which regulates both energy metabolism and inflammation. To this purpose, chow- and high fat diet (HFD)- fed mice lacking the S6 kinase 1 (S6K1 Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Ciliary Neurotrophic Factor; Diet, High-Fat; Eating; Energy Metabolism; Homeostasis; Hypothalamus; Leptin; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Neuroglia; Neuroimmunomodulation; Obesity; Ribosomal Protein S6 Kinases, 70-kDa | 2018 |
Food Restriction is Required to Preserve the Antisteatotic Effects of Central Leptin in the Liver of Middle-Aged Rats.
Aging is a significant risk factor for the development of obesity and hepatic steatosis associated with insulin and leptin resistance. Food restriction (FR) is commonly used for reducing body weight (BW), adiposity, and liver steatosis. Thus, this study aimed to determine whether FR in middle-aged rats can recover the central leptin antisteatotic effects observed in the liver in young animals.. Two groups of 4-month-old Wistar rats were fed ad libitum (AL) or were on FR for 3 months. At 7 months of age, both groups were centrally treated with rat leptin (0.2 μg/d, 7 days) or saline.. Central leptin reduced food intake and BW, but not the hepatic triglyceride content, in 7-month-old rats fed AL. However, in 7-month-old FR rats, leptin did not affect BW but markedly reduced serum leptin, serum and hepatic triglyceride levels, and the expression of hepatic lipogenic genes. In addition, central leptin decreased serum and hepatic endogenous norepinephrine levels of FR rats, exerting a homeostatic effect beyond its antisteatotic actions.. These findings suggest that in middle-aged rats, moderate FR is required for both preserving the antisteatotic actions of central leptin and avoiding excessive weight loss. Topics: Animals; Body Weight; Eating; Fatty Liver; Leptin; Male; Rats; Rats, Wistar | 2018 |
Geranylgeranylacetone prevents stress-induced decline of leptin secretion in mice.
Geranylgeranylacetone (GGA) is a chaperon inducer that protects various types of cell and tissue against stress. We examined whether GGA modulated energy intake and expenditure under stressful conditions. After mice were untreated or treated orally with GGA (0.16 g per kg body weight per day) for 10 days, they were subjected to 2-h restraint stress once or once a day for 5 consecutive days. GGA administration did not affect corticosterone response to the stress. Restraint stress rapidly decreased plasma leptin levels in control mice. GGA significantly increased circulating leptin levels without changing food intake and prevented the stress-induced decline of circulating leptin. However GGA-treated mice significantly reduced food intake during the repeated stress, compared with control mice. GGA prevented the stress-induced decline of leptin mRNA and its protein levels in epidydimal adipose tissues. We also found that GGA decreased ghrelin mRNA expression in gastric mucosa before the stress, whereas GGA-treated mice recovered the ghrelin mRNA expression to the baseline level after the repeated stress. Leptin and ghrelin are now recognized as regulators of anxiety and depressive mood. Our results suggest that GGA may regulate food intake and relief stress-induced mood disturbance through regulating leptin and ghrelin secretions. J. Med. Invest. 65:103-109, February, 2018. Topics: Animals; Body Weight; Diterpenes; Eating; Ghrelin; HSP70 Heat-Shock Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Stress, Psychological | 2018 |
The Effect of SH2B1 Variants on Expression of Leptin- and Insulin-Induced Pathways in Murine Hypothalamus.
We aimed to determine the effect of human SH2B1 variants on leptin and insulin signaling, major regulators of energy homeostasis, on the RNA level.. We analyzed the expression of infrequent alleles of seven SH2B1 variants (Arg67Cys, Lys150Arg, Thr175Ala, Thr343Met, Thr484Ala, Ser616Pro and Pro689Leu) in response to insulin or leptin cell stimulation. Two of these were identified in own mutation screens, the others were predicted to be deleterious or to serve as controls. The variants were analyzed in a homologous system of mouse hypothalamic cells. Changes in expression of downstream genes were measured. Student’s t-test for independent samples was applied and effect sizes using Cohen’s d were calculated.. In 34 of 54 analyzed genes involved in leptin (JAK/STAT or AKT) signaling, variants nominally changed expression. The expression of three genes was considerably increased (p values ≤ 0.001: Gbp2b (67Cys; d = 25.11), Irf9 (689Leu; d = 44.65) and Isg15 (150Arg; d = 20.35)). Of 32 analyzed genes in the insulin signaling pathway, the expression of 10 genes nominally changed (p ≤ 0.05), three resulted in p values ≤ 0.01 ( Cap1 (150Arg; d = 7.48), Mapk1 (343Met; d = –6.80) and Sorbs1 (689Leu; d = 7.82)).. The increased expression of genes in leptin (JAK/STAT or AKT) signaling implies that the main mode of action for human SH2B1 mutations might affect leptin signaling rather than insulin signaling. Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Animals; Body Weight; Cells, Cultured; Female; Gene Expression Regulation; Humans; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Knockout; Mutation; Signal Transduction; Young Adult | 2018 |
Vitamin D Status and Cardiovascular Risk in Obesity: Effect of Physical Activity in Nonvitamin D Supplemented Adolescents.
The relationship among inadequate vitamin D status, obesity, and cardiometabolic risk and the potential impact of physical activity-based interventions on vitamin D status are poorly characterized in children. This study aimed to address these issues.. We studied a total of 21 adolescents (15 obese and 6 normal weight; age: 14-18 years; Tanner stage>IV). Adolescents with obesity (n = 15) underwent a randomized controlled (8 in the intervention group and 7 in the control group) 3-month physical activity-based lifestyle intervention. 25-Hydroxy vitamin D [25(OH)D] by mass spectrometry, adiponectin, leptin, high-sensitivity C-reactive protein (CRP), insulin, and glucose were measured and body composition was assessed by dual-energy x-ray absorptiometry (DXA). Analysis of covariance and mixed-effects model were used to compare mean change in 25(OH)D between intervention and nonintervention groups. Bootstrap method was used to validate the estimates and principle component analysis reduced the variables in the data for adjustment.. 25(OH)D was lower (P < 0.001) in the obese versus lean adolescents. Homeostasis model assessment-insulin resistance, CRP, fat mass (FM), and body mass index z-score were negatively correlated with baseline 25(OH)D, while adiponectin showed a positive correlation. After adjustment for baseline biomarkers of cardiometabolic risk, the concentration of 25(OH)D increased in the obese intervention group (P = 0.06), but not in the nonintervention group. Fat-free mass increased and FM decreased (P < 0.05 for both) in the intervention group. The magnitudes of increase in 25(OH)D and decrease in FM directly correlated (P < 0.05).. The increase in circulating 25(OH)D concentration by physical activity-based lifestyle-only intervention in adolescents with obesity, who did not receive vitamin D supplementation, suggests a putative independent role of physical activity-based interventions in the regulation of vitamin D status and potentially in the mitigation of risk factors of cardiovascular disease. Topics: Adiponectin; Adolescent; Blood Glucose; Body Composition; Body Mass Index; Body Weight; C-Reactive Protein; Cardiovascular Diseases; Exercise; Female; Homeostasis; Humans; Insulin; Leptin; Life Style; Male; Mass Spectrometry; Pediatric Obesity; Risk Factors; Vitamin D | 2018 |
Genetic identification of leptin neural circuits in energy and glucose homeostases.
Leptin, a hormone produced in white adipose tissue, acts in the brain to communicate fuel status, suppress appetite following a meal, promote energy expenditure and maintain blood glucose stability Topics: Agouti-Related Protein; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Eating; Energy Metabolism; Female; GABAergic Neurons; Gene Editing; Homeostasis; Hyperglycemia; Hyperphagia; Leptin; Male; Mice; Neural Pathways; Neurons; Obesity; Potassium Channels; Presynaptic Terminals; Receptors, Leptin; Satiety Response | 2018 |
Novel fatty acid chain modified GLP-1 derivatives with prolonged in vivo glucose-lowering ability and balanced glucoregulatory activity.
Glucagon-like peptide-1 is a potent hypoglycemic hormone with beneficial properties for the treatment of diabetes. However, its half-life is short because the rapid metabolic degradation. This study aims to prolong the half-life of glucagon-like peptide-1 through conjugation with the fatty acid side chain which helps the conjugates to interact with the albumin. Firstly, we chose two optimized polypeptide chains which have tremendous hypoglycemic effect named Cys Topics: Adipocytes; Adiponectin; Animals; Blood Glucose; Body Weight; Cell Survival; Drug Stability; Fatty Acids; Glucagon-Like Peptide 1; Half-Life; HEK293 Cells; Humans; Hypoglycemic Agents; Leptin; Lipopeptides; Liraglutide; Male; Mice, Inbred C57BL; Molecular Structure; Pancreas; Rats, Sprague-Dawley; Serum Albumin, Human | 2018 |
Dietary challenges differentially affect activity and sleep/wake behavior in mus musculus: Isolating independent associations with diet/energy balance and body weight.
Associated with numerous metabolic and behavioral abnormalities, obesity is classified by metrics reliant on body weight (such as body mass index). However, overnutrition is the common cause of obesity, and may independently contribute to these obesity-related abnormalities. Here, we use dietary challenges to parse apart the relative influence of diet and/or energy balance from body weight on various metabolic and behavioral outcomes.. Seventy male mice (mus musculus) were subjected to the diet switch feeding paradigm, generating groups with various body weights and energetic imbalances. Spontaneous activity patterns, blood metabolite levels, and unbiased gene expression of the nutrient-sensing ventral hypothalamus (using RNA-sequencing) were measured, and these metrics were compared using standardized multivariate linear regression models.. Spontaneous activity patterns were negatively related to body weight (p<0.0001) but not diet/energy balance (p = 0.63). Both body weight and diet/energy balance predicted circulating glucose and insulin levels, while body weight alone predicted plasma leptin levels. Regarding gene expression within the ventral hypothalamus, only two genes responded to diet/energy balance (neuropeptide y [npy] and agouti-related peptide [agrp]), while others were related only to body weight.. Collectively, these results demonstrate that individual components of obesity-specifically obesogenic diets/energy imbalance and elevated body mass-can have independent effects on metabolic and behavioral outcomes. This work highlights the shortcomings of using body mass-based indices to assess metabolic health, and identifies novel associations between blood biomarkers, neural gene expression, and animal behavior following dietary challenges. Topics: Agouti-Related Protein; Animals; Behavior, Animal; Biomarkers; Body Weight; Circadian Rhythm; Diet; Energy Intake; Energy Metabolism; Gene Expression; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Sleep; Wakefulness | 2018 |
Time-resolved hypothalamic open flow micro-perfusion reveals normal leptin transport across the blood-brain barrier in leptin resistant mice.
The inability of leptin to suppress food intake in diet-induced obesity, sometimes referred to as leptin resistance, is associated with several distinct pathological hallmarks. One prevailing theory is that impaired transport of leptin across the blood-brain barrier (BBB) represents a molecular mechanism that triggers this phenomenon. Recent evidence, however, has challenged this notion, suggesting that leptin BBB transport is acquired during leptin resistance.. To resolve this debate, we utilized a novel cerebral Open Flow Microperfusion (cOFM) method to examine leptin BBB transport in male C57BL/6J mice, fed a chow diet or high fat diet (HFD) for 20 days.. Basal plasma leptin levels were 3.8-fold higher in HFD-fed mice (p < 0.05). Leptin administration (2.5 mg/kg) elicited similar pharmacokinetic profiles of circulating leptin. However, while leptin reduced food intake by 20% over 22 h in chow-fed mice, it did not affect food intake in HFD-fed mice. In spite of this striking functional difference, hypothalamic leptin levels, as measured by cOFM, did not differ between chow-fed mice and HFD-fed mice following leptin administration.. These data suggest that leptin transport across the BBB is not impaired in non-obese leptin resistant mice and thus unlikely to play a direct role in the progression of pharmacological leptin resistance. Topics: Animals; Biological Transport; Blood-Brain Barrier; Body Weight; Diet, High-Fat; Eating; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Perfusion Imaging | 2018 |
Leptin Aggravates Reflux Esophagitis by Increasing Tissue Levels of Macrophage Migration Inhibitory Factor in Rats.
Leptin, produced primarily by the adipose tissue, acts as a pro-inflammatory modulator, thereby contributing to the development of obesity-related disease. Although high levels of leptin in the obese are closely related to gastroesophageal reflux disease, the mechanism by which leptin influences esophageal inflammation remains unknown. Macrophage migration inhibitory factor (MIF) is produced by immune cells, such as T lymphocytes and macrophages, and MIF is known to induce the production of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6). We therefore investigated the mechanism whereby leptin aggravates reflux esophagitis, by focusing on esophageal tissue levels of MIF and CD3+ T lymphocytes, both of which are crucial for the reflux-induced epithelial damage. Esophageal inflammation was surgically induced in male Wistar rats by ligating the forestomach and narrowing the duodenum to facilitate gastroesophageal reflux, followed by administration of leptin or vehicle with an osmotic pump system for 1 week. We demonstrated that the administration of leptin exacerbated the reflux esophagitis with the apparent infiltration of CD3+ T lymphocytes and caused the significant increase in the esophageal tissue levels of MIF. Moreover, the leptin caused increases in the esophageal tissue levels of TNF-α, IL-1β and IL-6, downstream targets of MIF. Importantly, the increases in these pro-inflammatory cytokines were accompanied by increased protein levels of phospho-STAT3 and phospho-AKT, pivotal molecules of leptin signaling pathways. In conclusion, through enhancing the MIF-induced inflammatory signaling, leptin could contribute to the development of gastroesophageal reflux disease. Topics: Animals; Body Weight; CD3 Complex; Cytokines; Disease Models, Animal; Esophagitis, Peptic; Esophagus; Feeding Behavior; Inflammation Mediators; Leptin; Macrophage Migration-Inhibitory Factors; Male; Proto-Oncogene Proteins c-akt; Rats, Wistar; Signal Transduction; STAT3 Transcription Factor; T-Lymphocytes | 2018 |
Preoptic leptin signaling modulates energy balance independent of body temperature regulation.
The adipokine leptin acts on the brain to regulate energy balance but specific functions in many brain areas remain poorly understood. Among these, the preoptic area (POA) is well known to regulate core body temperature by controlling brown fat thermogenesis, and we have previously shown that glutamatergic, long-form leptin receptor (Lepr)-expressing neurons in the POA are stimulated by warm ambient temperature and suppress energy expenditure and food intake. Here we further investigate the role of POA leptin signaling in body weight regulation and its relationship to body temperature regulation in mice. We show that POA Lepr signaling modulates energy expenditure in response to internal energy state, and thus contributes to body weight homeostasis. However, POA leptin signaling is not involved in ambient temperature-dependent metabolic adaptations. Our study reveals a novel cell population through which leptin regulates body weight. Topics: Animals; Body Temperature Regulation; Body Weight; Energy Metabolism; Homeostasis; Leptin; Mice; Preoptic Area; Signal Transduction | 2018 |
The overweight increases circulating inflammatory mediators commonly associated with obesity in young individuals.
Obesity is a serious and growing world healthy problem affecting developed and developing countries. The new conception of obesity as a basal inflammatory condition has opened a new window of possibilities to identify inflammatory biomarkers to be used in the diagnosis or prognosis of obesity-associated comorbidities. This present work aims the identification of the adipokines (leptin and resistin), chemokines (CCL2, CCL5, CXCL16) and the BMP-2 and their association with the clinical, biochemical (fasting glucose, hemogram, cholesterol, T3, T4 and TSH) and anthropometric (weight, height, body circumferences, skinfold thickness and percentage of body fat) parameters in young adults (18-30 years old) presenting obesity and overweight. Our data showed increasing in anthropometric parameters and in the plasma inflammatory levels in those individuals presenting overweight and obesity. We observed a higher plasma levels of CCL2, CCL5, CXCL16, leptin and resistin in those overweigh and obese individuals. In addition, the CCL2, CCL5 presented a positive correlation with the body mass index and the body fat percentage. Assuming the obesity as a systemic inflammatory process, in this current study, the overweight individuals possess a close similar pattern of circulating inflammatory mediators which might be a potential risk of the development of obesity comorbidities. Further studies are still needed to precise the role of the biomarkers CCL2, CCL5, CXCL16 and BMP-2 in the clinical prognosis related to the overweight or obese individuals. Topics: Adipokines; Adiponectin; Adolescent; Adult; Biomarkers; Body Mass Index; Body Weight; Chemokines; Female; Humans; Inflammation; Inflammation Mediators; Leptin; Male; Obesity; Overweight; Resistin; Young Adult | 2018 |
The Gravitostat Regulates Fat Mass in Obese Male Mice While Leptin Regulates Fat Mass in Lean Male Mice.
Leptin has been the only known homeostatic regulator of fat mass, but we recently found evidence for a second one, named the gravitostat. In the current study, we compared the effects of leptin and increased loading (gravitostat stimulation) on fat mass in mice with different levels of body weight (lean, overweight, and obese). Leptin infusion suppressed body weight and fat mass in lean mice given normal chow but not in overweight or obese mice given a high-fat diet for 4 and 8 weeks, respectively. The maximum effect of leptin on body weight and fat mass was obtained already at <44 ng/mL of serum leptin. Increased loading using intraperitoneal capsules with different weights decreased body weight in overweight and obese mice. Although the implantation of an empty capsule reduced the body weight in lean mice, only a nonsignificant tendency of a specific effect of increased loading was observed in the lean mice. These findings demonstrate that the gravitostat regulates fat mass in obese mice, whereas leptin regulates fat mass only in lean mice with low endogenous serum leptin levels. We propose that activation of the gravitostat primarily protects against obesity, whereas low levels of leptin protect against undernutrition. Topics: Adipose Tissue; Animals; Body Weight; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Overweight; Thinness | 2018 |
Time course metabolome of Roux-en-Y gastric bypass confirms correlation between leptin, body weight and the microbiome.
Roux-en-Y gastric bypass (RYGB) is an effective way to lose weight and reverse type 2 diabetes. We profiled the metabolome of 18 obese patients (nine euglycemic and nine diabetics) that underwent RYGB surgery and seven lean subjects. Plasma samples from the obese patients were collected before the surgery and one week and three months after the surgery. We analyzed the metabolome in association to five hormones (Adiponectin, Insulin, Ghrelin, Leptin, and Resistin), four peptide hormones (GIP, Glucagon, GLP1, and PYY), and two cytokines (IL-6 and TNF). PCA showed samples cluster by surgery time and many microbially driven metabolites (indoles in particular) correlated with the three months after the surgery. Network analysis of metabolites revealed a connection between carbohydrate (mannosamine and glucosamine) and glyoxylate and confirms glyoxylate association to diabetes. Only leptin and IL-6 had a significant association with the measured metabolites. Leptin decreased immediately after RYGB (before significant weight loss), whereas IL-6 showed no consistent response to RYGB. Moreover, leptin associated with tryptophan in support of the possible role of leptin in the regulation of serotonin synthesis pathways in the gut. These results suggest a potential link between gastric leptin and microbial-derived metabolites in the context of obesity and diabetes. Topics: Body Weight; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Humans; Interleukin-6; Leptin; Metabolomics; Microbiota; Obesity; Time Factors | 2018 |
Phosphorus restriction does not prevent the increase in fibroblast growth factor 23 elicited by high fat diet.
This study was designed to evaluate the influence of phosphorus (P) restriction on the deleterious effects of high fat diets on mineral metabolism. Twenty-four rats were allotted to 3 groups (n = 8 each) that were fed different diets for 7 months. Rats in group 1 were fed normal fat-normal P (0.6%) diet (NF-NP), rats in group 2 were fed high fat- normal P diet (HF-NP) and rats in group 3 were fed high fat-low P (0.2%) diet (HF-LP). Blood, urine and tissues were collected at the end of the experiments. When compared with the control group (NF-NP), rats fed HF diets showed increases in body weight, and in plasma concentrations of triglycerides and leptin, and decreased plasma calcitriol concentrations. In rats fed HF-NP plasma fibroblast growth factor 23 (FGF23) was higher (279.6±39.4 pg/ml vs 160.6±25.0 pg/ml, p = 0.018) and renal klotho (ratio klotho/GAPDH) was lower (0.75±0.06 vs 1.06±0.08, p<0.01) than in rats fed NF-NP. Phosphorus restriction did not normalize plasma FGF23 or renal klotho; in fact, rats fed HF-LP, that only ingested an average of 22.9 mg/day of P, had higher FGF23 (214.7±32.4 pg/ml) concentrations than rats fed NF-NP (160.6±25.0 pg/ml), that ingested and average of 74.4 mg/day of P over a 7 month period. In conclusion, our results demonstrate that severe P restriction over a prolonged period of time (7 months) does not normalize the increase in circulating FGF23 induced by HF diets. These data indicate that the deleterious effects of high fat diet on the FGF23/klotho axis are not eliminated by reduced P intake. Topics: Animals; Body Weight; Diet, High-Fat; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Kidney; Klotho Proteins; Leptin; Phosphorus, Dietary; Rats; Rats, Wistar; Triglycerides | 2018 |
Qing Gan Zi Shen Tang alleviates adipose tissue dysfunction with up-regulation of SIRT1 in spontaneously hypertensive rat.
Qing Gan Zi Shen Tang (QGZST) is a famous traditional Chinese medicine formula in the Jiangsu Province Hospital of Traditional Chinese Medicine for its efficacy in treating hypertension, obesity, hyperlipidemia and insulin resistance. The current study further evaluated the effects and possible mechanisms of QGZST on epididymal white adipose tissue (eWAT) dysfunction in a high-fat-diet (HFD)-fed-spontaneously hypertensive rat (SHR) model. Results showed that QGZST significantly decreased the systolic blood pressure (SBP), mean arterial blood pressure (MAP), body weights and adipocyte size of HFD-fed SHRs. Moreover, QGZST remarkably reduced the serum levels of cholesterol, triglyceride, low-density lipoprotein cholesterol, fasting glucose, fasting insulin and HOMA-IR index, increased serum high-density lipoprotein cholesterol levels and improved glucose intolerance in HFD-fed SHRs. Furthermore, QGZST dramatically attenuated HFD-fed-induced hypersecretion of proinflammatory cytokines and hypoproduction of adiponectin in SHRs. Mechanistically, QGZST stimulated the activity of Sirtuin 1 (SIRT1) and Forkhead box protein O1 (FOXO1) and suppress the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT-enhancer-binding proteins-α(C/EBP-α), fatty acid binding protein 4 (FABP4), acetylated nuclear factor-kappa-B-p65 (acetyl-NF-кB-p65) and protein-tyrosine phosphatase 1B (PTP1B). More than that, QGZST also prevented acetyl-NF-кB-p65 nuclear accumulation. Collectively, our research demonstrated for the first time that QGZST is able to alleviate eWAT dysfunction with up-regulation of SIRT1 in HFD-fed SHRs, which might supply further insight into QGZST-mediated anti-hypertension and anti-obesity effects. Topics: Adipocytes; Adiponectin; Adipose Tissue; Angiotensin II; Animals; Antihypertensive Agents; Body Weight; Cell Size; Chromatography, High Pressure Liquid; Diet, High-Fat; Drugs, Chinese Herbal; Epididymis; Forkhead Box Protein O1; Glucose; Insulin; Interleukin-6; Leptin; Lipids; Male; Organ Size; PPAR gamma; Rats, Inbred SHR; Sirtuin 1; Tumor Necrosis Factor-alpha; Up-Regulation | 2018 |
Anti-Obesity Effect of Chitosan Oligosaccharide Capsules (COSCs) in Obese Rats by Ameliorating Leptin Resistance and Adipogenesis.
Obesity is a global disease that causes many metabolic disorders. However, effective agents for the prevention or treatment of obesity remain limited. This study investigated the anti-obesity effect and mechanism of chitosan oligosaccharide capsules (COSCs) on rats suffering from obesity induced by a high-fat diet (HFD). After the eight-week administration of COSCs on obese rats, the body weight gain, fat/body ratio, and related biochemical indices were measured. The hepatic expressions of the leptin signal pathway (JAK2-STAT3) and gene expressions of adipogenesis-related targets were also determined. Our data showed that COSCs can regulate body weight gain, lipids, serum alanine aminotransferase, and aspartate aminotransferase, as well as upregulate the hepatic leptin receptor-b (LepRb) and the phosphorylation of JAK2 and STAT3. Meanwhile, marked increased expressions of liver sterol regulatory element-binding protein-1c, fatty acid synthase, acetyl-CoA carboxylase, 3-hydroxy-3-methylglutaryl-CoA reductase, adiponectin, adipose peroxisome proliferator-activated receptor γ, CCAAT-enhancer binding protein α, adipose differentiation-related protein, and SREBP-1c were observed. The results suggested that COSCs activate the JAK2-STAT3 signaling pathway to alleviate leptin resistance and suppress adipogenesis to reduce lipid accumulation. Thus, they can potentially be used for obesity treatment. Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Capsules; Chitosan; Diet, High-Fat; Janus Kinase 2; Leptin; Lipids; Liver; Male; Obesity; Oligosaccharides; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor; Weight Gain | 2018 |
Induction of uterine hyperplasia after cafeteria diet exposure.
Our aim was to evaluate whether chronic administration of CAF affects the uterus and induces the morphological and molecular changes associated with endometrial hyperplasia. Female Wistar rats exposed to CAF from weaning for 20 weeks displayed increased energy intake, body weight and fat depots, but did not develop metabolic syndrome. The adult uteri showed an increase in glandular volume fraction and stromal area. The epithelial proliferation rate and protein expression of oestrogen receptor alpha (ERα) were also increased. The CAF diet enhanced leptin serum levels and the long form of leptin receptor (Ob-Rb) mRNA expression in the uterus. No changes were detected in either insulin serum levels or those of insulin growth factor I (IGF-I) mRNA expression. However the levels of IGF-I receptor (IGF-IR) mRNA were lower in CAF-fed animals. Overall, the results indicate that our rat model of the CAF diet produces morphological and molecular changes associated with uterine hyperplasia and could predispose to endometrial carcinogenesis. Topics: Adipose Tissue; Animals; Body Weight; Cell Proliferation; Diet; Endocrine System; Endpoint Determination; Estrogen Receptor alpha; Feeding Behavior; Female; Hormones; Hyperplasia; Leptin; Rats, Wistar; Uterus | 2018 |
Downregulation of leptin receptor and kisspeptin/GPR54 in the murine hypothalamus contributes to male hypogonadism caused by high-fat diet-induced obesity.
Obesity may lead to male hypogonadism, the underlying mechanism of which remains unclear. In the present study, we established a murine model of male hypogonadism caused by high-fat diet-induced obesity to verify the following hypotheses: 1) an increased leptin level may be related to decreased secretion of GnRH in obese males, and 2) repression of kisspeptin/GPR54 in the hypothalamus, which is associated with increased leptin levels, may account for the decreased secretion of GnRH and be involved in secondary hypogonadism (SH) in obese males.. Male mice were fed high-fat diet for 19 weeks and divided by body weight gain into diet-induced obesity (DIO) and diet-induced obesity resistant (DIO-R) group. The effect of obesity on the reproductive organs in male mice was observed by measuring sperm count and spermatozoid motility, relative to testis and epididymis weight, testosterone levels, and pathologic changes. Leptin, testosterone, estrogen, and LH in serum were detected by ELISA method. Leptin receptor (Ob-R), Kiss1, GPR54, and GnRH mRNA were measured by real-time PCR in the hypothalamus. Expression of kisspeptin and Ob-R protein was determined by Western blotting. Expression of GnRH and GPR54 protein was determined by immunohistochemical analysis.. We found that diet-induced obesity decreased spermatozoid motility, testis and epididymis relative coefficients, and plasma testosterone and luteinizing hormone levels. An increased number and volume of lipid droplets in Leydig cells were observed in the DIO group compared to the control group. Significantly, higher serum leptin levels were found in the DIO and DIO-R groups. The DIO and DIO-R groups showed significant downregulation of the GnRH, Kiss1, GPR54, and Ob-R genes. We also found decreased levels of GnRH, kisspeptin, GPR54, and Ob-R protein in the DIO and DIO-R groups.. These lines of evidence suggest that downregulation of Ob-R and kisspeptin/GPR54 in the murine hypothalamus may contribute to male hypogonadism caused by high-fat diet-induced obesity. Topics: Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Gonadotropin-Releasing Hormone; Hypogonadism; Hypothalamus; Kisspeptins; Leptin; Male; Mice; Obesity; Receptors, Kisspeptin-1; Receptors, Leptin; Sperm Motility; Testis | 2018 |
Role for fatty acid amide hydrolase (FAAH) in the leptin-mediated effects on feeding and energy balance.
Endocannabinoid signaling regulates feeding and metabolic processes and has been linked to obesity development. Several hormonal signals, such as glucocorticoids and ghrelin, regulate feeding and metabolism by engaging the endocannabinoid system. Similarly, studies have suggested that leptin interacts with the endocannabinoid system, yet the mechanism and functional relevance of this interaction remain elusive. Therefore, we explored the interaction between leptin and endocannabinoid signaling with a focus on fatty acid amide hydrolase (FAAH), the primary degradative enzyme for the endocannabinoid Topics: Amidohydrolases; Animals; Arachidonic Acids; Body Weight; Dietary Fats; Eating; Endocannabinoids; Energy Metabolism; Gene Knock-In Techniques; Hypothalamus; Leptin; Male; Mice; Mice, Knockout; Polymorphism, Genetic; Polyunsaturated Alkamides | 2018 |
Telmisartan prevents diet-induced obesity and preserves leptin transport across the blood-brain barrier in high-fat diet-fed mice.
Obesity is a global health problem and treatment options are still insufficient. When chronically treated with the angiotensin II receptor blocker telmisartan (TEL), rodents do not develop diet-induced obesity (DIO). However, the underlying mechanism for this is still unclear. Here we investigated whether TEL prevents leptin resistance by enhancing leptin uptake across the blood-brain barrier (BBB). To address this question, we fed C57BL/6 mice a high-fat diet (HFD) and treated them daily with TEL by oral gavage. In addition to broadly characterizing the metabolism of leptin, we determined leptin uptake into the brain by measuring BBB transport of radioactively labeled leptin after long-term and short-term TEL treatment. Additionally, we assessed BBB integrity in response to angiotensin II in vitro and in vivo. We found that HFD markedly increased body weight, energy intake, and leptin concentration but that this effect was abolished under TEL treatment. Furthermore, glucose control and, most importantly, leptin uptake across the BBB were impaired in mice on HFD, but, again, both were preserved under TEL treatment. BBB integrity was not impaired due to angiotensin II or blocking of angiotensin II receptors. However, TEL did not exhibit an acute effect on leptin uptake across the BBB. Our results confirm that TEL prevents DIO and show that TEL preserves leptin transport and thereby prevents leptin resistance. We conclude that the preservation of leptin sensitivity is, however, more a consequence than the cause of TEL preventing body weight gain. Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Anti-Obesity Agents; Blood-Brain Barrier; Body Weight; Cell Line; Diet, High-Fat; Energy Metabolism; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Telmisartan | 2018 |
Lateral Hypothalamic Area Neurotensin Neurons Are Required for Control of Orexin Neurons and Energy Balance.
The lateral hypothalamic area (LHA) is essential for motivated ingestive and locomotor behaviors that impact body weight, yet it remains unclear how the neurochemically defined subpopulations of LHA neurons contribute to energy balance. In particular, the role of the large population of LHA neurotensin (Nts) neurons has remained ambiguous due to the lack of methods to easily visualize and modulate these neurons. Because LHA Nts neurons are activated by leptin and other anorectic cues and they modulate dopamine or local LHA orexin neurons implicated in energy balance, they may have important, unappreciated roles for coordinating behaviors necessary for proper body weight. In this study, we genetically ablated or chemogenetically inhibited LHA Nts neurons in adult mice to determine their necessity for control of motivated behaviors and body weight. Genetic ablation of LHA Nts neurons resulted in profoundly increased adiposity compared with mice with intact LHA Nts neurons, as well as diminished locomotor activity, energy expenditure, and water intake. Complete loss of LHA Nts neurons also led to downregulation of orexin, revealing important cross-talk between the LHA Nts and orexin populations in maintenance of behavior and body weight. In contrast, chemogenetic inhibition of intact LHA Nts neurons did not disrupt orexin expression, but it suppressed locomotor activity and the adaptive response to leptin. Taken together, these data reveal the necessity of LHA Nts neurons and their activation for controlling energy balance, and that LHA Nts neurons influence behavior and body weight via orexin-dependent and orexin-independent mechanisms. Topics: Adaptation, Physiological; Adiposity; Animals; Behavior, Animal; Body Weight; Down-Regulation; Drinking Behavior; Energy Metabolism; Feeding Behavior; Gene Expression; Hypothalamic Area, Lateral; Leptin; Locomotion; Mice; Neurons; Neurotensin; Obesity; Orexins | 2018 |
Use of a gene score of multiple low-modest effect size variants can predict the risk of obesity better than the individual SNPs.
Obesity is a complex disorder, the development of which is modulated by a multitude of environmental, behavioral and genetic factors. The common forms of obesity are polygenic in nature which means that many variants in the same or different genes act synergistically and affect the body weight quantitatively. The aim of the current study was to use information from many common variants previously identified to affect body weight to construct a gene score and observe whether it improves the associations observed. The SNPs selected were G2548A in leptin (LEP) gene, Gln223Arg in leptin receptor (LEPR) gene, Ala54Thr in fatty acid binding protein 2 (FABP2) gene, rs1121980 in fat mass and obesity associated (FTO) gene, rs3923113 in Growth Factor Receptor Bound Protein 14 (GRB14), rs16861329 in Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1), rs1802295 in Vacuolar protein sorting-associated protein 26A (VPS26A), rs7178572 in high mobility group 20A (HMG20A), rs2028299 in adaptor-related protein complex 3 (AP3S2), and rs4812829 in Hepatocyte Nuclear Factor 4 Alpha (HNF4A).. A total of 475 subjects were genotyped for the selected SNPs in different genes using different genotyping techniques. The study subjects' age, weight, height, BMI, waist and hip circumference, serum total cholesterol, triglycerides, LDL and HDL were measured. A summation term, genetic risk score (GRS), was calculated using SPSS.. The results showed a significantly higher mean gene score in obese cases than in non-obese controls (9.1 ± 2.26 vs 8.35 ± 2.07, p = 2 × 10. In conclusion, the use of gene score is a better way to calculate the overall genetic risk from common variants rather than individual risk variants. Topics: Adaptor Protein Complex 3; Adaptor Proteins, Signal Transducing; Adult; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Antigens, CD; Body Height; Body Weight; Case-Control Studies; Fatty Acid-Binding Proteins; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Hepatocyte Nuclear Factor 4; High Mobility Group Proteins; Humans; Leptin; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Multifactorial Inheritance; Obesity; Polymorphism, Single Nucleotide; Receptors, Leptin; Research Design; Risk; Sialyltransferases; Triglycerides; Vesicular Transport Proteins; Waist Circumference | 2018 |
Prenatal undernutrition attenuates fasting-induced reproductive dysfunction in pre-pubertal male rats.
Prenatal undernutrition affects various physiological functions, such as metabolic and reproductive functions, after birth, and such changes are associated with the pathogeneses of certain diseases. It has been hypothesized that these changes are predictive adaptive responses that help individuals to endure similar conditions in the postnatal period. Thus, we evaluated the effects of prenatal undernutrition on the responses of the body weight (BW) regulation system and reproductive functions to fasting in the pre-pubertal period in male rats. Prenatally normally nourished and undernourished rats exhibited similar reductions in BW and visceral fat after 48 h fasting in the pre-pubertal period. Furthermore, these two groups displayed similar fasting-induced patterns of change in their hypothalamic levels of appetite regulatory factors; i.e., neuropeptide Y and pro-opiomelanocortin. These results indicate that prenatal undernutrition had no marked effects on BW regulation in male rats. On the other hand, serum luteinizing hormone and testosterone levels were decreased by 48 h fasting in the prenatally normally nourished rats, whereas the levels of these hormones did not change in the prenatally undernourished rats. However, the hypothalamic mRNA level of kisspeptin 1 (Kiss1), which is a positive regulator of gonadotropin-releasing hormone/gonadotropins, was reduced by fasting in both groups. These results indicate that prenatal undernutrition might attenuate fasting-induced reproductive dysfunction in the postnatal period; however, these changes might not be induced by alterations in the hypothalamic Kiss1 system. Further studies are needed to clarify the mechanisms involved in these changes in reproductive function. Topics: Animals; Animals, Newborn; Body Weight; Disorders of Sex Development; Fasting; Female; Gene Expression Regulation, Developmental; Kisspeptins; Leptin; Luteinizing Hormone; Male; Malnutrition; Neuropeptide Y; Organ Size; Pregnancy; Pregnancy Complications; Pro-Opiomelanocortin; Rats; Rats, Wistar; Receptors, Leptin; Testis; Testosterone | 2018 |
Cachexia-associated adipose loss induced by tumor-secreted leukemia inhibitory factor is counterbalanced by decreased leptin.
Cachexia syndrome consists of adipose and muscle loss, often despite normal food intake. We hypothesized that cachexia-associated adipose wasting is driven in part by tumor humoral factors that induce adipocyte lipolysis. We developed an assay to purify secreted factors from a cachexia-inducing colon cancer line that increases lipolysis in adipocytes and identified leukemia inhibitory factor (LIF) by mass spectrometry. Recombinant LIF induced lipolysis in vitro. Peripheral LIF administered to mice caused >50% loss of adipose tissue and >10% reduction in body weight despite only transient hypophagia due to decreasing leptin. LIF-injected mice lacking leptin (ob/ob) resulted in persistent hypophagia and loss of adipose tissue and body weight. LIF's peripheral role of initiating lipolysis in adipose loss was confirmed in pair-fed ob/ob mouse studies. Our studies demonstrate that (a) LIF is a tumor-secreted factor that promotes cachexia-like adipose loss when administered peripherally, (b) LIF directly induces adipocyte lipolysis, (c) LIF has the ability to sustain adipose and body weight loss through an equal combination of peripheral and central contributions, and (d) LIF's central effect is counterbalanced by decreased leptin signaling, providing insight into cachexia's wasting, despite normophagia. Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Cachexia; Cell Line; Cytokine Receptor gp130; Cytokines; Disease Models, Animal; Leptin; Leukemia Inhibitory Factor; Lipase; Lipolysis; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms; Recombinant Proteins; STAT Transcription Factors | 2018 |
Sulforaphane improves leptin responsiveness in high-fat high-sucrose diet-fed obese mice.
Diet-induced obesity (DIO) is commonly associated with hyperleptinemia and leptin resistance. Leptin acts centrally to inhibit food intake and increase energy expenditure, thereby preventing body weight gain. Resistance to the biological effects of leptin represents a major obstacle in utilizing exogenously administered leptin as a treatment option for obesity. Of importance, recent studies demonstrate that naturally occurring compounds improve leptin sensitivity in DIO mice, as revealed by anorectic and body weight-lowering effects. To date, the role of sulforaphane (SFN, an isothiocyanate derived from cruciferous vegetables) on leptin responsiveness has not been examined, in spite of its known beneficial effects toward lowering body weight gain in DIO. In the present study, we determined the extent to which SFN regulates leptin responsiveness in high-fat high-sucrose (HFHS) diet-fed obese mice. SFN treatment (0.5 mg/kg/day, s.c.) for 23 days in HFHS-fed mice improved the responsiveness to intraperitoneally-injected leptin by promoting significant decreases in cumulative food intake and body weight gain. A single leptin injection (2 mg/kg; i.p.) resulted in significant decreases in food intake at 24 h and 38 h time points. In addition, a triple leptin injection (1 mg/kg/day, 3 days; i.p.) led to significant decreases in food intake at 14 h, 24 h, 38 h, 48 h, and 62 h time points. Furthermore, single and triple leptin injections prevented body weight gain at 38 h and 62 h time points, respectively. The present findings suggest that intervention with SFN, a naturally occurring isothiocyanate, has the potential to improve leptin responsiveness in DIO. Topics: Animals; Body Weight; Diet, High-Fat; Eating; Isothiocyanates; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Sucrose; Sulfoxides | 2018 |
Short-term time-restricted feeding during the resting phase is sufficient to induce leptin resistance that contributes to development of obesity and metabolic disorders in mice.
Feeding at unusual times of the day is thought to be associated with obesity and metabolic disorders in both experimental animals and humans. We previously reported that time-imposed feeding during the sleep phase (daytime feeding, DF) induces obesity and metabolic disorders compared with mice fed only during the active phase (nighttime feeding, NF). The present study aimed to determine whether leptin resistance is caused by DF, and whether it is involved in the underlying mechanisms of DF-induced obesity in mice, since leptin plays an essential role in regulating energy expenditure and adiposity in addition to food intake. We compared leptin sensitivity by evaluating the effects of exogenous injected leptin on food intake and body weight in wild-type C57BL/6J mice under NF and DF. The mice were fed with a high-fat high-sucrose diet throughout the study. To determine whether leptin resistance is a cause or a result of DF-induced obesity with metabolic disorders, we restricted the feeding times of leptin resistant db/db mice. We also examined leptin sensitivity in leptin deficient ob/ob mice under NF and DF to elucidate the underlying mechanisms of DF-induced leptin resistance. C57BL/6J mice under DF gained more weight and adiposity compared with mice under NF, and developed hyperleptinemia and hypothermia. We found that six days of DF abolished exogenous leptin-induced hypophagia and reduction in body weight in mice. We also found that the leptin injection significantly suppressed the mRNA expression of lipogenic genes in the liver of NF, but not in DF mice, suggesting that short-term DF was sufficient to induce metabolic leptin resistance. The DF-induced increases in body weight gain, food efficiency, adipose tissue mass, lipogenic gene expression in metabolic tissues, and hepatic lipid accumulation were abolished in db/db mice, suggesting that the leptin resistance is a cause of DF-induced metabolic disorders. DF resulted in deep hypothermia in db/db, as well as in wild-type mice, suggesting that a decrease in energy expenditure was not the main cause of DF-induced obesity. Exogenous leptin reduced the body weight of ob/ob mice under both NF and DF, and the effect was significantly higher in DF- than in NF-ob/ob mice. Therefore, the development of DF-induced leptin resistance requires endogenous leptin, and central leptin sensitivity fluctuates in a circadian manner. The present findings suggest that leptin resistance is responsible for DF-induced obesi Topics: Adipose Tissue; Adipose Tissue, White; Animals; Body Weight; Circadian Rhythm; Eating; Energy Metabolism; Leptin; Male; Metabolic Diseases; Mice, Inbred C57BL; Obesity; Rest; Triglycerides | 2018 |
Effects of leptin on neurocognitive and motor functions in juvenile rats in a preterm brain damage model.
Preterm infants face lifelong disabilities, including learning disorders, as well as visual, auditory and behavioral problems. Recent studies have demonstrated that leptin, an adipocytokine encoded by a gene associated with obesity and expressed in adipose tissue, affects neurocognitive and motor function; however, the mechanisms of brain damage in preterm infants are unclear. In the present study, the neuroprotective effects of leptin in a rat model of preterm hypoxic‑ischemic brain damage were investigated. Rats (2‑days‑old) were subjected to brain damage (ligation of the common carotid artery followed by exposure to 6% oxygen for 2 h) and treated with vehicle (control) or leptin. Spatial memory was analyzed in the present study using the Morris water maze test 19 days following ligation. Over the 24‑day post‑surgical observation period, capture‑resistance test, forelimb suspension and open field tests were conducted to evaluate motor function and anxiety‑associated behavior. Treatment with leptin did not affect survival rate or body weight. Treatment with leptin increased the number of platform crossings in rats with premature brain damage in the Morris water maze test, which was used to assess spatial memory. Multivariate analysis revealed that leptin reduced the latency to finding the platform location, independent of gender and weight. In the capture‑resistance, forelimb suspension and open field tests, there were no differences between animals administered leptin and the sham group. Collectively, the results of the present study suggested that leptin may alleviate spatial memory impairment resulting from premature brain damage, independent of gender or weight. These results may improve understanding of the neuroprotective effects exhibited by leptin in infants with preterm brain damage. Topics: Animals; Body Weight; Brain Injuries; Cognition; Disease Models, Animal; Humans; Infant; Leptin; Linear Models; Maze Learning; Mice; Motor Activity; Multivariate Analysis; Premature Birth; Rats, Sprague-Dawley | 2018 |
Physical fitness, hormonal, and immunological responses during prolonged military field training.
Physical fitness is crucial to warfighters' performance in the battlefield. Previous studies have shown negative changes in their hormonal and neuromuscular responses induced by military field training (MFT). The purpose of this study was to investigate the changes in hormonal and immunological values and body composition during a prolonged MFT and to find out how warfighters' physical condition influences these changes. Conscripts (n = 49, age 20 ± 1 years, height 179 ± 9 cm, body mass 73.8 ± 7.8 kg, fat 12.6 ± 3.7% and BMI 23 kg/m²) were measured before, during, after MFT, and after a 4-day recovery period. Serum insulin-like growth factor-1 (IGF-1), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) concentrations, creatine kinase (CK) activity and leptin concentration were analyzed as well as body composition throughout MFT. Neuromuscular performance was assessed via lower and upper body muscle endurance at the beginning of the study. During MFT, there was a significant decrease (P < 0.05) in body mass (2.3%), fat mass (7.7%) and in muscle mass (2.2%), but all of these values recovered to PRE-levels after the recovery period. Serum IGF-1 (22%) and leptin decreased (66%) while CK increased (88%) significantly (P < 0.05) during MFT but recovered at the end of MFT. Upper body dynamic and trunk isometric muscular endurance had a positive correlation (r = 0.37. P < 0.05) with the change in IGF-1 during MFT and a negative correlation with the changes in CK (-0.34, P < 0.05). The results show that there were negative changes in conscript's body composition and hormonal and immunological values during the prolonged MFT. These changes suggest that the physiological stress was high during MFT. High levels of upper body and trunk muscular strength were negatively correlated with warfighters' physiological effects and should therefore be developed prior to actual deployment to reduce the physical decline experienced during prolonged MFTs. Topics: Adiposity; Body Weight; Creatine Kinase; Exercise; Humans; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Male; Military Personnel; Muscle, Skeletal; Physical Fitness; Tumor Necrosis Factor-alpha; Young Adult | 2018 |
Cognitive Impairment Due to Leptin Withdrawal in Rat Offspring of Dams with Maternal Diet-Induced Obesity.
BACKGROUND Obesity during pregnancy is a potential threat to the health and neurodevelopment of the offspring. This study investigated the effect of maternal diet-induced obesity (DIO) on the cognitive abilities of the offspring in rats. MATERIAL AND METHODS Female Sprague-Dawley rats were fed a high-fat diet to induce obesity, and the leptin levels in dams and offspring were evaluated using ELISA. The effect of DIO on the learning and memory in offspring was measured using electrophysiology and the Morris water maze test. In addition, the expression of molecules related to synaptic plasticity was investigated. Furthermore, the effect of leptin on neuronal cells was investigated, and the influence of leptin on the regulation of calcium current activity was evaluated in vitro. RESULTS Results showed that DIO dams had increased leptin levels during gestation, and offspring had drastically decreased leptin levels after delivery. The cognitive ability of offspring with maternal DIO was mildly impaired after delivery. Furthermore, long-term potentiation in DIO neonatal offspring was lower than in the control group at 2-3 weeks old; decreased expression of the leptin receptor was accompanied by N-methyl-D-aspartate receptor (NMDAR) downregulation during neonatal development. In addition, it was demonstrated that leptin enhanced NMDAR activity and promoted calcium current activity in a concentration-dependent manner. CONCLUSIONS The results indicated that the neonatal offspring of DIO dams showed cognitive impairment during neonatal development, which may be attributed to leptin withdrawal. Topics: Animals; Body Weight; Cognition; Cognitive Dysfunction; Diet, High-Fat; Female; Glucose Tolerance Test; Leptin; Male; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Weight Gain | 2018 |
Central action of CART induces neuronal activation in the paraventricular and dorsomedial hypothalamus of diet-induced obese and lean mice.
The cocaine- and amphetamine-regulated transcript (CART) is a peptide commonly studied in the feeding behavior, but it exerts an important role in the autonomic and cardiovascular control as well. It is known that exogenous administration of CART in the central nervous system can elicit increase in blood pressure of both conscious and anesthetized rodents, but little is known whether these central effects might differ between lean and obese animals. We have recently shown that diet-induced obese mice that developed hypertension presented an upregulation of CART levels in the dorsomedial nucleus of hypothalamus, while obese normotensive ones had not. Herein we investigate whether the central action of CART could activate differently the hypothalamic nuclei of diet-induced obese mice compared to the lean counterparts by using Fos protein expression, C57BL/6 mice were randomly assigned to two cohorts, one fed with a high-fat diet for 8 weeks (obese), and the other fed with regular rodent chow (lean). Both groups received an ICV injection of CART at the dose of 400μM, 1 mM or vehicle. Subsequently, the brains were processed for Fos protein immunohistochemical in order to identify hypothalamic neuronal activation. Significantly greater numbers of Fos-positive neurons were observed in the PVN and DMH of obese mice that received CART 1 mM, when compared to the lean control. These results indicate that the central action of CART induces neuronal activation in the hypothalamic nuclei of obese and lean mice, and this could be relevant to the different autonomic and cardiovascular adjustments that an organism exposed to different diet and metabolic condition. Topics: Animals; Body Weight; Diet, High-Fat; Feeding Behavior; Gene Expression Regulation; Hypothalamus; Leptin; Male; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurons; Obesity; Paraventricular Hypothalamic Nucleus | 2018 |
The association of serum leptin levels with food addiction is moderated by weight status in adolescent psychiatric inpatients.
Leptin is essential for the control of energy homeostasis and eating behaviour. We investigated potential associations between serum leptin levels and food addiction in adolescent psychiatric inpatients (n = 228). The most frequent psychiatric diagnoses were mood disorders, anxiety disorders, and substance use disorders. More than three quarters of the study group suffered from more than one psychiatric disorder. Food addiction was assessed with the Yale Food Addiction Scale. Leptin was determined in serum. Analyses were conducted for the whole body weight range and for distinct weight categories to evaluate a potential impact of known nonlinearity between leptin levels and satiety due to leptin resistance in obese. A weak negative association between food addiction and leptin in normal weight patients (ß = -0.11, p = .022) was detected. In contrast, food addiction was associated with a significantly higher serum leptin (ß = 0.16. p = .038) in overweight patients. Food addiction in normal weight patients might be associated with restrained eating, previously shown to involve reduced leptin levels. The small positive association of food addiction with higher serum leptin in overweight patients might reflect leptin resistance and overeating. Topics: Adolescent; Body Weight; Female; Food Addiction; Humans; Inpatients; Leptin; Male; Mental Disorders | 2018 |
Chronic Liquid Fructose, but not Glucose, Supplementation Selectively Induces Visceral Adipose Tissue Leptin Resistance and Hypertrophy in Female Sprague-Dawley Rats.
The effect of chronic supplementation with simple-sugar solutions on leptin signaling in liver, hypothalamus, and visceral white adipose tissue (vWAT) is studied, which is designed to mimic the temporal pattern of consumption by humans.. Solutions of fructose or glucose are isocalorically supplemented (7 months) in female Sprague-Dawley rats consuming ad libitum rodent chow. After sacrifice, plasma and tissue samples (liver, hypothalamus, and vWAT) are collected. Zoometric parameters, plasma analytes, and the tissue expression and activity of markers of leptin signaling are determined by biochemical and molecular biological methods. The two sugars cause different types of adiposopathy. Both sugars induce increases in plasma nonesterified fatty acids, and leptin resistance in the liver and the hypothalamus. Only fructose-supplemented rats show hyperleptinemia, and increased body weight due to a hypertrophy of vWAT, with no signs of leptin-mediated lipolysis. Glucose-supplemented rats show no significant changes in these parameters but present elevated plasma adiponectin concentrations, lipolysis, and inflammatory markers in vWAT, indicating a shift to a nonexpandable adipose tissue phenotype.. Chronic consumption of fructose places a greater burden on metabolic homeostasis than equivalent consumption of glucose, inducing hyperleptinemia, generalized leptin resistance, and increased body weight due to expanded, hypertrophic vWAT. Topics: Adipocytes; Adipose Tissue, White; Agouti-Related Protein; Animals; Body Weight; Female; Fructose; Glucose; Hypothalamus; Intra-Abdominal Fat; Leptin; Liver; Rats, Sprague-Dawley; Receptors, Leptin | 2018 |
Leptin and insulin do not exert redundant control of metabolic or emotive function via dopamine neurons.
Leptin and insulin's hunger-suppressing and activity-promoting actions on hypothalamic neurons are well characterized, yet the mechanisms by which they modulate the midbrain dopamine system to influence energy balance remain less clear. A subset of midbrain dopamine neurons express receptors for leptin (Lepr) and insulin (Insr). Leptin-dopamine signaling reduces running reward and homecage activity. However, dopamine-specific deletion of Lepr does not affect body weight or food intake in mice. We hypothesized insulin-dopamine signaling might compensate for disrupted leptin-dopamine signaling. To investigate the degree to which insulin and leptin exert overlapping (i.e. redundant) versus discrete control over dopamine neurons, we generated transgenic male and female mice exhibiting dopamine-specific deletion of either Lepr (Lepr KO), Insr (Insr KO) or both Lepr and Insr (Dbl KO) and assessed their feeding behavior, voluntary activity, and energy expenditure compared to control mice. No differences in body weight, daily food intake, energy expenditure or hyperphagic feeding of palatable chow were observed between Lepr, Insr or Dbl KO mice and control mice. However, consistent with previous findings, Lepr KO (but not Insr or Dbl KO) male mice exhibited significantly increased running wheel activity compared to controls. These data demonstrate that insulin and leptin do not exert redundant control of dopamine neuron-mediated modulation of energy balance. Furthermore, our results indicate neither leptin nor insulin plays a critical role in the modulation of dopamine neurons regarding hedonic feeding behavior or anxiety-related behavior. Topics: Animals; Anxiety; Body Weight; Dopamine; Dopaminergic Neurons; Eating; Emotions; Energy Metabolism; Feeding Behavior; Female; Hypothalamus; Insulin; Leptin; Male; Mesencephalon; Mice, Inbred C57BL; Mice, Knockout; Receptor, Insulin; Receptors, Leptin; Signal Transduction | 2018 |
Associations of breast milk adiponectin, leptin, insulin and ghrelin with maternal characteristics and early infant growth: a longitudinal study.
Breast milk (BM) hormones have been hypothesised as a nutritional link between maternal and infant metabolic health. This study aimed to evaluate hormone concentrations in BM of women with and without gestational diabetes mellitus (GDM), and the relationship between maternal factors, BM hormones and infant growth. We studied ninety-six nulliparous women with (n 48) and without GDM and their exclusively breastfed term singletons. Women with GDM received dietary therapy or insulin injection for euglycaemia during pregnancy. Hormone concentrations in BM, maternal BMI and infant growth were longitudinally evaluated on postnatal days 3, 42 and 90. Mothers with GDM had decreased concentrations of adiponectin (P colostrum<0·001; P mature-milk=0·009) and ghrelin (P colostrum=0·011; P mature-milk<0·001) and increased concentration of insulin in BM (P colostrum=0·047; P mature-milk=0·021). Maternal BMI was positively associated with adiponectin (β=0·06; 95 % CI 0·02, 0·1; P=0·001), leptin (β=0·16; 95 % CI 0·12, 0·2; P<0·001) and insulin concentrations (β=0·06; 95 % CI 0·02, 0·1; P<0·001), and inversely associated with ghrelin concentration in BM (β=-0·08; 95 % CI -0·1, -0·06; P<0·001). Among the four hormones, adiponectin was inversely associated with infant growth in both the GDM (β weight-for-height=-2·49; 95 % CI -3·83, -1·15; P<0·001; β head-circumference=-0·39; 95 % CI -0·65, -0·13; P=0·003) and healthy groups (β weight-for-height=-1·42; 95 % CI -2·38, -0·46; P=0·003; β head-circumference=-0·15; 95 % CI -0·27, -0·03; P=0·007). Maternal BMI and GDM are important determinants of BM hormone concentrations. Milk-borne adiponectin is determined by maternal metabolic status and plays an independent down-regulating role in early infant growth. Topics: Adiponectin; Anthropometry; Blood Glucose; Body Mass Index; Body Weight; Breast Feeding; Colostrum; Diabetes, Gestational; Down-Regulation; Female; Ghrelin; Glucose Tolerance Test; Humans; Infant; Infant, Newborn; Insulin; Leptin; Longitudinal Studies; Male; Milk, Human; Mothers; Nutritional Sciences; Pediatric Obesity; Pregnancy | 2018 |
MicroRNAs are involved in the hypothalamic leptin sensitivity.
The central nervous system monitors modifications in metabolic parameters or hormone levels (leptin) and elicits adaptive responses such as food intake and glucose homeostasis regulation. Particularly, within the hypothalamus, pro-opiomelanocortin (POMC) neurons are crucial regulators of energy balance. Consistent with a pivotal role of the melanocortin system in the control of energy homeostasis, disruption of the Pomc gene causes hyperphagia and obesity. Pomc gene expression is tightly controlled by different mechanisms. Interestingly, recent studies pointed to a key role for micro ribonucleic acid (miRNAs) in the regulation of gene expression. However, the role of miRNAs in the leptin sensitivity in hypothalamic melanocortin system has never been assessed. We developed a transgenic mouse model (PDKO) with a partial deletion of the miRNA processing enzyme DICER specifically in POMC neurons. PDKO mice exhibited a normal body weight but a decrease of food intake. Interestingly, PDKO mice had decreased metabolic rate by reduction of VO Topics: Adipose Tissue, Brown; Animals; Body Weight; Eating; Hypothalamus; Leptin; Male; Mice; MicroRNAs; Neurons; Oxygen Consumption; Pro-Opiomelanocortin; Ribonuclease III | 2018 |
Regulation of Leptin Methylation Not via Apoptosis by Melatonin in the Rescue of Chronic Programming Liver Steatosis.
We examined the mechanisms of chronic liver steatosis after prenatal dexamethasone exposure and whether melatonin rescues adult offspring with liver steatosis. Melatonin rescued prenatal dexamethasone-exposed livers with steatosis in young rats. Sprague-Dawley rats pregnant at gestational day 14⁻21 were administered with intraperitoneal dexamethasone (DEX) or prenatal dexamethasone and melatonin between gestational day 14 and postnatal day ~120 (DEX+MEL). Chronic programming effects in the liver were assessed at day ~120. Liver steatosis increased in the DEX compared with that in the vehicle group and decreased in the DEX+MEL group ( Topics: Acetylation; Animals; Apoptosis; Body Weight; DNA (Cytosine-5-)-Methyltransferases; Fatty Liver; Histones; Inflammation; Leptin; Liver; Methylation; Organ Size; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha | 2018 |
Inhibition of Cannabinoid Receptor 1 Can Influence the Lipid Metabolism in Mice with Diet-Induced Obesity.
A growing number of evidences accumulated about critical metabolic role of cannabinoid type 1 receptor (CB1), carnitine palmitoyltransferase-1 (CPT1) and peroxisome proliferator-activated receptors (PPARs) in some peripheral tissues, including adipose tissue, liver, skeletal muscle and heart. To better understand the interactions of CB1, CPT1 and PPARs in these tissues, 30 diet-induced obese (DIO) C57BL/6J male mice were obtained, weight-matched and divided into two groups (15 in each group): (i) DIO/vehicle mice (D-Veh) and (ii) DIO/SR141716 mice (D-SR) treated with SR141716 (or rimonabant, a selective CB1 receptor blocker) administered orally (10 mg/kg daily). Another 15 mice fed standard diet (STD) formed the STD/vehicle group (S-Veh). At the end of 3-week treatment, mean body weight was 28.4 ± 0.5, 36.5 ± 0.8, and 30.3 ± 1.2 g for the S-Veh, D-Veh, and D-SR group, respectively (p < 0.05; D-Veh vs. D-SR). Liver weight in the D-SR group was also decreased significantly compared to the D-Veh group (p < 0.05). Serum levels of total cholesterol, high-density lipoprotein cholesterol, leptin and adiponectin in the D-SR group were ameliorated compared to the D-Veh group (p < 0.05). Both qRT-PCR and Western blot assay revealed that CB1 expression levels were efficiently blocked by SR141716 in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscles and liver (D-SR vs. D-Veh; p < 0.05), whereas there was no significant difference between S-Veh and D-Veh mice (p > 0.05). Simultaneously with the reduction of CB1 expression in the D-SR group, the expression levels of CPT1A isoform (protein) in the liver and heart and CPT1B isoform (protein) in the SAT, VAT, liver and skeletal muscles were significantly increased (p < 0.05; D-SR vs. D-Veh). Interestingly, the CPT1A and CPT1B expression levels in heart were detected slightly. The expression levels of PPARα in the SAT, VAT, liver and skeletal muscles and PPARγ in the SAT and skeletal muscles in the D-SR group were significantly increased compared to the D-Veh mice (p < 0.05). However, the PPARβ expression level differed from that of PPARα and PPARγ. Taken together, these data indicate that the inhibition of CB1 could ameliorate lipid metabolism via the stimulation of the CPT1A and CPT1B expression in vivo. Simultaneously, the PPARα and PPARγ expression levels significantly differed compared to that of PPARβ in obesity and lipid metabolism-related disorders under blockade of CB1. Both the mec Topics: Adipose Tissue; Administration, Oral; Animals; Body Weight; Cannabinoid Receptor Antagonists; Carnitine O-Palmitoyltransferase; Cholesterol; Diet, High-Fat; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Myocardium; Obesity; PPAR alpha; Receptor, Cannabinoid, CB1; Rimonabant | 2018 |
A high-fat diet alters genome-wide DNA methylation and gene expression in SM/J mice.
While the genetics of obesity has been well defined, the epigenetics of obesity is poorly understood. Here, we used a genome-wide approach to identify genes with differences in both DNA methylation and expression associated with a high-fat diet in mice.. We weaned genetically identical Small (SM/J) mice onto a high-fat or low-fat diet and measured their weights weekly, tested their glucose and insulin tolerance, assessed serum biomarkers, and weighed their organs at necropsy. We measured liver gene expression with RNA-seq (using 21 total libraries, each pooled with 2 mice of the same sex and diet) and DNA methylation with MRE-seq and MeDIP-seq (using 8 total libraries, each pooled with 4 mice of the same sex and diet). There were 4356 genes with expression differences associated with diet, with 184 genes exhibiting a sex-by-diet interaction. Dietary fat dysregulated several pathways, including those involved in cytokine-cytokine receptor interaction, chemokine signaling, and oxidative phosphorylation. Over 7000 genes had differentially methylated regions associated with diet, which occurred in regulatory regions more often than expected by chance. Only 5-10% of differentially methylated regions occurred in differentially expressed genes, however this was more often than expected by chance (p = 2.2 × 10. Discovering the gene expression and methylation changes associated with a high-fat diet can help to identify new targets for epigenetic therapies and inform about the physiological changes in obesity. Here, we identified numerous genes with altered expression and methylation that are promising candidates for further study. Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; DNA Methylation; Female; Gene Expression Regulation; Genetic Association Studies; Genome; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Male; Mice; Obesity; Triglycerides | 2018 |
Carnosic Acid Modulates Increased Hepatic Lipogenesis and Adipocytes Differentiation in Ovariectomized Mice Fed Normal or High-Fat Diets.
As postmenopausal women experience a rapid increase in cardiovascular disease (CVD) risk with an increase in abdominal fat, dietary interventions to reduce CVD risk have been emphasized. This study was aimed at investigating the effect of a high-fat diet (HFD) in combination with an ovariectomy on liver and adipose tissue fat metabolism. The efficacy of carnosic acid (CA) supplementation in the suppression of HFD- and ovariectomy-induced obesity was also evaluated. Ovariectomized (OVX) or sham-operated mice at eight weeks of age were fed with a normal diet (ND), HFD, ND and 0.02% CA, or HFD and 0.02% CA for 12 weeks. All of the animals were sacrificed at the age of 20 weeks. The blood and tissue markers of the lipogenesis and adipocyte differentiation were measured. As expected, ovariectomy decreased the uterus weight and serum 17β-estradiol concentration. The HFD and ovariectomy significantly contributed to increases in the body weight and total fat mass, which were effectively inhibited by CA supplementation. The circulating concentrations of insulin, leptin, and TG (triglyceride) were significantly higher in the HFD group, and the concentrations were two to five times higher in the OVX and HFD group compared with those of the ND group. The CA supplementation significantly lowered the insulin, leptin, and TG concentrations in the OVX and HFD mice. The hepatic protein expressions of pAMPK and pACC were up-regulated by CA supplementation in OVX mice fed either ND or HFD. The expressions of hepatic SREBP1c and FAS mRNA were the highest in the OVX and HFD group, which were suppressed by CA supplementation. The adipose tissue PPARγ, aP2, and lipoprotein lipase (LPL) mRNA expressions were up-regulated by a HFD or ovariectomy, while they were significantly reduced in the mice fed a CA supplemented diet. The TNF-α and IL-6 mRNA levels in the adipose tissue were decreased by providing CA in the OVX groups. These results suggest that HFD and ovariectomy independently contribute to body fat accumulation, and CA effectively alleviated the ovariectomy-induced increases in lipogenesis and adipocyte differentiation. Further human trials are required in order to evaluate the efficacy of rosemary-derive CA as natural anti-adipogenic compounds, especially in postmenopausal women. Topics: Abietanes; Adipocytes; Adipogenesis; Adipose Tissue; Animals; Body Weight; Cell Differentiation; Diet; Diet, High-Fat; Dietary Supplements; Female; Insulin; Leptin; Lipogenesis; Liver; Mice, Inbred C57BL; Obesity; Ovariectomy; Phytotherapy; Plant Extracts; Postmenopause; Rosmarinus; Triglycerides | 2018 |
Oxytocin Administration Alleviates Acute but Not Chronic Leptin Resistance of Diet-Induced Obese Mice.
Whereas leptin administration only has a negligible effect on the treatment of obesity, it has been demonstrated that its action can be improved by co-administration of leptin and one of its sensitizers. Considering that oxytocin treatment decreases body weight in obese animals and humans, we investigated the effects of oxytocin and leptin cotreatment. First, lean and diet-induced obese (DIO) mice were treated with oxytocin for 2 weeks and we measured the acute leptin response. Second, DIO mice were treated for 2 weeks with saline, oxytocin (50 μg/day), leptin (20 or 40 µg/day) or oxytocin plus leptin. Oxytocin pre-treatment restored a normal acute leptin response, decreasing food intake and body weight gain. Chronic continuous administration of oxytocin or leptin at 40 µg/day decreased body weight in the presence (leptin) or in the absence (oxytocin) of cumulative differences in food intake. Saline or leptin treatment at 20 µg/day had no impact on body weight. Oxytocin and leptin cotreatments had no additional effects compared with single treatments. These results point to the fact that chronic oxytocin treatment improves the acute, but not the chronic leptin response, suggesting that this treatment could be used to improve the short-term satiety effect of leptin. Topics: Animals; Body Weight; Diet, High-Fat; Eating; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oxytocin | 2018 |
Protective Effects of Chaihu Shugan San () on Nonalcoholic Fatty Liver Disease in Rats with Insulin Resistance.
To investigate the protective effects of Chinese medicine formulation Chaihu Shugan San (, CHSGS) on nonalcoholic fatty liver disease (NAFLD) in rats with insulin resistance (IR) and its molecular mechanisms.. Male Sprague-Dawley rats were randomly divided into six groups: the control group, the model group, Dongbao Gantai group (, DBGT, 0.09 g methionine/kg), CHSGS high-dose group (CHSG-H, 12.6 g crude drug/kg), CHSGS medium-dose group (CHSG-M, 6.3 g crude drug/kg), and CHSGS low-dose group (CHSG-L, 3.15 g crude drug/kg). After establishing the NAFLD rat model and treatment for 8 weeks, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), free fatty acid (FFA), fasting blood glucose (FBG), fasting insulin (FINS) contents in blood serum, and TC, TG contents in the hepatic homogenate were measured by an automatic biochemical analyzer, and a homeostasis model assessment was applied to assess the status of IR, insulin sensitivity index (ISI), and homeostasis model assessment for insulin secretion (HOMA-IS). The expression levels of adiponectin and leptin mRNA in liver tissue were analyzed by reverse transcription polymerase chain reaction. Pathological changes of livers were observed by hematoxylin-eosin staining of paraffin section.. Compared with the model group, the serum levels of TC, TG, FFA, FBG, FINS, IRI, ISI, and the liver levels of TC and TG in CHSG-H, CHSG-M, CHSG-L groups showed significant declines (P<0.01 or P<0.05); the serum levels of HDL-C, HOMA-IS were significantly increased (P<0.01 or P<0.05); the expression of leptin mRNA was dramatically decreased and the expression of adiponectin mRNA was increased in the hepatic tissue (P<0.01 or P<0.05). The fatty deposition of liver cells could also be alleviated.. CHSGS could up-regulate the expression of adiponectin mRNA and down-regulate the expression of leptin mRNA on the liver, suggesting the CHSGS had positive therapeutic effect on NAFLD in rats with IR. Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Fasting; Homeostasis; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Non-alcoholic Fatty Liver Disease; Plant Extracts; Protective Agents; Rats, Sprague-Dawley; RNA, Messenger | 2018 |
Perinatal Exposure to Low-Dose Bisphenol-A Disrupts the Structural and Functional Development of the Hypothalamic Feeding Circuitry.
Bisphenol-A (BPA) is a component of polycarbonate and other plastics to which humans are regularly exposed at low levels. BPA is characterized as an endocrine disruptor because of observations of its estrogenic activity in various experimental models. We have previously shown evidence of disrupted hypothalamic feeding circuitry and leptin sensitivity in adult BPA-exposed animals subjected to a high-fat diet, but because these animals were already exhibiting a diet-induced obese phenotype, we could not rule out the possibility that these observations were simply consequences of the obesity, not a preexisting phenotype produced by BPA exposure. Here, we studied leptin sensitivity and hypothalamic structure in young BPA-exposed animals before the onset of a body weight or metabolic phenotype. Pregnant and lactating CD-1 mice were exposed to either BPA or diethylstilbestrol (DES) at low, environmentally relevant doses via their diet. Studies of leptin function and neurobiology were conducted on offspring at several time points. Young adult offspring from this experiment were resistant to leptin-induced suppression of food intake, body weight loss, and hypothalamic pro-opiomelanocortin (POMC) upregulation. Both male and female BPA-exposed mice showed a reduced density of POMC projections into the paraventricular nucleus of the hypothalamus (PVN). BPA- and DES-exposed pups had respectively delayed and blunted postnatal leptin surges, and POMC projections into the PVN were rescued in female BPA-exposed animals given daily injections of supplemental leptin. Our findings suggest that BPA, a putative obesogen, may exert its effects through developmental programming of the hypothalamic melanocortin circuitry, permanently altering the neurobiology of metabolic homeostasis. Topics: Animals; Benzhydryl Compounds; Body Weight; Eating; Endocrine Disruptors; Female; Homeostasis; Hypothalamus; Leptin; Male; Mice; Nerve Net; Neurons; Phenols; Pregnancy; Prenatal Exposure Delayed Effects; Pro-Opiomelanocortin | 2017 |
Association between urinary metabolic profile and the intestinal effects of cocoa in rats.
The aim of this study was to elucidate the relationship between the urinary metabolic fingerprint and the effects of cocoa and cocoa fibre on body weight, hormone metabolism, intestinal immunity and microbiota composition. To this effect, Wistar rats were fed, for 3 weeks, a diet containing 10 % cocoa (C10) or two other diets with same the proportion of fibres: one based on cocoa fibre (CF) and another containing inulin as a reference (REF) diet. The rats' 24 h urine samples were analysed by an untargeted 1H NMR spectroscopy-based metabonomic approach. Concentrations of faecal IgA and plasma metabolic hormones were also quantified. The C10 diet decreased the intestinal IgA, plasma glucagon-like peptide-1 and glucagon concentrations and increased ghrelin levels compared with those in the REF group. Clear differences were observed between the metabolic profiles from the C10 group and those from the CF group. Urine metabolites derived from cocoa correlated with the cocoa effects on body weight, immunity and the gut microbiota. Overall, cocoa intake alters the host and bacterial metabolism concerning energy and amino acid pathways, leading to a metabolic signature that can be used as a marker for consumption. This metabolic profile correlates with body weight, metabolic hormones, intestinal immunity and microbiota composition. Topics: Amino Acids; Animals; Body Weight; Cacao; Diet; Dietary Fiber; Energy Metabolism; Feces; Female; Gastrointestinal Microbiome; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Hormones; Immunoglobulin A; Intestines; Leptin; Metabolome; Rats; Rats, Wistar; Urine | 2017 |
Stress, cortisol, and other appetite-related hormones: Prospective prediction of 6-month changes in food cravings and weight.
To examine whether baseline chronic stress, morning cortisol, and other appetite-related hormones (leptin, ghrelin, and insulin) predict future weight gain and food cravings in a naturalistic, longitudinal, 6-month follow-up study.. A prospective community cohort of 339 adults (age 29.1 ± 9.0 years; BMI = 26.7 ± 5.4 kg/m. Over the 6-month period, 49.9% of the sample gained weight. Food cravings and chronic stress decreased over 6 months (Ps < 0.05). However, after adjusting for covariates, individuals with higher baseline total ghrelin had significantly higher food cravings at 6 months (P = 0.04). Furthermore, higher cortisol, insulin, and chronic stress were each predictive of greater future weight gain (Ps < 0.05).. These results suggest that ghrelin plays a role in increased food cravings and reward-driven eating behaviors. Studies are needed that examine the utility of stress reduction methods for normalizing disrupted cortisol responses and preventing future weight gain. Topics: Adult; Appetite; Body Mass Index; Body Weight; Craving; Fasting; Feeding Behavior; Female; Follow-Up Studies; Ghrelin; Heat-Shock Proteins; Humans; Hydrocortisone; Insulin; Leptin; Linear Models; Longitudinal Studies; Male; Predictive Value of Tests; Prospective Studies; Weight Gain; Young Adult | 2017 |
Beneficial Effects of Phyllanthus amarus Against High Fructose Diet Induced Insulin Resistance and Hepatic Oxidative Stress in Male Wistar Rats.
Insulin resistance (IR) is a characteristic feature of obesity, type 2 diabetes mellitus, and cardiovascular diseases. Emerging evidence suggests that the high-fructose consumption is a potential and important factor responsible for the rising incidence of IR. The present study investigates the beneficial effects of aqueous extract of Phyllanthus amarus (PAAE) on IR and oxidative stress in high-fructose (HF) fed male Wistar rats. HF diet (66% of fructose) and PAAE (200 mg/kg body weight/day) were given concurrently to the rats for a period of 60 days. Fructose-fed rats showed weight gain, hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired insulin sensitivity, dyslipidemia, hyperleptinemia, and hypoadiponectinemia (P < 0.05) after 60 days. Co-administration of PAAE along with HF diet significantly ameliorated all these alterations. Regarding hepatic antioxidant status, higher lipid peroxidation and protein oxidation, lower reduced glutathione levels and lower activities of enzymatic antioxidants, and the histopathological changes like mild to severe distortion of the normal architecture as well as the prominence and widening of the liver sinusoids observed in the HF diet-fed rats were significantly prevented by PAAE treatment. These findings indicate that PAAE is beneficial in improving insulin sensitivity and attenuating metabolic syndrome and hepatic oxidative stress in fructose-fed rats. Topics: Adiponectin; Animals; Antioxidants; Blood Glucose; Body Weight; Diet; Dose-Response Relationship, Drug; Fasting; Fructose; Homeostasis; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Organ Size; Oxidative Stress; Phyllanthus; Plant Extracts; Rats; Rats, Wistar; Water | 2017 |
Preliminary investigation for effects of hypothalamic Leptin/Ghrelin and arcuate nucleus pro-opiomelanocortin system on regulation of high-altitude acclimatization.
This study aims to investigate the mechanism of hypothalamic Leptin/Ghrelin and arcuate nucleus pro-opiomelanocortin (POMC) system in the regulation of high-altitude acclimatization. SD rats (male) were divided into two groups and separately fed at the 2260m and 4700m altitude. Tow groups contained 5 small groups separately, including 1 d, 3 d, 7 d, 15 d and 30 d, and 8 rats in each group. Blood, cerebrospinal fluid and tissues were taken at setting time. Leptin and Ghrelin were detected by using radioactivity immuno-assay. RNA expression of NPY and POMC were detected by using RT-PCR assay. The number of NPY positive neurons was detected by using immunofluorescence (IF) and cell counting. Other rats were sent to the 4300m and fed in animal room with regular diet and drinking. The results indicated that after being sent to high altitude region, Leptin levels at the 3rd and 7th day were significantly higher than the 1st day, while decreased at 15th, and the level at 30th day was closed to the 1st day. Ghrelin levels decreased at the 3rd, 7th and 15th day, and were lower at the 30th day. Comparing to the 1st day, NPY transcription levels increased at the 7th day, while decreased at the 30th. POMC transcription level decreased at the 7th day, while increased at the 30th gradually. The feeding of the rats fed at the 4300m decreased at the 3rd and the 5th, while increased at the 7th, 15th and 30th day. The weight of the rats changed as the feeding changing. In conclusion, after being sent to the high region, the rats were adaptive to the hypoxia environment gradually, and the steady of neuro-endocrine regulation recovered or established. Topics: Acclimatization; Altitude; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Ghrelin; Hypothalamus; Leptin; Male; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Leptin | 2017 |
Protein malnutrition promotes dysregulation of molecules involved in T cell migration in the thymus of mice infected with Leishmania infantum.
Protein malnutrition, the most deleterious cause of malnutrition in developing countries, has been considered a primary risk factor for the development of clinical visceral leishmaniasis (VL). Protein malnutrition and infection with Leishmania infantum leads to lymphoid tissue disorganization, including changes in cellularity and lymphocyte subpopulations in the thymus and spleen. Here we report that protein malnutrition modifies thymic chemotactic factors by diminishing the CCL5, CXCL12, IGF1, CXCL9 and CXCL10 protein levels in infected animals. Nevertheless, T cells preserve their migratory capability, as they were able to migrate ex vivo in response to chemotactic stimuli, indicating that malnutrition may compromise the thymic microenvironment and alter in vivo thymocyte migration. Decrease in chemotactic factors protein levels was accompanied by an early increase in the parasite load of the spleen. These results suggest that the precondition of malnutrition is affecting the cell-mediated immune response to L. infantum by altering T cell migration and interfering with the capacity of protein-deprived animals to control parasite spreading and proliferation. Our data provide evidence for a disturbance of T lymphocyte migration involving both central and peripheral T-cells, which likely contribute to the pathophysiology of VL that occurs in malnourished individuals. Topics: Animals; Apoptosis; Atrophy; Body Weight; Cell Movement; Chemotaxis; Cytokines; Insulin-Like Growth Factor I; Leishmania infantum; Leishmaniasis, Visceral; Leptin; Ligands; Macrophages; Malnutrition; Mice, Inbred BALB C; Parasite Load; Parasites; Receptors, CXCR3; Spleen; T-Lymphocytes; Thymocytes; Thymus Gland | 2017 |
β
The main hypothesis of the study is that stress associated with repeated immune challenge has an impact on β Topics: Adipokines; Adiponectin; Adipose Tissue; Aldosterone; Animals; Anxiety; Behavior, Animal; Body Weight; Brain; Dehydroepiandrosterone; Female; Gene Expression; Hippocampus; Interleukin-6; Leptin; Lipopolysaccharides; Male; PPAR gamma; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta-3; RNA, Messenger | 2017 |
Metabolic and affective consequences of fatherhood in male California mice.
Physiological and affective condition can be modulated by the social environment and parental state in mammals. However, in species in which males assist with rearing offspring, the metabolic and affective effects of pair bonding and fatherhood on males have rarely been explored. In this study we tested the hypothesis that fathers, like mothers, experience energetic costs as well as behavioral and affective changes (e.g., depression, anxiety) associated with parenthood. We tested this hypothesis in the monogamous, biparental California mouse (Peromyscus californicus). Food intake, blood glucose and lipid levels, blood insulin and leptin levels, body composition, pain sensitivity, and depression-like behavior were compared in males from three reproductive groups: virgin males (VM, housed with another male), non-breeding males (NB, housed with a tubally ligated female), and breeding males (BM, housed with a female and their first litter). We found statistically significant (P<0.007, when modified for Adaptive False Discovery Rate) or nominally significant (0.007 Topics: Adipose Tissue; Affect; Animals; Biomarkers; Blood Glucose; Body Weight; Cholesterol; Eating; Fathers; Insulin; Leptin; Litter Size; Male; Pain Threshold; Pair Bond; Peromyscus; Predatory Behavior; Random Allocation; Reproduction; Testis; Triglycerides | 2017 |
Physiological Changes Following Competition in Male and Female Physique Athletes: A Pilot Study.
The purpose of the current study was to evaluate changes in body composition, metabolic rate, and hormones during postcompetition recovery. Data were collected from natural physique athletes (7 male/8 female) within one week before (T1) competition, within one week after (T2), and 4-6 weeks after (T3) competition. Measures included body composition (fat mass [FM] and lean mass [LM] from ultrasongraphy), resting metabolic rate (RMR; indirect calorimetry), and salivary leptin, testosterone, cortisol, ghrelin, and insulin. Total body water (TBW; bioelectrical impedance spectroscopy) was measured at T1 and T2 in a subsample (n = 8) of athletes. Significant (p < .05) changes were observed for weight (T1 = 65.4 ± 12.2 kg, T2 = 67.4 ± 12.6, T3 = 69.3 ± 13.4; T3 > T2 > T1), LM (T1 = 57.6 ± 13.9 kg, T2 = 59.4 ± 14.2, T3 = 59.3 ± 14.2; T2 and T3 > T1), and FM (T1 = 7.7 ± 4.4 kg, T2 = 8.0 ± 4.4, T3 = 10.0 ± 6.2; T3 > T1 and T2). TBW increased from T1 to T2 (Δ=1.9 ± 1.3 L, p < .01). RMR increased from baseline (1612 ± 266 kcal/day; 92.0% of predicted) to T2 (1881 ± 329, 105.3%; p < .01) and T3 (1778 ± 257, 99.6%; p < .001). Cortisol was higher (p < .05) at T2 (0.41 ± 0.31 μg/dL) than T1 (0.34 ± 0.31) and T3 (0.35 ± 0.27). Male testosterone at T3 (186.6 ± 41.3 pg/mL) was greater than T2 (148.0 ± 44.6, p = .04). RMR changes were associated (p ≤ .05) with change in body fat percent (ΔBF%; r = .59) and T3 protein intake (r= .60); male testosterone changes were inversely associated (p≤ .05) with ΔBF%, ΔFM, and Δweight (r=-0.81--0.88). TBW increased within days of competition. Precompetition RMR suppression appeared to be variable and markedly reversed by overfeeding, and reverted toward normal levels following competition. RMR and male testosterone increased while FM was preferentially gained 4-6 weeks postcompetition. Topics: Athletes; Basal Metabolism; Body Composition; Body Weight; Calorimetry, Indirect; Diet; Electric Impedance; Female; Ghrelin; Humans; Hydrocortisone; Insulin; Leptin; Male; Pilot Projects; Rest; Saliva; Testosterone | 2017 |
Leptin Immunohistochemical Staining in the Porcine Ovary.
This study aimed to investigate leptin immuno-staining of the porcine ovary in different reproductive stages. Ovaries from 21 gilts were collected from slaughterhouses. The ovarian tissue sections were incubated with a polyclonal anti-leptin as a primary antibody. The immuno-staining in ovarian tissue compartments was calculated using imaging software. Leptin immuno-staining was found in primordial, primary, preantral and antral follicles. Leptin immuno-staining was expressed in the oocyte and granulosa and theca interna layers in both preantral and antral follicles. In the corpora lutea, leptin immuno-staining was found in the cytoplasm of the luteal cells. The leptin immuno-staining in the granulosa cell layer of preantral follicles did not differ compared to antral follicles (90.7 and 91.3%, respectively, P > 0.05). However, the leptin immuno-staining in the theca interna layer of preantral follicles was lower than antral follicles (49.4 and 74.3%, respectively, P < 0.001). There was no difference in leptin immuno-staining in the granulosa cell layer between follicular and luteal phases (92.4 and 89.7%, respectively, P > 0.05). However, the leptin immuno-staining in the theca interna layer of follicular phase was greater than that in the luteal phase (72.7 and 51.0%, respectively, P < 0.001). These findings indicated that leptin exists in different compartments of the porcine ovary, including the oocyte, granulosa cells, theca interna cells, corpus luteum, blood vessel and smooth muscles. Therefore, this morphological study confirmed a close relationship between leptin and ovarian function in the pig. Topics: Angiogenic Proteins; Animals; Body Weight; Corpus Luteum; Female; Follicular Phase; Granulosa Cells; Image Processing, Computer-Assisted; Immunohistochemistry; Leptin; Luteal Phase; Oocytes; Ovarian Follicle; Ovary; Swine; Theca Cells; Weight Gain | 2017 |
Salivary leptin levels in normal weight and overweight individuals and their correlation with orthodontic tooth movement.
To assess and compare the concentration of leptin in saliva between normal weight and overweight individuals and to evaluate the rate of orthodontic tooth movement.. Thirty female subjects were divided into two groups: I (normal weight) and II (overweight group) based on their body mass index. All subjects underwent fixed appliance therapy requiring upper first premolar extraction and distal movement of the canine. Distal force was applied to the maxillary right canine using active lacebacks. Salivary samples were collected just before force application (T. At all three time intervals, mean leptin concentration was greater in overweight individuals than normal weight individuals. In both groups at T. Overweight individuals had greater salivary leptin concentration. There was a positive correlation between salivary leptin concentration and rate of tooth movement in both normal and overweight individuals. The rate of tooth movement is decreased in overweight individuals as compared with normal weight individuals. Topics: Adolescent; Adult; Analysis of Variance; Bicuspid; Body Weight; Cuspid; Dental Stress Analysis; Female; Humans; Leptin; Nickel; Orthodontic Appliance Design; Orthodontic Brackets; Orthodontic Wires; Orthodontics, Corrective; Overweight; Saliva; Time Factors; Titanium; Tooth Extraction; Tooth Movement Techniques; Young Adult | 2017 |
Role of Arcuate Nucleus in the Regulation of Feeding Behavior in the Process of Altitude Acclimatization in Rats.
Liu, Xiang-Wen, Jie Yin, Qi-Sheng Ma, Chu-Chu Qi, Ji-Ying Mu, Lang Zhang, Li-Ping Gao, and Yu-Hong Jing. Role of arcuate nucleus in the regulation of feeding behavior in the process of altitude acclimatization in rats. High Alt Med Biol. 18:234-241, 2017.-Highly efficient energy utilization and metabolic homeostasis maintenance rely on neuromodulation. Altitude exposure is known to stimulate neuroendocrine systems to respond to acute hypoxia and adaptive acclimatization. However, limited data on how the adaptive regulation of the arcuate nucleus performs in the process of altitude acclimatization are available. In the present study, male Sprague Dawley rats were transported to Huashixia, Qinghai (with an altitude of 4400 m) from Xian (with an altitude of 300 m) by air; rats were consistently raised in Xian as control. Food uptake and body weight were measured consecutively after being subjected to high-altitude condition. Contents of plasma leptin and ghrelin were analyzed by the Enzyme Linked Immunosorbent Assay (ELISA) Kits. Brain coronal sections were obtained, and neuropeptide Y (NPY), proopiomelanocotin (POMC), and c-fos immunoreactivity in arcuate nucleus were observed. Arcuate nucleus was isolated from the hypothalamus, and the mRNA of NPY and POMC were measured by quantitative real-time polymerase chain reaction. Our results showed both food consumption and body weight decreased in the high plateau compared with rats raised in the low-altitude condition. Plasma leptin increased at the early stage, and ghrelin decreased at a later stage after reaching the high plateau. The peak of c-fos immunoreactivity in the arcuate nucleus was at day 3 after reaching the high plateau. The expression level of NPY increased, and POMC decreased in the arcuate nucleus at day 7 after reaching the high plateau compared with the plain control group. These results indicate that the arcuate nucleus of hypothalamus performs an important function in regulating feeding behavior during altitude acclimatization. Our study suggested that altitude acclimation is regulated by the hypothalamus that received leptin and ghrelin signals to response by its microcircuit, including NPY- and POMC-neurons in the arcuate nucleus. Topics: Acclimatization; Altitude; Altitude Sickness; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; China; Feeding Behavior; Genes, fos; Ghrelin; Hypothalamus; Leptin; Male; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2017 |
Egg White Hydrolysate Can Be a Low-Allergenic Food Material to Suppress Ectopic Fat Accumulation in Rats Fed an Equicaloric Diet.
Egg white (EW) is known as a nutritional protein but can induce allergic reactions in humans. We investigated the dietary effects of EW and its hydrolysate (EWH), which contains less allergen, on body fat accumulation in Wistar rats fed an equicaloric high-fat and high-sucrose diet for 8 wk (Exp A). The pair-feeding of EW and equicaloric-feeding of EWH increased fecal fat excretion and suppressed lipid accumulation in the liver and muscles but not in the abdominal adipose tissues, carcass, or total body. Dietary EWH also suppressed the serum glucose level and alkaline phosphatase activity. Further, we showed a higher dispersibility of EW and EWH in physicochemical assay (Exp B). Next, we investigated the suppressive effects of a single administration of EW and EWH on lipid-induced hypertriglyceridemia and small intestinal meal transit in ddY mice (Exp C). However, a single administration of EW or EWH did not suppress the lipid-induced hypertriglyceridemia nor did it delay the rate of small intestinal transit. These findings indicated that dietary EW and EWH reduce hepatic and muscular (ectopic) fat accumulation mainly by suppressing fat absorption and supplying fat to the liver and muscles. Therefore, the low-allergenic EWH can be effective for the prevention of high-fat-diet-induced obesity. Topics: Alkaline Phosphatase; Animals; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; Dietary Fats; Egg Hypersensitivity; Egg White; Glycated Hemoglobin; Hypertriglyceridemia; Insulin; Intestine, Small; Leptin; Liver; Male; Mice; Muscle, Skeletal; Obesity; Protein Hydrolysates; Rats; Rats, Wistar; Triglycerides | 2017 |
Protective effects of green tea on olanzapine-induced-metabolic syndrome in rats.
Atypical antipsychotics particularly olanzapine are associated with obesity and serious metabolic disturbances. As green tea (Camellia sinensis) is generally associated with beneficial effects on obesity and other metabolic disturbances, this study was undertaken to evaluate the effect of green tea aqueous extract (GTAE) on olanzapine induced weight gain and metabolic abnormalities in rats. Male Wistar rats were divided into eight groups: control, olanzapine (5mg/kg/day, IP.), GTAE (25, 50 and 100mg/kg/day, IP.) plus olanzapine and GTAE (25, 50 and 100mg/kg/day, IP.). Treatments were continued for 11 days. Body weight gain, average food and water intake were measured during the experiment. Plasma lipid, glucose and leptin levels, mean systolic blood pressure and total locomotion were evaluated at the end of experiment. Olanzapine induced significant weight gain at the end of treatment (10.38% of body weight) when compared to control (3.13% of body weight) in male Wistar rats. Average food and water intake were increased by olanzapine treatment. 11days olanzapine administration led to hyperleptinemia, hyperglycemia and dyslipidemia. Olanzapine also increased mean systolic blood pressure and decreased total locomotion. GTAE decreased significantly body weight gain and average food and water intake, improved the changes in lipid profile as well as fasting blood glucose, and finally decreased hyperleptinemia and hypertension induced by olanzapine. Results of this study demonstrated that GTAE could exert protective effects against olanzapine induced obesity partially due to its lowering effect on leptin. GTAE improved other metabolic abnormalities including dyslipidemia, hyperglycemia and hypertension induced by olanzapine in rats. Topics: Animals; Benzodiazepines; Blood Glucose; Blood Pressure; Body Weight; Drinking; Feeding Behavior; Leptin; Lipids; Male; Metabolic Syndrome; Motor Activity; Olanzapine; Polyphenols; Protective Agents; Rats, Wistar; Systole; Tea; Triglycerides | 2017 |
Maternal high-fat diet leads to hippocampal and amygdala dendritic remodeling in adult male offspring.
Early-life exposure to calorie-dense food, rich in fat and sugar, contributes to the increasing prevalence of obesity and its associated adverse cognitive and emotional outcomes at adulthood. It is thus critical to determine the impact of such nutritional environment on neurobehavioral development. In animals, maternal high-fat diet (HFD) consumption impairs hippocampal function in adult offspring, but its impact on hippocampal neuronal morphology is unknown. Moreover, the consequences of perinatal HFD exposure on the amygdala, another important structure for emotional and cognitive processes, remain to be established. In rats, we show that adult offspring from dams fed with HFD (45% from fat, throughout gestation and lactation) exhibit atrophy of pyramidal neuron dendrites in both the CA1 of the hippocampus and the basolateral amygdala (BLA). Perinatal HFD exposure also impairs conditioned odor aversion, a task highly dependent on BLA function, without affecting olfactory or malaise processing. Neuronal morphology and behavioral alterations elicited by perinatal HFD are not associated with body weight changes but with higher plasma leptin levels at postnatal day 15 and at adulthood. Taken together, our results suggest that perinatal HFD exposure alters hippocampal and amygdala neuronal morphology which could participate to memory alterations at adulthood. Topics: Adult Children; Amygdala; Animals; Body Weight; Dendrites; Diet, High-Fat; Female; Hippocampus; Leptin; Male; Maternal Exposure; Memory; Neuronal Plasticity; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Temporal Lobe | 2017 |
Aripiprazole-induced adverse metabolic alterations in polyI:C neurodevelopmental model of schizophrenia in rats.
Schizophrenia appears to be linked to higher incidence of metabolic syndrome even in the absence of antipsychotic treatment. Atypical antipsychotics substantially differ in their propensity to induce metabolic alterations. Aripiprazole is considered to represent an antipsychotic drug with low risk of metabolic syndrome development. The aim of this study was to evaluate metabolic phenotype of neurodevelopmental polyI:C rat model and assess metabolic effects of chronic aripiprazole treatment with regard to complex neuroendocrine regulations of energy homeostasis. Polyinosinic:polycytidylic acid (polyI:C) was administered subcutaneously at a dose of 8 mg/kg in 10 ml on gestational day 15 to female Wistar rats. For this study 20 polyI:C and 20 control adult male offspring were used, randomly divided into 2 groups per 10 animals for chronic aripiprazole treatment and vehicle. Aripiprazole (5 mg/kg, dissolved tablets, ABILIFY Topics: Administration, Oral; Animals; Antipsychotic Agents; Aripiprazole; Body Weight; Cytokines; Disease Models, Animal; Ghrelin; Glucagon-Like Peptide 1; Leptin; Male; Metabolic Syndrome; Poly I-C; Random Allocation; Rats, Wistar; Schizophrenia | 2017 |
Effects of exogenous leptin on seasonal reproductive responses to interacting environmental cues in female Siberian hamsters.
Animals living in temperate climates respond to environmental cues that signal current and future resource availability to ensure that energy resources are available to support reproduction. Siberian hamsters (Phodopus sungorus) undergo robust gonadal regression in short, winter-like photoperiods as well as in response to mild food restriction in intermediate photoperiods. The goal of the present study was to investigate whether leptin is a relevant metabolic signal in regulating gonadal regression in response to diminishing food availability. Adult female hamsters housed in short-day (winter-like) or intermediate (fall-like) photoperiods received either ad libitum access to food or mild food restriction (90% of ad libitum intake) and were treated with either leptin or a vehicle for five weeks in order to determine the ability of leptin to inhibit gonadal regression. At the end of five weeks, vehicle-treated hamsters showed physiological signs associated with ongoing gonadal regression, such as decreases in body mass and food intake, cessation of estrous cycling, and small decreases in reproductive tissue mass. Leptin did not modify changes in body mass, food intake, hormone concentration, or tissue mass, but showed a tendency to support estrous cycling, particularly in response to food restriction in the intermediate photoperiod treatment. Overall, leptin appears to play a minor role in coordinating reproductive responses to multiple environmental cues, at least in the early stages of gonadal regression. Topics: Animals; Body Weight; Cricetinae; Cues; Eating; Environment; Estrous Cycle; Female; Leptin; Luteinizing Hormone; Phodopus; Photoperiod; Reproduction; Seasons | 2017 |
A High-Fructose-High-Coconut Oil Diet Induces Dysregulating Expressions of Hippocampal Leptin and Stearoyl-CoA Desaturase, and Spatial Memory Deficits in Rats.
We investigated the effects of high-fructose-high-fat diets with different fat compositions on metabolic parameters, hippocampal-dependent cognitive function, and brain leptin (as well as stearoyl-CoA desaturase (SCD1) mRNA expressions). Thirty-two male Wistar rats were divided into 3 groups, a control group ( Topics: Animal Feed; Animals; Blood Glucose; Body Weight; Coconut Oil; Diet; Dietary Carbohydrates; Dietary Fats; Fructosamine; Fructose; Gene Expression Regulation; Hippocampus; Leptin; Male; Rats; Rats, Wistar; Spatial Memory; Stearoyl-CoA Desaturase | 2017 |
Polymorphisms in Lep and Lepr Genes in Infants: Correlation with Serum Leptin Values in the First 6 Months of Life.
Because several studies indicate that polymorphisms in leptin (Lep) and leptin receptor (Lepr) genes play a central role in determining obesity, we analyzed 2 single nucleotide polymorphisms (SNPs) in the Lep gene (Lep G2548A and A19G) and one in the Lepr gene (Lepr A668G) to verify the effect of the 3 SNPs on leptin concentrations in infancy.. We enrolled 80 healthy Caucasian infants under 6 months of age, who were genotyped for the 3 SNPs with amplification refractory mutation system-mismatch amplification mutation assay (ARMS-MAMA) real-time polymerase chain reaction (PCR). Serum leptin values were measured with a radioimmunoassay method. Statistical significance was set at p < 0.05.. There were no significant differences between individually analyzed leptin polymorphisms Lep G2548A and A19G and serum leptin levels (p > 0.05). Because we found that Lep G2548A and A19G are in linkage disequilibrium on chromosome 7, we performed the haplotype analysis for Lep G2548A and Lep A19G. We obtained higher serum leptin levels in infants with the GG/GG haplotype (p < 0.05). Regarding receptor, we found higher leptin levels in GG-genotype infants for Lepr A668G (p < 0.001). Considering the 3 SNPs together, we found higher serum leptin values in GG/GG-GG infants (LepG2548A/A19G-Lepr A668G; p < 0.001).. We obtained higher serum leptin levels in infants with the GG genotype for Lepr A668G, with haplotype GG/GG for Lep G2548A/A19G, and with GG/GG-GG (LepG2548A/A19G-Lepr A668G); thus, it seems that the genotype GG could be a protector against obesity development in infancy and adulthood. Moreover, these data confirm that not variations in the Lep gene as well as in the Lepr gene could play a role in weight gain. Further studies are needed to evaluate the role of genetics and the environment in a predisposition toward obesity later in life. Topics: Body Weight; Female; Gene Expression Regulation, Developmental; Haplotypes; Humans; Infant; Infant, Newborn; Leptin; Male; Polymorphism, Genetic; Receptors, Leptin | 2017 |
Effects of mild calorie restriction on lipid metabolism and inflammation in liver and adipose tissue.
Calorie restriction (CR) has been reported to improve lipid metabolism and to decrease inflammatory diseases. However, most existing CR models use 30-50% calorie reduction, which is hard to achieve in humans. We investigated the effects of mild CR on lipid metabolism and inflammatory responses. Male C57BL/6 mice were fed control diet (10% kcal fat, Control) or high fat diet (60% kcal fat, HFD) ad libitum or reduced amount of control diet to achieve 15% CR for 16 wks. Body weights, white adipose tissue weights, liver triacylglycerol levels, and serum fetuin-A levels were lower in CR than in the Control. Serum adiponectin levels were higher in CR and lower in HFD compared with the Control. Liver and adipose tissue Mcp-1 mRNA levels were significantly lower in CR compared with the Control. Adipose tissue mRNA levels of Mcp-1, Il-6, Tnf-α and Socs3 were significantly higher in HFD than in the Control and CR, and levels of these negatively correlated with serum adiponectin levels. CR group had the lowest leptin levels and the highest liver Lepr expression, and Lepr mRNA levels positively correlated with liver Socs3 mRNA levels. Our findings showed that mild CR lowered adiposity which resulted in higher adiponectin and lower fetuin-A levels, and might have contributed to alleviation of inflammatory status in the liver and adipose tissue. Furthermore, mild CR might have affected leptin sensitivity by up-regulating Lepr expression. Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Caloric Restriction; Gene Expression Regulation; Inflammation; Leptin; Lipid Metabolism; Lipids; Liver; Male; Mice, Inbred C57BL; Signal Transduction; Transaminases | 2017 |
Correlation of disease severity with body weight and high fat diet in the FATZO/Pco mouse.
Obesity in many current pre-clinical animal models of obesity and diabetes is mediated by monogenic mutations; these are rarely associated with the development of human obesity. A new mouse model, the FATZO mouse, has been developed to provide polygenic obesity and a metabolic pattern of hyperglycemia and hyperinsulinemia, that support the presence of insulin resistance similar to metabolic disease in patients with insulin resistance/type 2 diabetes. The FATZO mouse resulted from a cross of C57BL/6J and AKR/J mice followed by selective inbreeding for obesity, increased insulin and hyperglycemia. Since many clinical studies have established a close link between higher body weight and the development of type 2 diabetes, we investigated whether time to progression to type 2 diabetes or disease severity in FATZO mice was dependent on weight gain in young animals. Our results indicate that lighter animals developed metabolic disturbances much slower and to a lesser magnitude than their heavier counterparts. Consumption of a diet containing high fat, accelerated weight gain in parallel with disease progression. A naturally occurring and significant variation in the body weight of FATZO offspring enables these mice to be identified as low, mid and high body weight groups at a young age. These weight groups remain into adulthood and correspond to slow, medium and accelerated development of type 2 diabetes. Thus, body weight inclusion criteria can optimize the FATZO model for studies of prevention, stabilization or treatment of type 2 diabetes. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Eating; Insulin; Leptin; Male; Mice; Obesity; Pancreas | 2017 |
Administration of a leptin antagonist during the neonatal leptin surge induces alterations in the redox and inflammatory state in peripubertal /adolescent rats.
The importance of the neonatal leptin surge in rodents in neurodevelopmental processes has aroused curiosity in its implication in other physiological systems. Given the role of leptin in neuro-immune interactions, we hypothesized that the neonatal leptin surge could have an effect on the oxidative and inflammatory stress situations of both systems. We blocked the neonatal leptin surge by a leptin antagonist and measured several parameters of oxidative and inflammatory stress in the spleen, hypothalamus and adipose tissue of peripubertal/adolescent rats. The treated rats showed lower activity of several antioxidant enzymes in the spleen and their leukocytes released lower levels of mitogen-stimulated IL-10 and IL-13 and higher levels of TNF-alpha. In conclusion, the neonatal leptin surge may have a key role in the establishment of adequate redox and inflammatory states in the immune system, which is important for the generation of adequate immune responses and to obtain and maintain good health. Topics: Adipose Tissue, White; Animals; Animals, Newborn; Body Weight; Catalase; Cytokines; Female; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Hypothalamus; Inflammation; Leptin; Male; Organ Size; Oxidation-Reduction; Oxidative Stress; Rats, Wistar; RNA, Messenger; Sexual Maturation; Superoxide Dismutase | 2017 |
Effects of central administration of resistin on renal sympathetic nerve activity in rats fed a high-fat diet: a comparison with leptin.
Similar to leptin, resistin acts centrally to increase renal sympathetic nerve activity (RSNA). In high-fat fed animals, the sympatho-excitatory effects of leptin are retained, in contrast to the reduced actions of leptin on dietary intake. In the present study, we investigated whether the sympatho-excitatory actions of resistin were influenced by a high-fat diet. Further, because resistin and leptin combined can induce a greater sympatho-excitatory response than each alone in rats fed a normal chow diet, we investigated whether a high-fat diet (22%) could influence this centrally-mediated interaction. Mean arterial pressure (MAP), heart rate (HR) and RSNA were recorded before and for 3 hours after i.c.v. saline (control; n=5), leptin (7 μg; n=4), resistin (7 μg; n=5) and leptin and resistin combined (n=6). Leptin alone and resistin alone significantly increased RSNA (71±16%, 62±4%, respectively). When leptin and resistin were combined, there was a significantly greater increase in RSNA (195±41%) compared to either hormone alone. MAP and HR responses were not significantly different between hormones. When the responses in high-fat fed rats were compared to normal chow fed rats, there were no significant differences in the maximum RSNA responses. The findings indicate that sympatho-excitatory effects of resistin on RSNA are not altered by high-fat feeding, including the greater increase in RSNA observed when resistin and leptin are combined. Our results suggest that diets rich in fat do not induce resistance to the increase in RSNA induced by resistin alone or in combination with leptin. Topics: Animals; Arterial Pressure; Body Weight; Diet, High-Fat; Energy Intake; Heart Rate; Kidney; Leptin; Male; Rats, Sprague-Dawley; Resistin; Sympathetic Nervous System | 2017 |
High, but not low, exercise volume shifts the balance of renin-angiotensin system toward ACE2/Mas receptor axis in skeletal muscle in obese rats.
Metabolic syndrome is a cluster of metabolic risk factors that is linked to central obesity, elevated blood pressure, insulin resistance (IR), and dyslipidemia, where the renin-angiotensin system (RAS) may provide a link among them. This study aimed to evaluate volume exercise effects comparing low vs. high volume of chronic aerobic exercise on RAS axes in skeletal muscle in a diet-induced obesity (DIO) rat model. For this, male Wistar-Kyoto rats were fed a standard chow (SC) diet or a high-fat (HF) diet for 32 wk. Animals receiving the HF diet were randomly divided into low exercise volume (LEV, 150 min/wk) and high exercise volume (HEV, 300 min/wk) at the 20th week. After 12 wk of aerobic treadmill training, the body mass and composition, blood pressure, glucose and lipid metabolism, RAS axes, insulin signaling, and inflammatory pathway were performed. HEV slowed the body mass gain, reduced intra-abdominal fat pad and leptin levels, improved total and peripheral body composition and inflammatory cytokine, reduced angiotensin II type 1 receptor expression, and increased Mas receptor protein expression compared with the HF animals. Sedentary groups (SC and HF) presented lower time to exhaustion and maximal velocity compared with the LEV and HEV groups. Both exercise training groups showed reduced resting systolic blood pressure and heart rate, improved glucose tolerance, IR, insulin signaling, and lipid profile. We conclude that the HEV, but not LEV, shifted the balance of RAS toward the ACE2/Mas receptor axis in skeletal muscle, presenting protective effects against the DIO model. Topics: Absorptiometry, Photon; Animals; Blood Glucose; Blood Pressure; Body Composition; Body Weight; Cholesterol; Cytokines; Diet, High-Fat; Glucose Tolerance Test; Immunoblotting; Insulin; Interleukin-6; Intra-Abdominal Fat; Leptin; Lipid Metabolism; Male; Muscle, Skeletal; Physical Conditioning, Animal; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Triglycerides; Tumor Necrosis Factor-alpha | 2017 |
Neu-P11, a novel MT1/MT2 agonist, reverses diabetes by suppressing the hypothalamic-pituitary-adrenal axis in rats.
Excessive glucocorticoid (GC) in type 2 diabetes mellitus (T2DM) reduces insulin sensitivity, impairs β-cell function, increases gluconeogenesis and glycogenolysis, impairs glucose uptake and metabolism, and reduces the insulinotropic effects of glucagon-like peptide 1. Melatonin, which serves as a physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis, has been suggested to have anti-diabetic effects. The objective of the present study was to investigate the effect of the MT1/MT2 melatonin agonist Neu-P11 on glucose and lipid metabolism in T2DM rats induced by a high fat diet combined with low doses of streptozotocin. T2DM rats were intragastrically administered melatonin (20mg/kg), Neu-P11 (20, 10, 5mg/kg), or a vehicle for 4 weeks. The results showed that the increased food intake, water consumption, hyperglycemia, glucose intolerance, and insulin resistance in T2DM rats were all improved by Neu-P11 treatment. Neu-P11 increased GC receptor expression and suppressed 11β-hydroxysteroid dehydrogenase 1 activity in the hippocampus by enhancing GC sensitivity and HPA feedback, thus decreasing the high GC levels. Transcript levels of the glucose metabolism-related genes peroxisome proliferator-activated receptor-γ, glucose transporter type-4, and adiponectin in adipose tissue were significantly increased after Neu-P11 treatment, while leptin mRNA was significantly decreased. Furthermore, MT1 and MT2 protein levels were enhanced by Neu-P11. These data suggest that normalization of the hyperactivated HPA axis by melatonin and Neu-P11 in T2DM regulates metabolic profiles and insulin sensitivity, which may attenuate insulin resistance and glucose homeostasis. Because Neu-P11 has superior pharmacokinetics and a longer half-life than melatonin, it might be beneficial in treating obesity and T2DM. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Type 2; Drinking; Fasting; Female; Gene Expression Regulation, Enzymologic; Glucose Transporter Type 4; Hippocampus; Hypothalamus; Indoles; Insulin Resistance; Leptin; Pituitary-Adrenal System; PPAR gamma; Pyrans; Rats; Rats, Wistar; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; RNA, Messenger | 2017 |
Differentiating constitutional thinness from anorexia nervosa in DSM 5 era.
Constitutional thinness (CT) is an underweight state characterized by normal menstruations and no change in feeding behaviour. Thinness is the only resemblance between Anorexia Nervosa (AN) and CT. Removal of amenorrhea from the new DSM 5 definition of AN might result in misdiagnosis between these two populations. The objective of this study was to compare CT, AN and Control subjects in terms of biological, anthropometric, and psychological markers in order to better distinguish AN from CT subjects.. Body composition, nutritional markers, pituitary hormones, bone markers and psychological scores were evaluated in three groups of young women: fifty-six CT, forty restrictive-type AN and fifty-four Control subjects. For every marker, a receiver Operator Characteristics (ROC) curve was calculated to evaluate the accuracy of differentiation between AN and CT groups.. For most studied parameters, CT subjects were similar to Controls but dramatically different from AN subjects. DEBQ Restrained Eating subscale score was identified by ROC data analysis as the only psychological parameter tested to successfully differentiate AN from CT. Free-T3 and Leptin were shown to be powerful markers to differentiate AN and CT populations as they were highly specific and sensitive ones.. The exclusive use of psychological testing criteria is not always sufficient to differentiate AN and CT patients. Minimally, additional testing of Free T3 levels, which is cheap and widely accessible for general practitioners, should be completed to avoid misdiagnosis which could result in the implementation of ineffective treatment plans and social stigmatization for CT women. Topics: Adult; Anorexia Nervosa; Anthropometry; Biomarkers; Body Composition; Body Mass Index; Body Weight; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Leptin; Thinness; Thyroid Hormones | 2017 |
Inhibition of N-methyl-N-nitrosourea-induced gastric tumorigenesis by Liuwei Dihuang Pill in db/db mice.
To investigate the inhibitory effect of Liuwei Dihuang Pill (LDP) on gastric tumorigenesis induced by N-methyl-N-nitrosourea (MNU) in diabetic mice.. Four-week-old mice were divided into four groups: A, 12 db/m mice treated with MNU and saline, as the non-diabetic control; B, 12 db/db mice treated with MNU and saline, as the diabetic control; C, 12 db/db mice treated with MNU and metformin, as the positive control; and D, 12 db/db mice treated with MNU and LDP. MNU was administrated for 20 wk to induce gastric carcinogenesis. LDP was administrated for 10 wk for improvement of insulin resistance. Body weight and food intake were measured every week. Blood samples were collected for assays of fasting blood glucose, insulin, insulin-like growth factor (IGF)-1, adiponectin and leptin. Stomach tissues were collected for histopathological analysis, immunohistochemical staining of Ki67, quantitative reverse transcription-polymerase chain reaction and western blotting.. The incidence of MNU-induced gastric dysplasia was significantly elevated in diabetic (db/db) mice relative to the control (db/m) mice. The incidence of gastric dysplasia was significantly reduced by LDP with suppression of cell proliferation, as demonstrated by a decrease in Ki67 staining. Hyperglycemia, hyperinsulinemia and serum IGF-1 were inhibited by LDP. Expression of IGF-1 and insulin receptor mRNAs was decreased, phosphorylation of IGF-1 receptor and AKT protein was reduced in the stomach tissues by LDP. In addition, adiponectin was increased and leptin was decreased in the serum by LDP.. LDP decreased risk of gastric dysplasia in type 2 diabetic mice by down-regulation of IGF and insulin activity and correction of adipokines disorders. Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Carcinogenesis; Cell Transformation, Neoplastic; Diabetes Mellitus, Experimental; Drugs, Chinese Herbal; Immunohistochemistry; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Ki-67 Antigen; Leptin; Male; Methylnitrosourea; Mice; Stomach Neoplasms | 2017 |
Short-term high-fat diet increases the presence of astrocytes in the hypothalamus of C57BL6 mice without altering leptin sensitivity.
Diet-induced obesity is associated with hypothalamic inflammation and this phenomenon has been proposed to explain leptin resistance. In the present study, we used a short-term high-fat diet (HFD) paradigm for 10 days and analysed the cellular and physiological responses to leptin administration in C57BL6 mice. In parallel, we performed glial fibrillary acidic protein immunostaining to measure the presence of astrocytes in the arcuate nucleus of the hypothalamus (ARH) after 10 days and 20 weeks of HFD. Interestingly, the results obtained demonstrate that the presence of star-like astrocytes is significantly increased after 10 days of HFD, although this is not associated with the absence of cellular and physiological response to leptin administration in mice. Taken together, the results of the present study suggest that star-like astrocytes rapidly increase in numbers in the ARH in response to HFD, although this phenomenon cannot explain the development of leptin resistance by itself. Topics: Animals; Arcuate Nucleus of Hypothalamus; Astrocytes; Body Weight; Diet, High-Fat; Energy Intake; Leptin; Male; Mice, Inbred C57BL; STAT3 Transcription Factor | 2017 |
A Botanical Composition from Morus alba, Ilex paraguariensis, and Rosmarinus officinalis for Body Weight Management.
Obesity is the largest and fastest growing public health catastrophe in the world affecting both adults and children with a prevalence impacting more than one-third of United States (US) adult population. Although the long-term solution lies in lifestyle changes in the form of dieting and exercise, intervention is required for those who are already obese. Unfortunately, treatment options remain quite limited due to associated side effects of conventional therapeutics. As a natural alternative, in this study we describe the beneficial effect of a standardized composition (UP603) comprised of extracts from Morus alba, Ilex paraguariensis, and Rosmarinus officinalis in improving metabolic disorders in high fat diet (HFD) and high fat & high fructose diet (HFFD) induced obese C57BL/6J mice. Mice treated with UP603 showed dose-correlated decrease in body weight gains compared to vehicle treated HFFD group. Following 7 weeks of treatment, the changes in body weight gains from baseline were found as 6.4%, 27.3%, 2.0%, 3.1%, 0.4%, and -2.9% for normal control diet, HFFD, Orlistat, 450, 650, and 850 mg/kg UP603 treated animals, respectively. Reductions of 7.9-21.1% in total cholesterol, 25.4-44.6% in triglyceride, and 22.5-38.2% in low-density lipoprotein were observed for mice treated with 450-850 mg/kg of UP603. In a dual energy X-ray absorptiometry scan, percentage body fat of 18.9%, 47.8%, 46.1%, and 40.4% were found for mice treated with normal control, HFD, Orlistat, and UP603, respectively. Reductions of 65.5% and 16.4% in insulin and leptin, respectively, and 2.1-fold increase in ghrelin level were also observed for the UP603 group. Statistically significant improvements in nonalcoholic steatohepatitis scores were also observed from liver histology for mice treated with UP603. Hence, UP603, a standardized botanical composition from M. alba, I. paraguariensis, and R. officinalis could potentially be considered as a natural alternative to maintain healthy body weight and to manage metabolic syndrome. Topics: Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Humans; Ilex paraguariensis; Leptin; Lipoproteins, LDL; Liver; Male; Mice; Mice, Inbred C57BL; Morus; Obesity; Plant Extracts; Rosmarinus; Triglycerides | 2017 |
Beta Palmitate Improves Bone Length and Quality during Catch-Up Growth in Young Rats.
Palmitic acid (PA) is the most abundant saturated fatty acid in human milk, where it is heavily concentrated in the Topics: Animals; Body Weight; Bone Development; Fatty Acids; Growth Plate; Insulin-Like Growth Factor I; Leptin; Male; Palmitates; Plant Oils; Rats; Rats, Sprague-Dawley | 2017 |
Cinnamaldehyde Ameliorates Diet-Induced Obesity in Mice by Inducing Browning of White Adipose Tissue.
Obesity has become a major health concern with few effective medications. Cinnamaldehyde (CA) has been reported to exhibit anti-diabetic and anti-inflammatory properties. However, whether CA shows anti-obesity activity remains unknown. Therefore, the present study aimed to investigate the potential anti-obesity effects of CA on mice fed a high-fat diet (HFD) and to explore the possible mechanisms involved.. Male C57BL/6J mice fed an HFD for 12 weeks were supplemented with CA (40 mg/kg/day) via gavage for an additional 8 weeks. Mice fed a standard diet were used as normal controls.. The results revealed that CA treatment decreased body weight, fat mass, food intake, and serum lipid, free fatty acid and leptin levels. CA administration also improved insulin sensitivity in HFD-induced obese mice. Additionally, CA inhibited the hypertrophy of adipose tissue and induced browning of white adipose tissue. Uncoupling protein 1 (UCP1) was expressed in white adipose tissue after the oral administration of CA. Furthermore, CA enhanced the expression of the peroxisome proliferator-activated receptor γ (PPARγ), PR domain-containing 16 (PRDM16) and PPARγ coactivator 1α (PGC-1α) proteins in both brown and white adipose tissues.. The results suggest that CA exhibits therapeutic potency against obesity by inducing the browning of white adipose tissue in HFD-fed mice. Topics: Acrolein; Adipose Tissue, Brown; Adipose Tissue, White; Administration, Oral; Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; DNA-Binding Proteins; Eating; Energy Metabolism; Fatty Acids, Nonesterified; Gene Expression Regulation; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma; Transcription Factors; Uncoupling Protein 1 | 2017 |
Loss of ERα partially reverses the effects of maternal high-fat diet on energy homeostasis in female mice.
Maternal high-fat diet (HFD) alters hypothalamic developmental programming and disrupts offspring energy homeostasis in rodents. 17β-estradiol (E2) also influences hypothalamic programming through estrogen receptor (ER) α. Therefore, we hypothesized that females lacking ERα would be more susceptible to maternal HFD. To address this question, heterozygous ERα knockout (WT/KO) dams were fed a control breeder chow diet (25% fat) or a semi-purified HFD (45% fat) 4 weeks prior to mating with WT/KO males or heterozygous males with an ERα DNA-binding domain mutation knocked in (WT/KI) to produce WT, ERα KO, or ERα KIKO females lacking ERE-dependent ERα signaling. Maternal HFD increased body weight in WT and KIKO, in part, due to increased adiposity and daytime carbohydrate utilization in WT and KIKO, while increasing nighttime fat utilization in KO. Maternal HFD also increased plasma leptin, IL-6, and MCP-1 in WT and increased arcuate expression of Kiss1 and Esr1 (ERα) and liver expression of G6pc and Pepck in WT and KIKO. Contrary to our hypothesis, these data suggest that loss of ERα signaling blocks the influence of maternal HFD on energy homeostasis, inflammation, and hypothalamic and liver gene expression and that restoration of ERE-independent ERα signaling partially reestablishes susceptibility to maternal HFD. Topics: Animals; Body Weight; Chemokine CCL2; Diet, High-Fat; Estradiol; Estrogen Receptor alpha; Female; Gene Knockout Techniques; Homeostasis; Interleukin-6; Leptin; Male; Mice; Mutation; Pregnancy; Prenatal Exposure Delayed Effects; Sex Factors; Signal Transduction | 2017 |
Neonatal leptin treatment reverses the bone-suppressive effects of maternal undernutrition in adult rat offspring.
Alterations in the early life environment, including maternal undernutrition (UN) during pregnancy, can lead to increased risk of metabolic and cardiovascular disorders in offspring. Leptin treatment of neonates born to UN rats reverses the programmed metabolic phenotype, but the possible benefits of this treatment on bone tissue have not been defined. We describe for the first time the effects of neonatal leptin treatment on bone in adult offspring following maternal UN. Offspring from either UN or ad libitum-fed (AD) rats were treated with either saline or leptin (2.5 µg/ g.d on postnatal days (D)3-13) and were fed either a chow or high fat (HF) diet from weaning until study completion at D170. Analysis of micro-tomographic data of the left femur showed highly significant effects of UN on cortical and trabecular bone tissue indices, contributing to inferior microstructure and bone strength, almost all of which were reversed by early leptin life treatment. The HF fat diet negatively affected trabecular bone tissue, but the effects of only trabecular separation and number were reversed by leptin treatment. The negative effects of maternal UN on skeletal health in adult offspring might be prevented or attenuated by various interventions including leptin. Establishment of a minimal efficacious leptin dose warrants further study. Topics: Animals; Body Composition; Body Weight; Bone and Bones; Female; Leptin; Malnutrition; Maternal Exposure; Pregnancy; Prenatal Exposure Delayed Effects; Rats | 2017 |
High-fat diet-induced acceleration of osteoarthritis is associated with a distinct and sustained plasma metabolite signature.
Metabolic changes induced by high fat diet (HFD) that contribute to osteoarthritis (OA) are poorly understood. We investigated longitudinal changes to metabolites and their contribution to OA pathogenesis in response to HFD. HFD-fed mice exhibited acceleration of spontaneous age-related and surgically-induced OA compared to lean diet (LD)-fed mice. Using metabolomics, we identified that HFD-fed mice exhibited a distinct and sustained plasma metabolite signature rich in phosphatidylcholines (PC) and lysophosphatidylcholines (lysoPCs), even after resumption of normal chow diet. Using receiver operator curve analysis and prediction modelling, we showed that the concentration of these identified metabolites could efficiently predict the type of diet and OA risk with an accuracy of 93%. Further, longitudinal evaluation of knee joints of HFD- compared to LD- fed mice showed a greater percentage of leptin-positive chondrocytes. Mechanistic data showed that leptin-treated human OA chondrocytes exhibited enhanced production of lysoPCs and expression of autotaxin and catabolic MMP-13. Leptin-induced increased MMP13 expression was reversed by autotaxin inhibition. Together, this study is the first to describe a distinct and sustained HFD-induced metabolite signature. This study suggests that in addition to increased weight, identified metabolites and local leptin-signaling may also contribute in part, towards the accelerated OA-phenotype observed in HFD mice. Topics: Animals; Biomarkers; Biopsy; Blood Glucose; Body Weight; Cartilage, Articular; Diet, High-Fat; Disease Models, Animal; Immunohistochemistry; Insulin; Leptin; Metabolome; Mice; Osteoarthritis; ROC Curve | 2017 |
Intraventricular administration of Tenebrio molitor larvae extract regulates food intake and body weight in mice with high-fat diet-induced obesity.
We recently reported the in vitro and in vivo antiobesity effects of Tenebrio molitor larvae, a traditional food in many countries, but it remains unknown how the larvae affect appetite regulation in mice with diet-induced obesity. We hypothesized that the extract of T molitor larvae mediates appetite by regulating neuropeptide expression. We investigated T molitor larvae extract's (TME's) effects on anorexigenesis and endoplasmic reticulum (ER) stress-induced orexigenic neuropeptide expression in the hypothalami of obese mice. Intracerebroventricular TME administration suppressed feeding by down-regulating the expression of the orexigenic neuropeptides neuropeptide Y and agouti-related protein. T molitor larvae extract significantly reduced the expression of ER stress response genes. These results suggest that TME and its bioactive components are potential therapeutics for obesity and ER stress-driven disease states. Topics: Agouti-Related Protein; Animals; Biological Products; Body Weight; Cell Line; Diet; Diet, High-Fat; Disease Models, Animal; Endoplasmic Reticulum Stress; Gene Expression Regulation; Ghrelin; Hypothalamus; Larva; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mitogen-Activated Protein Kinases; Neuropeptide Y; Obesity; Tenebrio; TOR Serine-Threonine Kinases | 2017 |
Diet-induced obesity alters memory consolidation in female rats.
Obesity is a multifactorial disease characterized by the abnormal or excessive fat accumulation, which is caused by an energy imbalance between consumed and expended calories. Obesity leads to an inflammatory response that may result in peripheral and central metabolic changes, including insulin and leptin resistance. Insulin and leptin resistance have been associated with metabolic and cognitive dysfunctions. Obesity and some neurodegenerative diseases that lead to dementia affect mainly women. However, the effects of diet-induced obesity on memory consolidation in female rats are poorly understood. Therefore, the aim of this study was to evaluate the effect of a hypercaloric diet on the object recognition memory of female rats and on possible related metabolic changes. The animals submitted to the hypercaloric diet presented a higher food intake in grams and in calories, resulting in increased weight gain and liposomatic index in comparison with the animals exposed to the control diet. These animals presented a memory deficit in the object recognition test and increased serum levels of glucose and leptin. However, no significant differences were found in the serum levels of insulin, TNF-α and IL-1β, in the index of insulin resistance (HOMA), in the hippocampal levels of insulin, TNF-α and IL-1β, as well as on Akt expression or activation in the hippocampus. Our findings indicate that adult female rats submitted to a hypercaloric diet present memory consolidation impairment, which could be associated with diet-induced weight gain and leptin resistance, even without the development of insulin resistance. Topics: Animals; Blood Glucose; Body Weight; Diet; Disease Models, Animal; Eating; Energy Intake; Exploratory Behavior; Female; Insulin; Leptin; Liposomes; Memory Consolidation; Memory Disorders; Obesity; Rats; Rats, Wistar; Recognition, Psychology; Tumor Necrosis Factor-alpha | 2017 |
The Beneficial Effect of Anthocyanidin-Rich Vitis vinifera L. Grape Skin Extract on Metabolic Changes Induced by High-Fat Diet in Mice Involves Antiinflammatory and Antioxidant Actions.
We hypothesized that a polyphenol-rich extract from Vitis vinifera L. grape skin (GSE) may exert beneficial effects on obesity and related metabolic disorders induced by a high-fat diet (HFD). C57/BL6 mice were fed a standard diet (10% fat, control, and GSE groups) or an HFD (60% fat, high fat (HF), and HF + GSE) with or without GSE (200 mg/kg/day) for 12 weeks. GSE prevented weight gain; dyslipidemia; insulin resistance; the alterations in plasma levels of leptin, adiponectin, and resistin; and the deregulation of leptin and adiponectin expression in adipose tissue. These beneficial effects of GSE may be related to a positive modulation of insulin signaling proteins (IR, pIRS, PI3K, pAKT), pAMPK/AMPK ratio, and GLUT4 expression in muscle and adipose tissue. In addition, GSE prevented the oxidative damage, evidenced by the restoration of antioxidant activity and decrease of malondialdehyde and carbonyl levels in muscle and adipose tissue. Finally, GSE showed an anti-inflammatory action, evidenced by the reduced plasma and adipose tissue inflammatory markers (TNF-α, IL-6). Our results suggest that GSE prevented the obesity and related metabolic disorders in HF-fed mice by regulating insulin sensitivity and GLUT4 expression as well as by preventing the oxidative stress and inflammation in skeletal muscle and adipose tissue. Copyright © 2017 John Wiley & Sons, Ltd. Topics: Adiponectin; Adipose Tissue; Animals; Anthocyanins; Anti-Inflammatory Agents; Antioxidants; Body Weight; Diet, High-Fat; Fruit; Glucose Transporter Type 4; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Leptin; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Oxidative Stress; Phosphatidylinositol 3-Kinases; Plant Extracts; Polyphenols; Tumor Necrosis Factor-alpha; Vitis | 2017 |
Whey Protein Components - Lactalbumin and Lactoferrin - Improve Energy Balance and Metabolism.
Whey protein promotes weight loss and improves diabetic control, however, less is known of its bioactive components that produce such benefits. We compared the effects of normal protein (control) diet with high protein diets containing whey, or its fractions lactalbumin and lactoferrin, on energy balance and metabolism. Diet-induced obese rats were randomized to isocaloric diets: Control, Whey, Lactalbumin, Lactoferrin, or pair-fed to lactoferrin. Whey and lactalbumin produced transient hypophagia, whereas lactoferrin caused prolonged hypophagia; the hypophagia was likely due to decreased preference. Lactalbumin decreased weight and fat gain. Notably, lactoferrin produced sustained weight and fat loss, and attenuated the reduction in energy expenditure associated with calorie restriction. Lactalbumin and lactoferrin decreased plasma leptin and insulin, and lactalbumin increased peptide YY. Whey, lactalbumin and lactoferrin improved glucose clearance partly through differential upregulation of glucoregulatory transcripts in the liver and skeletal muscle. Interestingly, lactalbumin and lactoferrin decreased hepatic lipidosis partly through downregulation of lipogenic and/or upregulation of β-oxidation transcripts, and differentially modulated cecal bacterial populations. Our findings demonstrate that protein quantity and quality are important for improving energy balance. Dietary lactalbumin and lactoferrin improved energy balance and metabolism, and decreased adiposity, with the effects of lactoferrin being partly independent of caloric intake. Topics: Adiposity; Animals; Body Weight; Diet; Energy Intake; Energy Metabolism; Insulin; Lactalbumin; Lactoferrin; Leptin; Male; Obesity; Peptide YY; Rats; Whey Proteins | 2017 |
Dual specificity phosphatase 6 deficiency is associated with impaired systemic glucose tolerance and reversible weight retardation in mice.
Here, we aimed to investigate the potential role of DUSP6, a dual specificity phosphatase, that specifically inactivates extracellular signal-regulated kinase (ERK), for the regulation of body weight and glucose homeostasis. We further assessed whether metabolic challenges affect Dusp6 expression in selected brain areas or white adipose tissue. Hypothalamic Dusp6 mRNA levels remained unchanged in chow-fed lean vs. high fat diet (HFD) fed obese C57Bl/6J mice, and in C57Bl/6J mice undergoing prolonged fasting or refeeding with fat free diet (FFD) or HFD. Similarly, Dusp6 expression levels were unchanged in selected brain regions of Lepob mice treated with 1 mg/kg of leptin for 6 days, compared to pair-fed or saline-treated Lepob controls. Dusp6 expression levels remained unaltered in vitro in primary adipocytes undergoing differentiation, but were increased in eWAT of HFD-fed obese C57Bl/6J mice, compared to chow-fed lean controls. Global chow-fed DUSP6 KO mice displayed reduced body weight and lean mass and slightly increased fat mass at a young age, which is indicative for early-age weight retardation. Subsequent exposure to HFD led to a significant increase in lean mass and body weight in DUSP6 deficient mice, compared to WT controls. Nevertheless, after 26 weeks of high-fat diet exposure, we observed comparable body weight, fat and lean mass in DUSP6 WT and KO mice, suggesting overall normal susceptibility to develop obesity. In line with the increased weight gain to compensate for early-age weight retardation, HFD-fed DUSP6 KO displayed increased expression levels of anabolic genes involved in lipid and cholesterol metabolism in the epididymal white adipose tissue (eWAT), compared to WT controls. Glucose tolerance was perturbed in both chow-fed lean or HFD-fed obese DUSP6 KO, compared to their respective WT controls. Overall, our data indicate that DUSP6 deficiency has limited impact on the regulation of energy metabolism, but impairs systemic glucose tolerance. Our data are in conflict to earlier reports that propose protection from diet-induced obesity and glucose intolerance in DUSP6 deficient mice. Reasons for the discrepancies remain elusive, but may entail differential genetic backgrounds, environmental factors such as the type and source of HFD, or alterations in the gut microbiome between facilities. Topics: Adipose Tissue, White; Animals; Body Composition; Body Weight; Diet, High-Fat; Dual Specificity Phosphatase 6; Epididymis; Fasting; Gene Expression Profiling; Glucose Intolerance; Homeostasis; Leptin; Lipid Metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Nutritional Physiological Phenomena; Obesity; RNA, Messenger | 2017 |
Contribution of polymorphisms in the LEP, LEPR and RETN genes on serum leptin and resistin levels in young adults from Mexico.
Polymorphisms in the LEP (G-2548A and A19G), LEPR (A326G, A668G and G3057A) and RETN (C-420G and G+62A) genes were documented according to their association with alterations in biochemical parameters such as glucose, insulin and lipid profiles, along with serum leptin and resistin concentrations. The aim of the study was to establish any contribution of the G-2548A and A19G polymorphisms of the LEP gene, the A326G, A668G and G3057A polymorphisms of the LEPR gene, and the C-420G and G+62A polymorphisms of the RETN gene to serum leptin and resistin levels in Mexican young adults. Clinical and biochemical variables, serum leptin and resistin levels, and genotype profiles were analysed in 66 Mexican young adults. Seven polymorphisms in the LEP, LEPR and RETN genes were genotyped using polymerase chain reaction-restriction fragment length polymorphisms analysis. Individuals carrying allele 3057A of the G3057A polymorphism in the LEPR gene showed significantly higher leptin concentrations than those bearing the genotype G/G (43.78 ± 39.11 vs 28.20 ± 14.12 ng/mL; p = 0.021). There were no associations of serum leptin or resistin levels according to the genotype of the other six analysed polymorphisms. Our results suggest that the allele 3057A of the LEPR G3057A polymorphism contributes to increased serum leptin levels in Mexican young adults. Topics: Adolescent; Adult; Alleles; Body Fat Distribution; Body Weight; Cross-Sectional Studies; Female; Gene Expression; Gene Frequency; Genotype; Humans; Leptin; Male; Mexico; Polymorphism, Single Nucleotide; Receptors, Leptin; Resistin; Students; Waist Circumference; Waist-Hip Ratio | 2017 |
Early Exposure to a High Fat/High Sugar Diet Increases the Mammary Stem Cell Compartment and Mammary Tumor Risk in Female Mice.
Obesity and alterations in metabolic programming from early diet exposures can affect the propensity to disease in later life. Through dietary manipulation, developing mouse pups were exposed to a hyperinsulinemic, hyperglycemic milieu during three developmental phases: gestation, lactation, and postweaning. Analyses showed that a postweaning high fat/high sugar (HF/HS) diet had the main negative effect on adult body weight, glucose tolerance, and insulin resistance. However, dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis revealed that animals born to a mother fed a HF/HS gestation diet, nursed by a mother on a mildly diet-restricted, low fat/low sugar diet (DR) and weaned onto a HF/HS diet (HF/DR/HF) had the highest mammary tumor incidence, while HF/HF/DR had the lowest tumor incidence. Cox proportional hazards analysis showed that a HF/HS postweaning diet doubled mammary cancer risk, and a HF/HS diet during gestation and postweaning increased risk 5.5 times. Exposure to a HF/HS diet during gestation, when combined with a postweaning DR diet, had a protective effect, reducing mammary tumor risk by 86% (HR = 0.142). Serum adipocytokine analysis revealed significant diet-dependent differences in leptin/adiponectin ratio and IGF-1. Flow cytometry analysis of cells isolated from mammary glands from a high tumor incidence group, DR/HF/HF, showed a significant increase in the size of the mammary stem cell compartment compared with a low tumor group, HF/HF/DR. These results indicate that dietary reprogramming induces an expansion of the mammary stem cell compartment during mammary development, increasing likely carcinogen targets and mammary cancer risk. Topics: 9,10-Dimethyl-1,2-benzanthracene; Adiponectin; Animals; Body Weight; Carcinogenesis; Diet, Fat-Restricted; Diet, High-Fat; Dietary Sugars; Feeding Behavior; Female; Insulin Resistance; Insulin-Like Growth Factor I; Lactation; Leptin; Mammary Glands, Animal; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Maternal Exposure; Mice; Mice, Inbred SENCAR; Obesity; Risk Factors; Stem Cells; Time Factors | 2017 |
PTPRJ Inhibits Leptin Signaling, and Induction of PTPRJ in the Hypothalamus Is a Cause of the Development of Leptin Resistance.
Leptin signaling in the hypothalamus plays a crucial role in the regulation of body weight. Leptin resistance, in which leptin signaling is disrupted, is a major obstacle to the improvement of obesity. We herein demonstrated that protein tyrosine phosphatase receptor type J (Ptprj) is expressed in hypothalamic neurons together with leptin receptors, and that PTPRJ negatively regulates leptin signaling by inhibiting the activation of JAK2, the primary tyrosine kinase in leptin signaling, through the dephosphorylation of Y813 and Y868 in JAK2 autophosphorylation sites. Leptin signaling is enhanced in Ptprj-deficient mice, and they exhibit lower weight gain than wild-type mice because of a reduced food intake. Diet-induced obesity and the leptin treatment up-regulated PTPRJ expression in the hypothalamus, while the overexpression of PTPRJ induced leptin resistance. Thus, the induction of PTPRJ is a factor contributing to the development of leptin resistance, and the inhibition of PTPRJ may be a potential strategy for improving obesity. Topics: Adaptor Proteins, Signal Transducing; Animal Feed; Animals; Body Weight; Cell Line; Gene Expression; Gene Expression Regulation; Humans; Hypothalamus; Janus Kinase 2; Leptin; Mice; Mice, Knockout; Mice, Transgenic; Models, Biological; Obesity; Phenotype; Phosphorylation; Pyramidal Cells; Receptor-Like Protein Tyrosine Phosphatases, Class 3; Signal Transduction; STAT3 Transcription Factor | 2017 |
SOCS3 ablation in SF1 cells causes modest metabolic effects during pregnancy and lactation.
Previous studies have shown that leptin resistance is a key feature that leads to gestational metabolic adaptions. We hypothesized that leptin sensitivity in the ventromedial nucleus of the hypothalamus (VMH) plays a critical role regulating gestational metabolic changes. In the present study, we generated a mouse model carrying ablation of the suppressor of cytokine signaling 3 (SOCS3) in steroidogenic factor-1 (SF1) cells, which include the VMH, in order to investigate whether increased leptin sensitivity in this neuronal population prevents at least part of the metabolic changes typically observed during gestation and lactation. As predicted by the inhibitory effects of SOCS3 in leptin signaling, pregnant SF1 SOCS3 KO mice exhibited increased leptin sensitivity in the VMH, since an acute leptin injection induced a 95% increase in the STAT3 phosphorylation in this nucleus, compared to control animals (p = 0.02). Despite that, SF1 SOCS3 KO mice showed similar weight gain, food intake, hypothalamic neuropeptide expression and serum leptin levels during pregnancy compared to control littermates. Unexpectedly, SF1 SOCS3 KO mice exhibited glucose intolerance during pregnancy. SF1 SOCS3 KO mice also presented a lower body weight (-3%; p < 0.05) during mid and late lactation, although food intake, litter size and offspring growth were not affected. Our findings suggest that increased leptin sensitivity in the VMH causes modest metabolic effects and is not sufficient to prevent major metabolic adaptations of pregnancy and lactation. Topics: Adiposity; Animals; Body Weight; Energy Metabolism; Female; Gene Expression Regulation; Glucose Tolerance Test; Insulin; Lactation; Leptin; Mice; Mice, Transgenic; Neurons; Pregnancy; RNA, Messenger; Steroidogenic Factor 1; Suppressor of Cytokine Signaling 3 Protein; Ventromedial Hypothalamic Nucleus | 2017 |
Glucocorticoid treatment facilitates development of a metabolic syndrome in ovariectomized Macaca Mulatta fed a high fat diet.
Metabolic syndrome (MetS) is characterized by a cluster of key features, which include abdominal obesity, insulin resistance, hypertension, and dyslipidemia. The aim of this study was to assess the impact of elevated glucocorticoid levels on the development of MetS in middle-aged female rhesus monkeys (Macaca Mulatta) after ovariectomy. Six female ovariectomized rhesus monkeys (9-13years) were randomly assigned to either a control group (normal diet, n=3) or a group in which MetS was facilitated (n=3). The MetS group fed with HFD (15% fat) and received oral prednisone acetate treatment (50mg/day). After 24months, the GCs treatment was withdrawn with continuation of high-fat feeding for a further 12months. After 24months, the MetS group displayed a significant increase in body weight and abdominal circumference. Additionally, the MetS animals displayed abnormal serum lipids, insulin resistance and impaired glucose tolerance. Histology of liver biopsies indicated marked accumulation of lipid droplets in hepatocytes of MetS animals. Withdrawal of GCs treatment led to recovery from above-mentioned metabolic disorders. Whereas GCs treatment increased leptin expression, it lowered expression of adiponectin and other factors in adipose tissue. Expression of Hydroxy-steroid dehydrogenase-1 and glucose transporter type-4 in the livers of MetS animals were reduced. We conclude that in the context of high fat diet, high levels of exogenous GCs contribute to the development of MetS in non-human primates. Topics: Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Glucocorticoids; Humans; Insulin; Leptin; Liver; Macaca mulatta; Metabolic Syndrome; Ovariectomy | 2017 |
Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling.
In visceral obesity, an overactive endocannabinoid/CB. We analyzed the hypothalamic circuitry targeted by leptin following chronic treatment of DIO mice with JD5037.. Leptin treatment or an increase in endogenous leptin following fasting/refeeding induced STAT3 phosphorylation in neurons in the arcuate nucleus (ARC) in lean and JD5037-treated DIO mice, but not in vehicle-treated DIO animals. Co-localization of pSTAT3 in leptin-treated mice was significantly less common with NPY. Peripheral CB Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Cannabinoids; Diet, High-Fat; Dietary Fats; Eating; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Melanocortin, Type 4; Receptors, Cannabinoid; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Sulfonamides | 2017 |
Differential physiological responses to central leptin overexpression in male and female rats.
Brains of females are more sensitive to the acute catabolic actions of leptin. However, sex differences in the long-term physiological responses to central leptin receptor modulation are unknown. Accordingly, we centrally delivered a viral vector to overexpress leptin (Leptin), a neutral leptin receptor antagonist (Leptin-Antagonist) or a green fluorescence protein (GFP) (Control). We examined chronic changes in body weight and composition in male and female rats. Females displayed greater and sustained responses to Leptin, whereas males rapidly lost physiological effects and developed leptin resistance as confirmed by lower acute leptin-mediated phosphorylation of signal transducer and activator of transcription 3 (P-STAT3). Surprisingly, despite persistent physiological responses, Leptin-females also exhibited reduced acute leptin-mediated P-STAT3, suggesting an onset of leptin resistance near time of death. In line with this interpretation, Leptin-females and Control-females consumed the same amount of food on the last day of the experiment. Both Leptin-Antagonist groups gained similar percentages of their initial body weight and fat mass, whereas only Leptin-Antagonist-females gained lean body mass. Consequently, the lean/fat mass ratio with Leptin-Antagonist was preserved in females and decreased in males, suggesting a deterioration of body composition in males. In summary, the present study establishes that females are more responsive to long-term central leptin overexpression than males and that leptin antagonism has a greater physiological impact in males. The hormone environment may have played a role in these processes; however, future studies are needed to establish whether such physiological responses are mediated by female or male sex hormones. Topics: Animals; Body Composition; Body Weight; Eating; Female; Leptin; Male; Organ Size; Phosphorylation; Rats, Sprague-Dawley; Sex Characteristics; STAT3 Transcription Factor | 2017 |
High Fat Diet with a High Monounsaturated Fatty Acid and Polyunsaturated/Saturated Fatty Acid Ratio Suppresses Body Fat Accumulation and Weight Gain in Obese Hamsters.
The aim of this study was to investigate the effect of a high fat diet with experimental oil consisting of 60% MUFAs (monounsaturated fatty acids) with a P/S ratio of 5 on fat deposition and lipid metabolism in obese hamsters. Hamsters were randomly assigned to a control group and a diet-induced obesity group for nine weeks. Then an additional eight-week experimental period began, during which obese hamsters were randomly divided into three groups and fed different amounts of the experimental oil mixture in their diets as follows: 5%, 15%, and 20% w/w (OB-M5, OB-M15, and OB-M20 groups, respectively). The results showed that the OB-M15 and OB-M20 groups had significantly lower blood cholesterol and higher insulin levels. Compared to the control group, the three obese groups exhibited higher hepatic fatty acid synthase activity; however, the acyl-CoA oxidase activities were also enhanced. Although dietary fat content differed, there were no differences in energy intake, final body weights, and epididymal fat weights among the four groups. These results suggest that regardless of whether the specimens had a high fat intake or not, dietary fat containing high MUFAs with a high P/S ratio had beneficial effects on maintaining blood lipid profiles and may not result in body fat accumulation in obese hamsters, possibly by promoting lipolytic enzyme activities. Topics: Adiponectin; Adiposity; Animals; Blood Glucose; Body Weight; Cholesterol; Cricetinae; Diet, High-Fat; Dietary Fats; Fatty Acid Synthases; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Insulin; Leptin; Lipid Metabolism; Lipoprotein Lipase; Liver; Male; Obesity; PPAR gamma; RNA, Messenger; Sterol Esterase; Triglycerides; Weight Gain | 2017 |
Body Weight Cycling with Identical Diet Composition Does Not Affect Energy Balance and Has No Adverse Effect on Metabolic Health Parameters.
Body weight (BW) cycling, the yo-yo effect, is generally thought to have adverse effects on human metabolic health. However, human and animal experiments are limited in number and do not provide clear answers, partly due to large variations in experimental design, parameters measured, and definitions of BW cycling. Here, we examined the effect of repetitive BW cycling versus single- and non-cycling control groups, without alterations in diet composition, on steady state BW and metabolic parameters.. We induced well-defined BW cycles on a semi-purified high fat diet in C57BL/6J mice, a well-described animal model for diet-induced obesity, and measured energy expenditure and relevant metabolic parameters.. Our setup indeed resulted in the intended BW changes and always reached a stage of energy balance. A history of weight cycling did not result in increased BW or fat mass compared with the control group, nor in deteriorated serum concentrations of glucose, adipokines and serum triglyceride and free fatty acid (FFA) concentrations. If anything, BW tended to be reduced, presumably because of a reduced overall energy intake in BW cycling animals.. Repeated cycling in BW without changes in diet composition does not lead to impaired metabolic health nor increased BW (gain). Topics: Adiponectin; Adiposity; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Endpoint Determination; Energy Metabolism; Fatty Acids, Nonesterified; Leptin; Male; Mice; Mice, Inbred C57BL; Triglycerides; Weight Gain | 2017 |
Weight loss-dependent and -independent effects of moderate calorie restriction on endothelial cell markers in obesity.
Endothelial cell dysfunction in obesity can be reduced by calorie restriction (CR), however it is unclear whether this benefit requires a concomitant weight loss or is it simply related to the reduced calorie intake per se. In our study serum was drawn from 41 obese women who were undergoing an 8-week dietary intervention with 15 - 30% energy deficit, and from 48 age- and sex-matched controls of normal weight. Serum was analysed for biomarkers of endothelial cell function, oxidative stress and inflammation. Compared with non-obese individuals, the obese patients had lower serum levels of nitric oxide (NO), adiponectin, and decreased serum antioxidant status. They also had significantly higher levels of adhesive molecules, thrombomodulin (TM), von Wilebrand factor (vWF), asymmetric dimethylarginine (ADMA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and leptin. To further characterize the effect of moderate CR, the patients were ranked into two comparable groups according to the extent of weight loss - below and above the median (-5.8 kg). A moderate dietary intervention did not correct adiponectin, antioxidant status, vWF, TM, and plasminogen activator inhibitor-1 (PAI-1) but ameliorated changes in other parameters. Only changes in NO and - to a lesser degree - in sE-selectin showed a clear relationship with the magnitude of weight reduction. By contrast, a beneficial reduction in TNF-α occurred equally in patients who lost more or less weight after caloric restriction. We concluded that moderate calorie restriction could still improve several parameters of endothelial cell function irrespective of whether it was accompanied by changes in body mass. However, a significant improvement in nitric oxide, a key mediator of endothelial well-being, requires a substantial reduction in body weight. Topics: Adiponectin; Adult; Antioxidants; Biomarkers; Body Weight; Caloric Restriction; Endothelial Cells; Endothelium, Vascular; Female; Humans; Inflammation; Leptin; Nitric Oxide; Obesity; Oxidative Stress; Weight Loss | 2017 |
Long-lived weight-reduced αMUPA mice show higher and longer maternal-dependent postnatal leptin surge.
We investigated whether long-lived weight-reduced αMUPA mice differ from their wild types in postnatal body composition and leptin level, and whether these differences are affected by maternal-borne factors. Newborn αMUPA and wild type mice had similar body weight and composition up to the third postnatal week, after which αMUPA mice maintained lower body weight due to lower fat-free mass. Both strains showed a surge in leptin levels at the second postnatal week, initiating earlier in αMUPA mice, rising higher and lasting longer than in the wild types, mainly in females. Leptin level in dams' serum and breast milk, and in their pup's stomach content were also higher in αMUPA than in the WT during the surge peak. Leptin surge preceded the strain divergence in body weight, and was associated with an age-dependent decrease in the leptin:fat mass ratio-suggesting that postnatal sex and strain differences in leptin ontogeny are strongly influenced by processes independent of fat mass, such as production and secretion, and possibly outside fat tissues. Dam removal elevated corticosterone level in female pups from both strains similarly, yet mitigated the leptin surge only in αMUPA-eliminating the strain differences in leptin levels. Overall, our results indicate that αMUPA's postnatal leptin surge is more pronounced than in the wild type, more sensitive to maternal deprivation, less related to pup's total adiposity, and is associated with a lower post-weaning fat-free mass. These strain-related postnatal differences may be related to αMUPA's higher milk-borne leptin levels. Thus, our results support the use of αMUPA mice in future studies aimed to explore the relationship between maternal (i.e. milk-borne) factors, postnatal leptin levels, and post-weaning body composition and energy homeostasis. Topics: Animals; Body Composition; Body Weight; Female; Leptin; Mice; Milk; Pregnancy; Weaning | 2017 |
Energy homeostasis in leptin deficient Lepob/ob mice.
Maintenance of reduced body weight is associated both with reduced energy expenditure per unit metabolic mass and increased hunger in mice and humans. Lowered circulating leptin concentration, due to decreased fat mass, provides a primary signal for this response. However, leptin deficient (Lepob/ob) mice (and leptin receptor deficient Zucker rats) reduce energy expenditure following weight reduction by a necessarily non-leptin dependent mechanisms. To identify these mechanisms, Lepob/ob mice were fed ad libitum (AL group; n = 21) or restricted to 3 kilocalories of chow per day (CR group, n = 21). After losing 20% of initial weight (in approximately 2 weeks), the CR mice were stabilized at 80% of initial body weight for two weeks by titrated refeeding, and then released from food restriction. CR mice conserved energy (-17% below predicted based on body mass and composition during the day; -52% at night); and, when released to ad libitum feeding, CR mice regained fat and lean mass (to AL levels) within 5 weeks. CR mice did so while their ad libitum caloric intake was equal to that of the AL animals. While calorically restricted, the CR mice had a significantly lower respiratory exchange ratio (RER = 0.89) compared to AL (0.94); after release to ad libitum feeding, RER was significantly higher (1.03) than in the AL group (0.93), consistent with their anabolic state. These results confirm that, in congenitally leptin deficient animals, leptin is not required for compensatory reduction in energy expenditure accompanying weight loss, but suggest that the hyperphagia of the weight-reduced state is leptin-dependent. Topics: Animals; Blood Glucose; Body Composition; Body Temperature; Body Weight; Caloric Restriction; Cell Respiration; Energy Metabolism; Feeding Behavior; Homeostasis; Insulin; Leptin; Male; Mice; Mice, Obese; Pilot Projects | 2017 |
IGF-1R and Leptin Expression Profile and the Effects of Metformin Treatment on Metabolic and Endocrine Parameters in PCOS Mice.
We aim to assess the effects of metformin treatment on metabolic and endocrine parameters and genes expression related to the insulin-responsive pathway in polycystic ovary syndrome (PCOS). This study comprises twenty-eight obese mice divided into three metformin-treated groups for seven and twenty days and eight nonobese and nontreated ones. We found a significant decrease in glycemia after metformin treatment at days seven and twenty. However, we did not observe differences in body weight measurement. Histologically, after twenty days we observed follicular development with regression of androgenic effects. Levels of IGF-1R protein expression were low after twenty days of treatment, but LEP proteins showed an overexpression in the ovarian stroma. We assessed the IGF-1R and LEP mRNAs levels; data showed a significant overexpression of LEP after seven days of treatment, while the IGF-1R was downregulated. Metformin therapy seems to exert a beneficial effect on histological and anovulatory features, reducing follicular number and pyknosis formation, possibly involved in the reversion of androgenic stimulus. Expression of IGF-1 and LEPR indicates a relevant role in androgenic features reversion present in PCOS, hormonal equilibrium, body weight regulation, and glucose metabolism, therefore, under phenotype obesity and infertility regulation in this model. Topics: Animals; Blood Glucose; Body Weight; Female; Gene Expression Regulation; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Metformin; Mice; Mice, Obese; Polycystic Ovary Syndrome; Receptor, IGF Type 1; Receptors, Leptin | 2017 |
[The effect of leptin transgenic Plasmodium yoelii on mouse body weight].
To investigate the effect of leptin transgenic Plasmodium yoelii on mouse body weight.. To construct the leptin gene-containing CRISPR/Cas9 recombinant plasmid which had the 5′UTR and 3′UTR of MIF(macrophage migration inhibitory factor) of Plasmodium yoelli 17XNL strain at two ends, the exogenous mouse leptin gene was inserted downstream of MIF coding region through homologous recombination, resulting in the PYC-MIF-Leptin recombinant plasmid. The recombinant plasmid was then electroporated into P. y 17XNL mature schizonts, and the transgenic schizonts were used to infect a Kunming mouse via tail vein injection. The trangenic P. y clone was screened by pyrimethamine selection and identified by PCR. The trangenic or wild-type P. y was used to infect a C57BL/6 mouse respectively. Blood sample was collected through eye ball and tail vein, and immunofluorescence and RT-PCR were performed to determine the expression of leptin protein in the parasites. Finally, PBS (200 μl) containing trangenic or wild-type P. y (1 × 104) was injected through the tail vein into C57BL/6 mice(n = 5 respectively). The negative control received a same volume of PBS. The changes of parasitemia and body weight were recorded every two days.. The leptin-expressing recombinant plasmid PYC-MIF-Leptin was constructed successfully. Results of DNA sequencing of transgenic parasites confirmed the integration of leptin gene at the downstream of MIF gene and successful transcription. Immunofluorescence results indicated successful expression of mouse leptin protein. The weight loss was significant in mice infected with transgenic parasites on day 17(17.26 ± 1.40)g, decreased by 10.7%, but not in the other two groups. Both transgenic and wild-type parasites began to decline when parasitemia reached about 10%, but the transgenic parasites proliferated more rapidly. Both disappeared at 23 days.. Infection with leptin transgenic parasites decreases the body weight of the infected mice. Topics: Animals; Body Weight; Leptin; Malaria; Mice; Mice, Inbred C57BL; Mice, Transgenic; Parasitemia; Plasmodium yoelii | 2017 |
Deteriorated glucose metabolism with a high-protein, low-carbohydrate diet in db mice, an animal model of type 2 diabetes, might be caused by insufficient insulin secretion.
We previously showed the deleterious effects of increased dietary protein on renal manifestations and glucose metabolism in leptin receptor-deficient (db) mice. Here, we further examined its effects on glucose metabolism, including urinary C-peptide. We also orally administered mixtures corresponding to low- or high-protein diets to diabetic mice.. In diet experiments, under pair-feeding (equivalent energy and fat) conditions using a metabolic cage, mice were fed diets with different protein content (L diet: 12 % protein, 71 % carbohydrate, 17 % fat; H diet: 24 % protein, 59 % carbohydrate, 17 % fat) for 15 days. In oral administration experiments, the respective mixtures (L mixture: 12 % proline, 71 % maltose or starch, 17 % linoleic acid; H mixture: 24 % proline, 59 % maltose or starch, 17 % linoleic acid) were supplied to mice. Biochemical parameters related to glucose metabolism were measured.. The db-H diet mice showed significantly higher water intake, urinary volume, and glucose levels than db-L diet mice but similar levels of excreted urinary C-peptide. In contrast, control-H diet mice showed significantly higher C-peptide excretion than control-L diet mice. Both types of mice fed H diet excreted high levels of urinary albumin. When maltose mixtures were administered, db-L mixture mice showed significantly higher blood glucose after 30 min than db-H mixture mice. However, db mice administered starch-H mixture showed significantly higher blood glucose 120-300 min post-administration than db-L mixture mice, although both groups exhibited similar insulin levels.. High-protein, low-carbohydrate diets deteriorated diabetic conditions and were associated with insufficient insulin secretion in db mice. Our findings may have implications for dietary management of diabetic symptoms in human patients. Topics: Albuminuria; Animals; Blood Glucose; Body Weight; C-Peptide; Carbohydrate Metabolism; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Dietary Carbohydrates; Dietary Proteins; Insulin; Insulin Secretion; Leptin; Male; Maltose; Mice; Mice, Inbred C57BL; Mice, Knockout; Starch | 2017 |
Short-Term High-Fat Diet Feeding Provides Hypothalamic but Not Hippocampal Protection against Acute Infection in Male Mice.
Obesity is associated with increased fever and sickness behavior in response to infection. The hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the reaction to immune stimuli. Bacterial infection, or bacterial lipopolysaccharide (LPS), induces the expression of peripheral cytokines that stimulate the hypothalamus and the hippocampus and activate the HPA axis. In this study, we explored whether the hypothalamic and hippocampal responses to infection are altered during the development of diet-induced obesity. Male mice were exposed to a high-fat diet (HFD) or a low-fat diet (LFD) for 15 days. They were then administered a single intraperitoneal injection of bacterial LPS or vehicle and sacrificed 24 h later. LPS increased circulating levels of insulin and leptin, but only in LFD animals. LPS induced a significant decrease in hypothalamic corticotrophin-releasing hormone and glucocorticoid receptor mRNA levels in LFD animals but exerted the opposite effect in HFD-fed mice. LPS increased the hypothalamic expression of molecules involved in the leptin signaling pathway (SOCS3 and STAT3), nuclear factor-κB pathway members, inflammatory mediators (tumor necrosis factor-α and interleukin-6) and glial proliferation markers (Emr1 and CD68) in LFD animals. These effects were dampened in HFD-fed mice. In contrast, the hippocampal responses to LPS were largely insensitive to HFD. These results suggest that HFD feeding reduced the inflammatory response induced by LPS in the hypothalamus but not in the hippocampus. Topics: Adiponectin; Analysis of Variance; Animals; Body Weight; Corticotropin-Releasing Hormone; Cytokines; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Eating; Gene Expression Regulation; Hippocampus; Hypothalamus; Inflammation; Insulin; Leptin; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Obesity; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor | 2017 |
Role of Leptin and Orexin-A Within the Suprachiasmatic Nucleus on Anxiety-Like Behaviors in Hamsters.
It is well established that the maintenance of energy expenditure is linked to active hypothalamic neural mechanisms controlling adaptive stimuli such as food intake. Variations of glucose levels and hormonal (leptin plus orexin-A) parameters, which are involved with energy homeostasis during different behavioral states, have not yet been fully defined. In this first study, behavioral analyses of an unpredictable stress model dealing with the actions of a sub-chronic administration of orexin-A (ORX-A) and the anti-hunger neuropeptide, i.e., leptin (LEP) within the hypothalamic suprachiasmatic (SCH) nucleus, were conducted on the valuable hibernating rodent (hamster; Mesocricetus auratus) model noted for its distinct depression and anxiety states. Treatment with LEP accounted for a notable reduction (p < 0.01) of body weight in stressed hamsters that not only executed very evident (p < 0.001) movements to and from elevated plus maze (EPM) but also spent less time in the dark area of the light-dark box test (LDT). Conversely, ORX-A predominantly evoked anxiogenic effects that were inverted by LEP. Interestingly, the anti-hunger neuropeptide accounted for both down-regulated NPY1 transcripts in mostly lateral-posterior hypothalamic areas while up-regulated levels were detected in the parietal cerebral cortex, hippocampus, and amygdala, which largely behaved in an opposite manner to ORX-A-dependent effects. Overall, the present findings corroborate a predominating LEPergic effect of the SCH toward the reduction of hamster anxiety-like behaviors with respect to that of ORX-A signaling, which may constitute useful therapeutic targets for stress-related obesity states. Topics: Animals; Anxiety; Behavior, Animal; Body Weight; Circadian Rhythm; Cricetinae; Feeding Behavior; In Situ Hybridization; Leptin; Male; Maze Learning; Neuropeptides; Orexins; RNA, Messenger; Suprachiasmatic Nucleus | 2017 |
Hypothalamic Phosphodiesterase 3B Pathway Mediates Anorectic and Body Weight-Reducing Effects of Insulin in Male Mice.
Insulin action in the hypothalamus plays a critical role in the regulation of energy homeostasis, yet the intracellular signaling mechanisms mediating insulin action are incompletely understood. Although phosphodiesterase 3B (PDE3B) mediates insulin action in the adipose tissue and it is highly expressed in the hypothalamic areas implicated in energy homeostasis, its role, if any, in mediating insulin action in the hypothalamus is unknown. We tested the hypothesis that insulin action in the hypothalamus is mediated by PDE3B.. Using enzymatic assay, we examined the effects of peripheral or central administration of insulin on hypothalamic PDE3B activity in adult mice. Western blotting and immunohistochemistry also examined p-Akt and p-STAT3 levels in the hypothalamus. Effects of leptin on these parameters were also compared. We injected cilostamide, a PDE3 inhibitor, prior to central injection of insulin and examined the 12- to 24-hour food intake and 24-hour body weight. Finally, we examined the effect of cilostamide on insulin-induced proopiomelanocortin (Pomc), neurotensin (Nt), neuropeptide Y (Npy) and agouti-related peptide (Agrp) gene expression in the hypothalamus by qPCR.. Peripheral or central injection of insulin significantly increased PDE3B activity in the hypothalamus in association with increased p-Akt levels but without any change in p-STAT3 levels. However, leptin-induced increase in PDE3B activity was associated with an increase in both p-Akt and p-STAT3 levels in the hypothalamus. Prior administration of cilostamide reversed the anorectic and body weight-reducing effects as well as stimulatory effect of insulin on hypothalamic Pomc mRNA levels. Insulin did not alter Nt, Npy and Agrp mRNA levels.. Insulin induction of hypothalamic PDE3B activity and the reversal of the anorectic and body weight-reducing effects and stimulatory effect of insulin on hypothalamic Pomc gene expression by cilostamide suggest that activation of PDE3B is a novel mechanism of insulin signaling in the hypothalamus. Topics: Animals; Body Weight; Cyclic Nucleotide Phosphodiesterases, Type 3; Eating; Gene Expression; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Phosphodiesterase Inhibitors; Phosphorylation; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-akt; Quinolones; Signal Transduction; STAT3 Transcription Factor; Weight Loss | 2017 |
Free-choice high-fat diet alters circadian oscillation of energy intake in adolescent mice: role of prefrontal cortex.
Our aim was to characterize the effect of an unfamiliar high-fat diet (HFD) on circadian feeding behaviour, plasma parameters, body weight (BW), and gene expression in the prefrontal cortex (PFC) of adolescent male mice. To this end, mice were allowed to consume a HFD during 48 h, but one group was allowed a free choice of HFD or normal chow (FC-HFD), while the other was restricted to a non-optional unfamiliar HFD feeding (NOP-HFD).. Energy intake was monitored at 6-h intervals during 48 h. Mice cohorts were killed at 6-h intervals after 48-h dietary treatment, and PFC samples dissected for RT-PCR analysis.. Mice on the FC-HFD protocol avoided eating the standard chow, showed lower energy intake and lower BW increase than NOP-HFD mice. All animals with access to HFD exhibited nocturnal overeating, but diurnal hyperphagia was more prominent in the FC-HFD cohort. A robust increase in tyrosine hydroxylase (Th) gene expression was detected specifically during the light period of the circadian cycle in FC-HFD mice. In contrast, both protocols similarly up-regulated the expression of cytosolic malic enzyme (Me1), which is very sensitive to HFD.. Our data show that the PFC participates in driving motivational feeding during HFD-evoked hyperphagia and also suggest that sensory neural pathways might be relevant for the onset of eating disorders and overweight. Moreover, we have observed that animals that had the possibility of choosing between standard chow and HFD were more hyperphagic and specifically displayed an overexpression of the tyrosine hydroxylase gene. Topics: Animals; Blood Glucose; Body Weight; Choice Behavior; Circadian Rhythm; Diet, High-Fat; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; Gene Expression Regulation; Hyperphagia; Insulin; Leptin; Malate Dehydrogenase; Male; Mice; Mice, Inbred C57BL; Overweight; Prefrontal Cortex; Receptors, Leptin; Tyrosine 3-Monooxygenase; Weight Gain | 2017 |
The effects of antipsychotics on weight gain, weight-related hormones and homocysteine in children and adolescents: a 1-year follow-up study.
To analyze weight gain, metabolic hormones, and homocysteine (Hcys) levels in children and adolescents on antipsychotics (AP) during a year-long follow-up. 117 patients, AP-naïve or quasi-naïve (less than 30 days on AP), were included. Weight, body mass index (BMI), BMI z-score (z-BMI), and levels of leptin, insulin, insulin resistance (HOMA-IR), adiponectin, ghrelin, thyroid stimulating hormone (TSH), free thyroxine (FT4), and Hcys were measured at baseline, and at 3, 6, and 12 months, while patients remained on the same AP. Patients (mean age: 14.4 ± 3 years; 64.1 % male) were on risperidone (N = 84), olanzapine (N = 20) or quetiapine (N = 13) from baseline up to 1-year follow-up and significantly increased weight (5.8 ± 4.3 kg at 3-month, 8.1 ± 6.1 kg at 6-month, and 11.6 ± 7.0 kg at 1 year), BMI, and z-BMI. Leptin levels significantly increased from baseline to 3 and 6 months, as did TSH levels from baseline to 3 months, while FT4 levels decreased from baseline to 3 and 6 months. Patients with BMI >85th percentile at baseline (N = 16) significantly increased weight, BMI, and z-BMI, more than patients with normal BMI over time. Higher baseline levels of insulin, HOMA-IR, and leptin were associated with increased weight/BMI during follow-up, while higher baseline levels of FT4, adiponectin, and ghrelin were associated with lower weight/BMI during follow-up. All AP were associated with increased weight and BMI/z-BMI in all of the assessments; however, at 1-year assessment, this increase was significantly higher for patients on quetiapine. Both higher baseline levels of insulin, HOMA-IR, and leptin, as well as being overweight/obese at baseline were associated with increased weight/BMI during 1-year follow-up in children and adolescents on AP. Awareness of weight-related parameters in this population may help inform decisions regarding AP prescriptions. Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Weight; Child; Child, Preschool; Female; Follow-Up Studies; Ghrelin; Homocysteine; Humans; Insulin; Leptin; Male; Obesity; Olanzapine; Prospective Studies; Risperidone; Time Factors; Treatment Outcome; Weight Gain | 2017 |
The impact of rapid weight loss (4%) on leptin, adiponectin, and insulin resistance in elite adult free style wrestlers.
The effect of rapid weight loss program on adipocytokines is not yet clear. Therefore the aim of the present study was the effect of rapid weight loss (4%) on leptin, adiponectin, and insulin resistance in elite free style wrestlers.. For this purpose, fifteen young freestyle wrestlers (weight 67.6±0.8, BMI 22.5±0.21 kg/m², body fat percent 6.12±0.18, waist to hip circumference ratio 0.82±0.08) in two weight categories (60 and 66 kg) were randomly selected. Caloric intake (mean 7 days measured by Food analyzer software) measured at 1 week before weight loss program by standard methods. Wrestlers performed a week rapid weight loss (average of 4% of body weight loss) protocol by caloric and water restriction by 60% (600-700 kcal per day), under the supervision of their coach. Anthropometric characteristics, leptin, adiponectin and insulin resistance were measured before and 12 and 36 hours after rapid weight loss program.. Rapid weight loss program with 4% of weight loss had a significantly reduced impact on anthropometric factors; leptin level, insulin resistance, and increased beta cell function, while the changes of adiponectin were not significant after rapid weight loss.. Findings of this study shows that rapid weight loss program significantly decreased leptin, L/A ratio and HOMA-IR, without significant changes on adiponectin levels. These changes may have harmful physiological effects on wrestlers' bodies but they can be useful to regulate of fatty acid, glucose metabolism, and insulin resistance. Topics: Adiponectin; Anthropometry; Body Mass Index; Body Weight; Humans; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Weight Loss; Weight Reduction Programs; Wrestling; Young Adult | 2017 |
Effects of Exercise Intervention on Preventing Letrozole-Exposed Rats From Polycystic Ovary Syndrome.
Polycystic ovary syndrome (PCOS) is a prevalent endocrinological disorder in reproductive-age women and is often associated with a metabolic syndrome. To investigate whether exercise intervention promotes PCOS prevention, a rat model was used. Polycystic ovary syndrome was induced by letrozole administration, and animals presented with obesity, sex hormone disorder, no ovulation, large cystic follicles, and increasing fasting insulin (FINS) and leptin levels. The intervention was set at 3 different intensities of swimming exercise: low (0.5 h/d), moderate (1 h/d), and high (2 h/d), and compared with a PCOS model group (letrozole administration without exercise intervention) and a control group. The exercise intervention in the low-intensity group did not produce changes in obesity, testosterone, progesterone (P), and follicle-stimulating hormone (FSH) levels. Moderate-intensity exercise reduced body weight, retained ovulation, and P levels were increased but remained lower than those in the control group. The FSH levels were significantly higher, and FINS and leptin levels were lower than in the model group ( P < 0.05) but not in the control group. The high-intensity group demonstrated the greatest effect of PCOS prevention. Testosterone, luteinizing hormone, FINS, and leptin levels were significantly lower in the high-intensity group, and FSH and P levels were higher compared with the model group. These results suggest that high-intensity exercise intervention can effectively prevent PCOS development. Topics: Animals; Aromatase Inhibitors; Body Weight; Disease Models, Animal; Female; Follicle Stimulating Hormone; Insulin; Leptin; Letrozole; Nitriles; Obesity; Physical Conditioning, Animal; Polycystic Ovary Syndrome; Progesterone; Rats; Testosterone; Triazoles | 2017 |
Control of leptin by metabolic state and its regulatory interactions with pituitary growth hormone and hepatic growth hormone receptors and insulin like growth factors in the tilapia (Oreochromis mossambicus).
Leptin is an important cytokine for regulating energy homeostasis, however, relatively little is known about its function and control in teleost fishes or other ectotherms, particularly with regard to interactions with the growth hormone (GH)/insulin-like growth factors (IGFs) growth regulatory axis. Here we assessed the regulation of LepA, the dominant paralog in tilapia (Oreochromis mossambicus) and other teleosts under altered nutritional state, and evaluated how LepA might alter pituitary growth hormone (GH) and hepatic insulin-like growth factors (IGFs) that are known to be disparately regulated by metabolic state. Circulating LepA, and lepa and lepr gene expression increased after 3-weeks fasting and declined to control levels 10days following refeeding. This pattern of leptin regulation by metabolic state is similar to that previously observed for pituitary GH and opposite that of hepatic GHR and/or IGF dynamics in tilapia and other fishes. We therefore evaluated if LepA might differentially regulate pituitary GH, and hepatic GH receptors (GHRs) and IGFs. Recombinant tilapia LepA (rtLepA) increased hepatic gene expression of igf-1, igf-2, ghr-1, and ghr-2 from isolated hepatocytes following 24h incubation. Intraperitoneal rtLepA injection, on the other hand, stimulated hepatic igf-1, but had little effect on hepatic igf-2, ghr1, or ghr2 mRNA abundance. LepA suppressed GH accumulation and gh mRNA in pituitaries in vitro, but had no effect on GH release. We next sought to test if abolition of pituitary GH via hypophysectomy (Hx) affects the expression of hepatic lepa and lepr. Hypophysectomy significantly increases hepatic lepa mRNA abundance, while GH replacement in Hx fish restores lepa mRNA levels to that of sham controls. Leptin receptor (lepr) mRNA was unchanged by Hx. In in vitro hepatocyte incubations, GH inhibits lepa and lepr mRNA expression at low concentrations, while higher concentration stimulates lepa expression. Taken together, these findings indicate LepA gene expression and secretion increases with fasting, consistent with the hormones function in promoting energy expenditure during catabolic stress. It would also appear that LepA might play an important role in stimulating GHR and IGFs to potentially spare declines in these factors during catabolism. Evidence also suggests for the first time in teleosts that GH may exert important regulatory effects on hepatic LepA production, insofar as physiological levels (0.05-1 nM) suppresse le Topics: Animals; Body Weight; Fasting; Feeding Behavior; Gene Expression Regulation; Growth Hormone; Hepatocytes; Hypophysectomy; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Liver; Male; Pituitary Gland; Receptors, Somatotropin; RNA, Messenger; Tilapia | 2017 |
Effects of Ilex paraguariensis (yerba mate) on the hypothalamic signalling of insulin and leptin and liver dysfunction in adult rats overfed during lactation.
Ilex paraguariensis (yerba mate) has a beneficial effect in the management of obesity. Here, we studied the effects of yerba mate on hypothalamic changes in leptin and insulin signalling, oxidative stress and liver morphology and metabolism in postnatal early overfeeding (EO) Wistar rats. To induce EO, the litter size was reduced to three pups per dam, and litters with 10 pups per dam were used as a control (10 litters each). On postnatal day (PN) 150, EO offspring were subdivided into EO and EO+mate groups (10 animals each), which were treated with water or mate tea [1 g/kg body weight (BW)/day, by gavage], respectively, for 30 days. The C offspring received water. On PN180, yerba mate treatment prevented BW gain and reduced total body fat, visceral fat and food intake in comparison with the EO group. Leptin and insulin signalling in the hypothalamus measured by Western blotting was reduced only in the EO group. Yerba mate treatment had a greater impact on insulin signalling normalization. In the liver, yerba mate treatment normalized antioxidant enzyme activities and, consequently, decreased lipid peroxidation, determined by malondialdehyde content. In addition, the steatosis level and the liver triglyceride content were also restored. Thus, for the first time, yerba mate was demonstrated to increase antioxidant defences and improve liver metabolism in adult rats that were overfed during lactation, possibly through improvements in the hypothalamic action of insulin. These findings may be important for the treatment of obesity-related disorders. Topics: Animals; Body Weight; Breast Feeding; Eating; Female; Gene Expression Regulation; Hypothalamus; Ilex paraguariensis; Insulin; Lactation; Leptin; Liver Diseases; Male; Overnutrition; Plant Extracts; Rats; Rats, Wistar; Signal Transduction | 2017 |
The Effects of Maternal Under-Nutrition and a Post-Natal High Fat Diet on Lens Growth, Transparency and Oxidative Defense Systems in Rat Offspring.
A poor early life nutrition environment is well established to result in a range of cardiometabolic disorders in offspring in later life. These effects can be exacerbated via exposure to an obesogenic dietary environment. To date, the effect of maternal diet and/or a post-natal obesogenic nutritional environment on key characteristics related to lens growth and oxidative stress has not been undertaken. The present study, therefore, examined the characteristics and oxidative status of the lens.. Using a model of moderate maternal under-nutrition, rat dams were fed either a control diet (100% ad libitum, CON) or undernourished throughout pregnancy (50% of ad libitum intake, UN) and offspring fed either a control (5% fat, C) or high fat (30% fat, HF) diet post-weaning, resulting in four nutritional groups; CON-C, CON-HF, UN-C, and UN-HF. Offspring lenses were extracted at 160 days of age, weighed, imaged under dark and bright field microscopy, and then dissected into cortical and core fractions for biochemical analyses of oxidative stress markers.. Our findings reveal that lenses from all groups were transparent. However, gender specific changes were evident at the biochemical level with increased oxidative stress detected in the cortex and core of female but not male UN-C lenses, and in the cortex of male but not female CON-HF lenses. The greatest increase in oxidative stress was detected in the UN-HF group in the cortex and core regions of the lens and for both genders.. These findings show that oxidative stress is exacerbated in the lens as a result of a combination of altered pre-natal and post-natal diet. This demonstrates a novel interaction between the two developmental windows and warrants further investigations toward devising appropriate nutritional strategies for minimizing oxidative stress in the lens. Topics: Adiposity; Animals; Ascorbic Acid; Biomarkers; Blood Glucose; Body Weight; Diet, High-Fat; Female; Glutathione; Insulin; Lens Diseases; Lens, Crystalline; Leptin; Male; Malnutrition; Maternal Nutritional Physiological Phenomena; Obesity; Oxidative Stress; Pregnancy; Rats; Rats, Sprague-Dawley; Vitamin E | 2017 |
Effects of bingeing on fat during adolescence on the reinforcing effects of cocaine in adult male mice.
Binge eating is a specific form of overeating characterized by intermittent excessive eating. In addition to altering the neurobiological reward system, several studies have highlighted that consumption of palatable food increases vulnerability to drug use. The aim of the present study was to evaluate the effects of a high-fat diet consumed in a binge pattern during adolescence on the reinforcing effects of cocaine. After 40 days of binge-eating for 2 h, three days a week (PND 29-69), the reinforcing effects of cocaine on conditioning place preference and intravenous self-administration paradigm were evaluated in adolescent male mice. Circulating leptin and ghrelin levels and the effects of bingeing on fat on CB1 mu opioid receptor (MOr) and ghrelin receptor (GHSR) gene expression in the Nucleus Accumbens (NAcc) and Ventral Tegmental Area (VTA) were also assessed. Our results showed a significant escalation in the consumption of a high-fat diet between the first and last week. High-fat binge (HFB) animals were more sensitive to the reinforcing effects of a subthreshold dose of cocaine in the paradigms assayed, and animals under fat withdrawal were more vulnerable to the reinstatement of conditioned place preference. HFB mice also showed enhanced cocaine self-administration. After fat withdrawal, exposure to a new fat binge reinstated cocaine seeking. Although HFB did not modify leptin levels, a decrease in plasmatic ghrelin was observed. Moreover, this pattern of fatty diet resulted in a reduction of MOr and CB1 gene expression in the NAcc and an increase in GHSR expression in the VTA. We propose that bingeing on fat during adolescence induces long-lasting changes in the brain through the sensitization of brain reward circuits, which predisposes individuals to seek cocaine during adulthood. Topics: Animals; Anxiety; Body Weight; Bulimia; Cocaine; Conditioning, Classical; Corticosterone; Diet, High-Fat; Drug-Seeking Behavior; Gene Expression; Ghrelin; Leptin; Male; Mice; Nucleus Accumbens; Receptor, Cannabinoid, CB1; Receptors, Opioid, mu; Reward; Self Administration; Ventral Tegmental Area | 2017 |
Proanthocyanidins potentiate hypothalamic leptin/STAT3 signalling and Pomc gene expression in rats with diet-induced obesity.
Dietary obesity is usually linked with hypothalamic leptin resistance, in which the primary impact is an interference in the homeostatic control of body weight and appetite. Notably, proanthocyanidins (PACs), which are the most abundant phenolic compounds present in human diet, modulate adiposity and food intake. The aim of this study was to assess whether PACs could re-establish appropriate leptin signalling in both the hypothalamus and peripheral tissues.. Male Wistar rats were fed either a standard chow diet (STD group, n=7) or a cafeteria diet (CD) for 13 weeks. The CD-fed rats were treated with either grape-seed PAC extract (GSPE) at 25 mg per kg of body weight per day (CD+GSPE group, n=7) or with the vehicle (CD group, n=7) for the last 21 days of the study period. Specific markers for intracellular leptin signalling, inflammation and endoplasmic reticulum stress in the hypothalamus, liver, mesenteric white adipose tissue and skeletal muscle were analysed using immunoblotting and quantitative PCR.. GSPE treatment significantly reduced the food intake but did not reverse the hyperleptinemia and body wt gain assessed. However, the animals treated with GSPE exhibited greater hypothalamic activation of signal transducer and activator of transcription-3, which was associated with a rise in the Pomc mRNA levels compared with the CD group. In addition, this restoration of leptin responsiveness was accompanied by lower local inflammation and increased Sirt1 gene expression. The effects of the GSPE treatment in the peripheral tissues were not as evident as those in the hypothalamus, although the GSPE treatment significantly restored the mRNA levels of Socs3 and Ptp1b in the skeletal muscle.. The use of GSPE reduces hyperphagia and improves the central and peripheral leptin resistance associated with diet-induced obesity. Our results suggest that GSPE could exert these effects partially by increasing Sirt1 expression and preventing hypothalamic inflammation. Topics: Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Gene Expression Regulation; Grape Seed Extract; Hypothalamus; Leptin; Lipid Metabolism; Male; Obesity; Pro-Opiomelanocortin; Proanthocyanidins; Rats; Rats, Wistar; Signal Transduction; STAT3 Transcription Factor | 2017 |
Effect of dietary macronutrients on the expression of cholecystokinin, leptin, ghrelin and neuropeptide Y in gilthead sea bream (Sparus aurata).
Endocrine factors released from the central nervous system, gastrointestinal tract, adipose tissue and other peripheral organs mediate the regulation of food intake. Although many studies have evaluated the effect of fed-to-starved transition on the expression of appetite-related genes, little is known about how the expression of appetite-regulating peptides is regulated by the macronutrient composition of the diet. The aim of the present study was to examine the effect of diet composition and nutritional status on the expression of four peptides involved in food intake control in gilthead sea bream (Sparus aurata): neuropeptide Y (NPY), ghrelin, cholecystokinin (CCK) and leptin. Quantitative real-time RT-PCR showed that high protein/low carbohydrate diets stimulated the expression of CCK and ghrelin in the intestine and leptin in the adipose tissue, while downregulation of ghrelin and NPY mRNA levels was observed in the brain. Opposite effects were found for the expression of the four genes in fish fed low protein/high carbohydrate diets or after long-term starvation. Our findings indicate that the expression pattern of appetite-regulating peptides, particularly CCK and ghrelin, is modulated by the nutritional status and diet composition in S. aurata. Topics: Animals; Body Composition; Body Weight; Cholecystokinin; Diet; Gene Expression Regulation; Ghrelin; Leptin; Linear Models; Neuropeptide Y; RNA, Messenger; Sea Bream; Starvation | 2017 |
Prepuberal light phase feeding induces neuroendocrine alterations in adult rats.
Feeding patterns are important factors in obesity evolvement. Time-restricted feeding schedules (tRF) during resting phase change energy homeostasis regulation, disrupting the circadian release of metabolism-regulating hormones, such as leptin, insulin and corticosterone and promoting body weight gain. Thyroid (HPT) and adrenal (HPA) axes exhibit a circadian regulation and are involved in energy expenditure, thus studying their parameters in tRF paradigms will elucidate their role in energy homeostasis impairments under such conditions. As tRF in young animals is poorly studied, we subjected prepuberal rats to a tRF either in light (LPF) or in darkness phase (DPF) and analyzed HPT and HPA response when they reach adulthood, as well as their arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei neurons' sensitivity to leptin in subsets of 10-week-old animals after fasting and with i.p. leptin treatment. LPF group showed high body weight and food intake, along with increased visceral fat pads, corticosterone, leptin and insulin serum levels, whereas circulating T Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Circadian Rhythm; Corticosterone; Corticotropin-Releasing Hormone; Eating; Energy Metabolism; Feeding Behavior; Insulin; Leptin; Neurons; Paraventricular Hypothalamic Nucleus; Rats; Thyroxine | 2017 |
Leptin resistance elicits depressive-like behaviors in rats.
There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS) and include increased risk for development of neuropsychiatric co-morbidities such as depressive illness. The neurological consequences of obesity may develop as a continuum and involve a progression of pathological features which is initiated by leptin resistance. Leptin resistance is a hallmark feature of obesity, but it is unknown whether leptin resistance or blockage of leptin action is casually linked to the neurological changes which underlie depressive-like phenotypes. Accordingly, the aim of the current study was to examine whether chronic administration of a pegylated leptin receptor antagonist (Peg-LRA) elicits depressive-like behaviors in adult male rats. Peg-LRA administration resulted in endocrine and metabolic features that are characteristic of an obesity phenotype. Peg-LRA rats also exhibited increased immobility in the forced swim test, depressive-like behaviors that were accompanied by indices of peripheral inflammation. These results demonstrate that leptin resistance elicits an obesity phenotype that is characterized by peripheral immune changes and depressive-like behaviors in rats, supporting the concept that co-morbid obesity and depressive illness develop as a continuum resulting from changes in the peripheral endocrine and metabolic milieu. Topics: Animals; Behavior, Animal; Body Weight; Depression; Inflammation; Leptin; Male; Obesity; Rats, Sprague-Dawley | 2017 |
Diets High in Fat or Fructose Differentially Modulate Bone Health and Lipid Metabolism.
Diets high in fat or carbohydrates can lead to obesity and diabetes, two interrelated conditions that have been associated with osteoporosis. Here, we contrasted the effects of a high fat (HF) versus fructose-enriched carbohydrate (CH) versus regular chow (SC) diet on bone morphology, fat content and metabolic balance in BALB/cByJ mice over a 15-week period. For 13 weeks, there were no differences in body mass between groups with small differences in the last 2 weeks. Even without the potentially confounding factor of altered body mass and levels of load bearing, HF consumption was detrimental to bone in the distal femur with lower trabecular bone volume fraction and thinner cortices than controls. These differences in bone were accompanied by twofold greater abdominal fat content and fourfold greater plasma leptin concentrations. High-fat feeding caused a decrease in de-novo lipid synthesis in the liver, kidney, white adipose and brown adipose tissue. In contrast to HF, the fructose diet did not significantly impact bone quantity or architecture. Fructose consumption also did not significantly alter leptin levels or de-novo lipid synthesis but reduced epididymal adipose tissue and increased brown adipose tissue. Cortical stiffness was lower in the CH than in HF mice. There were no differences in glucose or insulin levels between groups. Together, a diet high in fat had a negative influence on bone structure, adipose tissue deposition and lipid synthesis, changes that were largely avoided with a fructose-enriched diet. Topics: Adipose Tissue; Animals; Body Weight; Bone and Bones; Diet, High-Fat; Feeding Behavior; Fructose; Leptin; Lipid Metabolism; Liver; Mice; Obesity | 2017 |
Robust Reductions of Excess Weight and Hyperphagia by Beloranib in Rat Models of Genetic and Hypothalamic Obesity.
Hypothalamic lesions or deficient melanocortin (MC) signaling via MC4 receptor (MC4r) mutations often lead to hyperphagia and severe treatment-resistant obesity. We tested the methionine aminopeptidase 2-inhibitor beloranib (ZGN-440) in 2 male rat models of obesity, one modeling hypothalamic obesity with a combined medial hypothalamic lesion (CMHL) and the other modeling a monogenic form of obesity with MC4r mutations (MC4r knockout [MC4rKO]). In CMHL rats (age 3 months), postsurgery excess weight gain was significantly inhibited (ZGN-440, 0.2 ± 0.7 g/d; vehicle, 3.8 ± 0.6 g/d; P < 0.001) during 12 days of ZGN-440 treatment (0.1 mg/kg daily subcutaneously) together with a 30% reduction of daily food intake vs vehicle injection. In addition, ZGN-440 treatment improved glucose tolerance and reduced plasma insulin, and circulating levels of α-melanocyte stimulating hormone were increased. Serum lipid levels did not differ significantly in ZGN-440-treated vs vehicle-treated rats. Similar results were found in MC4rKO rats: ZGN-440 treatment (14-21 d) was associated with significant reductions of body weight gain (MC4rKO, -1.7 ± 0.6 vs 2.8 ± 0.4 g/d; lean wild-type controls, -0.7 ± 0.2 vs 1.7 ± 0.7 g/d; ZGN-440 vs vehicle, respectively), reduction of food intake (MC4rKO, -28%; lean controls, -7.5%), and insulin resistance, whereas circulating levels of interleukin-1β did not change. In both obesity models, body temperature and locomotor activity were not affected by ZGN-440 treatment. In conclusion, the robust reduction of body weight in response to ZGN-440 observed in rats with severe obesity is related to a strong reduction of food intake that is likely related to changes in the central regulation of feeding. Topics: Aminopeptidases; Animals; Body Temperature; Body Weight; Cinnamates; Cyclohexanes; Disease Models, Animal; Drug Evaluation, Preclinical; Eating; Epoxy Compounds; Gene Expression; Glucose Tolerance Test; Hyperphagia; Hypothalamus, Middle; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Metalloendopeptidases; Obesity; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Melanocortin, Type 4; Sesquiterpenes | 2017 |
The effect of mare obesity and endocrine function on foal birthweight in Thoroughbreds.
Birthweight of Thoroughbred foals has increased in recent years. It is unknown whether this is associated with increased broodmare obesity or endocrine dysfunction.. To determine insulin, leptin and triglyceride concentrations in Thoroughbred mares throughout gestation and investigate their association with obesity and foal birthweight.. Cohort study.. A total of 66 mares were included from 40 days post-breeding. Body condition score (BCS), weight and blood samples were obtained every 60 days throughout gestation. Serum/plasma insulin, leptin and triglyceride concentrations and foal birthweight were recorded. Associations between hormone/triglyceride concentration with BCS, stage of gestation and birthweight were analysed using a linear mixed effects model.. Serum insulin concentrations were greater at 1-60 days (4.31 μiu/mL) compared with 241-300 days (3.13 μiu/mL) and 61-120 days (5.33 μiu/mL) compared with 181-240, 241-300 and 301-360 days (3.78, 3.13, 3.37 μiu/mL) gestation (P<0.05). There was no significant hyperinsulinaemia and no association of insulin concentration with BCS. Leptin concentration was greater at 181-240 days (2.28 μg/L, P<0.0001) compared with all other time points and correlated with BCS (P<0.0003). Triglyceride concentration was greater at 241-300 days (0.245 mmol, P<0.02) compared with earlier time points, but was not associated with BCS. Foal birthweight was weakly positively correlated with BCS (r = 0.13, P<0.001) and inversely correlated with leptin concentrations at 61-120 and 241-300 days gestation (r = -0.64, P<0.05).. Reduction in sample size over the study and tight clustering of BCS.. Mare BCS correlated with foal birthweight; obese mares had heavier foals. Significant hyperinsulinaemia was not identified in this population. Increased leptin concentration in early and late gestation was associated with decreased foal birthweight. Further work is required to establish whether leptin concentration in late gestation could predict foal birthweight. Topics: Animals; Animals, Newborn; Birth Weight; Body Weight; Cohort Studies; Female; Horse Diseases; Horses; Insulin; Leptin; Obesity; Pregnancy; Pregnancy, Animal | 2017 |
Curcumin improves the metabolic syndrome in high-fructose-diet-fed rats: role of TNF-α, NF-κB, and oxidative stress.
This study aimed to investigate effects of curcumin on high fructose diet (HFD)-induced metabolic syndrome (MetS) in rats and the possible mechanisms involved. MetS was induced in male albino rats (n = 20), over 8 weeks, by 65% HFD. For 8-week experiment period, rats were assigned to 2 equal groups: curcumin-treated rats received curcumin (200 mg/kg, p.o, once daily) along with HFD, and untreated rats were fed with HFD only. We evaluated body mass (BM), systolic blood pressure (SBP), homeostasis model assessment of insulin resistance (HOMA-IR), and serum levels of glucose, insulin, leptin, total cholesterol (TC), triglycerides (TGs), uric acid, malondialdehyde (MDA; lipid peroxidation product), and tumor necrosis factor-α (TNF-α; inflammatory cytokine), and serum catalase (endogenous antioxidant) activity and immunohistochemical expression of nuclear factor κB (NF-κB; inflammation-related transcription factor) in hepatocytes. HFD produced increases in BM, SBP, HOMA-IR, and serum levels of glucose, insulin, leptin, TC, TGs, uric acid, MDA, and TNF-α, a decrease in catalase activity, and strong positive expression of NF-κB in hepatocytes. Curcumin, in presence of HFD, produced significant improvements in all glucose and fat metabolism parameters, and in oxidative stress and inflammation biomarkers. Curcumin may potentially be useful in the treatment of MetS through its ability to modulate oxidation stress status and inflammation cascades. Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Catalase; Cholesterol; Curcumin; Fructose; Hepatocytes; Insulin; Leptin; Liver; Male; Malondialdehyde; Metabolic Syndrome; NF-kappa B; Oxidative Stress; Rats; Tumor Necrosis Factor-alpha; Uric Acid | 2017 |
Inhibiting Microglia Expansion Prevents Diet-Induced Hypothalamic and Peripheral Inflammation.
Cell proliferation and neuroinflammation in the adult hypothalamus may contribute to the pathogenesis of obesity. We tested whether the intertwining of these two processes plays a role in the metabolic changes caused by 3 weeks of a high-saturated fat diet (HFD) consumption. Compared with chow-fed mice, HFD-fed mice had a rapid increase in body weight and fat mass and specifically showed an increased number of microglia in the arcuate nucleus (ARC) of the hypothalamus. Microglia expansion required the adequate presence of fats and carbohydrates in the diet because feeding mice a very high-fat, very low-carbohydrate diet did not affect cell proliferation. Blocking HFD-induced cell proliferation by central delivery of the antimitotic drug arabinofuranosyl cytidine (AraC) blunted food intake, body weight gain, and adiposity. AraC treatment completely prevented the increase in number of activated microglia in the ARC, the expression of the proinflammatory cytokine tumor necrosis factor-α in microglia, and the recruitment of the nuclear factor-κB pathway while restoring hypothalamic leptin sensitivity. Central blockade of cell proliferation also normalized circulating levels of the cytokines leptin and interleukin 1β and decreased peritoneal proinflammatory CD86 immunoreactive macrophage number. These findings suggest that inhibition of diet-dependent microglia expansion hinders body weight gain while preventing central and peripheral inflammatory responses due to caloric overload. Topics: Adiposity; Animals; Antimitotic Agents; Arabinonucleosides; Arcuate Nucleus of Hypothalamus; Body Weight; Cell Proliferation; Cytarabine; Cytidine; Diet, High-Fat; Eating; Hypothalamus; Inflammation; Interleukin-1beta; Leptin; Macrophages, Peritoneal; Male; Mice; Microglia; NF-kappa B; Obesity; Tumor Necrosis Factor-alpha; Weight Gain | 2017 |
Ameliorating effects of fennel and cumin extracts on sperm quality and spermatogenic cells apoptosis by inducing weight loss and reducing leptin concentration in diet-induced obese rats.
This study was established a model of obesity to estimate the impact of fennel and cumin as anti-obesity extracts on body weight, body mass index (BMI), food consumption, leptin concentration, sperm quality and testis architecture to determine the reversibility of reproductive function of obese animals. Male rats were randomly assigned to either a normal or high-fat diet for 8 weeks. Then, we divided 56 adult rats into seven groups: control (CO); obesity (OB); fennel 100 and 200 mg/kg; cumin 50 and 100 mg/kg; and fennel 100 mg/kg plus cumin 50 mg/kg. From weeks 9-16, the animals treated extracts by gavages daily. We analysed leptin concentration, sperm quality and apoptosis of testis along with evaluating changes in body weight. Body weight of animals increased 25% at week 8. However, body weight, BMI, leptin concentration and apoptosis indices of OB rats increased at the end of study. However, the relative sperm parameters decreased. Nevertheless, fennel and cumin treatment improved sperm quality, and spermatogenic cells apoptosis following weight loss. Concomitant with weight loss, leptin concentration and food consumption decreased. In conclusion, fennel and cumin as supplements may ameliorate sperm quality of obese animals following weight loss and reduction in leptin concentration. Topics: Animals; Apoptosis; Body Weight; Cuminum; Diet, High-Fat; Foeniculum; Leptin; Male; Obesity; Plant Extracts; Rats; Rats, Wistar; Semen Analysis; Spermatogenesis; Spermatozoa; Testis; Weight Loss | 2017 |
Thermogenesis, fatty acid synthesis with oxidation, and inflammation in the brown adipose tissue of ob/ob (-/-) mice.
Brown adipose tissue (BAT) is specialized in heat production, but its metabolism in ob/ob mice is still a matter of debate. We aimed to verify ob/ob mice BAT using C57Bl/6 male mice (as the wild-type, WT) and leptin-deficient ob/ob mice (on the C57Bl/6 background strain), at three months of age (n=10/group). At euthanasia, animals had their interscapular BAT weighed, and prepared for analysis (Western blot, and RT-qPCR). In comparison with the WT group, the ob/ob group showed reduced thermogenic signaling markers (gene expression of beta 3-adrenergic receptor, beta3-AR; PPARgamma coactivator 1 alpha, PGC1alpha, and uncoupling protein 1, UCP1). The ob/ob group also showed impaired gene expression for lipid utilization (perilipin was increased, while other markers were diminished: carnitine palmitoyltransferase-1b, CPT-1b; cluster of differentiation 36, CD36; fatty acid binding protein 4, FABP4; fatty acid synthase, FAS, and sterol regulatory element-binding protein 1c, SREBP1c), and altered protein expression of insulin signaling (diminished pAKT, TC10, and GLUT-4). Lastly, the ob/ob group showed increased gene expression of markers of inflammation (interleukin 1 beta, IL-1beta; IL-6, tumor necrosis factor alpha, TNFalpha; and monocyte chemotactic protein-1, MCP-1). In conclusion, the ob/ob mice have decreased thermogenic markers associated with reduced gene expression related to fatty acid synthesis, mobilization, and oxidation. There were also alterations in insulin signaling and protein and gene expressions of inflammation. The findings suggest that the lack of substrate for thermogenesis and the local inflammation negatively regulated thermogenic signaling in the ob/ob mice. Topics: Adipose Tissue, Brown; Animals; Body Weight; Fatty Acids; Genetic Markers; Glucose; Inflammation; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Oxidation-Reduction; Thermogenesis | 2017 |
Long-Term Energy Deficit in Mice Causes Long-Lasting Hypothalamic Alterations after Recovery.
Although the short-term effects of fasting or energy deficit on hypothalamic neuropeptide circuitries are now better understood, the effects of long-term energy deficit and refeeding remain to be elucidated. We showed that after a long-term energy deficit, mice exhibited persistent hypoleptinemia following the refeeding period despite restoration of fat mass, ovarian activity, and feeding behavior. We aimed to examine the hypothalamic adaptations after 10 weeks of energy deficit and after 10 further weeks of nutritional recovery. To do so, we assessed the mRNA levels of the leptin receptor and the main orexigenic and anorexigenic peptides, and their receptors regulated by leptin. Markers of hypothalamic inflammation were assessed as leptin can also participate in this phenomenon. Long-term time-restricted feeding and separation induced significant increase in mRNA levels of hypothalamic orexigenic peptides, while both Y1 and Y5 receptor mRNAs were downregulated. No changes occurred in the mRNA levels of orexin (OX), melanin-concentrating hormone, pro-opiomelanocortin, 26RFa (26-amino acid RF-amide peptide), and their receptors despite an increase in the expression of melanocortin receptors (MC3-R and MC4-R) and OXR1 (OX receptor 1). The refeeding period induced an overexpression of leptin receptor mRNA in the hypothalamus. The other assessed mRNA levels were normalized except for Y2, Y5, MC3-R, and MC4-R, which remained upregulated. No convincing changes were observed in neuroinflammatory markers, even if interleukin-1β mRNA levels were increased in parallel with those of Iba1 (ionized calcium-binding adaptor molecule 1), a marker of microglial activation. Normalization of leptin-regulated functions and hypothalamic gene expressions in refed mice with low plasma leptin levels could be sustained by recalibration of hypothalamic sensitivity to leptin. Topics: Agouti-Related Protein; Animals; Body Weight; Cytokines; Disease Models, Animal; Eating; Female; Hypolipoproteinemias; Hypothalamic Hormones; Hypothalamus; Leptin; Melanins; Mice; Mice, Inbred C57BL; Neuropeptide Y; Neuropeptides; Orexins; Pituitary Hormones; Receptors, Leptin; Receptors, Neuropeptide; RNA, Messenger | 2017 |
Correlations between serum adipocytokine concentrations, disease stage, radiological status and total body fat content in the patients with primary knee osteoarthritis.
The study was designed to investigate whether serum concentrations of leptin, resistin and adiponectin in obese and normal-weight patients with primary knee osteoarthritis (OA) correlate with clinical and radiological stages of the disease and percentage of total body fat.. Seventy-three patients with knee OA, divided into obese and normal-weight groups, were clinically evaluated according to the Knee Society Score (KSS), and radiologically assessed using Kellgren and Lawrence scale. The percentage of total body fat and some anthropometric data were also given. Serum leptin, resistin and adiponectin concentrations were measured by Elisa and were correlated with the clinical, radiological and anthropometric parameters.. Leptin concentrations were significantly higher (p = 0.001) in the obese patients and positively correlated (R = 0.63) with radiologically assessed OA grade, but only in the normal-weight group. Resistin and adiponectin concentrations were identical in obese and normal-weight patients and negatively correlated (R = -0.41) with the clinical status of obese patients. In both groups, percentage of total body fat positively correlated (R = 0.29 and R = 0.53 for obese and normal-weight respectively) with radiologically assessed OA grade. However, no correlations were found with clinical status of the patients.. It was found that in the obese patients with knee OA, increased percentage of total body fat and elevated serum leptin concentration might favour the advancement of clinical but not radiologically assessed changes in the joint structures, while in normal-weight patients it correlates only with radiologically assessed changes but does not affect to an appreciable extent the clinical status of the patients. Topics: Adiponectin; Adipose Tissue; Aged; Anthropometry; Body Mass Index; Body Weight; Enzyme-Linked Immunosorbent Assay; Female; Humans; Knee Joint; Leptin; Male; Middle Aged; Obesity; Osteoarthritis, Knee; Resistin | 2017 |
Determination of the half-life of circulating leptin in the mouse.
The adipokine hormone, leptin, is a major component of body weight homeostasis. Numerous studies have been performed administering recombinant mouse leptin as an experimental reagent; however, the half-life of circulating leptin following exogenous administration of recombinant mouse leptin has not been carefully evaluated.. Exogenous leptin was administered (3 mg leptin per kg body weight) to 10-week-old fasted non-obese male mice and plasma was serially collected at seven time points; plasma leptin concentration was measured by enzyme-linked immunosorbent assay at each time point to estimate the circulating half-life of mouse leptin.. Under the physiological circumstances tested, the half-life of mouse leptin was 40.2 (±2.2) min. Circulating leptin concentrations up to 1 h following exogenous leptin administration were 170-fold higher than endogenous levels at fasting.. The half-life of mouse leptin was determined to be 40.2 min. These results should be useful in planning and interpreting experiments employing exogenous leptin. The unphysiological elevations in circulating leptin resulting from widely used dosing regimens for exogenous leptin are likely to confound inferences regarding some aspects of the hormone's clinical biology. Topics: Animals; Biological Availability; Body Weight; Enzyme-Linked Immunosorbent Assay; Half-Life; Leptin; Male; Mice; Mice, Inbred C57BL; Peptide Fragments | 2017 |
The relationships between body fatness, leptin, testosterone, and reproductive performance in ram lambs as affected by level and frequency of feeding.
This study was carried out using 24 Najdi ram lambs of approximately 6.5 months old to evaluate the effects of feed restriction and frequency of feeding on hormone concentrations of leptin and testosterone, sexual behavior, and semen traits. Ram lambs were allotted equally into three feeding groups. The first group was used as a control and fed ad libitum. The second and third groups were restricted fed at 0.85 ad libitum and fed either once (R1M) or twice daily (R2M). Sexual behavior and semen evaluation were assessed during the sixth, seventh, and eighth weeks of the study. Blood samples were drawn at 1-hour pre-feeding on days 41, 48, and 55 of the study for the determination of serum leptin and testosterone concentrations. All lambs were slaughtered after 8 weeks of experimentation. Results showed that the restricted-fed groups had lower (P < 0.01) values for slaughter body weight, average daily gain, dry matter intake, internal fat, tail fat, body fat thickness, body wall thickness, and testes weight than the ad libitum group; these corresponding traits did not differ between both restricted-fed treatments. Leptin and testosterone concentrations in restricted-fed rams were (P < 0.01) lower and higher, respectively, than in the ad libitum rams; there were no differences between R1M and R2M groups. The restricted-fed rams had lower (P < 0.01) ejaculation latency time compared with control, whereas the percentage of sexually active rams and sexual desire score were not affected by feeding restriction or frequency of feeding. Sperm motility, progressive motility, and percentage of sperm moving at rapid speed were higher (P < 0.01) in feed-restricted rams than in the ad libitum rams. R1M rams had higher (P < 0.01) value for straightness and lower (P < 0.01) value for curvilinear velocity in comparison with the ad libitum group. Testosterone was correlated positively (P < 0.05) with sperm motility and progressive motility and negatively (P < 0.04) with fat measurements, leptin, and ejaculation latency time. In conclusion, moderate intake restriction can optimize body fatness and testosterone concentrations in rams, which helped to improve some reproductive traits. Topics: Adipose Tissue; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Ejaculation; Leptin; Male; Reproduction; Semen Analysis; Sexual Behavior, Animal; Sheep, Domestic; Sperm Motility; Testis; Testosterone | 2017 |
Injections of Galanin-Like Peptide directly into the nucleus of the tractus solitarius (NTS) reduces food intake and body weight but increases metabolic rate and plasma leptin.
Galanin-Like Peptide (GALP) is a hypothalamic neuromediator of metabolism and reproduction. GALP is known to stimulate reproduction and alter food intake and body weight in multiple species. The regulation of body weight involves control of both energy intake and energy expenditure. Since GALP is known to alter food intake - possibly via the autonomic nervous system - we first hypothesized that GALP would increase metabolic rate. First, male Sprague-Dawley rats were implanted with intracerebroventricular (ICV) cannulae and abdominal radiotelemetry temperature transmitters. Following ICV injection with either 5nmol GALP or vehicle, the oxygen consumption of each rat was monitored for 8h. Food intake, core temperature, and general motor activity were monitored for 24h. GALP significantly increased oxygen consumption, an indirect estimator of metabolic rate, without having any significant effect on motor activity. Compared to controls, GALP increased core body temperature during the photophase and reduced food intake over the 24h period following injection. ICV GALP also increased plasma levels of luteinizing hormone (LH). A second group of male Sprague-Dawley rats were implanted with abdominal transmitters and given injections of GALP directly into the nucleus of the tractus solitarius (NTS). These injections resulted in a significant reduction in food intake, and a significant increase in both oxygen consumption and core body temperature compared to vehicle injections. Direct injections of GALP into the NTS compared to vehicle also resulted in a significant increase in plasma leptin levels, but not LH levels. GALP appears to increase energy expenditure in addition to decreasing energy input by actions within the NTS and thus may play an important role in the hypothalamic regulation of body weight. Topics: Animals; Body Weight; Eating; Energy Metabolism; Galanin-Like Peptide; Hypothalamus; Injections, Intraventricular; Leptin; Luteinizing Hormone; Male; Rats, Sprague-Dawley; Solitary Nucleus | 2017 |
Competition for Materno-Fetal Resource Partitioning in a Rabbit Model of Undernourished Pregnancy.
The major goal of animal production is to obtain abundant and healthy meat for consumers. Maternal food restriction (MFR) is often applied in farms to reduce production costs. However, the suitability of MFR in livestock animals is questionable, as this management may compromise maternal fitness due to a severe negative energetic balance and can induce Intrauterine Growth Restriction (IUGR) and prenatal programming in the offspring. Here, we sought to determine, using pregnant rabbits, the consequences of MFR on maternal endocrine and metabolic status and conceptus development. Pregnant dams were distributed into three groups: CONTROL (ad libitum feeding throughout the entire pregnancy; mean pregnancy length being around 31 days), UNDERFED (50% MFR during the entire pregnancy) and EARLY-UNDERFED (50% MFR only during the preimplantation period, Days 0-7). Maternal leptin concentrations and glycemic and lipid profiles were determined throughout pregnancy, whilst conceptus development was assessed ex-vivo at Day 28. Placental parameters were determined by macroscopic and histological evaluations and apoptotic assessments (TUNEL and Caspase-3). The main results of the study showed that, despite MFR altered maternal plasma lipid concentration (P<0.05), there were no effects on maternal bodyweight, plasma leptin concentration or glycemic profile. Fetal crown-rump lengths were reduced in both undernourished groups (P<0.001), but a significant reduction in fetal weight was only observed in the UNDERFED group (P<0.001). Growth in both undernourished groups was asymmetrical, with reduced liver weight (P<0.001) and significantly increased brain: fetal weight-ratio (P<0.001) and brain: liver weight-ratio (P<0.001) when compared to the CONTROL group. A significant reduction in placental weight was only observed in the UNDERFED group (P<0.001), despite both undernourished groups showing higher apoptotic rates at decidua and labyrinth zone (P<0.05) than the CONTROL group. Thus, these groups evidenced signs of placental degeneration, necrosis and stromal collapse. In summary, MFR may encourage the mother to make strategic decisions to safeguard her metabolic status and fitness at the expense of growth reduction in the litter, resulting in enhanced apoptotic and pathological processes at placental level and IUGR. Topics: Animals; Apoptosis; Blastocyst; Blood Glucose; Body Weight; Crown-Rump Length; Disease Models, Animal; Female; Fetal Growth Retardation; Fetal Weight; Fetus; Leptin; Lipid Metabolism; Malnutrition; Placenta; Pregnancy; Pregnancy Complications; Pregnancy, Animal; Rabbits | 2017 |
Maternal undernutrition programs the apelinergic system of adipose tissue in adult male rat offspring.
Based on the Developmental Origin of Health and Disease concept, maternal undernutrition has been shown to sensitize adult offspring to metabolic pathologies such as obesity. Using a model of maternal 70% food restriction in pregnant female rats throughout gestation (called FR30), we previously reported that obesity-prone adult male rat offspring displayed hyperleptinemia with modifications in leptin and leptin receptor messenger RNA (mRNA) levels in white adipose tissue (WAT). Apelin is a member of the adipokine family that regulates various aspects of energy metabolism and WAT functionality. We investigated whether apelin and its receptor APJ could be a target of maternal undernutrition. Adult male rat offspring from FR30 dams showed increased plasma apelin levels and apelin gene expression in WAT. Post-weaning high-fat diet led to marked increase in APJ mRNA and protein levels in offspring's WAT. We demonstrate that maternal undernutrition and post-weaning diet have long-term consequences on the apelinergic system of adult male rat offspring. Topics: Adipose Tissue; Animals; Apelin; Apelin Receptors; Body Weight; Energy Metabolism; Female; Leptin; Male; Malnutrition; Pregnancy; Rats | 2017 |
A Leptin Analog Locally Produced in the Brain Acts via a Conserved Neural Circuit to Modulate Obesity-Linked Behaviors in Drosophila.
Leptin, a typically adipose-derived "satiety hormone," has a well-established role in weight regulation. Here we describe a functionally conserved model of genetically induced obesity in Drosophila by manipulating the fly leptin analog unpaired 1 (upd1). Unexpectedly, cell-type-specific knockdown reveals upd1 in the brain, not the adipose tissue, mediates obesity-related traits. Disrupting brain-derived upd1 in flies leads to all the hallmarks of mammalian obesity: increased attraction to food cues, increased food intake, and increased weight. These effects are mediated by domeless receptors on neurons expressing Drosophila neuropeptide F, the orexigenic mammalian neuropeptide Y homolog. In vivo two-photon imaging reveals upd1 and domeless inhibit this hedonic signal in fed animals. Manipulations along this central circuit also create hypersensitivity to obesogenic conditions, emphasizing the critical interplay between biological predisposition and environment in overweight and obesity prevalence. We propose adipose- and brain-derived upd/leptin may control differing features of weight regulation through distinct neural circuits. Topics: Animals; Behavior, Animal; Body Weight; Brain; Drosophila melanogaster; Drosophila Proteins; Feeding Behavior; Female; Gene Knockdown Techniques; Humans; Leptin; Nerve Net; Obesity; Odorants; Phenotype; Signal Transduction; Transcription Factors | 2017 |
Aronia melanocarpa Extract Ameliorates Hepatic Lipid Metabolism through PPARγ2 Downregulation.
Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Studies have demonstrated that anthocyanin-rich foods may improve hyperlipidemia and ameliorate hepatic steatosis. Here, effects of Aronia melanocarpa (AM), known to be rich of anthocyanins, on hepatic lipid metabolism and adipogenic genes were determined. AM was treated to C57BL/6N mice fed with high fat diet (HFD) or to FL83B cells treated with free fatty acid (FFA). Changes in levels of lipids, enzymes and hormones were observed, and expressions of adipogenic genes involved in hepatic lipid metabolism were detected by PCR, Western blotting and luciferase assay. In mice, AM significantly reduced the body and liver weight, lipid accumulation in the liver, and levels of biochemical markers such as fatty acid synthase, hepatic triglyceride and leptin. Serum transaminases, indicators for hepatocyte injury, were also suppressed, while superoxide dismutase activity and liver antioxidant capacity were significantly increased. In FL83B cells, AM significantly reduced FFA-induced lipid droplet accumulation. Protein synthesis of an adipogenic transcription factor, peroxisome proliferator-activated receptor γ2 (PPARγ2) was inhibited in vivo. Furthermore, transcriptional activity of PPARγ2 was down-regulated in vitro, and mRNA expression of PPARγ2 and its downstream target genes, adipocyte protein 2 and lipoprotein lipase were down-regulated by AM both in vitro and in vivo. These results show beneficial effects of AM against hepatic lipid accumulation through the inhibition of PPARγ2 expression along with improvements in body weight, liver functions, lipid profiles and antioxidant capacity suggesting the potential therapeutic efficacy of AM on NAFLD. Topics: Animals; Body Weight; Cell Line; Diet, High-Fat; Down-Regulation; Fatty Acids, Nonesterified; Leptin; Lipid Metabolism; Lipoprotein Lipase; Liver; Male; Mice; Mice, Inbred C57BL; Photinia; Plant Extracts; PPAR gamma; RNA Interference; Superoxide Dismutase; Transaminases; Triglycerides | 2017 |
Cinnamaldehyde potentially attenuates gestational hyperglycemia in rats through modulation of PPARγ, proinflammatory cytokines and oxidative stress.
Cinnamon has a history of use for medicinal purposes and its major benefits have been linked to cinnamaldehyde. The present study aimed to investigate the hypoglycemic action of cinnamaldehyde against fatty-sucrosed diet/streptozotocin (FSD/STZ)-rat model of gestational diabetes. Female albino rats were divided into three groups. Group I fed with normal diet (ND) while group II and III were fed with FSD for eight weeks (five weeks pre-gestational and three weeks gestational). Rats of group III were administered with a daily oral dose of 20mg/kg cinnamaldehyde one week before mating onward. At the 7th day of gestation, FSD-fed rats were injected intraperitoneally with STZ (25mg/kg b.wt.) to induce gestational diabetes. Pre-mating treatment of cinnamaldehyde controls hyperphagia and glucose intolerance during the gestational period than in diabetic rats. It also reduced levels of fructosamine, total cholesterols, triglycerides, leptin, tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA) and nitric oxide (NO), while it significantly increased levels of high-density lipoprotein (HDL)-cholesterol, adiponectin, liver glycogen, reduced glutathione (GSH) and catalase activity at term pregnancy. In addition, cinnamaldehyde administration up-regulated the mRNA expression of peroxisome proliferated activated receptor-gamma (PPARγ) and also ameliorated the number of viable fetuses, implantation loss sites, fetal glucose and insulin levels. In conclusion, cinnamaldehyde has safe hypoglycemic action on gestational diabetes by potentiating insulin secretion and sensitivity through activating the antioxidant defense system, suppressing pro-inflammatory cytokines production, upregulating PPARγ gene expression and alleviating the reproductive performance. Topics: Acrolein; Adipose Tissue; Animals; Antioxidants; Biomarkers; Blood Glucose; Body Weight; Cholesterol; Cytokines; Diabetes, Gestational; Feeding Behavior; Female; Fetus; Fructosamine; Glucose Tolerance Test; Glycogen; Hyperglycemia; Inflammation Mediators; Insulin; Leptin; Liver; Oxidative Stress; PPAR gamma; Pregnancy; Pregnancy Outcome; Rats; RNA, Messenger; Triglycerides | 2017 |
Role of leptin in conditioned place preference to high-fat diet in leptin-deficient ob/ob mice.
Leptin is an adipocyte-derived anorexic hormone that exerts its effects via the hypothalamus and other brain regions, including the reward system. Leptin-deficient ob/ob mice that present morbid obesity, hyperphagia, insulin resistance, and infertility are one of the most investigated mouse models of obesity. Conditioned place preference (CPP) paradigm is a standard behavioral model to evaluate the rewarding value of substrates. While leptin is reported to decrease the CPP of lean mice for high fat diet (HFD), it is unknown how CPP toward HFD is affected by leptin replacement in the pathophysiological condition of ob/ob mice. In the present study, we performed the CPP test in order to clarify the effect of leptin on the preference of ob/ob mice for HFD. Ob/ob mice had a significantly higher HFD preference in CPP test when compared with wild-type (WT) mice and this preference was suppressed to the levels comparable to the WT mice by leptin replacement with or without normalization of body weight. These results demonstrate that leptin decreases the reward value of HFD independently of obesity, suggesting that leptin reduces food intake by suppressing the hedonic feeding pathway in ob/ob mice. Topics: Animals; Body Weight; Conditioning, Classical; Diet, High-Fat; Eating; Food Preferences; Leptin; Mice, Inbred C57BL; Mice, Obese; Obesity; Reward | 2017 |
Vertical sleeve gastrectomy reduces blood pressure and hypothalamic endoplasmic reticulum stress in mice.
Bariatric surgery, such as vertical sleeve gastrectomy (VSG), causes remarkable improvements in cardiometabolic health, including hypertension remission. However, the mechanisms responsible remain undefined and poorly studied. Therefore, we developed and validated the first murine model of VSG that recapitulates the blood pressure-lowering effect of VSG using gold-standard radiotelemetry technology. We used this model to investigate several potential mechanisms, including body mass, brain endoplasmic reticulum (ER) stress signaling and brain inflammatory signaling, which are all critical contributors to the pathogenesis of obesity-associated hypertension. Mice fed on a high-fat diet underwent sham or VSG surgery and radiotelemeter implantation. Sham mice were fed Topics: Animals; Blood Pressure; Body Weight; Cecum; Endoplasmic Reticulum Stress; Energy Intake; Fasting; Gastrectomy; Gastrointestinal Microbiome; Ghrelin; Hypothalamus; Inflammation; Leptin; Male; Mice, Inbred C57BL; Norepinephrine; Signal Transduction | 2017 |
TrpC5 Mediates Acute Leptin and Serotonin Effects via Pomc Neurons.
The molecular mechanisms underlying acute leptin and serotonin 2C receptor-induced hypophagia remain unclear. Here, we show that neuronal and pro-opiomelanocortin (Pomc)-specific loss of transient receptor potential cation 5 (TrpC5) subunits is sufficient to decrease energy expenditure and increase food intake resulting in elevated body weight. Deficiency of Trpc5 subunits in Pomc neurons is also sufficient to block the anorexigenic effects of leptin and serotonin 2C receptor (Ht2Cr) agonists. The loss of acute anorexigenic effects of these receptors is concomitant with a blunted electrophysiological response to both leptin and Ht2Cr agonists in arcuate Pomc neurons. We also demonstrate that the Ht2Cr agonist lorcaserin-induced improvements in glucose and insulin tolerance are blocked by TrpC5 deficiency in Pomc neurons. Together, our results link TrpC5 subunits in the brain with leptin- and serotonin 2C receptor-dependent changes in neuronal activity, as well as energy balance, feeding behavior, and glucose metabolism. Topics: Animals; Appetite Depressants; Benzazepines; Body Weight; Eating; Energy Metabolism; Glucose; Glucose Tolerance Test; Insulin Resistance; Leptin; Male; Membrane Potentials; Mice; Mice, Knockout; Neurons; Patch-Clamp Techniques; Pro-Opiomelanocortin; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Tamoxifen; TRPC Cation Channels | 2017 |
Effects of obesity and exercise on testicular leptin signal transduction and testosterone biosynthesis in male mice.
To explore the role of the testicular leptin and JAK-STAT[leptin (LEP)-JAK-STAT] pathway in testosterone biosynthesis during juvenile stages and exercise for weight loss, male C57BL/6J mice were randomly divided into normal-diet and high-fat diet groups. After 10 wk, mice in the high-fat diet-fed group were further divided randomly into obese control, obese moderate-volume exercise, and obese high-volume exercise groups. Mice in the obese moderate-volume exercise group were provided with 2 h/day, 6 days/wk swimming exercise for 8 wk, and mice in the obese high-volume exercise group underwent twice the amount of daily exercise intervention as the obese moderate-volume exercise group. The results showed that a high-fat diet causes obesity, leptin resistance, inhibition of the testicular LEP-JAK-STAT pathway, decreased mRNA and protein expression of steroidogenic factor-1, steroidogenic acute regulatory protein, and the Topics: Animals; Body Weight; Exercise Therapy; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Physical Conditioning, Animal; Physical Exertion; Signal Transduction; Testis; Testosterone; Treatment Outcome | 2017 |
Weight Perturbation Alters Leptin Signal Transduction in a Region-Specific Manner throughout the Brain.
Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin in 4 different groups of weight- and/or diet-perturbed mice. Responses to leptin were assessed by quantifying pSTAT3 levels in brain nuclei 30 minutes following 3 mg/kg intraperitoneal leptin. HFD attenuated leptin sensing throughout the brain, but weight loss did not restore central leptin signaling to control levels in several brain regions important in energy homeostasis, including the arcuate and dorsomedial hypothalamic nuclei. Effects of diet on leptin signaling varied by brain region, with results dependent on the method of weight loss (restriction of calories of HFD, ad lib intake of standard mouse chow). High fat diet attenuates leptin signaling throughout the brain, but some brain regions maintain their ability to sense leptin. Weight loss restores leptin sensing to some degree in most (but not all) brain regions, while other brain regions display hypersensitivity to leptin following weight loss. Normal leptin sensing was restored in several brain regions, with the pattern of restoration dependent on the method of weight loss. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Brain; Diet; Energy Intake; Energy Metabolism; Homeostasis; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Signal Transduction | 2017 |
In utero exposure to germinated brown rice and its oryzanol-rich extract attenuated high fat diet-induced insulin resistance in F1 generation of rats.
The development of insulin resistance is multifactorial, with maternal pre- and postnatal nutrition having significant influences. In this regard, high fat diet (HFD) feeding in pregnancy has been shown to increase risks of metabolic diseases. Thus, we investigated the effects of supplementation of HFD with germinated brown rice (GBR) and GBR-derived gamma oryzanol-rich extract (OE) on insulin resistance and its epigenetic implications in pregnant rats and their offsprings.. Pregnant female Sprague dawley rats were fed with HFD alone, HFD + GBR or HFD + OE (100 or 200 mg/kg/day) throughout pregnancy and lactation. Their offsprings were weaned at 4 weeks post-delivery and were followed up until 8 weeks. Serum levels of adipokines were measured in dams and their offsprings, and global DNA methylation and histone acetylation patterns were estimated from the liver.. The dams and offsprings of the GBR and OE groups had lower weight gain, glycemic response, 8-Iso prostaglandin, retinol binding protein 4 and fasting insulin, and elevated adiponectin levels compared with the HFD group. Fasting leptin levels were lower only in the GBR groups. Hepatic global DNA methylation was lower in the GBR groups while hepatic H4 acetylation was lower in both GBR and OE dams. In the offsprings, DNA methylation and H4 acetylation were only lower in the OE group. However, dams and offsprings of the GBR and OE groups had higher hepatic H3 acetylation.. GBR and OE can be used as functional ingredients for the amelioration of HFD-induced epigeneticallymediated insulin resistance. Topics: Acetylation; Adiponectin; Animals; Body Weight; Diet, High-Fat; DNA Methylation; Female; Germination; Histones; Insulin Resistance; Leptin; Oryza; Plant Extracts; Plant Preparations; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Retinol-Binding Proteins, Plasma | 2017 |
Endospanin1 affects oppositely body weight regulation and glucose homeostasis by differentially regulating central leptin signaling.
The hypothalamic arcuate nucleus (ARC) is a major integration center for energy and glucose homeostasis that responds to leptin. Resistance to leptin in the ARC is an important component of the development of obesity and type 2 diabetes. Recently, we showed that Endospanin1 (Endo1) is a negative regulator of the leptin receptor (OBR) that interacts with OBR and retains the receptor inside the cell, leading to a decreased activation of the anorectic STAT3 pathway. Endo1 is up-regulated in the ARC of high fat diet (HFD)-fed mice, and its silencing in the ARC of lean and obese mice prevents and reverses the development of obesity.. Herein we investigated whether decreased Endo1 expression in the hypothalamic ARC, associated with reduced obesity, could also ameliorate glucose homeostasis accordingly.. We studied glucose homeostasis in lean or obese mice silenced for Endo1 in the ARC via stereotactic injection of shRNA-expressing lentiviral vectors.. We observed that despite being leaner, Endo1-silenced mice showed impaired glucose homeostasis on HFD. Mechanistically, we show that Endo1 interacts with p85, the regulatory subunit of PI3K, and mediates leptin-induced PI3K activation.. Our results thus define Endo1 as an important hypothalamic integrator of leptin signaling, and its silencing differentially regulates the OBR-dependent functions. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Carrier Proteins; Diabetes Mellitus, Type 2; Diet, High-Fat; Glucose; Homeostasis; Hypothalamus; Intracellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor | 2017 |
Leptin and Leptin-to-Adiponectin Ratio Predict Adiposity Gain in Nonobese Children over a Six-Year Period.
Previous longitudinal studies have shown inconsistent results regarding the influence of adipokines on changes in weight and body fat. We aimed to determine the predictive value of serum leptin, adiponectin, and their ratio on subsequent changes in obesity measures in children.. Two hundred forty-six obese and 532 nonobese children aged 6-11 years were remeasured for BMI and waist circumference after 6.4 ± 0.2 years. Z-score of BMI was used to standardize for age and sex. Obesity was defined using the international BMI cutoffs. Waist-to-height ratio (WHtR) was calculated to define central obesity using a boundary value of 0.5. Fasting serum leptin and adiponectin levels were measured at baseline.. Newly identified obese children had significantly higher levels of leptin and leptin-to-adiponectin ratio than nonobese children. There were lower adiponectin levels in boys with persistent obesity versus those with transient obesity. After adjusting for age, Tanner stage, and corresponding adiposity measures at baseline, leptin levels and leptin-to-adiponectin ratio were positively associated with BMI Z-score gain in girls and WHtR gain in boys. An inverse association between leptin and BMI Z-score gain was detected in boys. Stratified analyses revealed significant associations only in the nonobese and prepubertal group. There were no significant associations between adiponectin and changes in obesity measures.. High leptin levels and leptin-to-adiponectin ratio are sex-specific predictors of obesity measures gain in nonobese and prepubertal children. Body composition measurement is necessary to assess fat mass growth and distribution during childhood and adolescence. Topics: Adiponectin; Adiposity; Body Height; Body Mass Index; Body Weight; Child; China; Fasting; Female; Humans; Leptin; Male; Pediatric Obesity; Prospective Studies; Sex Factors; Waist Circumference; Weight Gain | 2017 |
Treatment of obese asthma in a mouse model by simvastatin is associated with improving dyslipidemia and decreasing leptin level.
Obesity can cause or worsen asthma. Compared with common asthma, obese asthma is difficult to control. Statins are effective serum cholesterol-lowering agents in clinical practice, and they also have anti-inflammatory properties, which in theory are potentially beneficial in asthma. Many studies have shown that simvastatin has good therapeutic effect in animal models of asthma. However, the therapeutic effect and action mechanism of simvastatin for obese asthma remain unclear. Leptin, a satiety hormone, is in positive correlation with total body fat mass and may also play a significant role in the pathogenesis of asthma. In this study, we use the method of high-fat diet and ovalbumin (OVA) sensitization and challenge to establish the mouse model of obesity and asthma, and find that obese asthmatic mice has higher levels of glucose, lipid and leptin in serum, and neutrophil percentage in bronchoalveolar lavage fluid (BALF), and more severe airway inflammation and structural changes in lung tissues than non-obese asthmatic mice, and respond poorly to dexamethasone treatment, which indicates that obese asthma might belong to steroid-resistant (SR) asthma. Simvastatin treatment reduces the levels of glucose, lipid, leptin and neutrophil percentage, and improves airway inflammation and remodeling, which can be as a potential therapeutic target used in the treatment of obese asthma in humans. Correlation analysis shows that there is positive correlation between neutrophil percentage and serum leptin/cholesterol level, which indicates that the therapeutic efficacy of simvastatin on obese asthma might be associated with improving dyslipidemia and decreasing leptin level. Topics: Animals; Asthma; Blood Glucose; Body Weight; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Dyslipidemias; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leptin; Leukocyte Count; Lipids; Lung; Mice; Mice, Inbred C57BL; Obesity; Simvastatin | 2017 |
Chronic administration of grape-seed polyphenols attenuates the development of hypertension and improves other cardiometabolic risk factors associated with the metabolic syndrome in cafeteria diet-fed rats.
The effects of grape-seed polyphenols against the development of hypertension and other cardiometabolic conditions associated with the metabolic syndrome (MetS) were studied in rats fed a high-fat, high-carbohydrate diet, known as the cafeteria (CAF) diet. Two groups of Wistar rats were fed standard (STD) or CAF diets for 12 weeks. The CAF diet-fed rats were administered different doses of a low-molecular-weight grape-seed polyphenol extract (LM-GSPE) (25, 100 and 200 mg/kg per d) or vehicle daily, and the STD diet-fed rats were administered LM-GSPE (100 mg/kg per d) or vehicle using ten animals per group. Body weight (BW), waist perimeter (WP) and systolic and diastolic blood pressures (BP) by the tail-cuff method were recorded weekly. The animals were housed in metabolic chambers every 2 weeks to estimate daily food and liquid intakes and to collect faeces and urine samples. The plasma lipid profile was analysed at time 0 and on the 4th, 7th, 10th and 12th weeks of the experiment. Moreover, plasma leptin was measured at the end of the experiment. Results demonstrated that LM-GSPE, when administered with the CAF diet, attenuated the increase in BP, BW, WP and improved lipid metabolism in these animals. However, although the 25- and 100-mg/kg per d doses were sufficient to produce beneficial effects on BP and lipid metabolism, a 200-mg/kg per d dose was necessary to have an effect on BW and WP. The present findings suggest that LM-GSPE is a good candidate for a BP-lowering agent that can also ameliorate other conditions associated with the MetS. Topics: Animals; Blood Pressure; Body Weight; Cardiovascular Diseases; Diet; Grape Seed Extract; Hypertension; Leptin; Lipids; Male; Metabolic Syndrome; Phytotherapy; Polyphenols; Rats, Wistar; Risk Factors; Time Factors; Waist Circumference | 2017 |
High-fat diet alters weight, caloric intake, and haloperidol sensitivity in the context of effort-based responding.
High-fat (HF) diets result in weight gain, hyperphagia, and reduced dopamine D2 signaling; however, these findings have been obtained only under free-feeding conditions. This study tested the extent to which HF diet affects effort-dependent food procurement and the extent to which dopamine signaling is involved. Male Sprague-Dawley rats consumed either a HF (n=20) or a standard-chow (n=20) diet. We assessed the sensitivity to effort-based reinforcement in 10 rats from each group by measuring consumption across a series of fixed-ratio schedules (FR 5-FR 300) under a closed economy and quantified performance using the exponential-demand equation. For each FR, acute injections of 0 or 0.1 mg/kg of haloperidol, a D2 antagonist, were administered to assess dopamine-related changes in consumption. Rats fed a HF diet consumed more calories and weighed significantly more than rats fed standard-chow. Food consumption decreased in both groups in an effort-dependent manner, but there were no group differences. Haloperidol reduced responding in an FR-dependent manner for both groups. Animals exposed to a HF diet showed an altered sensitivity to haloperidol relative to rats fed a standard diet, suggesting that HF diet alters sensitivity to DA signaling underlying effort-based food procurement. Topics: Animals; Body Weight; Diet, High-Fat; Dietary Fats; Dopamine; Energy Intake; Feeding Behavior; Haloperidol; Hyperphagia; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Weight Gain | 2017 |
WIP1 phosphatase is a critical regulator of adipogenesis through dephosphorylating PPARγ serine 112.
WIP1, as a critical phosphatase, plays many important roles in various physiological and pathological processes through dephosphorylating different substrate proteins. However, the functions of WIP1 in adipogenesis and fat accumulation are not clear. Here, we report that WIP1-deficient mice show impaired body weight growth, dramatically decreased fat mass, and significantly reduced triglyceride and leptin levels in circulation. This dysregulation of adipose development caused by the deletion of WIP1 occurs as early as adipogenesis. In contrast, lentivirus-mediated WIP1 phosphatase overexpression significantly increases the adipogenesis of pre-adipocytes via an enzymatic activity-dependent mechanism. PPARγ is a master gene of adipogenesis, and the phosphorylation of PPARγ at serine 112 strongly inhibits adipogenesis; however, very little is known about the negative regulation of this phosphorylation. Here, we show that WIP1 phosphatase plays a pro-adipogenic role by interacting directly with PPARγ and dephosphorylating p-PPARγ S112 in vitro and in vivo. Topics: Adipocytes; Adipogenesis; Adiposity; Animals; Body Weight; Cell Line; Cell Size; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Leptin; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Phosphoserine; PPAR gamma; Protein Binding; Protein Phosphatase 2C; Triglycerides | 2017 |
Maternal consumption of a cafeteria diet during lactation in rats leads the offspring to a thin-outside-fat-inside phenotype.
The suckling period is a critical phase of development, in which maternal overnutrition may program the susceptibility of developing chronic diseases and disorders, such as obesity and metabolic alterations, in adult life. Here, we questioned whether the consumption of a cafeteria diet throughout lactation in rats affects the macronutrient composition of milk and whether it results in permanent metabolic effects in the offspring.. Nursing rats were fed a control diet or a cafeteria diet during lactation. Milk was obtained at different time points of lactation. Offspring (males and females) were weaned onto a control diet until the age of 6 months. Circulating parameters were measured under ad libitum feeding and under 12-h fasting conditions at weaning and at 3 and 6 months of age. An oral glucose tolerance test (OGTT) was performed at 3 and 6 months of age.. Rats fed a cafeteria diet during lactation consumed an unbalanced diet, with lower protein and higher fat content versus controls, which was reflected in the composition of the milk. The offspring of rats fed a cafeteria diet during lactation showed lower body weight and lower lean mass, but greater fat accumulation, compared with controls. They also displayed hyperleptinaemia, altered lipid profile and impaired response to an OGTT.. Maternal consumption of a cafeteria diet throughout lactation in rats produces lasting effects in the metabolic health of their offspring, which are not associated with a higher body weight but with a greater fat accumulation, similarly to the thin-outside-fat-inside phenotype. Topics: Adiposity; Animals; Blood Glucose; Body Weight; Diet, Protein-Restricted; Disease Models, Animal; Female; Glucose Tolerance Test; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Milk; Nutritive Value; Overnutrition; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Thinness; Weaning | 2017 |
Unique effect of 4-hydroxyestradiol and its methylation metabolites on lipid and cholesterol profiles in ovariectomized female rats.
Animal studies have shown that endogenous estrogens such as 17β-estradiol (E Topics: Adipose Tissue; Animals; Body Weight; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Eating; Estrogens, Catechol; Female; Gene Expression Regulation, Enzymologic; Leptin; Liver; Liver X Receptors; Methylation; Ovariectomy; PPAR gamma; Rats; Rats, Sprague-Dawley | 2017 |
Early life stress experience may blunt hypothalamic leptin signalling.
The aim of this study was to investigate whether neonatal maternal separation (MS) - chronic stress experience in early life - affects the anorectic efficacy of leptin in the offspring at adolescence. Sprague-Dawley pups were separated from the dam daily for 3 h during postnatal day 1-14 or left undisturbed as non-handled controls (NH). NH and MS male pups received an intraperitoneal leptin (100 μg/kg) or saline on postnatal day (PND) 28, and then food intake and body weight gain were recorded. The hypothalamic levels of leptin-signalling-related genes, phosphorylated signal transducer and activator of transcription-3 (pSTAT3) and protein-tyrosine phosphatase 1B (PTP1B) were examined at 40 min after a single injection of leptin on PND 39 by immunohistochemistry and Western blot analysis. Leptin-induced suppressions in food intake and weight gain was observed in NH pups, but not in MS. Leptin increased pSTAT3 in the hypothalamic arcuate nucleus of NH pups, but not of MS. Interestingly, basal levels of the hypothalamic PTP1B and pSTAT3 were increased in MS pups compared with NH controls. The results suggest that neonatal MS experience may blunt the anorectic efficacy of leptin later in life, possibly in relation with increased expressions of PTP1B and/or pSTAT3 in the hypothalamus. Topics: Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Hypothalamus; Leptin; Male; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor; Stress, Psychological | 2017 |
Switching harmful visceral fat to beneficial energy combustion improves metabolic dysfunctions.
Visceral fat is considered the genuine and harmful white adipose tissue (WAT) that is associated to development of metabolic disorders, cardiovascular disease, and cancer. Here, we present a new concept to turn the harmful visceral fat into a beneficial energy consumption depot, which is beneficial for improvement of metabolic dysfunctions in obese mice. We show that low temperature-dependent browning of visceral fat caused decreased adipose weight, total body weight, and body mass index, despite increased food intake. In high-fat diet-fed mice, low temperature exposure improved browning of visceral fat, global metabolism via nonshivering thermogenesis, insulin sensitivity, and hepatic steatosis. Genome-wide expression profiling showed upregulation of WAT browning-related genes including Topics: Adiponectin; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Apoptosis Regulatory Proteins; Body Temperature; Body Weight; Cold Temperature; Diet, High-Fat; DNA-Binding Proteins; Eating; Energy Metabolism; Fatty Liver; Gene Knockdown Techniques; Insulin Resistance; Intra-Abdominal Fat; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Leptin; Mice; Mice, Obese; Organ Size; Thermogenesis; Transcription Factors; Uncoupling Protein 1; Up-Regulation | 2017 |
Intramuscular injection of exogenous leptin induces adiposity, glucose intolerance and fatty liver by repressing the JAK2-STAT3/PI3K pathway in a rat model.
Obesity, diabetes and fatty liver disease are extremely common in leptin-resistant patients. Dysfunction of leptin or its receptor is associated with obesity. The present study aimed to assess the effects of intramuscular injection of exogenous leptin or its receptor on fat deposition and leptin-insulin feedback regulation. Forty-five 40-day old female Sprague Dawley (SD) rats were injected thrice with leptin or its receptor intramuscularly. Adiposity and fat deposition were assessed by assessing the Lee's index, body weight, food intake, and total cholesterol, high density lipoprotein, low density lipoprotein, and triglyceride levels, as well as histological properties (liver and adipose tissue). Serum glucose, leptin, and insulin amounts were evaluated, and glucose tolerance assessed to monitor glucose metabolism in SD rats; pancreas specimens were analyzed immunohistochemically. Hypothalamic phosphorylated Janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and phosphatidylinositol-3-kinase (PI3K) signaling, and hepatic sterol regulatory element binding protein-1 (SREBP-1) were qualified by Western blotting. Leptin receptor immunogen reduced fat deposition, increased appetite, and lowered serum leptin levels, enhancing STAT3 signaling in hypothalamus and down-regulating hepatic SREBP-1. In contrast, SD rats administered leptin immunogen displayed significantly increased body weight and fat deposition, with up-regulated SREBP-1, indicating adiposity occurrence. SD rats administered leptin immunogen also showed glucose intolerance, β- cell reduction in the pancreas, and deregulation of JAK2-STAT3/PI3K signaling, indicating that Lep rats were at risk of diabetes. In conclusion, intramuscular injection of exogenous leptin or its receptor, a novel rat model approach, can be used in obesity pathogenesis and therapeutic studies. Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Disease Models, Animal; Eating; Fatty Liver; Female; Glucose Intolerance; Hyperglycemia; Immunity; Injections, Intramuscular; Insulin; Insulin-Secreting Cells; Janus Kinase 2; Leptin; Lipids; Liver; Phosphatidylinositol 3-Kinase; Phosphorylation; Rats, Sprague-Dawley; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Sterol Regulatory Element Binding Protein 1 | 2017 |
The effects of intracerebroventricular infusion of irisin on feeding behaviour in rats.
Irisin, a novel exercise-induced myokine, has attracted attention with its effects on energy metabolism. This study was conducted to determine the possible effects of irisin on nutritional behaviour. In this study, 40 male Wistar Albino rats were separated into 4 groups (n=10 for each group). Osmotic mini-pumps were connected to metal cannulas implanted to lateral ventricle; and artificial cerebrospinal fluid (vehicle), and 10 and 100nM of irisin was infused for 7days. The daily food and water consumptions and body weights of rats were followed up. After the infusion, the animals were killed, and the hypothalamus and blood samples were collected. NPY, POMC, and UCP2 mRNA levels in the hypothalamus were examined by RT-PCR. In serum, leptin and ghrelin levels as well as the levels of metabolic parameters were measured by using ELISA. It was determined that irisin administration increased the daily food consumption (p<0.05), without causing significant changes in water consumption and body weight. Irisin also caused increases in ghrelin level in circulation and NPY and UCP2 mRNA levels in the hypothalamus, whereas it decreased the leptin level in circulation and POMC mRNA levels in the hypothalamus (p<0.05). Otherwise, irisin caused decrease in LDL, triglycerides and cholesterol levels, while increasing HDL and glucose levels (p<0.05). Results indicates that long-term irisin treatment increases food intake without increasing body weight associated with increased ghrelin, NPY and UCP2 mRNAs, and decreased leptin and POMC mRNA in the hypothalamus. Topics: Animals; Body Weight; Drinking Behavior; Feeding Behavior; Fibronectins; Ghrelin; Hypothalamus; Infusions, Intraventricular; Leptin; Male; Neurons; Neuropeptide Y; Pro-Opiomelanocortin; Rats, Wistar; RNA, Messenger; Uncoupling Protein 2 | 2017 |
Cholinergic neurons in the dorsomedial hypothalamus regulate food intake.
Central cholinergic neural circuits play a role in the regulation of feeding behavior. The dorsomedial hypothalamus (DMH) is considered the appetite-stimulating center and contains cholinergic neurons. Here, we study the role of DMH cholinergic neurons in the control of food intake.. To selectively stimulate DMH cholinergic neurons, we expressed stimulatory designer receptors exclusively activated by designer drugs (DREADDs) and channelrhodopsins in DMH cholinergic neurons by injection of adeno-associated virus (AAV) vectors into the DMH of choline acetyltransferase (ChAT)-IRES-Cre mice. We also generated transgenic mice expressing channelrhodopsins in cholinergic neurons with the Cre-LoxP technique. To delete the. Mice lacking the. ACh released from DMH cholinergic neurons regulates food intake and body weight. This effect is mediated in part through regulation of ARC POMC neurons. Activation of muscarinic receptors on GABAergic axon terminals enhances inhibitory tone to ARC POMC neurons. Hence, this novel DMH Topics: Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Body Weight; Choline O-Acetyltransferase; Cholinergic Neurons; Dependovirus; Dorsomedial Hypothalamic Nucleus; Eating; Feeding Behavior; Hypothalamus; Hypothalamus, Middle; Integrases; Leptin; Male; Mice; Mice, Transgenic; Pro-Opiomelanocortin | 2017 |
Age-related changes in central effects of corticotropin-releasing factor (CRF) suggest a role for this mediator in aging anorexia and cachexia.
Hypothalamic corticotropin-releasing factor (CRF) lays downstream to catabolic melanocortins and at least partly mediates their catabolic effects. Age-related changes in the melanocortin system (weak responsiveness in middle-aged and a strong one in old rats) have been shown to contribute to middle-aged obesity and later to aging anorexia and cachexia of old age groups. We hypothesized that catabolic (anorexigenic and hypermetabolic) CRF effects vary with aging similarly to those of melanocortins. Thus, we aimed to test whether age-related variations of CRF effects may also contribute to middle-aged obesity and aging anorexia leading to weight loss of old age groups. Food intake, body weight, core temperature, heart rate, and activity were recorded in male Wistar rats of young, middle-aged, aging, and old age groups (from 3 to 24 months) during a 7-day intracerebroventricular CRF infusion (0.2 μg/μl/h) in a biotelemetric system. In addition, CRF gene expression was also assessed by quantitative RT-PCR in the paraventricular nucleus (PVN) of intact animals of the same age groups. The infusion suppressed body weight in the young, aging, and old rats, but not in middle-aged animals. Weak anorexigenic and hypermetabolic effects were detected in the young, whereas strong anorexia (without hypermetabolism) developed in the oldest age groups in which post mortem analysis showed also a reduction of retroperitoneal fat mass. CRF gene expression in the PVN increased with aging. Our results support the potential contribution of age-related changes in CRF effects to aging anorexia and cachexia. The role of the peptide in middle-aged obesity cannot be confirmed. Topics: Age Factors; Aging; Animals; Anorexia; Body Weight; Cachexia; Corticotropin-Releasing Hormone; Eating; Energy Metabolism; Humans; Infusions, Parenteral; Leptin; Male; Models, Animal; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA; Sensitivity and Specificity | 2017 |
The rs10401670 variant in resistin gene improved insulin resistance response and metabolic parameters secondaries to weight loss after a hypocaloric diet.
The SNP 3'UTR C/T (rs10401670), it is a polymorphism that has been associated with diabetes mellitus and it has been scarcely studied before. As far as we know, no studies on interaction among diet intervention, rs10401670 variant of RETN and metabolic response has been realized.. Our aim was to analyze the effects of the rs10401670 RETN gene polymorphism on insulin resistance response and metabolic changes secondary to weight loss after 3 months of a hypocaloric diet in adults obese patients without diabetes mellitus.. A Caucasian population of 135 obese patients without diabetes mellitus was analyzed. Before and after 3 months on a low fat hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for the combined CT and TT as a group (minor allele group) and wild type CC as second group (major allele group) (dominant model).. Forty nine patients (36.3%) had the genotype CC (major allele group) and 86 (63.7%) patients had the next genotypes; CT (67 patients, 49.6%) or TT (19 patients, 14.1%) (minor allele group). After dietary treatment and in major allele group, weight, BMI, fat mass, systolic blood pressure and waist circumference decreases were similar than minor allele group. In T allele carriers, fasting plasma glucose, insulin, HOMA-IR, total cholesterol and LDL cholesterol levels decreased significantly. In non T allele carriers and after dietary treatment, only LDL cholesterol and total cholesterol decreased. In non T Allele carriers, the decrease in total cholesterol was -15.1 ± 18.3 mg/dl (decrease in T Allele carriers -18.3 ± 15.7 mg/dl: p > 0.05), LDL-cholesterol was -14.3 ± 18.5 mg/dl (decrease in T Allele carriers -17.3 ± 10.1 mg/dl:p > 0.05), fasting glucose plasma -2.2 ± 1.5 mg/dL (decrease in T Allele carriers -4.8 ± 1.2 mg/dL: p = 0.02), insulin -1.1 ± 2.0 mUI/L (decrease in T Allele carriers -6.3 ± 1.9 mUI/L: p = 0.001) and HOMA-IR -0.2 ± 1.0 (decrease in T Allele carriers -1.8 ± 1.4: p = 0.005). Leptin levels decrease in both genotypes after dietary treatment (-21.1 ± 8.5 ng/dL in nonT Allele carriers vs -16.2 ± 10.2 ng/dL in T Allele carriers:p > 0.05). Resistin remained unchanged in both groups.. In our study in non-diabetic obese subjects, we describe an association of rs10401670T allele with a better metabolic response (glucose, insulin and HOMA-IR) secondary to weight loss with a hypocaloric diet. Topics: Adult; Alleles; Anthropometry; Blood Pressure; Body Mass Index; Body Weight; Cholesterol; Diabetes Complications; Diabetes Mellitus; Diet, Reducing; Female; Genotype; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Resistin; Waist Circumference; Weight Loss | 2016 |
Differentiating the Influences of Aging and Adiposity on Brain Weights, Levels of Serum and Brain Cytokines, Gastrointestinal Hormones, and Amyloid Precursor Protein.
Aging and obesity exert important effects on disease. Differentiating these effects is difficult, however, because weight gain often accompanies aging. Here, we used a nested design of aged, calorically restricted, and refed rats to measure changes in brain and blood levels of cytokines and gastrointestinal hormones, brain amyloid precursor protein levels, and brain and body weights. By comparing groups and using path analysis, we found divergent influences of chronological aging versus body weight, our main findings being (i) changes in whole brain weight and serum macrophage colony-stimulating factor levels correlated better with body weight than with chronological aging, (ii) a decrease in brain cytokines and brain plasminogen activator inhibitor levels correlated better with chronological aging than with body weight, (iii) serum erythropoietin levels were influenced by both body weight and aging, (iv) serum plasminogen activator inhibitor, serum cytokines, and brain tumor necrosis factor were not influenced by aging or body weight, and (v) brain amyloid precursor protein more closely related to body weight and serum levels of gastrointestinal hormones than to brain weight, chronological aging, or cytokines. These findings show that although aging and body weight interact, their influences are distinct not only among various cytokines and hormones but also between the central nervous system and the peripheral tissue compartments. Topics: Adipose Tissue; Aging; Amyloid beta-Protein Precursor; Animals; Body Weight; Brain; Erythropoietin; Gastrointestinal Hormones; Leptin; Macrophage Colony-Stimulating Factor; Male; Obesity; Organ Size; Plasminogen Inactivators; Rats; Statistics as Topic; Tumor Necrosis Factor-alpha | 2016 |
Rapamycin Normalizes Serum Leptin by Alleviating Obesity and Reducing Leptin Synthesis in Aged Rats.
This investigation examines whether a low intermittent dose of rapamycin will avoid the hyperlipidemia and diabetes-like syndrome associated with rapamycin while still decreasing body weight and adiposity in aged obese rats. Furthermore, we examined if the rapamycin-mediated decrease in serum leptin was a reflection of decreased adiposity, diminished leptin synthesis, or both. To these ends, rapamycin (1mg/kg) was administered three times a week to 3 and 24-month old rats. Body weight, food intake, body composition, mTORC1 signaling, markers of metabolism, as well as serum leptin levels and leptin synthesis in adipose tissue were examined and compared to that following a central infusion of rapamycin. Our data suggest that the dosing schedule of rapamycin acts on peripheral targets to inhibit mTORC1 signaling, preferentially reducing adiposity and sparing lean mass in an aged model of obesity resulting in favorable outcomes on blood triglycerides, increasing lean/fat ratio, and normalizing elevated serum leptin with age. The initial mechanism underlying the rapamycin responses appears to have a peripheral action and not central. The peripheral rapamycin responses may communicate an excessive nutrients signal to the hypothalamus that triggers an anorexic response to reduce food consumption. This coupled with potential peripheral mechanism serves to decrease adiposity and synthesis of leptin. Topics: Adiposity; Aging; Animals; Body Weight; Dose-Response Relationship, Drug; Glucose Metabolism Disorders; Immunosuppressive Agents; Leptin; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Obesity; Rats; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome | 2016 |
Physical activity, lipid profiles and leptin.
Physical activity and the component of body composition can determine lipid profiles and Leptin concentration plasma.. Thirty-two untrained females (20-25 yrs.) (aged 20.9±.33 y, weight 57.50±7.52 Kg, height 159.56±4.97 cm, and BMI 22.55 ±2.51 kg.m-2), participated in our study. They randomly were divided into two equal groups, trained and control group (N.=16). The trained group was assigned to a five week aerobic training program (three times/week), with intensity 60-70% HRR (heart rate reserve). The control group continued their normal lifestyle. Body weight (BW) was measured. Body fat percent (FP) and fat mass (FM), and fat free mass (FFM) were assessed, also the concentration of high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG), total cholesterol (TC), and leptin were measured.. Analysis of covariance (ANCOVA) indicated that BW (F=4.20, P=0.05) significantly decreased and HDL (F=43.32, P=0.01) significantly increased in the trained group (P-value<0.05), whereas we had no significant difference in BMI, FP, FM, FFM, and the serum concentration of LDL, TG, TC, and Leptin between groups and time × group interaction, after the five weeks aerobic training period (P<0.05).. These results suggest the five-week moderate- intensity aerobic training had significant changes in BW and HDL in young female, but had no significant impact on BMI, FP, FM, FFM, LDL, TG, TC, and Leptin concentration, which are required to increase duration or increase the intensity of physical activity. Topics: Adult; Analysis of Variance; Body Composition; Body Weight; Case-Control Studies; Cholesterol; Exercise; Female; Heart Rate; Humans; Leptin; Lipids; Random Allocation; Triglycerides; Young Adult | 2016 |
Fructose only in pregnancy provokes hyperinsulinemia, hypoadiponectinemia, and impaired insulin signaling in adult male, but not female, progeny.
Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and cardiovascular diseases. However, consumption of beverages containing fructose is allowed during gestation. Recently, we found that an intake of fructose (10 % wt/vol) throughout gestation produces impaired fetal leptin signaling and hepatic steatosis. Therefore, we have investigated whether fructose intake during pregnancy produces subsequent changes in the progeny, when adult.. Fed 261-day-old male and female descendants from fructose-fed, control or glucose-fed mothers were used. Plasma was used to analyze glucose, insulin, leptin, and adiponectin. Hepatic expression of proteins related to insulin signaling was determined.. Fructose intake throughout pregnancy did not produce alterations in the body weight of the progeny. Adult male progeny of fructose-fed mothers had elevated levels of insulin without a parallel increase in phosphorylation of protein kinase B. However, they displayed an augmented serine phosphorylation of insulin receptor substrate-2, indicating reduced insulin signal transduction. In agreement, adiponectin levels, which have been positively related to insulin sensitivity, were lower in male descendants from fructose-fed mothers than in the other two groups. Furthermore, mRNA levels for insulin-responsive genes were not affected (phosphoenolpyruvate carboxykinase, glucose-6-phosphatase) or they were decreased (sterol response element-binding protein-1c) in the livers of male progeny from fructose-supplemented rats. On the contrary, adult female rats from fructose-fed mothers did not exhibit any of these disturbances.. Maternal fructose, but not glucose, intake confined to the prenatal stage provokes impaired insulin signal transduction, hyperinsulinemia, and hypoadiponectinemia in adult male, but not female, progeny. Topics: Adiponectin; Animals; Animals, Newborn; Blood Glucose; Body Weight; Fatty Liver; Female; Fetus; Fructose; Glucose-6-Phosphatase; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Liver; Male; Maternal Nutritional Physiological Phenomena; Metabolism, Inborn Errors; Phosphoenolpyruvate Carboxykinase (ATP); Phosphorylation; Pregnancy; Prenatal Exposure Delayed Effects; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Sterol Regulatory Element Binding Protein 1 | 2016 |
Fasting for 3 days during the suckling-weaning transient period in male rats induces metabolic abnormalities in the liver and is associated with impaired glucose tolerance in adulthood.
Recent studies suggest that nutritional status during developmental periods is associated with subsequent development of metabolic abnormalities. In this study, we examined whether malnutrition by fasting for 3 days during the suckling-weaning transient period induces subsequent development of metabolic abnormalities in rats.. Male Sprague-Dawley rats were fasted for 3 days during the suckling-weaning transient period. They are subsequently fed a high-fat, high-sucrose (HF) or low-fat, high-starch (LF) diet for 14 weeks from 17 weeks of age, and the liver and blood samples were collected for measuring mRNA and protein levels of metabolic genes and blood concentrations of glucose and insulin, respectively.. Fasting for 3 days during the suckling-weaning transient period induced impaired glucose tolerance in rats fed the LF diet in adulthood. Liver triglycerides in rats fed the HF diet in adulthood increased to 140 % in rats fasted for 3 days during the suckling-weaning transient period compared with those non-fasted. Furthermore, liver expression of FBP1 and ACCα genes in adult rats fed the LF diet increased to 125 and 145 %, respectively, in rats fasted for 3 days during the suckling-weaning transient period compared to non-fasted rats. PEPCK1 protein expression levels in rats fed the LF diet were higher in rats fasted for 3 days during the suckling-weaning transient period than in non-fasted rats.. Fasting for 3 days in rats during the suckling-weaning transient period enhances metabolic abnormalities in animals fed a HF or LF diet in adulthood by confounding metabolism of lipid and sugar in the liver. Topics: Adiponectin; Animal Nutritional Physiological Phenomena; Animals; Animals, Suckling; Blood Glucose; Body Weight; Diet, High-Fat; Dietary Fats; Disease Models, Animal; DNA-Binding Proteins; Fasting; Fatty Acids, Nonesterified; Gluconeogenesis; Glucose Intolerance; Insulin; Leptin; Lipogenesis; Liver; Male; Malnutrition; Metabolic Diseases; Organ Size; Rats; Rats, Sprague-Dawley; RNA, Messenger; Triglycerides; Weaning | 2016 |
NMR-based metabolomics highlights differences in plasma metabolites in pigs exhibiting diet-induced differences in adiposity.
A better understanding of the control of body fat mass and distribution is required for both human health and animal production. The current study investigates plasma parameters in response to changes in body fat mass.. Pigs from two lines divergently selected for residual feed intake were fed diets contrasted in energy sources and nutrients. Between 74 and 132 days of age, pigs (n = 12 by diet and by line) received isoproteic and isoenergetic diets, either rich in starch (LF) or in lipids and fibres (HF). At the end of the feeding trial, plasma samples were analysed by (1)H NMR spectroscopy and standard hormonal and biochemical assays.. Pigs fed the HF diet had lower (P < 0.01) perirenal and subcutaneous adipose tissue relative masses than pigs fed the LF diet. Metabolomic approach showed a clear discrimination between diets, with lower (P < 0.05) plasma levels of creatinine-lysine, creatine, tyrosine, proline, histidine, lysine, phenylalanine and formate but higher (P < 0.001) plasma VLDL-LDL levels in HF pigs than in LF pigs. Plasma concentrations of triglycerides were higher (P < 0.001), while plasma concentrations of β-hydroxybutyrate, leptin, glucose, insulin and urea were lower (P ≤ 0.05) in HF pigs than in LF pigs. Plasma levels of leptin, creatine and urea were positively correlated (r = 0.3, P < 0.05) with relative adipose tissue masses.. These data indicate that metabolites associated with energy and protein metabolism were involved in the response to a high-fat, high-fibre diet. Relevant plasma indicators of metabolic flexibility related to changes in body adiposity were then proposed. Topics: 3-Hydroxybutyric Acid; Adipose Tissue; Adiposity; Animal Feed; Animals; Biomarkers; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Creatine; Creatinine; Diet; Dietary Fats; Dietary Fiber; Histidine; Insulin; Leptin; Linear Models; Lipid Metabolism; Lysine; Magnetic Resonance Spectroscopy; Male; Metabolomics; Phenylalanine; Proline; Swine; Triglycerides; Tyrosine | 2016 |
Fenugreek Seed Extract Prevents Fat Deposition in Monosodium Glutamate (MSG)-Obese Rats.
To evaluate the preventive effects of an aqueous extract of Trigonella foenum-graecum seeds (AqE-TFG) on fat deposition and dyslipidemia in monosodium glutamate (MSG)-obese rats.. Neonatal male Wistar rats were injected with MSG (4 g/kg b. w., subcutaneously) from day 2 to 14 after birth, on alternate days. From day 43 to 70, MSG treated rats were administered orally with AqE-TFG (0.5 and 1.0 g/kg b. w.). The anthropometric and biochemical parameters were analyzed on day 71.. Treatment with AqE-TFG produced significant (P < 0.05 or P < 0.01) reduction in body weight gain, Lee's index, white adipose tissue (WAT) weights, adiposity index, blood glucose, serum insulin, leptin, lipids (low density lipoprotein cholesterol and very low density lipoprotein cholesterol), cardiac risk indexes (atherogenic index and coronary risk index), and homeostatic model assessment index. AqE-TFG treatment restored the activities of liver and epididymal WAT lipogenic enzymes (fatty acid synthetase and glucose-6-phosphate dehydrogenase) towards normal levels. Histological studies of liver also supported the experimental findings.. These findings demonstrated the preventive effect of AqE-TFG on fat deposition and dyslipidemia possibly by improvement in glucose and lipid metabolism, enhancement of insulin sensitivity and down regulation of lipogenic enzymes. Topics: Adipose Tissue, White; Adiposity; Animals; Blood Glucose; Body Weight; Cholesterol; Fatty Acid Synthases; Glucosephosphate Dehydrogenase; Insulin; Leptin; Lipids; Male; Obesity; Plant Extracts; Rats; Seeds; Sodium Glutamate; Trigonella | 2016 |
Chronic Hormonal Imbalance and Adipose Redistribution Is Associated with Hypothalamic Neuropathology following Blast Exposure.
Endocrine disorders have been shown to be a consequence of blast traumatic brain injury in soldiers returning from military conflicts. Hormone deficiency and adrenocorticotropic hormone (ACTH) dysfunction can lead to symptoms such as fatigue, anxiety, irritability, insomnia, sexual dysfunction, and decreased quality of life. Given these changes following blast exposure, the current study focused on investigating chronic pathology within the hypothalamus following blast, in addition to systemic effects. An established rodent model of blast neurotrauma was used to induce mild blast-induced neurotrauma. Adipose tissue, blood, and brain samples were collected at one and three months following a single blast exposure. Adipose tissue and blood were evaluated for changes in ACTH, adiponectin, C-reactive protein, glial fibrillary acidic protein, interleukin (IL)-1β, and leptin. The hypothalamus was evaluated for injury using immunohistochemical techniques. The results demonstrated that the weight of the blast animals was significantly less, compared with the sham group. The slower rate of increase in their weight was associated with changes in ACTH, IL-1β, and leptin levels. Further, histological analysis indicated elevated levels of cleaved caspase-3 positive cells within the hypothalamus. The data suggest that long-term outcomes of brain injury occurring from blast exposure include dysfunction of the hypothalamus, which leads to compromised hormonal function, elevated biological stress-related hormones, and subsequent adipose tissue remodeling. Topics: Adiponectin; Adipose Tissue; Adrenocorticotropic Hormone; Animals; Blast Injuries; Body Weight; Brain Injuries; Disease Models, Animal; Endocrine System Diseases; Hypothalamic Diseases; Interleukin-1beta; Leptin; Male; Rats; Rats, Sprague-Dawley | 2016 |
Effects of methylphenidate on appetite and growth in children diagnosed with attention deficit and hyperactivity disorder.
The purpose of this study was to determine the levels of leptin, ghrelin, and nesfatin-1 to elucidate the causes of poor appetite and growth retardation in patients receiving methylphenidate therapy for attention deficit hyperactivity disorder. The study was performed on 89 male subjects; 48 patients and 41 healthy controls, aged 7-14 years. Following treatment, patients' leptin levels increased and ghrelin levels decreased while no significant change was found in nesfatin-1 levels. Of the 48 patients, 34 developed lack of appetite. In patients who developed lack of appetite, body weight SDS, body mass index (BMI), and BMI SDS were statistically significantly reduced; moreover, height SDS was reduced, though not to a statistically significant extent. This study attempted to elucidate the mechanisms that mediate the association between methylphenidate and appetite and growth, for which no studies have yet to be published. Topics: Adolescent; Appetite; Attention Deficit Disorder with Hyperactivity; Biomarkers; Body Height; Body Weight; Case-Control Studies; Central Nervous System Stimulants; Child; Developmental Disabilities; Ghrelin; Humans; Leptin; Male; Methylphenidate; Prospective Studies | 2016 |
Adverse effects of vitamin D deficiency on the Pi3k/Akt pathway and pancreatic islet morphology in diet-induced obese mice.
To investigate the impact of vitamin D deficiency on insulin resistance and abnormal glucose homeostasis in obesity.. Sixty male C57BL/6 mice (3 months old) were fed a control diet (C-10% energy as fat) or a high-fat diet (HF-50% energy as fat), with or without vitamin D, for 8 weeks. There was no difference in body mass between the HF and HF/VitD- groups. Vitamin D deficiency (VitD) in the diet-induced obese mice increased hyperinsulinemia (p = 0.04), hyperleptinemia (p = 0.0002), insulin resistance (HOMA-IR, p = 0.04), and islet changes, including alpha and beta cell disarray. In the insulin signaling pathway, insulin receptor substrate 2 expression was upregulated in the C/VitD- group (p = 0.001) and downregulated in the HF/VitD- group (p = 0.009). Interestingly, forkhead box protein O1 expression was higher in the HF/VitD- group than in the HF group (p = 0.03), and pancreatic and duodenal homeobox 1 expression was lower in the HF/VitD-group than in the HF group (p = 0.025), indicating that the HF diet and vitamin D deficiency influenced the downregulation of the expression of these proteins (two-way ANOVA, p < 0.0001).. Vitamin D deficiency exacerbated the adverse structural and physiological remodeling of pancreatic islets due to obesity, contributing to abnormal glucose homeostasis. Topics: Adiponectin; Animals; Body Weight; Carbohydrate Metabolism; Diet, High-Fat; Insulin; Islets of Langerhans; Leptin; Male; Mice, Inbred C57BL; Obesity; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Vitamin D Deficiency | 2016 |
Body weight and reproductive parameters in fast and weak growing Awassi ram lambs during different age stages.
This study was carried out on 30 Syrian Awassi ram lambs around 3 months of age. Lambs were divided equally in 2 groups as fast growing (FG) and weak growing (WG) lambs to identify body weight and reproductive parameters in each group during different age stages. Blood samples were collected to determine testosterone and leptin concentrations using radioimmunoassay. At puberty, average body weight and age of FG and WG lambs was 52.4 and 43.1 kg, and 225.9 and 248.0 days, respectively, with a significant (P < 0.05) difference between them in both parameters. Testosterone concentration was very low at 3 months of age (below 1.0 nmol L(-1)) and increased with advancing age with a sharp increase occurring at 7 months of age and at puberty, averages were 12.58 and 11.86 nmol L(-1) for FG and WG groups, respectively, with no significant (P > 0.05) differences. At puberty, average leptin concentration was 3.16 and 2.98 ng mL(-1) for FG and WG groups, respectively, with no significant (P > 0.05) difference. Topics: Animals; Animals, Newborn; Body Weight; Leptin; Male; Reproduction; Sheep, Domestic; Syria; Testosterone | 2016 |
Combined parental obesity augments single-parent obesity effects on hypothalamus inflammation, leptin signaling (JAK/STAT), hyperphagia, and obesity in the adult mice offspring.
We aimed to evaluate the effects of maternal and/or paternal obesity on offspring body mass, leptin signaling, appetite-regulating neurotransmitters and local inflammatory markers. C57BL/6 mice received standard chow (SC, lean groups) or high-fat diet (HF, obese groups) starting from one month of age. At three months, HF mice became obese relative to SC mice. They were then mated as follows: lean mother and lean father, lean mother and obese father, obese mother and lean father, and obese mother and obese father. The offspring received the SC diet from weaning until three months of age, when they were sacrificed. In the offspring, paternal obesity did not lead to changes in the Janus kinase (JAK)/signal transducer and activation of the transcription (STAT) pathway or feeding behavior but did induce hypothalamic inflammation. On the other hand, maternal obesity resulted in increased weight gain, hyperleptinemia, decreased leptin OBRb receptor expression, JAK/STAT pathway impairment, and increased SOCS3 signaling in the offspring. In addition, maternal obesity elevated inflammatory markers and altered NPY and POMC expression in the hypothalamus. Interestingly, combined parental obesity exacerbated the deleterious outcomes compared to single-parent obesity. In conclusion, while maternal obesity is known to program metabolic changes and obesity in offspring, the current study demonstrated that obese fathers induce hypothalamus inflammation in offspring, which may contribute to the development of metabolic syndromes in adulthood. Topics: Animals; Body Weight; Diet, High-Fat; Energy Intake; Fathers; Female; Hyperphagia; Hypothalamus; Inflammation Mediators; Janus Kinase 1; Leptin; Male; Mice; Mothers; Neuropeptide Y; Obesity; Parents; Pro-Opiomelanocortin; Receptors, Leptin; Signal Transduction; STAT1 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins | 2016 |
Stimulant medication effects on growth and bone age in children with attention-deficit/hyperactivity disorder: a prospective cohort study.
Stimulant medication is known to cause transient weight loss and slowing down of growth, but whether it delays physical maturation is unclear. We studied growth and bone age over the first 3 years of treatment in children with attention-deficit/hyperactivity disorder (patients) compared with healthy siblings (controls). Bone age was estimated blindly by two independent radiologists using Tanner and Whitehouse version 3. Dexamphetamine or methylphenidate was titrated and continued when clinically indicated. Forty out of 73 patients, together with 22 controls, completed the study. There were no significant growth differences between the two groups at baseline. Despite slower growth on treatment [5.1 cm/year, 95% confidence interval (CI): 4.7-5.5, vs. 6.3 cm/year, 95% CI: 5.7-6.8, P=0.002; and 2.7 kg/year, 95% CI: 2.1-3.3, vs. 4.4 kg/year, 95% CI: 3.5-5.3, P=0.005], the patients showed no significant maturational delay (RUS score: 49 U/year, 95% CI: 44-55, vs. 55 U/year, 95% CI: 47-63, P=0.27). A subgroup of patients underwent serial biochemistry and dual-energy X-ray absorptiometry, recording a significant reduction in fat (5.61±3.56-4.22±3.09 kg, P<0.001) and leptin (3.88±2.87-2.57±1.94 ng/ml, P=0.017). The pattern of change in height z-score over time was modified by the dose of medication (P for interaction=0.024). We found no medication effect on the rate of maturation, which was instead predicted by baseline leptin (P=0.035 controlling for age and sex). Topics: Absorptiometry, Photon; Adiposity; Age Factors; Anthropometry; Attention Deficit Disorder with Hyperactivity; Biomarkers; Body Height; Body Weight; Bone Development; Case-Control Studies; Central Nervous System Stimulants; Child; Child Development; Dextroamphetamine; Female; Growth Disorders; Humans; Leptin; Male; Methylphenidate; Prospective Studies; Time Factors; Treatment Outcome | 2016 |
Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice.
The small intestine is the major site for nutrient absorption that is critical in maintenance of euglycemia. Leptin, a key hormone involved in energy homeostasis, directly affects nutrient transport across the intestinal epithelium. Catestatin (CST), a 21-amino acid peptide derived from proprotein chromogranin A, has been shown to modulate leptin signaling. Therefore, we reasoned that leptin and CST could modulate intestinal Na(+)-glucose transporter 1 (SGLT1) expression in the context of obesity and diabetes. We found that hyperleptinemic db/db mice exhibit increased mucosal mass, associated with an enhanced proliferative response and decreased apoptosis in intestinal crypts, a finding absent in leptin-deficient ob/ob mice. Intestinal SGLT1 abundance was significantly decreased in hyperleptinemic but not leptin-deficient mice, indicating leptin regulation of SGLT1 expression. Phlorizin, a SGLT1/2 inhibitor, was without effect in an oral glucose tolerance test in db/db mice. The alterations in architecture and SGLT1 abundance were not accompanied by changes in the localization of intestinal alkaline phosphatase, indicating intact differentiation. Treatment of db/db mice with CST restored intestinal SGLT1 abundance and intestinal turnover, suggesting a cross-talk between leptin and CST, without affecting plasma leptin levels. Consistent with this hypothesis, we identified structural homology between CST and the AB-loop of leptin and protein-protein docking revealed binding of CST and leptin with the Ig-like binding site-III of the leptin receptor. In summary, downregulation of SGLT1 in an obese type 2 diabetic mouse model with hyperleptinemia is presumably mediated via the short form of the leptin receptor and reduces overt hyperglycemia. Topics: Amino Acid Sequence; Animals; Apoptosis; Blood Glucose; Body Weight; Cell Proliferation; Chromogranin A; Diabetes Mellitus, Experimental; Gene Knockout Techniques; Jejunum; Leptin; Male; Mice; Mice, Transgenic; Models, Molecular; Molecular Sequence Data; Peptide Fragments; Sodium-Glucose Transporter 1 | 2016 |
Factors related to increased resting energy expenditure in men with liver cirrhosis.
Hypermetabolism in cirrhosis is associated with a high risk of complications and mortality. However, studies about underlying mechanisms are usually focussed on isolated potential determinants and specific etiologies, with contradictory results. We aimed at investigating differences in nutrition, metabolic hormones, and hepatic function between hypermetabolic and nonhypermetabolic men with cirrhosis of the liver.. We prospectively enrolled 48 male cirrhotic inpatients. We evaluated their resting energy expenditure (REE) and substrate utilization by indirect calorimetry, body composition by dual-energy X-ray absorptiometry, liver function, and levels of major hormones involved in energy metabolism by serum sample tests. Patients with ascites, specific metabolic disturbances, and hepatocellular carcinoma were excluded.. REE and REE adjusted per fat-free mass (FFM) were significantly increased in cirrhotic patients. Overall, 58.3% of cirrhotic patients were classified as hypermetabolic. Groups did not differ significantly in age, etiology of cirrhosis, liver function, presence of ascites, use of diuretics, β-blockers, or presence of transjugular intrahepatic portosystemic shunts. Hypermetabolic cirrhotic patients had lower weight, BMI (P<0.05), nonprotein respiratory quotient (P<0.01), leptin (P<0.05), and leptin adjusted per fat mass (FM) (P<0.05), but higher FFM% (P<0.05) and insulin resistance [homeostatic model assessment-insulin resistance (HOMA-IR)] (P<0.05). Only HOMA-IR, leptin/FM, and FFM% were independently related to the presence of hypermetabolism.. Hypermetabolic cirrhotic men are characterized by lower weight, higher FFM%, insulin resistance, and lower leptin/FM when compared with nonhypermetabolic men. HOMA-IR, FFM%, and leptin/FM were independently associated with hypermetabolism, and may serve as easily detectable markers of this condition in daily clinical practice. Topics: Absorptiometry, Photon; Adult; Basal Metabolism; Biomarkers; Blood Glucose; Body Composition; Body Weight; Calorimetry, Indirect; Case-Control Studies; Humans; Insulin; Insulin Resistance; Leptin; Liver Cirrhosis; Liver Function Tests; Male; Metabolic Diseases; Middle Aged; Nutritional Status; Predictive Value of Tests; Prospective Studies; Rest | 2016 |
Bone maturation along the spectrum from normal weight to obesity: a complex interplay of sex, growth factors and weight gain.
The aim of the study was to define the prevalence and degree of advanced bone age (ABA) in normal vs. excessive weight children, and identify variables affecting ABA.. We studied 167 children (3-18 years) with normal weight (28 F, 28 M), overweight (8 F, 12 M), and obesity (OB) (63 F, 28 M) at AI duPont Hospital for Children. We assessed bone age (BA), insulin, leptin, estradiol (E2), DHEAS, and IGF-1 levels.. Almost 25% of OB children have ABA>2 SDS, 33% >2 years (range 2-6.5 years advanced). ABA correlated with leptin, DHEAS and BMI z-score in girls, and with IGF-1 z-score and BMI z-score in boys (p<0.01). Girls with ABA had higher BMI z-score (p<0.001), insulin levels (p=0.02), and rates of weight gain (p=0.03). Boys with ABA had greater BMI z-score (p<0.001), but rate of weight gain did not differ. The greatest degree of ABA was found combining variables by tertiles. The top tertile of BA/CA had the highest insulin and IGF-1 z-scores. The top combined tertiles of DHEAS and BMI z-score or DHEAS and leptin in girls had the highest BA/CA. In boys, the top tertiles of BMI z-score and IGF-1 z-score produced the highest BA/CA. The lowest combined tertiles of any variables related to the lowest BA/CA.. Multiple factors influence skeletal maturation. Almost 25% of children with OB have ABA, associated with BMI z-score, and one or more of the following: insulin, leptin, DHEAS, IGF-1, and rate of weight gain. This report delineates the prevalence and degree of ABA by sex, in children with normal versus excessive weight. Topics: Adolescent; Age Determination by Skeleton; Body Mass Index; Body Weight; Bone Development; Bone Regeneration; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Obesity; Puberty; Sex Factors; Weight Gain | 2016 |
Paternal calorie restriction prior to conception alters anxiety-like behavior of the adult rat progeny.
The maternal environment influences a broad range of phenotypic outcomes for offspring, with anxiety-like behavior being particularly susceptible to maternal environmental perturbations. Much less is known regarding paternal environmental influences. To investigate this, adult male rats were exposed to 25% calorie restriction (CR) or glucocorticoid elevation (CORT; 200 μg/ml of corticosterone in drinking water) for ∼ 6 weeks prior to breeding. Elevated plus maze (EPM), open field (OF), predator odor (cat urine), and acoustic startle/pre-pulse inhibition (AS/PPI) were characterised in the adult male offspring. Plasma concentrations of corticotrophin-releasing hormone (CRF), adrenocorticotropin hormone (ACTH), and serum leptin were characterised in both sires and offspring. Maternal care received by litters was additionally observed. Expectedly, CR and CORT treatment attenuated weight gain, whilst only CR induced anxiolytic behavior in the EPM. The adult offspring sired by CR males also demonstrated a reduction in weight gain, food intake and serum leptin levels when compared to controls. Moreover, CR offspring demonstrated an anxiolytic-like profile in the EPM and OF, enhanced habituation to the AS pulse, reduced PPI, but no alteration to predator odor induced defensiveness compared to control. CORT offspring failed to demonstrate any behavioral differences from controls, however, exhibited a trend towards reduced ACTH and leptin concentration. Collectively, the results indicate that a reduction in calories in males prior to conception can affect the behavior of adult offspring. The phenotypic transmission of CR experiences from fathers to the progeny could potentially be mediated epigenetically. The role of glucocorticoid elevation and maternal care are also discussed. Topics: Adrenocorticotropic Hormone; Animals; Anxiety; Body Weight; Caloric Restriction; Corticosterone; Corticotropin-Releasing Hormone; Drinking; Eating; Fathers; Female; Leptin; Male; Maternal Behavior; Paternal Exposure; Pregnancy; Prenatal Exposure Delayed Effects; Prepulse Inhibition; Rats | 2016 |
Regulation of Blood Pressure, Appetite, and Glucose by CNS Melanocortin System in Hyperandrogenemic Female SHR.
Hyperandrogenemia in females may be associated with sympathetic nervous system (SNS) activation and increased blood pressure (BP). However the importance of hyperandrogenemia in causing hypertension in females and the mechanisms involved are still unclear. We tested whether chronic hyperandrogenemia exacerbates hypertension in young female spontaneously hypertensive rats (SHR) and whether endogenous melanocortin-3/4 receptor (MC3/4R) activation contributes to the elevated BP.. Cardiovascular and metabolic effects of chronic MC3/4R antagonism were assessed in female SHR treated with dihydrotestosterone (DHT, beginning at 5 weeks of age) and placebo-treated female SHR. BP and heart rate (HR) were measured by telemetry and an intracerebroventricular (ICV) cannula was placed in the lateral ventricle for infusions. After control measurements, the MC3/4R antagonist (SHU-9119) was infused for 10 days (1 nmol/hour, ICV, at 15 weeks of age) followed by a 5-day recovery period.. MC3/4R antagonism increased food intake and body weight in DHT-treated SHR (14±1 to 35±1g/day and 244±3 to 298±8g) and controls (14±1 to 34±2g/day and 207±4 to 269±8g). Compared to untreated SHR, DHT-treated SHR had similar BP but lower HR (146±3 vs. 142±4mm Hg and 316±2 vs. 363±4 bpm). Chronic SHU-9119 infusion reduced BP and HR in DHT-treated SHR (-12±2mm Hg and -14±4 bpm) and control female SHR (-19±2mm Hg and -21±6 bpm).. These results indicate that hyperandrogenemia does not exacerbate hypertension in female SHR. MC3/4R antagonism reduces BP and HR despite marked increases in food intake and body weight in hyperandrogenemic and control female SHR. Topics: Animals; Appetite; Blood Glucose; Blood Pressure; Body Weight; Central Nervous System; Dihydrotestosterone; Eating; Female; Hyperandrogenism; Insulin; Leptin; Rats, Inbred SHR; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Respiration | 2016 |
Effect of Obesity on the Preovulatory Follicle and Lipid Fingerprint of Equine Oocytes.
Obesity is associated with disrupted reproductive cycles in mares, but the impact of obesity on follicles and oocytes has received minimal attention. We investigated the impact of obesity on 1) expression of selected genes in follicle cells for carbohydrate metabolism, inflammatory cytokines, lipid homeostasis, endoplasmic reticulum stress, and mitochondrial function; 2) follicular fluid content of metabolic hormones and metabolites; and 3) lipid fingerprint of oocytes. Mares (9-13 yr) were classified as control (n = 8, normal weight, body condition score [BCS] 5.1, 10.4% body fat) or obese (n = 9, BCS 7.9, 16.2% body fat). Gene expression from granulosa cells (GC) and cumulus cells (CC) was evaluated by RT-PCR. Serum and follicular fluid were evaluated for insulin, leptin, adiponectin, and metabolite profiling. Oocyte lipid fingerprints were acquired using matrix-assisted laser desorption/ionization mass spectrometry. Several genes for lipid homeostasis, endoplasmic reticulum stress, and mitochondrial function were different between groups in GC and CC. Obese had (P < 0.05) or tended to have (0.05 < P < 0.1) lower insulin sensitivity and higher insulin and leptin in serum and follicular fluid. Many metabolites differed between control and obese in serum and/or follicular fluid and correlated with BCS and/or insulin sensitivity. Oocytes from control had greater concentrations of lipids consistent with phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins, while lipids consistent with triglycerides tended to be higher in obese. These findings suggest that maternal obesity causes alterations in the follicle and oocyte; the extent to which these alterations impact the conceptus and offspring is still to be determined. Topics: Animals; Body Composition; Body Weight; Cumulus Cells; Endoplasmic Reticulum Stress; Female; Follicular Phase; Granulosa Cells; Horses; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Metabolomics; Obesity; Oocytes; Ovarian Follicle | 2016 |
Photoperiodic and Diurnal Regulation of WNT Signaling in the Arcuate Nucleus of the Female Djungarian Hamster, Phodopus sungorus.
The WNT pathway was shown to play an important role in the adult central nervous system. We previously identified the WNT pathway as a novel integration site of the adipokine leptin in mediating its neuroendocrine control of metabolism in obese mice. Here we investigated the implication of WNT signaling in seasonal body weight regulation exhibited by the Djungarian hamster (Phodopus sungorus), a seasonal mammal that exhibits profound annual changes in leptin sensitivity. We furthermore investigated whether crucial components of the WNT pathway are regulated in a diurnal manner. Gene expression of key components of the WNT pathway in the hypothalamus of hamsters acclimated to either long day (LD) or short day (SD) photoperiod was analyzed by in situ hybridization. We detected elevated expression of the genes WNT-4, Axin-2, Cyclin-D1, and SFRP-2, in the hypothalamic arcuate nucleus, a key energy balance integration site, during LD compared with SD as well as a diurnal regulation of Axin-2, Cyclin-D1, and DKK-3. Investigating the effect of photoperiod as well as leptin on the activation (phosphorylation) of the WNT coreceptor LRP-6-(Ser1490) by immunohistochemistry, we found elevated activity in the arcuate nucleus during LD relative to SD as well as after leptin treatment (2 mg/kg body weight). These findings indicate that differential WNT signaling may be associated with seasonal body weight regulation and is partially regulated in a diurnal manner in the adult brain. Furthermore, they suggest that this pathway plays a key role in the neuroendocrine regulation of body weight and integration of the leptin signal. Topics: Animals; Arcuate Nucleus of Hypothalamus; Axin Protein; Body Weight; Circadian Rhythm; Cricetinae; Cyclin D1; Energy Metabolism; Female; Gene Expression Profiling; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Leptin; Membrane Proteins; Phodopus; Photoperiod; Seasons; Wnt Signaling Pathway; Wnt4 Protein | 2016 |
DEHP induces obesity and hypothyroidism through both central and peripheral pathways in C3H/He mice.
Di(2-ethylhexyl) phthalate (DEHP) is reported to cause obesity and hypothyroidism in both humans and rodents, but the underlying mechanisms were largely unknown. This study was designed to clarify the effects and the mechanisms of DEHP on the pathogenesis of obesity and hypothyroidism and to discover the relationship between them.. Male C3H/He mice were treated with DEHP for 5 weeks, and the body weight, food intake, and body temperature were recorded during the exposure. After exposure, key organs and serum were analyzed by Q-PCR, Western blot, and ELISA.. DEHP induced significant body weight gain and adipogenesis in all exposure groups except for 0.05 mg/kg. Marked hyperphagia and daytime hypothermia were also observed, which were accompanied by disturbed hypothalamic neuropeptide expression and reduced BAT UCP1 expression. In addition, WAT lipid metabolism was significantly deceased at low dose (0.5 mg/kg) and increased at high dose (50 and 200 mg/kg). DEHP also induced hypothyroidism, which was probably attributed to the combined effects of hepatic CAR activation and hypothalamic TRH inhibition induced by hypothalamic leptin resistance.. Chronic DEHP exposure could induce obesity by interrupting energy homeostasis, which is probably due to the synergistic effects of hypothyroidism and hypothalamic leptin resistance. Topics: Adipogenesis; Animals; Body Weight; Diethylhexyl Phthalate; Hypothalamus; Hypothyroidism; Leptin; Male; Mice; Mice, Inbred C3H; Obesity; Plasticizers; Real-Time Polymerase Chain Reaction; Weight Gain | 2016 |
High-Protein Exposure during Gestation or Lactation or after Weaning Has a Period-Specific Signature on Rat Pup Weight, Adiposity, Food Intake, and Glucose Homeostasis up to 6 Weeks of Age.
Early-life nutrition has a programming effect on later metabolic health; however, the impact of exposure to a high-protein (HP) diet is still being investigated.. This study evaluated the consequences on pup phenotype of an HP diet during gestation and lactation and after weaning.. Wistar rat dams were separated into 2 groups fed an HP (55% protein) or normal protein (NP) (control; 20% protein) isocaloric diet during gestation, and each group subsequently was separated into 2 subgroups that were fed an HP or NP diet during lactation. After weaning, male and female pups from each mother subgroup were separated into 2 groups that were fed either an NP or HP diet until they were 6 wk old. Measurements included weight, food intake, body composition, blood glucose, insulin, glucagon, leptin, insulin-like growth factor I, and lipids.. Feeding mothers the HP diet during gestation or lactation induced lower postweaning pup weight (gestation diet × time, P < 0.0001; lactation diet × time, P < 0.0001). Regardless of dams' diets, pups receiving HP compared with NP diet after weaning had 7% lower weight (NP, 135.0 ± 2.6 g; HP, 124.4 ± 2.5 g; P < 0.0001), 16% lower total energy intake (NP, 777 ± 14 kcal; HP, 649 ± 13 kcal; P < 0.0001) and 31% lower adiposity (P < 0.0001). Pups receiving HP compared with NP diet after weaning had increased blood glucose, insulin, and glucagon when food deprived (P < 0.0001 for all). The HP compared with the NP diet during gestation induced higher blood glucose in food-deprived rats (NP, 83.2 ± 2.1 mg/dL; HP, 91.2 ± 2.1 mg/dL; P = 0.046) and increased plasma insulin in fed pups receiving the postweaning NP diet (gestation diet × postweaning diet, P = 0.02).. Increasing the protein concentration of the rat dams' diet during gestation, and to a lesser extent during lactation, and of the pups' diet after weaning influenced pup phenotype, including body weight, fat accumulation, food intake, and glucose tolerance at 6 wk of age. Topics: Adiposity; Animals; Blood Glucose; Body Composition; Body Weight; Dietary Proteins; Energy Intake; Female; Gastrointestinal Microbiome; Glucagon; Homeostasis; Insulin; Insulin-Like Growth Factor I; Intestines; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Pregnancy; Rats; Rats, Wistar; Triglycerides; Weaning | 2016 |
Running Exercise in Obese Pregnancies Prevents IL-6 Trans-signaling in Male Offspring.
Maternal obesity is known to predispose the offspring to impaired glucose metabolism and obesity associated with low-grade inflammation and hypothalamic dysfunction. Because preventive approaches in this context are missing to date, we aimed to identify molecular mechanisms in the offspring that are affected by maternal exercise during pregnancy.. Diet-induced obese mouse dams were divided into a sedentary obese (high-fat diet [HFD]) group and an obese intervention (HFD-running intervention [RUN]) group, which performed voluntary wheel running throughout gestation. Male offspring were compared with the offspring of a sedentary lean control group at postnatal day 21.. HFD and HFD-RUN offspring showed increased body weight and white adipose tissue mass. Glucose tolerance testing showed mild impairment only in HFD offspring. Serum interleukin-6 (IL-6) levels, hypothalamic and white adipose tissue IL-6 gene expressions, and phosphorylation of signal transducer and activator of transcription 3 in HFD offspring were significantly increased, whereas HFD-RUN was protected against these changes. The altered hypothalamic global gene expression in HFD offspring showed partial normalization in HFD-RUN offspring, especially with respect to IL-6 action.. Maternal exercise in obese pregnancies effectively reduces IL-6 trans-signaling and might be the underlying mechanism for the amelioration of glucose metabolism at postnatal day 21 independent of body composition. Topics: Adipose Tissue, White; Adiposity; Animals; Body Weight; Diet, High-Fat; Female; Glucose; Glucose Tolerance Test; Hypothalamus; Insulin; Interleukin-6; Leptin; Male; Mice; Motor Activity; Obesity; Phenotype; Physical Conditioning, Animal; Pregnancy; Signal Transduction; STAT3 Transcription Factor; Transcriptome | 2016 |
The expression of orexigenic and anorexigenic factors in middle-aged female rats that had been subjected to prenatal undernutrition.
Fetal growth retardation, which affects short- and long-term fetal brain development, is associated with metabolic, hematological, and thermal disturbances, which can increase the risk of metabolic syndrome later in life. Orexigenic and anorexigenic factors regulate food intake and energy expenditure. We studied how the expression of these factors was affected by food deprivation (FD) in middle-aged female rats that had been subjected to prenatal undernutrition. Eight pregnant rats were divided into two groups, the normal nutrition (NN) (n=4) group and the undernutrition (UN) (n=4) group, which received 50% (approximately 11 g) of the daily food intake of the normal nutrition rats from day 13 of pregnancy to delivery. The pups from these dams were defined as the maternal NN (mNN) and maternal UN (mUN) groups, respectively. After weaning, all of the pups were housed and allowed ad libitum access to food and water. At the age of 6 months, both groups of pups were sub-divided into three groups. One group was allowed to consume normal amounts of food (Fed), and the other two groups were subjected to 24h or 48 h FD (n=7-8 per group). The rats' serum leptin levels and hypothalamic mRNA expression levels of various orexigenic or anorexigenic factors were measured. In both the mNN and mUN rats, the serum leptin levels of the 24h and 48 h FD groups tended to be lower than those of the Fed group, and the serum leptin levels of the 24h FD mUN rats and the Fed mUN rats differed significantly. The hypothalamic neuropeptide Y (NPY) mRNA expression levels of the 24h and 48 h FD groups were significantly higher in the mUN rats than in the mNN rats. In addition, among the mUN rats the hypothalamic NPY mRNA expression levels of the 48 h FD group were significantly higher than those of the Fed group. In both the mNN and mUN rats, prepro-orexin mRNA expression was lower in the 48 h FD group than in the corresponding Fed group. Among the mUN rats, the 48 h FD group exhibited significantly lower hypothalamic proopiomelanocortin (POMC) mRNA expression than the Fed group, and a similar tendency was seen among the mNN rats. Among the mNN rats, the 24h FD group displayed significantly higher hypothalamic leptin receptor (OBRb) mRNA levels than the Fed group. However, no such differences were seen among the mUN rats. As a result, the hypothalamic OBRb mRNA expression levels of the mUN rats in the 24h and 48 h FD groups were lower than those of the corresponding mNN rat groups. Thes Topics: Analysis of Variance; Animals; Body Weight; Female; Food Deprivation; Gene Expression Regulation; Hypothalamus; Leptin; Malnutrition; Neuropeptide Y; Pregnancy; Prenatal Nutritional Physiological Phenomena; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Leptin; RNA, Messenger; Time Factors | 2016 |
RYGB progressively increases avidity for a low-energy, artificially sweetened diet in female rats.
Weight re-gain within 2 y after Roux-en-Y gastric bypass (RYGB) is significantly associated with increased intake of and cravings for sweet foods. Here we describe a novel model of this late increase in sweet appetite. Ovariectomized RYGB and Sham-operated rats, with or without estradiol treatment, were maintained on Ensure liquid diet and offered a low-energy, artificially sweetened diet (ASD) 2 h/d. First, we tested rats more than six months after RYGB. ASD meals were larger in RYGB than Sham rats, whereas Ensure meals were smaller. General physical activity increased during ASD meals in RYGB rats, but not during Ensure meals. Second, new rats were adapted to ASD before surgery, and were then offered ASD again during 4-10 wk following surgery. Estradiol-treated RYGB rats lost the most weight and progressively increased ASD intake to >20 g/2 h in wk 9-10 vs. ∼3 g/2 h in Sham rats. Finally, the same rats were then treated with leptin or saline for 8 d. Leptin did not affect body weight, Ensure intake, or activity during meals, but slightly reduced ASD intake in estradiol-treated RYGB rats. Food-anticipatory activity was increased in estradiol-treated RYGB rats during the saline-injection tests. Because increased meal-related physical activity together with larger meals is evidence of hunger in rats, these data suggest that (1) RYGB can increase hunger for a low-energy sweet food in rats and (2) low leptin levels contribute to this hunger, but are not its only cause. This provides a unique rat model for the increased avidity for sweets that is significantly associated with weight recidivism late after RYGB. Topics: Animals; Body Weight; Dietary Sucrose; Energy Intake; Female; Food, Formulated; Gastric Bypass; Hunger; Leptin; Motor Activity; Non-Nutritive Sweeteners; Ovariectomy; Rats; Rats, Long-Evans; Weight Gain; Weight Loss | 2016 |
Fatness rather than leptin sensitivity determines the timing of puberty in female mice.
Leptin is a permissive factor for the onset of puberty. However, changes in adiposity frequently influence leptin sensitivity. Thus, the objective of the present study was to investigate how changes in body weight, fatness, leptin levels and leptin sensitivity interact to control the timing of puberty in female mice. Pre-pubertal obesity, induced by raising C57BL/6 mice in small litters, led to an early puberty onset. Inactivation of Socs3 gene in the brain or exclusively in leptin receptor-expressing cells reduced the body weight and leptin levels at pubertal onset, and increased leptin sensitivity. Notably, these female mice exhibited significant delays in vaginal opening, first estrus and onset of estrus cyclicity. In conclusion, our findings suggest that increased leptin sensitivity did not play an important role in favoring pubertal onset in female mice. Rather, changes in pubertal body weight, fatness and/or leptin levels were more important in influencing the timing of puberty. Topics: Animals; Body Weight; Estrous Cycle; Female; Gene Knockout Techniques; Hypothalamus; Leptin; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Nestin; Obesity; Receptors, Leptin; Sexual Maturation; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins | 2016 |
Maternal protein restriction during pregnancy and lactation alters central leptin signalling, increases food intake, and decreases bone mass in 1 year old rat offspring.
The effects of perinatal nutrition on offspring physiology have mostly been examined in young adult animals. Aging constitutes a risk factor for the progressive loss of metabolic flexibility and development of disease. Few studies have examined whether the phenotype programmed by perinatal nutrition persists in aging offspring. Persistence of detrimental phenotypes and their accumulative metabolic effects are important for disease causality. This study determined the effects of maternal protein restriction during pregnancy and lactation on food consumption, central leptin sensitivity, bone health, and susceptibility to high fat diet-induced adiposity in 1-year-old male offspring. Sprague-Dawley rats received either a control or a protein restricted diet throughout pregnancy and lactation and pups were weaned onto laboratory chow. One-year-old low protein (LP) offspring exhibited hyperphagia. The inability of an intraperitoneal (i.p.) leptin injection to reduce food intake indicated that the hyperphagia was mediated by decreased central leptin sensitivity. Hyperphagia was accompanied by lower body weight suggesting increased energy expenditure in LP offspring. Bone density and bone mineral content that are negatively regulated by leptin acting via the sympathetic nervous system (SNS), were decreased in LP offspring. LP offspring did not exhibit increased susceptibility to high fat diet induced metabolic effects or adiposity. The results presented here indicate that the programming effects of perinatal protein restriction are mediated by specific decreases in central leptin signalling to pathways involved in the regulation of food intake along with possible enhancement of different CNS leptin signalling pathways acting via the SNS to regulate bone mass and energy expenditure. Topics: Adiposity; Animals; Appetite; Biomarkers; Body Composition; Body Weight; Bone Density; Diet, High-Fat; Diet, Protein-Restricted; Eating; Female; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Signal Transduction | 2016 |
Role of the neural pathway from hindbrain to hypothalamus in the regulation of energy homeostasis in rats.
Recent evidence suggests that neural pathways from the hindbrain to the hypothalamus are important for informing the hypothalamus of the body's condition with regard to energy metabolism. Here we examined energy metabolism in rats with transections of the midbrain that severed the neural pathway from the hindbrain to the hypothalamus, and then investigated the levels of various molecules associated with control of energy metabolism in these rats. Food intake and body weight were higher in the midbrain-transected rats than in sham-operated rats. In addition, the midbrain-transected rats showed insulin resistance and hyperleptinemia. Furthermore, the hypothalamic mRNA levels of anorectic proopiomelanocortin and cocaine- and amphetamine-related transcript were significantly lower in midbrain-transected rats than in sham-operated rats. Our findings elucidate the mechanisms of food intake and energy balance from the perspective of multifactorial regulatory systems that underlie functions such as neurohormonal integration. Topics: Animals; Body Weight; Eating; Energy Metabolism; Glucose Tolerance Test; Homeostasis; Hypothalamus; Insulin Resistance; Leptin; Male; Neural Pathways; Pro-Opiomelanocortin; Rats, Wistar; Receptors, Leptin; Rhombencephalon; RNA, Messenger | 2016 |
Hypothermia mediates age-dependent increase of tau phosphorylation in db/db mice.
Accumulating evidence from epidemiological studies suggest that type 2 diabetes is linked to an increased risk of Alzheimer's disease (AD). However, the consequences of type 2 diabetes on AD pathologies, such as tau hyperphosphorylation, are not well understood. Here, we evaluated the impact of type 2 diabetes on tau phosphorylation in db/db diabetic mice aged 4 and 26weeks. We found increased tau phosphorylation at the CP13 epitope correlating with a deregulation of c-Jun. N-terminal kinase (JNK) and Protein Phosphatase 2A (PP2A) in 4-week-old db/db mice. 26-week-old db/db mice displayed tau hyperphosphorylation at multiple epitopes (CP13, AT8, PHF-1), but no obvious change in kinases or phosphatases, no cleavage of tau, and no deregulation of central insulin signaling pathways. In contrast to younger animals, 26-week-old db/db mice were hypothermic and restoration of normothermia rescued phosphorylation at most epitopes. Our results suggest that, at early stages of type 2 diabetes, changes in tau phosphorylation may be due to deregulation of JNK and PP2A, while at later stages hyperphosphorylation is mostly a consequence of hypothermia. These results provide a novel link between diabetes and tau pathology, and underlie the importance of recording body temperature to better understand the relationship between diabetes and AD. Topics: Aging; Analysis of Variance; Animals; Blood Glucose; Body Weight; Brain; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Regulation; Glycemic Index; Hypothermia, Induced; Insulin Resistance; Leptin; Male; MAP Kinase Kinase 4; Mice; Mice, Mutant Strains; Phosphorylation; Signal Transduction; tau Proteins | 2016 |
The lysyl oxidase inhibitor (β-aminopropionitrile) reduces leptin profibrotic effects and ameliorates cardiovascular remodeling in diet-induced obesity in rats.
Lysyl oxidase (LOX) is an extracellular matrix (ECM)-modifying enzyme that has been involved in cardiovascular remodeling. We explore the impact of LOX inhibition in ECM alterations induced by obesity in the cardiovascular system. LOX is overexpressed in the heart and aorta from rats fed a high-fat diet (HFD). β-Aminopropionitrile (BAPN), an inhibitor of LOX activity, significantly attenuated the increase in body weight and cardiac hypertrophy observed in HFD rats. No significant differences were found in cardiac function or blood pressure among any group. However, HFD rats showed cardiac and vascular fibrosis and enhanced levels of superoxide anion (O2(-)), collagen I and transforming growth factor β (TGF-β) in heart and aorta and connective tissue growth factor (CTGF) in aorta, effects that were attenuated by LOX inhibition. Interestingly, BAPN also prevented the increase in circulating leptin levels detected in HFD fed animals. Leptin increased protein levels of collagen I, TGF-β and CTGF, Akt phosphorylation and O2(-) production in both cardiac myofibroblasts and vascular smooth muscle cells in culture, while LOX inhibition ameliorated these alterations. LOX knockdown also attenuated leptin-induced collagen I production in cardiovascular cells. Our findings indicate that LOX inhibition attenuates the fibrosis and the oxidative stress induced by a HFD on the cardiovascular system. The reduction of leptin levels by BAPN in vivo and the ability of this compound to inhibit leptin-induced profibrotic mediators and ROS production in cardiac and vascular cells suggest that interactions between leptin and LOX regulate downstream events responsible for myocardial and vascular fibrosis in obesity. Topics: Aminopropionitrile; Animals; Aorta; Blood Pressure; Body Weight; Diet, High-Fat; Extracellular Matrix; Fibrosis; Gene Expression Regulation; Humans; Leptin; Myocardium; Obesity; Protein-Lysine 6-Oxidase; Rats; Reactive Oxygen Species | 2016 |
Early cardiac changes induced by a hypercaloric Western-type diet in "subclinical" obesity.
"Obesity cardiomyopathy" effects have been widely described; however, the specific contribution of metabolic changes and altered adipokine secretion are still uncharacterized. Moreover, a diagnosis based on body mass index might not be the most accurate to identify increased adiposity and its outcomes. In this study, we aimed to determine the impact of a Western-type diet [hypercaloric diet (HCD)] ingestion on biventricular structure and function, as well as the metabolic and endocrine changes that occur before the establishment of overt obesity. Wistar rats were fed for 6 wk with a regular diet or HCD. At the end of the protocol, metabolic tests, cardiac structure, and functional evaluation were performed, and blood and tissue samples collected to perform histological, molecular biology, and functional studies. The animals that ingested the HCD presented increased adiposity and larger adipocyte cross-sectional area, but similar body weight compared with the regular diet group. At the cardiac level, HCD induced biventricular cardiomyocyte hypertrophy, fibrosis, increased stiffness, and impaired relaxation. Galectin-3 plasma expression was likewise elevated in the same animals. The nutritional modulation also altered the secretory pattern of the adipose tissue, originating a proinflammatory systemic environment. In this study, we observed that before "clinical" overweight or frank obesity is established, the ingestion of a HCD-induced cardiac remodeling manifests by increased biventricular stiffness and diastolic dysfunction. The mechanism triggering the cardiac alterations appears to be the proinflammatory environment promoted by the adipose tissue dysfunction. Furthermore, galectin-3, a profibrotic molecule, might be a potential biomarker for the myocardial alterations promoted by the HCD before overweight or obesity. Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Cardiomyopathies; Cell Size; Collagen Type I; Collagen Type III; Diastole; Diet, Western; Echocardiography; Extracellular Matrix; Fibrosis; Galectin 3; Glucose Tolerance Test; Inflammation; Insulin Resistance; Interleukin-1beta; Leptin; Myocardium; Myocytes, Cardiac; Obesity; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Resistin; RNA, Messenger; Tumor Necrosis Factor-alpha; Ventricular Dysfunction; Ventricular Remodeling | 2016 |
Effects of combined PPAR-γ and PPAR-α agonist therapy on fructose induced NASH in rats: Modulation of gene expression.
Peroxisome proliferator-activated receptors (PPARs) gamma and alpha have been shown to play key roles in maintaining glucose and lipid homeostasis by acting as insulin sensitizers and lipid-lowering agents respectively, which would make them potential candidates for the treatment of non-alcoholic steatohepatitis (NASH) characterized by insulin resistance, hyperglycemia, and hypertriglyceridemia. The effects of pioglitazone, a PPAR-γ agonist, and fenofibrate, a PPAR-α agonist, as monotherapy and in combination on the expressions of key genes linked to the development of NASH were studied in rats with fructose-induced NASH. Fructose-enriched diet was given to rats for 12 weeks. Fenofibrate (100mg/kg), pioglitazone (4 mg/kg) and combined treatment with both in half doses were given. Body weight, liver index, insulin resistance indices, triglycerides, oxidative stress markers, AST/ALT ratio and TNF-α were measured. Additionally, hepatic genes expressions of SOCS-3, sterol regulatory element binding protein-1c, fatty acid synthase, malonyl CoA decarboxylase, TGF-β1, and adipose tissue genes expressions of leptin and adiponectin were investigated. The combination of both drugs, in half doses, improved NASH-related disturbances similar to, or even better than, a full dose of fenofibrate alone possibly due to attenuating effects of pioglitazone on expression of genes responsible for insulin resistance, fatty acid synthesis and fibrosis in addition to correcting the balance between leptin and adiponectin. Histopathology confirmed the ability of this combination to decrease steatosis area and to normalize hepatic tissue structure. In Conclusion, dual activation of PPAR-γ and PPAR-α has remarkable effect in ameliorating NASH by modulation of some hepatic and adipose tissue genes expressions. Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Dose-Response Relationship, Drug; Drug Interactions; Fenofibrate; Fructose; Gene Expression Regulation; Glutathione; Homeostasis; Insulin; Leptin; Liver; Male; Malondialdehyde; Non-alcoholic Fatty Liver Disease; Pioglitazone; PPAR alpha; PPAR gamma; Rats; Rats, Wistar; Thiazolidinediones; Triglycerides; Tumor Necrosis Factor-alpha | 2016 |
SOCS3 expression within leptin receptor-expressing cells regulates food intake and leptin sensitivity but does not affect weight gain in pregnant mice consuming a high-fat diet.
Pregnancy induces transitory metabolic changes including increases in food intake and body fat deposition, as well as leptin and insulin resistance. Recent findings have suggested that increased hypothalamic expression of suppressor of cytokine signaling-3 (SOCS3) is a key mechanism responsible for triggering those metabolic adaptations. Because obesity is a risk factor for gestational metabolic imbalances, we aimed to study the role of SOCS3 during pregnancy in obese mice. Female mice carrying a deletion of SOCS3 in leptin receptor-expressing cells (SOCS3 KO mice) were exposed to a chronic high-fat diet (HFD), and we then studied their energy balance and glucose homeostasis during pregnancy. SOCS3 deletion did not prevent diet-induced obesity or changes in body weight and adiposity observed during pregnancy. However, the typical increase in food intake during mid- and late-pregnancy was blunted in SOCS3 KO females. We also observed a slight improvement in glucose homeostasis and increased leptin sensitivity in the arcuate nucleus of the hypothalamus in pregnant SOCS3 KO mice on HFD. Despite this, SOCS3 KO mice had an increased number of uterine reabsorptions and fewer fetuses compared to the controls. Compared to control animals, a reduction in proopiomelanocortin and an increase in oxytocin mRNA levels were observed in the hypothalamus of pregnant SOCS3 KO mice. In contrast to previous studies using lean animals, conditional SOCS3 ablation did not prevent major gestational metabolic changes in diet-induced obese mice. Our findings contribute to the understanding of the role of SOCS3 in mediating pregnancy-induced metabolic adaptations. Topics: Analysis of Variance; Animals; Body Weight; Diet, High-Fat; Eating; Female; Gene Expression Regulation, Developmental; Glucose Tolerance Test; Hypothalamus; Leptin; Mice; Mice, Knockout; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, Leptin; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein | 2016 |
Weight-related and analytical maternal factors in gestational diabetes to predict birth weight and cord markers of diabetic fetopathy.
The objective was to determine the value of clinical and analytical maternal factors to predict birth weight and umbilical cord biochemical markers of diabetic fetopathy.. Prospective evaluation of gestational diabetes pregnancies (n = 50). Maternal weight-related clinical and analytical factors were collected during pregnancy. After birth, an umbilical cord sample was taken.. Univariate linear regression analysis showed relationship between maternal weight, glycated hemoglobin (HbA1c) and insulin-like growth factor 1 (IGF1) with birth weight percentile. A significant association was found between maternal weight and cord insulin and C-peptide. Maternal HbA1c, leptin and insulin during pregnancy showed a positive linear association to cord leptin, insulin and C-peptide. In multivariate analysis models, final maternal BMI showed an independent positive association with cord C-peptide.. Maternal weight-related and analytical parameters show diagnostic value to birth weight and cord markers. Topics: Adult; Birth Weight; Body Weight; C-Peptide; Diabetes, Gestational; Female; Fetal Blood; Fetal Diseases; Glycated Hemoglobin; Humans; Infant, Newborn; Insulin; Insulin-Like Growth Factor I; Leptin; Pregnancy | 2016 |
Effects of different periods of paradoxical sleep deprivation and sleep recovery on lipid and glucose metabolism and appetite hormones in rats.
Sleep has a fundamental role in the regulation of energy balance, and it is an essential and natural process whose precise impacts on health and disease have not yet been fully elucidated. The aim of this study was to assess the consequences of different periods of paradoxical sleep deprivation (PSD) and recovery from PSD on lipid profile, oral glucose tolerance test (OGTT) results, and changes in insulin, corticosterone, ghrelin, and leptin concentrations. Three-month-old male Wistar rats weighing 250-350 g were submitted to 24, 96, or 192 h of PSD or 192 h of PSD with 480 h of recovery. The PSD was induced by the multiple platforms method. Subsequently, the animals were submitted to an OGTT. One day later, the animals were killed and the levels of triglycerides, total cholesterol, lipoproteins (low-density lipoprotein, very-low-density lipoprotein, and high-density lipoprotein), insulin, ghrelin, leptin, and corticosterone in plasma were quantified. There was a progressive decrease in body weight with increasing duration of PSD. The PSD induced basal hypoglycemia over all time periods evaluated. Evaluation of areas under the curve revealed progressive hypoglycemia only after 96 and 192 h of PSD. There was an increase in corticosterone levels after 192 h of PSD. We conclude that PSD induces alterations in metabolism that are reversed after a recovery period of 20 days. Topics: Animals; Appetite Regulation; Biomarkers; Blood Glucose; Body Weight; Corticosterone; Disease Models, Animal; Eating; Energy Metabolism; Ghrelin; Glucose Tolerance Test; Hormones; Insulin; Leptin; Lipids; Male; Rats, Wistar; Recovery of Function; Sleep; Sleep Deprivation; Time Factors | 2016 |
Obestatin and Ghrelin May Have a Complementary Function During Acute and Chronic Period in Mice.
Obestatin is described as an anorexigenic peptide, and has adverse effects of ghrelin. It has no inhibitory effects on acute/chronic food intake, and it has been reported by several researchers. The role of obestatin in metabolism is still not clear. In the present study, the purpose is to determine the effects of chronically administrated obestatin. For this purpose, (1 µmol/kg; i.p.) or ghrelin (1 µmol/kg; i.p.) and food restriction (24h fast:24h fed) on plasma obestatin, ghrelin, leptin, insulin, cholecystokinin (CCK) and glucose levels, and body weight gain were investigated for 14 days in mice. Additionally, mice were treated with acute ip (100 nmol/kg) injections of obestatin or ghrelin to investigate the food consumptions, plasma obestatin and ghrelin levels to determine unknown acute effects of obestatin. Plasma ghrelin levels increased significantly in obestatin administered mice when compared with the control group for chronic treatment. This increase is consistent with immunohistochemical findings which claim that the number of ghrelin and obestatin immunopositive cells in fundus tissue of stomach are considerably high in obestatin treated animals. Plasma obestatin and ghrelin levels has shown an increase endogenously in food restricted mice, but plasma leptin and insulin levels have been found to be lower compared to the control group. Acute administration of obestatin caused a decrease in plasma obestatin level at 60 min after injection and had no effect on the reduction of food intake in each treatment time. These results imply that obestatin may not itself be involved in the metabolism regulation; however, obestatin accompanied by ghrelin may play a role in the long-term regulation of metabolism. Topics: Animals; Body Weight; Cholecystokinin; Eating; Gene Expression Regulation; Ghrelin; Injections; Insulin; Leptin; Mice; Peptide Hormones | 2016 |
Leptin levels in patients with anorexia nervosa following day/inpatient treatment do not predict weight 1 year post-referral.
Elevated serum leptin levels following rapid therapeutically induced weight gain in anorexia nervosa (AN) patients are discussed as a potential biomarker for renewed weight loss as a result of leptin-related suppression of appetite and increased energy expenditure. This study aims to analyze the predictive value of leptin levels at discharge as well as the average rate of weight gain during inpatient or day patient treatment for body weight at 1-year follow-up. 121 patients were recruited from the longitudinal Anorexia Nervosa Day patient versus Inpatient (ANDI) trial. Serum leptin levels were analyzed at referral and discharge. A multiple linear regression analysis to predict age-adjusted body mass index (BMI-SDS) at 1-year follow-up was performed. Leptin levels, the average rate of weight gain, premorbid BMI-SDS, BMI-SDS at referral, age and illness duration were included as independent variables. Neither leptin levels at discharge nor rate of weight gain significantly predicted BMI-SDS at 1-year follow-up explaining only 1.8 and 0.4 % of the variance, respectively. According to our results, leptin levels at discharge and average rate of weight gain did not exhibit any value in predicting weight at 1-year follow-up in our longitudinal observation study of adolescent patients with AN. Thus, research should focus on other potential factors to predict weight at follow-up. As elevated leptin levels and average rate of weight gain did not pose a risk for reduced weight, we found no evidence for the beneficial effect of slow refeeding in patients with acute AN. Topics: Adolescent; Anorexia Nervosa; Biomarkers; Body Mass Index; Body Weight; Child; Female; Humans; Inpatients; Leptin; Patient Discharge; Predictive Value of Tests; Treatment Outcome; Weight Gain | 2016 |
Adipocyte Versus Somatotrope Leptin: Regulation of Metabolic Functions in the Mouse.
Leptin regulates food intake and energy expenditure (EE) and is produced in adipocytes, the pituitary, and several other tissues. Animals that are leptin or leptin receptor deficient have major metabolic complications, including obesity. This study tests the hypothesis that the pituitary somatotrope may contribute a source of leptin that maintains some of these metabolic functions. We created 2 different tissue-specific leptin knockout animals: a Somatotrope-Lep-null model and an Adipocyte-Lep-null model. Metabolic analysis of both models, along with a global deletion model, was performed. The Somatotrope-Lep-null animals had fewer somatotropes, and females had a 76% decrease in serum prolactin. During the dark (feeding) phase, females had a 35% increase in ambulation coupled with a 4% increase in EE. Mutants showed no change in food intake or weight gain and EE was unchanged in males. During the light (sleep) phase, Somatotrope-Lep-null mutant males had lower EE and females continued to have higher EE. The respiratory quotients (RQs) of mutants and littermate controls were decreased in males and increased in females; all were within the range that indicates predominant carbohydrate burning. The massively obese Adipocyte-Lep-null animals, however, had significant increases in food intake, sleep, and increased EE, with decreased activity. Changes in RQ were sexually dimorphic, with female mutants having higher RQ and males having decreased RQ. We conclude that both adipocyte and somatotrope leptin contribute to the metabolic homeostasis of the mouse, and that extraadipocyte sources of leptin cannot overcome the major metabolic challenges seen in these animals. Topics: Adipocytes; Animals; Body Weight; Eating; Energy Metabolism; Female; Leptin; Male; Mice, Knockout; Mice, Transgenic; Oxygen Consumption; Prolactin; Sex Factors; Sleep; Somatotrophs | 2016 |
Stress during Adolescence Alters Palatable Food Consumption in a Context-Dependent Manner.
Food consumption and preferences may be shaped by exposure to stressful environments during sensitive periods in development, and even small changes in consumption can have important effects on long term health. Adolescence is increasingly recognized as a sensitive period, in which adverse experiences can alter development, but the specific programming effects that may occur during adolescence remain incompletely understood. The current study seeks to explore the effects of stress during late adolescence on consumption of a palatable, high-fat, high-sugar food in adulthood-under basal conditions, as well following acute stress. Male Long-Evans rats were exposed to a regimen of variable stress for seven days in late adolescence (PND 45-51). During the stress regimen, stressed animals gained significantly less weight than control animals, but weight in adulthood was unaffected by adolescent stress. Palatable food consumption differed between experimental groups, and the direction of effect depended on context; stressed rats ate significantly more palatable food than controls upon first exposure, but ate less following an acute stressor. Leptin levels and exploratory behaviors did not differ between stressed and non-stressed groups, suggesting that other factors regulate preference for a palatable food. Altered food consumption following adolescent stress suggests that rats remain sensitive to stress during late adolescence, and that adult feeding behavior may be affected by previous adverse experiences. Such programming effects highlight adolescence as a period of plasticity, with the potential to shape long term food consumption patterns and preferences. Topics: Animals; Behavior, Animal; Body Weight; Exploratory Behavior; Feeding Behavior; Food Preferences; Leptin; Male; Memory, Long-Term; Rats; Rats, Long-Evans; Stress, Psychological; Time Factors | 2016 |
Leptin secretory dynamics and associated disordered eating psychopathology across the weight spectrum.
Leptin secretory dynamics across the weight spectrum and their relationship with disordered eating psychopathology have not been studied. Our objective was to compare leptin secretory dynamics in 13 anorexia nervosa (AN), 12 overweight/obese (OB) and 12 normal-weight women using deconvolution analysis.. In this cross-sectional study conducted at a tertiary referral center, serum leptin levels were obtained every 20 min from 2000 to 0800 h. Dual energy X-ray absorptiometry was used to measure percent body fat. Disordered eating psychopathology was assessed by the Eating Disorders Examination-Questionnaire (EDE-Q) and the Eating Disorders Inventory-2 (EDI-2).. The groups differed for basal leptin secretion (BASAL) (P=0.02). Mean leptin pulse amplitude, pulse mass, total pulsatile secretion (TPS) and area under the curve (AUC) were significantly different between groups before and after adjustment for BASAL (P<0.0001 for all). Leptin AUC correlated strongly with TPS (r=0.97, P<0.0001) and less with BASAL (r=0.35, P=0.03). On multivariate analysis, only TPS was a significant predictor of leptin AUC (P<0.0001). TPS was inversely associated with most EDE-Q and EDI-2 parameters and the associations remained significant for EDE-Q eating concern (P=0.01), and EDI-2 asceticism, ineffectiveness and social insecurity (P<0.05) after adjusting for BASAL. These relationships were not significant when controlled for percent body fat.. Secretory dynamics of leptin differ across weight spectrum, with mean pulse amplitude, mean pulse mass and TPS being low in AN and high in OB. Pulsatile, rather than basal secretion, is the major contributor to leptin AUC. Decreased pulsatile leptin is associated with disordered eating psychopathology, possibly reflecting low percent body fat in AN. Topics: Adiposity; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Case-Control Studies; Cross-Sectional Studies; Feeding and Eating Disorders; Female; Humans; Leptin; Obesity; Overweight; Thinness; Young Adult | 2016 |
Leptin signaling regulates glucose homeostasis, but not adipostasis, in the zebrafish.
Leptin is the primary adipostatic factor in mammals. Produced largely by adipocytes in proportion to total adipose mass, the hormone informs the brain regarding total energy stored as triglycerides in fat cells. The hormone acts on multiple circuits in the brain to regulate food intake, autonomic outflow, and endocrine function to maintain energy balance. In addition to regulating adipose mass, mammalian leptin also plays a role in the regulation of glucose homeostasis and as a gating factor in reproductive competence. Leptin-deficient mice and people exhibit early onset profound hyperphagia and obesity, diabetes, and infertility. Although leptin and the leptin receptor are found in fish, the hormone is not expressed in adipose tissue, but is found in liver and other tissues. Here, we show that adult zebrafish lacking a functional leptin receptor do not exhibit hyperphagia or increased adiposity, and exhibit normal fertility. However, leptin receptor-deficient larvae have increased numbers of β-cells and increased levels of insulin mRNA. Furthermore, larval zebrafish have been shown to exhibit β-cell hyperplasia in response to high fat feeding or peripheral insulin resistance, and we show here that leptin receptor is required for this response. Adult zebrafish also have increased levels of insulin mRNA and other alterations in glucose homeostasis. Thus, a role for leptin in the regulation of β-cell mass and glucose homeostasis appears to be conserved across vertebrates, whereas its role as an adipostatic factor is likely to be a secondary role acquired during the evolution of mammals. Topics: Adiposity; Amino Acid Sequence; Animals; Body Size; Body Weight; Cell Count; Clustered Regularly Interspaced Short Palindromic Repeats; Dietary Fats; Fertility; Glucose; Glucose Tolerance Test; Glycogenolysis; Glycolysis; Homeostasis; Hyperphagia; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Larva; Leptin; Liver; Male; Molecular Sequence Data; Phenotype; Phosphoenolpyruvate Carboxykinase (ATP); Receptors, Leptin; RNA, Messenger; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction; Zebrafish; Zebrafish Proteins | 2016 |
Failure to upregulate Agrp and Orexin in response to activity based anorexia in weight loss vulnerable rats characterized by passive stress coping and prenatal stress experience.
We hypothesize that anorexia nervosa (AN) poses a physiological stress. Therefore, the way an individual copes with stress may affect AN vulnerability. Since prenatal stress (PNS) exposure alters stress responsivity in offspring this may increase their risk of developing AN. We tested this hypothesis using the activity based anorexia (ABA) rat model in control and PNS rats that were characterized by either proactive or passive stress-coping behavior. We found that PNS passively coping rats ate less and lost more weight during the ABA paradigm. Exposure to ABA resulted in higher baseline corticosterone and lower insulin levels in all groups. However, leptin levels were only decreased in rats with a proactive stress-coping style. Similarly, ghrelin levels were increased only in proactively coping ABA rats. Neuropeptide Y (Npy) expression was increased and proopiomelanocortin (Pomc) expression was decreased in all rats exposed to ABA. In contrast, agouti-related peptide (Agrp) and orexin (Hctr) expression were increased in all but the PNS passively coping ABA rats. Furthermore, DNA methylation of the orexin gene was increased after ABA in proactive coping rats and not in passive coping rats. Overall our study suggests that passive PNS rats have innate impairments in leptin and ghrelin in responses to starvation combined with prenatal stress associated impairments in Agrp and orexin expression in response to starvation. These impairments may underlie decreased food intake and associated heightened body weight loss during ABA in the passively coping PNS rats. Topics: Adaptation, Psychological; Agouti-Related Protein; Animals; Anorexia; Body Weight; DNA Methylation; Drinking; Eating; Female; Ghrelin; Leptin; Male; Motor Activity; Neuropeptide Y; Orexins; Pregnancy; Prenatal Exposure Delayed Effects; Pro-Opiomelanocortin; Rats; Up-Regulation | 2016 |
Classification of different degrees of adiposity in sedentary rats.
In experimental studies, several parameters, such as body weight, body mass index, adiposity index, and dual-energy X-ray absorptiometry, have commonly been used to demonstrate increased adiposity and investigate the mechanisms underlying obesity and sedentary lifestyles. However, these investigations have not classified the degree of adiposity nor defined adiposity categories for rats, such as normal, overweight, and obese. The aim of the study was to characterize the degree of adiposity in rats fed a high-fat diet using cluster analysis and to create adiposity intervals in an experimental model of obesity. Thirty-day-old male Wistar rats were fed a normal (n=41) or a high-fat (n=43) diet for 15 weeks. Obesity was defined based on the adiposity index; and the degree of adiposity was evaluated using cluster analysis. Cluster analysis allowed the rats to be classified into two groups (overweight and obese). The obese group displayed significantly higher total body fat and a higher adiposity index compared with those of the overweight group. No differences in systolic blood pressure or nonesterified fatty acid, glucose, total cholesterol, or triglyceride levels were observed between the obese and overweight groups. The adiposity index of the obese group was positively correlated with final body weight, total body fat, and leptin levels. Despite the classification of sedentary rats into overweight and obese groups, it was not possible to identify differences in the comorbidities between the two groups. Topics: Adiposity; Animals; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Cluster Analysis; Diet, High-Fat; Disease Models, Animal; Fatty Acids, Nonesterified; Insulin; Leptin; Male; Obesity; Rats, Wistar; Sedentary Behavior; Severity of Illness Index; Time Factors; Triglycerides | 2016 |
Associations between adiposity and indicators of thyroid status in children and adolescents.
In adults, obesity is associated with abnormalities of thyroid function; there are fewer studies in paediatric cohorts.. To examine associations of weight and adiposity with indices of thyroid function and thyroid-related metabolic factors in children.. A sample of 1203 children without obesity (body mass index [BMI] < 95th percentile; N = 631) and with obesity (BMI ≥ 95th percentile; N = 572), age 5-18 years, had height and weight measured (to calculate BMI-Z score for age and sex) and had blood collected in the morning for thyroid-stimulating hormone (TSH), free thyroxine (FT4) and leptin. A subset (N = 829) also underwent measurement of fat mass by dual-energy X-ray absorptiometry. Analyses examined associations of TSH and FT4 with adiposity and obesity-related conditions accounting for sociodemographic factors.. Thyroid-stimulating hormone was positively related to BMIz and fat mass (both p-values < 0.001). FT4 was negatively related to BMIz and fat mass (both p-values < 0.001). TSH was positively correlated to leptin (p = 0.001) even after accounting for fat mass.. Paediatric obesity is associated with higher TSH and lower FT4 concentrations and with a greater prevalence of abnormally high TSH. Leptin concentrations may in part explain obesity's effects on thyroid status, perhaps through leptin's effects on TSH secretion. Topics: Absorptiometry, Photon; Adiposity; Adolescent; Body Mass Index; Body Weight; Child; Female; Humans; Leptin; Male; Pediatric Obesity; Thyroid Gland; Thyrotropin; Thyroxine | 2016 |
d-Allulose supplementation normalized the body weight and fat-pad mass in diet-induced obese mice via the regulation of lipid metabolism under isocaloric fed condition.
A number of findings suggest that zero-calorie d-allulose, also known as d-psicose, has beneficial effects on obesity-related metabolic disturbances. However, it is unclear whether d-allulose can normalize the metabolic status of diet-induced obesity without having an impact on the energy density. We investigated whether 5% d-allulose supplementation in a high fat diet(HFD) could normalize body fat in a diet-induced obesity animal model under isocaloric pair-fed conditions.. Mice were fed an HFD with or without various sugar substitutes (d-glucose, d-fructose, erytritol, or d-allulose, n = 10 per group) for 16 wk. Body weight and fat-pad mass in the d-allulose group were dramatically lowered to that of the normal group with a simultaneous decrease in plasma leptin and resistin concentrations. d-allulose lowered plasma and hepatic lipids while elevating fecal lipids with a decrease in mRNA expression of CD36, ApoB48, FATP4, in the small intestine in mice. In the liver, activities of both fatty acid synthase and β-oxidation were downregulated by d-allulose to that of the normal group; however, in WAT, fatty acid synthase was decreased while β-oxidation activity was enhanced.. Taken together, our findings suggest that 5% dietary d-allulose led to the normalization of the metabolic status of diet-induced obesity by altering lipid-regulating enzyme activities and their gene-expression level along with fecal lipids. Topics: Adiposity; Animals; Apolipoprotein B-48; Blood Glucose; Body Weight; CD36 Antigens; Diet, High-Fat; Dietary Supplements; Fatty Acid Transport Proteins; Fructose; Gene Expression Regulation; Glucose; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Resistin; Sweetening Agents | 2016 |
Examining associations between dietary patterns and metabolic CVD risk factors: a novel use of structural equation modelling.
The association between dietary patterns and metabolic cardiovascular risk factors has long been addressed but there is a lack of evidence towards the effects of the overall diet on the complex net of biological inter-relationships between risk factors. This study aimed to derive dietary patterns and examine their associations with metabolic cardiovascular risk factors following a theoretic model for the relationship between them. Participants included 417 adults of both sexes, enrolled to the cross-sectional population-based study performed in Brazil. Body weight, waist circumference, high-sensitivity C-reactive protein, blood pressure, total cholesterol:HDL-cholesterol ratio, TAG:HDL-cholesterol ratio, fasting plasma glucose and serum leptin were evaluated. Food consumption was assessed by two non-consecutive 24-h dietary recalls adjusted for the within-person variation of intake. A total of three dietary patterns were derived by exploratory structural equation modelling: 'Traditional', 'Prudent' and 'Modern'. The 'Traditional' pattern had a negative and direct effect on obesity indicators (serum LEP, body weight and waist circumference) and negative indirect effects on total cholesterol:HDL-cholesterol ratio, TAG:HDL-cholesterol ratio and fasting plasma glucose. The 'Prudent' pattern had a negative and direct effect on systolic blood pressure. No association was observed for the 'Modern' pattern and metabolic risk factors. In conclusion, the 'Traditional' and 'Prudent' dietary patterns were negatively associated with metabolic cardiovascular risk factors among Brazilian adults. Their apparent protective effects against obesity and high blood pressure may be important non-pharmacological strategies for the prevention and control of obesity-related metabolic disorders and CVD. Topics: Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Brazil; C-Reactive Protein; Cardiovascular Diseases; Cross-Sectional Studies; Diet; Feeding Behavior; Female; Humans; Leptin; Lipids; Male; Middle Aged; Models, Biological; Obesity; Risk Factors; Waist Circumference | 2016 |
Leptin Signaling Is Not Required for Anorexigenic Estradiol Effects in Female Mice.
Estradiol and leptin are critical hormones in the regulation of body weight. The aim of this study was to determine whether this cross talk between leptin receptor (LepRb) and estrogen receptor-α (ERα) signaling is critical for estradiol's anorexigenic effects. Leprb-Cre mice were crossed with Cre-dependent Tau-green fluorescent protein (GFP) reporter, Stat3-flox or Erα-flox mice to generate female mice with GFP expression, signal transducer and activator of transcription 3 (STAT3) knockout (KO), or ERα KO, specifically in LepRb-expressing cells. The proportion of Leprb-GFP cells colocalizing ERα was high (∼80%) in the preoptic area but low (∼10%) in the mediobasal hypothalamus, suggesting that intracellular cross talk between these receptors is minimal for metabolic regulation. To test whether estradiol enhanced arcuate leptin sensitivity, ovarectomized mice received varying levels of estradiol replacement. Increasing estrogenic states did not increase the degree of leptin-induced STAT3 phosphorylation. LepRb-specific STAT3 KO mice and controls were ovarectomized and given either chronic estradiol or vehicle treatment to test whether STAT3 is required for estrogen-induced body weight suppression. Both groups of estradiol-treated mice showed an equivalent reduction in body weight and fat content compared with vehicle controls. Finally, mice lacking ERα specifically in LepRb-expressing neurons also showed no increase in body weight or impairments in metabolic function compared with controls, indicating that estradiol acts independently of leptin-responsive cells to regulate body weight. However, fecundity was impaired in in Leprb-ERα KO females. Contrary to the current dogma, we report that estradiol has minimal direct actions on LepRb cells in the mediodasal hypothalamus and that its anorexigenic effects can occur entirely independently of LepRb-STAT3 signaling in female mice. Topics: Animals; Body Weight; Eating; Estradiol; Estrogen Receptor alpha; Female; Hypothalamus; Leptin; Mice; Mice, Knockout; Neurons; Phosphorylation; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor | 2016 |
Parkinsonia aculeata (Caesalpineaceae) improves high-fat diet-induced insulin resistance in mice through the enhancement of insulin signaling and mitochondrial biogenesis.
The search for natural agents that minimize obesity-associated disorders is receiving special attention. Parkinsonia aculeata L. (Caesalpineaceae) has long been used in Brazil as a hypoglycaemic herbal medicine, without any scientific basis.. In this context, we aimed to use molecular and physiological methods to study the effect of a hydroethanolic extract partitioned with ethyl acetate from the aerial parts of Parkinsonia aculeata (HEPa/EtOAc) on insulin resistance in a mouse model of diet-induced obesity (DIO).. Firstly, C57BL/6J mice were fed either with standard rodent chow diet or a high-fat diet (HFD) for 12 consecutive weeks. Then, the animals were treated with HEPa/EtOAc at two doses (125 and 250mg/kg/day) or metformin (200mg/kg/day) for 16 days. At the end of the experiment, body weight, fat pad weight, fasting serum glucose (FSG), insulin (FSI) and leptin were measured. Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was also calculated. Glucose, insulin and pyruvate tolerance tests were performed. The expression and phosphorylation of IRβ(tyr), Akt(ser473), AMPKα and PGC1α in liver, muscle and adipose tissue were determined by Western blot analyses.. Herein we demonstrate for the first time an improvement in insulin resistance following HEPa/EtOAc administration in obese mice, as shown by increased glucose, insulin and pyruvate tolerance, as well as an improvement in FSG, FSI, HOMA-IR and circulating leptin levels, which together are in part due to enhancement of the insulin signaling pathway in its main target tissues. Surprisingly, the increase in activation of the AMPKα-PGC1-α axis by HEPa/EtOAc was similar to that produced by metformin treatment in the liver and muscle tissues.. In conclusion, P. aculeata appears to be a source of therapeutic agent against obesity-related complications. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Brazil; Diet, High-Fat; Dietary Fats; Fabaceae; Fasting; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mitochondria; Obesity; Plant Extracts; Signal Transduction | 2016 |
Orexin Plays a Role in Growth Impediment Induced by Obstructive Sleep Breathing in Rats.
The mechanisms linking sleep disordered breathing with impairment of sleep and bone metabolism/architecture are poorly understood. Here, we explored the role of the neuropeptide orexin, a respiratory homeostasis modulator, in growth retardation induced in an upper airway obstructed (AO) rat model.. The tracheae of 22-day-old rats were narrowed; AO and sham-control animals were monitored for 5 to 7 w. Growth parameters, food intake, sleep/wake activity, and serum hormones were measured. After euthanasia, growth plate (GP) histology, morphometry, orexin receptors (OXR), and related mediators were analyzed. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and GP histology were also investigated.. The AO group slept 32% less; the time spent in slow wave and paradoxical sleep during light period and slow wave activity was reduced. The AO group gained 46% less body weight compared to the control group, despite elevated food intake; plasma ghrelin increased by 275% and leptin level decreased by 44%. The impediment of bone elongation and bone mass was followed by a 200% increase in OX1R and 38% reduction of local GP ghrelin proteins and growth hormone secretagogue receptor 1a. Sry-related transcription factor nine (Sox9), a molecule mediating cartilage ossification, was downregulated and the level of transcription factor peroxisome proliferator-activated receptor gamma was upregulated, explaining the bone architecture abnormalities. Administration of almorexant restored sleep and improved GP width in AO animals.. In AO animals, enhanced expression of orexin and OX1R plays a role in respiratory induced sleep and growth abnormalities. Topics: Acetamides; Animals; Body Weight; Bone Development; Eating; Ghrelin; Growth Disorders; Homeostasis; Isoquinolines; Leptin; Male; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Rats; Rats, Sprague-Dawley; Respiration; Sleep; Sleep Apnea Syndromes; Sleep, REM; Wakefulness | 2016 |
Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction.
Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis. Topics: Adipose Tissue; Adult; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Evaluation, Preclinical; Energy Intake; Epididymis; Glucose; Glucosides; Humans; Hyperphagia; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Organ Size; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Weight Loss | 2016 |
Celastrol, an NF-κB inhibitor, ameliorates hypercalciuria and articular cartilage lesions in a mouse model of secondary osteoporosis.
Notwithstanding compelling contribution of NF-κB to the progression of osteoporosis has been reported, little is known regarding direct inhibition of NF-κB benefiting osteoporosis. In this study, therefore, we evaluated the role of celastrol, an NF-κB inhibitor, in a mouse model of secondary osteoporosis. Animals were divided into three groups as Sham (control), SO (secondary osteoporosis) and SO + CA (secondary osteoporosis treated with celastrol). Significant decreases in body weight and body fat were observed following celastrol treatment in SO group, but leptin levels were much higher. Celastrol also exhibited a significant decrease in urinary calcium excretion. Moreover, other important events were observed after celastrol treatment, covering substantial decrements in serum concentrations of PTH, TRAP-5b, CTX and DPD, improved structure of articular cartilage and cancellous bone (revealed by H&E and safranin-O staining), and significant decline in levels of NF-κB (P65), MMP-1, and MMP-9. These findings demonstrated that celastrol treatment not only improved abnormal lipid metabolism and hypercalciuria in mice subjected to secondary osteoporosis, but also ameliorated articular cartilage lesions. Our results provided evidence of targeted therapy for NF-κB in the clinical treatment of secondary osteoporosis. Topics: Adipose Tissue; Animals; Body Weight; Cartilage, Articular; Disease Models, Animal; Disease Progression; Hypercalciuria; Leptin; Lipid Metabolism; Male; Mice, Inbred C57BL; Molecular Targeted Therapy; NF-kappa B; Osteoporosis; Parathyroid Hormone; Pentacyclic Triterpenes; Triterpenes | 2016 |
High-Fat Diet-Induced Obesity Ablates Gastric Vagal Afferent Circadian Rhythms.
Rats with high-fat diet (HFD)-induced obesity increase daytime eating, suggesting an alteration in circadian food intake mechanisms. Gastric vagal afferents (GVAs) respond to mechanical stimuli to initiate satiety. These signals are dampened in HFD mice and exhibit circadian variations inversely with food intake in lean mice. Furthermore, leptin shows circadian variation in its circulating level and is able to modulate GVA mechanosensitivity. However, whether leptin's ability to modulate GVAs occurs in a circadian manner is unknown. Therefore, we investigated whether changes in the circadian intake of food in HFD-induced obesity is associated with a disruption in GVA circadian rhythms. Eight-week-old male C57BL/6 mice were fed a standard laboratory diet (SLD) or a HFD for 12 weeks. A subgroup of SLD and HFD mice were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at zeitgeber time 0 (ZT0) and stomach content was measured. After 12 weeks, HFD mice consumed more food during the light phase through larger and more frequent meals compared with SLD mice. SLD mice exhibited circadian fluctuation in stomach content, which peaked at ZT18 and reached a nadir at ZT9. At these time points, both tension and mucosal receptor mechanosensitivity were the lowest and highest, respectively. HFD mice exhibited little circadian variation in stomach content or GVA mechanosensitivity. Leptin potentiated mucosal receptor mechanosensitivity only in SLD mice and with reduced potency during the dark phase. In conclusion, loss of circadian variation in GVA signaling may underpin changes in eating behavior in HFD-induced obesity.. Appropriate circadian control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong circadian changes in food intake, but the contributing mechanisms have yet to be determined. Vagal afferents are involved in regulation of feeding behavior, particularly meal size, and have been shown to exhibit circadian fluctuation in mechanosensitivity, potentially allowing for time of day-specific levels of satiety signaling. Our study indicates that, in diet-induced obesity, these circadian fluctuations in gastric vagal afferent mechanosensitivity are lost. This was accompanied by increased light phase eating, particularly increased meal size. This is the first evidence that diet-induced disruption to vagal afferent signaling may cause a perturbation in circadian eating patterns. Topics: Action Potentials; Afferent Pathways; Animals; Body Weight; Circadian Rhythm; CLOCK Proteins; Diet, High-Fat; Disease Models, Animal; Eating; Energy Metabolism; Ghrelin; Leptin; Male; Mechanoreceptors; Mice; Mice, Inbred C57BL; Obesity; Physical Stimulation; Rats; Stomach; Vagus Nerve | 2016 |
Mechanical Vibration Mitigates the Decrease of Bone Quantity and Bone Quality of Leptin Receptor-Deficient Db/Db Mice by Promoting Bone Formation and Inhibiting Bone Resorption.
Leptin, a major hormonal product of adipocytes, is involved in regulating appetite and energy metabolism. Substantial studies have revealed the anabolic actions of leptin on skeletons and bone cells both in vivo and in vitro. Growing evidence has substantiated that leptin receptor-deficient db/db mice exhibit decreased bone mass and impaired bone microstructure despite several conflicting results previously reported. We herein systematically investigated bone microarchitecture, mechanical strength, bone turnover and its potential molecular mechanisms in db/db mice. More importantly, we also explored an effective approach for increasing bone mass in leptin receptor-deficient animals in an easy and noninvasive manner. Our results show that deterioration of trabecular and cortical bone microarchitecture and decreases of skeletal mechanical strength-including maximum load, yield load, stiffness, energy, tissue-level modulus and hardness-in db/db mice were significantly ameliorated by 12-week, whole-body vibration (WBV) with 0.5 g, 45 Hz via micro-computed tomography (μCT), three-point bending, and nanoindentation examinations. Serum biochemical analysis shows that WBV significantly decreased serum tartrate-resistant acid phosphatase 5b (TRACP5b) and CTx-1 levels and also mitigated the reduction of serum osteocalcin (OCN) in db/db mice. Bone histomorphometric analysis confirmed that decreased bone formation-lower mineral apposition rate, bone formation rate, and osteoblast numbers in cancellous bone-in db/db mice were suppressed by WBV. Real-time PCR assays show that WBV mitigated the reductions of tibial alkaline phosphatase (ALP), OCN, Runt-related transcription factor 2 (RUNX2), type I collagen (COL1), BMP2, Wnt3a, Lrp6, and β-catenin mRNA expression, and prevented the increases of tibial sclerostin (SOST), RANK, RANKL, RANL/osteoprotegerin (OPG) gene levels in db/db mice. Our results show that WBV promoted bone quantity and quality in db/db mice with obvious anabolic and anticatabolic effects. This study not only enriches our basic knowledge about bone quality and bone turnover mechanisms in leptin receptor-deficient animals, but also advances our understanding of the skeletal sensitivity of leptin-resistant db/db mice in response to external mechanical stimulation. © 2016 American Society for Bone and Mineral Research. Topics: Animals; Biomechanical Phenomena; Blood Glucose; Body Weight; Bone and Bones; Bone Resorption; Cancellous Bone; Gene Expression Regulation; Leptin; Male; Mice; Osteogenesis; Receptors, Leptin; Vibration; X-Ray Microtomography | 2016 |
CB2 cannabinoid receptor is involved in the anti-inflammatory effects of leptin in a model of traumatic brain injury.
The rates for traumatic brain injury (TBI) have risen in the last decade. Studies in animal models and clinical trials have not yet resulted in an effective treatment for TBI. Leptin, a 16kDa peptidic hormone is mainly known as a regulator of energy balance and has been shown to exert neuroprotective effects in different models of brain pathology. In this study, we have assessed whether leptin exerts protective actions in a TBI mouse model. In addition, the possible implication of CB2 cannabinoid receptor in leptin actions has been explored, since it is known that the endocannabinoid system interacts with leptin and actively participates in brain recovery after lesions.. Swiss (CD1) male mice were subjected to weigh-drop model for TBI. Prior to the lesion, mice were injected with an antagonist of CB2 receptor (AM630) or the vehicle and immediately after TBI, they received leptin or vehicle treatment. Data were analyzed using a two-way ANOVA or the non-parametric test Kruskal-Wallis when appropriate. For correlation analyses, Spearman's rho test, followed by linear regression test, was used.. TBI induced a neurological deficit, which was improved by leptin treatment. Leptin recovered several parameters affected by TBI, including the expression of cannabinoid receptors, axonal injury marker and neuroinflammatory components. The effects of leptin were prevented or reduced when it was administered in combination with the CB2 receptor antagonist, AM630.. Since some of the beneficial effects of leptin were not evident in the presence of AM630, our results suggest that CB2 receptor might be involved in the full expression of the neuroprotective effects of the hormone. These findings open new avenues for the study of leptin as a therapeutic treatment for TBI and enhance the importance of CB2 receptor in TBI pathophysiology and recovery. Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Axons; Behavior, Animal; Body Weight; Brain Injuries; Cannabinoid Receptor Antagonists; Cytokines; Indoles; Leptin; Male; Mice; Nervous System Diseases; Neuritis; Neuroprotective Agents; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2 | 2016 |
Protein Restriction During the Last Third of Pregnancy Malprograms the Neuroendocrine Axes to Induce Metabolic Syndrome in Adult Male Rat Offspring.
Metabolic malprogramming has been associated with low birth weight; however, the interplay between insulin secretion disruption and adrenal function upon lipid metabolism is unclear in adult offspring from protein-malnourished mothers during the last third of gestation. Thus, we aimed to study the effects of a maternal low-protein diet during the last third of pregnancy on adult offspring metabolism, including pancreatic islet function and morphophysiological aspects of the liver, adrenal gland, white adipose tissue, and pancreas. Virgin female Wistar rats (age 70 d) were mated and fed a protein-restricted diet (4%, intrauterine protein restricted [IUPR]) from day 14 of pregnancy until delivery, whereas control dams were fed a 20.5% protein diet. At age 91 d, their body composition, glucose-insulin homeostasis, ACTH, corticosterone, leptin, adiponectin, lipid profile, pancreatic islet function and liver, adrenal gland, and pancreas morphology were assessed. The birth weights of the IUPR rats were 20% lower than the control rats (P < .001). Adult IUPR rats were heavier, hyperphagic, hyperglycemic, hyperinsulinemic, hyperleptinemic, and hypercorticosteronemic (P < .05) with higher low-density lipoprotein cholesterol and lower high-density lipoprotein cholesterol, adiponectin, ACTH, and insulin sensitivity index levels (P < .01). The insulinotropic action of glucose and acetylcholine as well as muscarinic and adrenergic receptor function were impaired in the IUPR rats (P < .05). Maternal undernutrition during the last third of gestation disrupts the pancreatic islet insulinotropic response and induces obesity-associated complications. Such alterations lead to a high risk of metabolic syndrome, characterized by insulin resistance, visceral obesity, and lower high-density lipoprotein cholesterol. Topics: Adrenal Glands; Animals; Blood Glucose; Body Weight; Cholesterol; Diet, Protein-Restricted; Eating; Female; Insulin; Insulin Resistance; Leptin; Male; Maternal Nutritional Physiological Phenomena; Metabolic Syndrome; Pancreas; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar | 2016 |
Anti-obesity potential of enzymatic fragments of hyaluronan on high-fat diet-induced obesity in C57BL/6 mice.
Hyaluronan has diverse biological activities depending on its molecular size. The hyaluronan fragments (50 kDa) can decrease adipogenic differentiation in vitro. However, in vivo anti-obesitic effects of hyaluronan fragments have not been elucidated. Therefore, we examined the anti-obesity effects of hyaluronan fragments on high-fat diet induced obesity in C57BL/6 mice. Oral administration of hyaluronan fragments (200 mg/kg for 8 weeks) decreased body weight, adipose tissues, serum lipid (low-density lipoprotein cholesterol, triglyceride), and leptin level. Hyaluronan fragments decreased the hypertrophy of adipose tissue and ameliorated liver steatosis. The mRNA expression of leptin was reduced in adipocyte by treatment with hyaluronan fragments. Additionally, hyaluronan fragments enhanced the mRNA expression of PPAR-α and its target genes UCP-2 and decreased mRNA expression of PPAR- γ and fatty acid synthase in liver. In conclusions, hyaluronan fragments had marked effects on inhibiting the development of obesity in obese mice fed the high-fat diet. It suggested that enhancing PPAR-α and suppressing PPAR-γ expression are two possible mechanisms for the anti-obesitic effect of hyaluronan fragments. Topics: Adipocytes; Adiponectin; Animals; Body Weight; Diet, High-Fat; Fatty Liver; Hyaluronic Acid; Hyperlipidemias; Leptin; Lipid Metabolism; Lipids; Lipoproteins, LDL; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Weight; Obesity; PPAR alpha; Real-Time Polymerase Chain Reaction; Triglycerides | 2016 |
Onset of leptin resistance shows temporal differences related to dose or pulsed treatment.
Leptin administration results in leptin resistance presenting a significant barrier to therapeutic use of leptin. Consequently, we examined two hypotheses. The first examined the relationship between leptin dose and development of physiological and biochemical signs of leptin resistance. We hypothesized lower doses of leptin would produce proportional reductions in body weight without the adverse leptin-induced leptin resistance. The second compared pulsed central leptin infusion to continuous leptin infusion. We hypothesized that pulsed infusion at specific times of the day would evoke favorable body weight reductions while tempering the development of leptin-induced leptin resistance. The first experiment examined leptin responsiveness, including food intake, body weight and hypothalamic STAT3 phosphorylation to increasing doses of viral gene delivery of leptin. Varying the dose proved inconsequential with respect to long-term therapy and demonstrated proportional development of leptin resistance. The second experiment examined leptin responsiveness to pulsed central leptin infusion, comparing pulsed versus constant infusion of 3μg/day leptin or a 2h morning versus a 2h evening pulsed leptin infusion. Pulsed delivery of the supramaximal dose of 3μg/day was not different than constant delivery. Morning pulsed infusion of the submaximal dose of 0.25μg reduces food intake only over subsequent immediate meal period and was associated with body weight reductions, but results in cellular leptin resistance. Evening pulsed infusion did not decrease food intake but reduces body weight and maintains full leptin signaling. The positive benefit for pulsed delivery remains speculative, yet potentially may provide an alternative mode of leptin therapy. Topics: Adipose Tissue, Brown; Animals; Body Composition; Body Weight; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Eating; Gene Expression Regulation; Leptin; Male; Rats; Signal Transduction; Time Factors; Uncoupling Protein 1 | 2016 |
[Specific features of gastroesophageal reflux disease associated with obesity and overweight].
To reveal the specific features of gastroesophageal reflux disease (GERD) associated with obesity and overweight, by investigating the clinical and endoscopic manifestations of the disease, 24-hour pH-metry scores, and leptin levels.. A total of 131 patients with GERD were examined. The data about complaints and those from life and medical histories were collected; anthropometric measurements and the results of blood biochemical tests, esophagoduodenoscopy (EPDS), and pH-metry were assessed; and the serum levels of leptin and its receptor were estimated. The patients were allocated into a study group (104 obese and/or overweight patients) and a comparison one (27 normal weight people).. Waist circumference, hip circumference, and blood glucose levels proved to be statistically significantly higher in the study group (p<0.00000, p<0.00002, and p<0.02, respectively). The obese patients were found to have a statistically significantly higher level of leptin and a lower level of its soluble receptors: the median leptin levels were 30.42 (13.42-45.62) ng/ml in the study group and 5.47 (3.35-7.68) ng/ml in the comparison group; the median levels of the receptors were 18.83 (14.98-25.11) ng/ml and 30.93 (24.68-33.53) ng/ml, respectively). This group showed a moderate negative correlation between these indicators (rs=-0.451; p<0.0004). The study group displayed higher pH values in the gastric cardia and body (p<0.05 and p<0.04, respectively). The mucosal contact time with the refluxate having with a low pH value (<4) in the above segments turned out to be longer in the comparison group (p<0.05). There were weight-independent relationships of the leptin level to its spread, aggressiveness quotient, to the highest pH value in the gastric cardia and body, and to the mucosal contact time with the refluxate having a pH below 4.0 (rs=0.543; p<0.006; rs=0.432; p<0.04; rs=0.431; p<0.04; rs=-0.450; p<0.03, respectively), leptin receptors with a pH ratio in the gastric cardia and body, to the number of reflux episodes longer than 5 minutes in the esophagus, and to the De Meester index for this indicator (rs=0.471; p<0.04; rs=-0.455; p<0.04; rs=-0,454; p<0.04, respectively).. Obese and overweight patients develop GERD in the presence of leptin resistance and biliary tract disease, which determines the specific features of the disease (alkaline or mixed refluxate) and the need for individualized therapy.. Цель исследования. Выявление особенностей течения гастроэзофагеальной рефлюксной болезни (ГЭРБ), ассоциированной с ожирением и избыточной массой тела, на основании изучения клинических и эндоскопических проявлений заболевания, данных суточной рН-метрии и продукции лептина. Материалы и методы. Обследовали 131 больного ГЭРБ. Выполняли сбор жалоб, анамнеза жизни и заболевания, оценку антропометрических показателей, биохимического анализа крови, результатов эзофагодуоденоскопии (ЭФГДС), рН-метрии, уровней лептина и его рецептора в сыворотке крови. Пациентов распределили в основную группу (104 больных с ожирением и/или избытком массы тела) и группу сравнения (27 с нормальной массой тела). Результаты. Окружность талии, бедер, уровень глюкозы в крови оказались статистически значимо выше в основной группе (p<0,00000; p<0,00002 и p<0,02 соответственно). У пациентов с ожирением выявлены статистически значимо более высокий уровень лептина и более низкий уровень растворимых рецепторов к нему: медиана уровня лептина 30,42 (13,42; 45,62) нг/мл в основной группе против 5,47 (3,35-7,68) нг/мл, медиана рецепторов - 18,83 (14,98; 25,11) нг/мл против 30,93 (24,68; 33,53) нг/мл. Между данными показателями в этой группе обнаружена отрицательная связь умеренной силы (rs=–0,451; p<0,0004). В основной группе отмечены более высокие значения рН в кардиальном отделе и теле желудка (p<0,05 и p<0,04 соответственно). Длительность контакта забрасываемого содержимого с низким рН (<4) в указанных отделах оказалась больше в группе сравнения (p<0,05). Выявлены независимые от массы тела взаимосвязи уровня лептина с разбросом, индексом агрессивности, максимальным значением рН в кардии и теле желудка и длительностью контакта забрасываемого содержимого с рН менее 4,0 (rs=0,543, p<0,006; rs=0,432, p<0,04; rs=0,431, p<0,04; rs=–0,450, p<0,03 соответственно), рецепторов к лептину с индексом соотношения рН в кардии и теле желудка, числом рефлюксов более 5 мин в пищеводе и индексом De Meester по данному показателю (rs=0,471, p<0,04; rs=–0,455, p<0,04; rs=–0,454, p<0,04 соответственно). Заключение. ГЭРБ у лиц с ожирением и избыточной массой тела формируется в условиях лептинорезистентности и патологии билиарного тракта, что обусловливает особенности течения заболевания (щелочное, смешанное забрасываемое содержимое) и необходимость индивидуализации терапии. Topics: Adult; Biliary Tract Diseases; Body Mass Index; Body Weight; Comorbidity; Endoscopy, Digestive System; Esophageal pH Monitoring; Female; Gastroesophageal Reflux; Humans; Leptin; Male; Middle Aged; Obesity; Receptors, Leptin; Risk Factors; Russia; Statistics as Topic | 2016 |
Leptin regulates energy intake but fails to facilitate hibernation in fattening Daurian ground squirrels (Spermophilus dauricus).
Body fat storage before hibernation affects the timing of immergence in Daurian ground squirrels (Spermophilus dauricus). Leptin is an adipose signal and plays vital role in energy homeostasis mainly by action in brain. To test the hypothesis that leptin plays a role in facilitating the process of hibernation, squirrels were administrated with recombinant murine leptin (1μg/day) through intracerebroventricular (ICV) injection for 12 days during fattening. From day 7 to 12, animals were moved into a cold room (5±1°C) with constant darkness which functioned as hibernaculum. Energy intake, body mass and core body temperature (Tb) were continuously monitored throughout the course of experiment. Resting metabolic rate (RMR) was measured under both warm and cold conditions. At the end of leptin administration, we measured the serum concentration of hormones related to energy regulation, mRNA expression of hypothalamic neuropeptides and uncoupling protein 1 (UCP1) levels in brown adipose tissue (BAT). Our results showed that during leptin administration, the cumulative food intake and increase of body mass were suppressed while Tb and RMR were unaltered. The proportion of torpid squirrels was not different between two groups. At the end of leptin administration, the expressions of hypothalamic neuropeptide Y and agouti gene-related protein were suppressed. There were no differences in UCP1 mRNA expression or protein content in BAT between groups. Our data suggest that leptin can affect energy intake via hypothalamic neuropeptides, but is not involved in the initiation of hibernation in fattening Daurian ground squirrels. Topics: Adipose Tissue, Brown; Animals; Body Weight; Energy Intake; Hibernation; Hyperphagia; Hypothalamus; Leptin; Neuropeptide Y; Sciuridae; Thermogenesis; Uncoupling Protein 1 | 2016 |
p53-upregulated-modulator-of-apoptosis (PUMA) deficiency affects food intake but does not impact on body weight or glucose homeostasis in diet-induced obesity.
BCL-2 proteins have been implicated in the control of glucose homeostasis and metabolism in different cell types. Thus, the aim of this study was to determine the role of the pro-apoptotic BH3-only protein, p53-upregulated-modulator-of-apoptosis (PUMA), in metabolic changes mediated by diet-induced obesity, using PUMA deficient mice. At 10 weeks of age, knockout and wild type mice either continued consuming a low fat chow diet (6% fat), or were fed with a high fat diet (23% fat) for 14-17 weeks. We measured body composition, glucose and insulin tolerance, insulin response in peripheral tissues, energy expenditure, oxygen consumption, and respiratory exchange ratio in vivo. All these parameters were indistinguishable between wild type and knockout mice on chow diet and were modified equally by diet-induced obesity. Interestingly, we observed decreased food intake and ambulatory capacity of PUMA knockout mice on high fat diet. This was associated with increased adipocyte size and fasted leptin concentration in the blood. Our findings suggest that although PUMA is dispensable for glucose homeostasis in lean and obese mice, it can affect leptin levels and food intake during obesity. Topics: Adipose Tissue; Animals; Apoptosis Regulatory Proteins; Body Weight; Diet, High-Fat; Eating; Glucose; Glucose Tolerance Test; Homeostasis; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Recombinant Proteins; Tumor Suppressor Proteins | 2016 |
Effects of sodium butyrate supplementation on reproductive performance and colostrum composition in gilts.
Nutrients are essential for the health and survival of human beings and animals. Also, they play a major role in enhancing reproductive efficiency. The aim of the current study was to investigate the effects of sodium butyrate (SB) on reproductive performance and colostrum composition in gilts. A total of 40 Large White×Landrace replacement gilts (at the age of 160 to 175 days) were fed either a standard diet (control group, n=20) or standard diet top dressed with encapsulated SB at the level of 500 mg/kg (SB group, n=20) from 1 month before mating to 7 days after farrowing. The rate of gilts regular return to estrus after insemination was lower in SB group than the control group. The total number of piglets born (P=0.179) and the litter weight at birth (P=0.063) did not differ between the two treatment groups. However, the mean BW at day 7 tended to be greater in SB group (P=0.051) and average daily gain of piglets was greater (P=0.011) compared with control group. Colostrum samples were collected at parturition and the concentrations of total protein (P=0.197), cholesterol (P=0.161) and lactose (P=0.923) were not influenced by SB supplementation. However, compared with control gilts, colostrum from SB-treated gilts contained lower triglyceride (P=0.050). Moreover, colostrum concentrations of prolactin (P=0.005) and leptin (P=0.006) were significantly lower in SB group. No significant differences were noted for the colostral concentrations of cortisol (P=0.899), thyroxine (P=0.891) or triiodothyronine (P=0.194). The concentration of lipopolysaccharide in colostrum was not influenced by SB supplementation (P=0.972). However, colostrum from SB-treated gilts had significantly lower tumor necrosis factor α (TNFα) (P=0.030) and higher immunoglobulin A (IgA) (P=0.042). Collectively, SB supplementation could reduce the rate of gilts return to estrus, alter the composition of colostrum and enhance the growth rate of piglets. Moreover, SB could alter the immune function of newborn piglets through decreased production of TNFα and increased IgA concentration in colostrum. Topics: Animals; Animals, Newborn; Body Weight; Butyric Acid; Colostrum; Diet; Dietary Supplements; Estrus; Female; Leptin; Pregnancy; Prolactin; Reproduction; Swine | 2016 |
Changes in hunger and fullness in relation to gut peptides before and after 8 weeks of alternate day fasting.
Alternate day fasting (ADF; 25% energy intake "fast day", alternated with an ad libitum intake "feed day") is effective for weight loss. Whether or not ADF modulates hunger, fullness and gut peptides in a way that enhances dietary compliance and weight loss, remains unknown. Accordingly, this study examined the effect of ADF on postprandial appetite ratings and gut peptides.. Obese subjects (n = 59) participated in an 8-week ADF protocol where food was provided on the fast day.. Body weight decreased (P < 0.0001) by 3.9 ± 0.6 kg after 8 weeks of diet. Reductions (P < 0.05) in fat mass (-2.2 ± 0.2 kg), fat free mass (-1.4 ± 0.2 kg), visceral fat mass (-0.1 ± 0.1 kg), and resting metabolic rate (RMR; -104 ± 28 kcal/day) were also observed. Fasting leptin and insulin decreased (P < 0.05), while AUC ghrelin levels increased (P < 0.05). Despite these metabolic changes, there was no increase in subjective hunger by the end of the study. Furthermore, fullness and PYY increased (P < 0.05). Fat free mass and RMR were not related to hunger or ghrelin at any time point.. These findings suggest that the absence of a compensatory increase in hunger in conjunction with an increase in sensations of fullness may contribute to the weight loss efficacy of an 8-week ADF regimen. Topics: Basal Metabolism; Blood Glucose; Body Composition; Body Mass Index; Body Weight; Diet; Diet Records; Exercise; Fasting; Female; Ghrelin; Humans; Hunger; Insulin; Leptin; Male; Middle Aged; Patient Compliance; Peptide YY; Satiation | 2016 |
Prenatal caprine milk oligosaccharide consumption affects the development of mice offspring.
The composition of the gastrointestinal (GIT) microbiota, particularly in early life, influences the development of metabolic diseases later in life. The maternal microbiota is the main source of bacteria colonising the infant GIT and can be modified by dietary prebiotics. Our objective was to determine the effects of prenatal consumption of prebiotic caprine milk oligosaccharides (CMO) on the large intestine of female mice, milk composition, and offspring's development.. C57BL/6 mice were fed either a control diet, CMO diet, or galacto-oligosaccharide diet from mating to weaning. From weaning, some pups nursed by CMO, GOS, and control-dams were fed the control diet for 30 days. CMO or GOS-fed dams had increased colon length and milk protein concentration compared to control-fed dams. At weaning, pups from CMO-fed dams had increased body weight and colon length and increased proportions of colonic Bifidobacterium spp compared to the pups from control-fed dams. Thirty days after weaning, pups from CMO-fed dams had increased visceral fat weight compared to pups from control-fed dams.. Consumption of CMO by the dams during gestation and lactation improved the development of the pups, and the relative abundance of bifidobacteria and butyric acid in the colon, at weaning. Topics: Animals; Body Weight; Colon; Diet; Female; Femur; Gastrointestinal Microbiome; Goats; Leptin; Male; Maternal Nutritional Physiological Phenomena; Mice, Inbred C57BL; Milk; Oligosaccharides; Prebiotics; Pregnancy; Weaning | 2016 |
Fermented Barley Supplementation Modulates the Expression of Hypothalamic Genes and Reduces Energy Intake and Weight Gain in Rats.
Dietary fiber and proteins are individually known to decrease feeding, but could result greater weight management benefit when both are combined. We hypothesized that supplementing the diet with fermented barley, being rich in both dietary fiber and proteins, could lower energy intake by modulating the mRNA expression level of hypothalamic genes associated with the regulation of feeding behavior and satiety; thereby decreasing body weight gain. To test our hypothesis, four groups of Sprague Dawley rats were arranged in a 2 × 2 factorial design (n = 6), low-fat diet with either guar gum (LFD-G) or fermented barley (LFD-FB) and high-fat diet with either guar gum (HFD-G) or fermented barley (HFD-FB). Using oral gavage, fermented barley was given at a dosage of 1500 mg/kg body weight and guar gum was supplemented in an equivalent quantity to that of the fiber in the fermented barley. After 19 weeks, the fermented barley-supplemented groups showed a significant reduction in energy intake, triglyceride, body weight gain, and serum leptin, compared to the guar gum-supplemented groups in both the low- and high-fat diet groups. Likewise, the anorexigenic gene proopiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) mRNA level were significantly higher in the fermented barley-supplemented groups compared to the guar gum-supplemented groups in rats fed on both high- and low-fat diets. In conclusion, fermented barley supplementation upregulated hypothalamic POMC/CART, decreased energy intake in both low- and high-fat diet groups, and prevented excessive weight gain in rats. Topics: Animals; Body Weight; Dietary Fiber; Dietary Supplements; Energy Intake; Fermentation; Hordeum; Humans; Hypothalamus; Leptin; Male; Nerve Tissue Proteins; Obesity; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Weight Gain | 2016 |
Energy stores, lipid mobilization and leptin endocrinology of rainbow trout.
The physiological role of leptin in fish is not fully elucidated. In the present study, the involvement of the leptin system in lipid deposition and mobilization in rainbow trout during feeding and 1, 2 and 4 weeks of fasting was investigated in two lines of rainbow trout with different muscle and visceral adiposity: a fat line (FL) with high total energy reserves, high muscle adiposity, but low visceral adiposity and a lean line (LL) with lower total energy reserves and lower muscle adiposity, but higher visceral adiposity. During 4 weeks of fasting, muscle lipids decreased by 63 % in the FL fish, while no such energy mobilization from muscle occurred in the LL fish. On the other hand, lipid stores in liver and visceral adipose tissue was utilized to a similar extent by the two fish lines during fasting. Under normal feeding conditions, plasma leptin levels were higher in the LL than the FL fish, suggesting a possible contribution of visceral adipocytes to plasma leptin levels. Plasma leptin-binding protein levels did not differ between the lines and were not affected by fasting. After 4 weeks of fasting, the long leptin receptor and the leptin-binding protein isoforms 1 and 3 muscle expression increased in the LL fish, as well as hepatic expression of leptin A1 and the two binding protein isoforms. These responses were not seen in the FL fish. The data suggest that the Lep system in rainbow trout is involved in regulation of energy stores and their mobilization. Topics: Animals; Body Weight; Energy Metabolism; Fasting; Female; Fish Proteins; Gastrointestinal Tract; Leptin; Liver; Muscles; Nutritional Status; Oncorhynchus mykiss; Protein Isoforms; Receptors, Leptin | 2016 |
Serum leptin, adiponectin and ghrelin concentrations in post-menopausal women: Is there an association with bone mineral density?
Adipokines and ghrelin exert well-documented effects on energy expenditure and glucose metabolism. Experimental data also support a role in bone metabolism, although data from clinical studies are conflicting. The purpose of this cross-sectional study was to investigate the association of serum concentrations of leptin, adiponectin and ghrelin with bone mineral density (BMD) in post-menopausal women.. BMD in lumbar spine and femoral neck, and circulating leptin, adiponectin and ghrelin concentrations were measured in 110 healthy post-menopausal women. Patients with secondary causes of osteoporosis were excluded.. Osteoporosis was diagnosed in 30 (27%) women and osteopenia in 54 (49%). Serum leptin concentrations were positively correlated with both lumbar spine (r=0.343, p<0.01) and femoral neck BMD (r=0.370, p<0.01). Adiponectin concentrations were negatively associated with BMD at both sites (r=-0.321, p<0.01 and r=-0.448, p<0.01 respectively). No significant correlation between ghrelin concentrations and BMD was found. Osteoporotic women had lower body weight, body mass index (BMI) and leptin concentrations, but higher adiponectin concentrations compared with non-osteoporotic women. In multivariate stepwise regression analysis, the association of adiponectin concentrations with BMD remained significant only for femoral neck, after adjustment for body weight or BMI.. An inverse association between adiponectin and femoral neck BMD was found in post-menopausal women, independently of body weight. The positive association between leptin and BMD was dependent on body weight, whereas no effect of ghrelin on BMD was evident. Topics: Adiponectin; Aged; Aged, 80 and over; Body Mass Index; Body Weight; Bone Density; Bone Diseases, Metabolic; Cross-Sectional Studies; Female; Femur Neck; Ghrelin; Humans; Leptin; Lumbar Vertebrae; Middle Aged; Osteoporosis; Postmenopause | 2016 |
Effect of trans-chalcone on atheroma plaque formation, liver fibrosis and adiponectin gene expression in cholesterol-fed NMRI mice.
Trans-chalcone is the precursor molecule to flavonoids and possesses antioxidant and anti-inflammatory properties. This study aimed to evaluate the effects of trans-chalcone on atheroma plaque formation and the relevant biochemical parameters in high cholesterol diet (HCD)-fed NMRI mice.. Fifty male NMRI mice were divided into 5 groups (n=10 per group): control (received a normal diet); HCD (received an additional 2% cholesterol for 18 weeks); sham (received a HCD for 12 weeks and were then shifted to a normal diet and trans-chalcone vehicle (sunflower oil) for 6 weeks), and two experimental groups (received a HCD for 12 weeks and were then shifted to a normal diet and either 12mg/kg or 24mg/kg trans-chalcone for 6 weeks).. After 12 weeks, HCD-induced atheroma plaques were observed by hematoxylin and eosin staining of aortic sections. At the end of experiment, the following factors had significantly increased in the HCD group: body weight, insulin resistance, and serum levels of triglycerides, total-cholesterol, glucose, insulin, leptin, liver enzymes (AST and ALT), malondialdehyde and direct bilirubin. The serum levels of high-density lipoprotein cholesterol, adiponectin, superoxide dismutase, and glutathione had considerably decreased. Histologic analysis of liver sections indicated hepatic fibrosis and steatosis. Treatment by both doses of trans-chalcone, particularly the 24mg/kg dose, significantly attenuated these alterations.. Administration of trans-chalcone improved the consequences of atheroma plaque formation and liver fibrosis via increased expression of adiponectin, generation of higher levels of antioxidant enzymes, as well as modulation of serum leptin and lipid profiles. Topics: Adiponectin; Animals; Bilirubin; Blood Glucose; Body Weight; Chalcone; Cholesterol; Cholesterol, HDL; Fatty Liver; Gene Expression; Glutathione; Insulin; Insulin Resistance; Leptin; Liver Cirrhosis; Male; Malondialdehyde; Mice; Plaque, Atherosclerotic; Superoxide Dismutase; Triglycerides | 2016 |
Effects of chronic testosterone administration on body weight and food intake differ among pre-pubertal, gonadal-intact, and ovariectomized female rats.
In females, estrogens play pivotal roles in preventing excessive body weight gain. On the other hand, the roles of androgen in female appetite and body weight regulation have not been fully studied. In this study, whether the roles of androgen in the regulation of body weight and appetite were different among ages and/or the estrogen milieu in females was evaluated. Body weight gain and food intake were increased by chronic testosterone administration in pre-pubertal and gonadal-intact female rats, but not in ovariectomized female rats. Testosterone administration also affected the serum leptin level and adipose leptin gene expression levels differently in each experimental condition. Hypothalamic mRNA levels of ERα, which plays pivotal roles in regulation of body weight and metabolism, were decreased by chronic testosterone administration in pre-pubertal and gonadal-intact female rats, but not in ovariectomized female rats. These results indicate that the effects of testosterone on body weight and appetite differed among ages and/or estrogen milieu in female rats, and that attenuation of estrogens' actions on the hypothalamus might be partly involved in the androgen-induced increases of body weight gain and food intake in females. Topics: Aging; Androgens; Animals; Body Weight; Eating; Estrogen Receptor alpha; Estrogens; Female; Hypothalamus; Leptin; Ovariectomy; Random Allocation; Rats, Sprague-Dawley; RNA, Messenger; Testosterone | 2016 |
Bisphenol A Promotes Adiposity and Inflammation in a Nonmonotonic Dose-response Way in 5-week-old Male and Female C57BL/6J Mice Fed a Low-calorie Diet.
A growing body of epidemiological research show that Bisphenol A (BPA) is positively correlated with obesity and metabolic disorders. However, the mechanisms of BPA on adiposity remain largely unknown. In this study, we found that 5-week-old male and female C57BL/6J mice exposed to four dosages of BPA (5, 50, 500, and 5000 μg/kg/d) by oral intake for 30 days showed significantly increased body weight and fat mass in a nonmonotonic dose-dependent manner when fed a chow diet. The effect occurred even at the lowest concentration (5μg/kg/d), lower than the tolerable daily intake of 50 μg/kg/day for BPA. However, no significant difference in body weight and fat mass was observed in either male or female mice fed a high-fat diet, suggesting that BPA may interact with diet in promoting obesity risk. In vitro study showed that BPA treatment drives the differentiation of white adipocyte progenitors from the stromal vascular fraction, partially through glucocorticoid receptor. BPA exposure increased circulating inflammatory factors and the local inflammation in white adipose tissues in both genders fed a chow diet, but not under high-fat diet. We further found that BPA concentration was associated with increased circulating inflammatory factors, including leptin and TNFα, in lean female subjects (body mass index < 23.0 kg/m(2)) but not in lean male subjects or in both sexes of overweight/obese subjects (body mass index > 25.0 kg/m(2)). In conclusion, we demonstrated the nonmonotonic dose effects of BPA on adiposity and chronic inflammation in 5-week-old mice, which is related to caloric uptake. Topics: Adiposity; Aged; Animals; Benzhydryl Compounds; Body Weight; Caloric Restriction; Cell Differentiation; Diet, High-Fat; Female; Humans; Inflammation; Leptin; Male; Mice; Mice, Inbred C57BL; Middle Aged; Obesity; Phenols; Real-Time Polymerase Chain Reaction; Receptors, Glucocorticoid | 2016 |
Salidroside improves glucose homeostasis in obese mice by repressing inflammation in white adipose tissues and improving leptin sensitivity in hypothalamus.
Salidroside is a functionally versatile natural compound from the perennial flowering plant Rhodiola rosea L. Here, we examined obese mice treated with salidroside at the dosage of 50 mg/kg/day for 48 days. Mice treated with salidroside showed slightly decreased food intake, body weight and hepatic triglyceride content. Importantly, salidroside treatment significantly improved glucose and insulin tolerance. It also increased insulin singling in both liver and epididymal white adipose tissue (eWAT). In addition, salidroside markedly ameliorated hyperglycemia in treated mice, which is likely due to the suppression of gluconeogenesis by salidroside as the protein levels of a gluconeogenic enzyme G6Pase and a co-activator PGC-1α were all markedly decreased. Further analysis revealed that adipogenesis in eWAT was significantly decreased in salidroside treated mice. The infiltration of macrophages in eWAT and the productions of pro-inflammatory cytokines were also markedly suppressed by salidroside. Furthermore, the leptin signal transduction in hypothalamus was improved by salidroside. Taken together, these euglycemic effects of salidroside may due to repression of adipogenesis and inflammation in eWAT and stimulation of leptin signal transduction in hypothalamus. Thus, salidroside might be used as an effective anti-diabetic agent. Topics: Adipose Tissue, White; Animals; Body Weight; Eating; Epididymis; Glucose-6-Phosphatase; Glucosides; Hyperglycemia; Hypothalamus; Inflammation; Leptin; Liver; Male; Mice; Mice, Obese; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phenols; Triglycerides | 2016 |
Voluntary physical activity abolishes the proliferative tumor growth microenvironment created by adipose tissue in animals fed a high fat diet.
The molecular mechanisms behind the obesity-breast cancer association may be regulated via adipokine secretion by white adipose tissue. Specifically, adiponectin and leptin are altered with adiposity and exert antagonistic effects on cancer cell proliferation. We set out to determine whether altering adiposity in vivo via high fat diet (HFD) feeding changed the tumor growth supporting nature of adipose tissue and whether voluntary physical activity (PA) could ameliorate these HFD-dependent effects. We show that conditioned media (CM) created from the adipose tissue of HFD fed animals caused an increase in the proliferation of MCF7 cells compared with cells exposed to CM prepared from the adipose of lean chow diet fed counterparts. This increased proliferation was driven within the MCF7 cells by an HFD-dependent antagonism between AMP-activated protein kinase (AMPK) and protein kinase B (Akt) signaling pathways, decreasing p27 protein levels via reduced phosphorylation at T198 and downregulation of adiponectin receptor 1 (AdipoR1). PA can ameliorate these proliferative effects of HFD-CM on MCF7 cells, increasing p27(T198) by AMPK, reducing pAkt(T308), and increasing AdipoR1, resulting in cell cycle withdrawal in a manner that depends on the PA intensity. High physical activity (>3 km/day) completely abolished the effects of HFD feeding. In addition, AdipoR1 overexpression mimics the effects of exercise, abolishing the proliferative effects of the HFD-CM on MCF7 cells and further enhancing the antiproliferative effects of PA on the HFD-CM. Thus voluntary PA represents a means to counteract the proliferative effects of adipose tissue on breast cancers in obese patients. Topics: Adipokines; Adiponectin; Adipose Tissue; Adiposity; AMP-Activated Protein Kinases; Animals; Body Weight; Cell Proliferation; Culture Media, Conditioned; Diet, High-Fat; Humans; Leptin; Male; MCF-7 Cells; Neoplasms; Obesity; Physical Conditioning, Animal; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Tumor Microenvironment | 2016 |
Memory impairment is associated with the loss of regular oestrous cycle and plasma oestradiol levels in an activity-based anorexia animal model.
Patients with anorexia nervosa (AN) suffer from neuropsychological deficits including memory impairments. Memory partially depends on 17β-oestradiol (E2), which is reduced in patients with AN. We assessed whether memory functions correlate with E2 plasma levels in the activity-based anorexia (ABA) rat model.. Nine 4-week-old female Wistar rats were sacrificed directly after weight loss of 20-25% (acute starvation), whereas 17 animals had additional 2-week weight-holding (chronic starvation). E2 serum levels and novel object recognition tasks were tested before and after starvation and compared with 21 normally fed controls.. Starvation disrupted menstrual cycle and impaired memory function, which became statistically significant in the chronic state (oestrous cycle (P < 0.001), E2 levels (P = 0.011) and object recognition memory (P = 0.042) compared to controls). E2 reduction also correlated with the loss of memory in the chronic condition (r = 0.633, P = 0.020).. Our results demonstrate that starvation reduces the E2 levels which are associated with memory deficits in ABA rats. These effects might explain reduced memory capacity in patients with AN as a consequence of E2 deficiency and the potentially limited effectiveness of psychotherapeutic interventions in the starved state. Future studies should examine whether E2 substitution could prevent cognitive deficits and aid in earlier readiness for therapy. Topics: Animals; Anorexia Nervosa; Body Weight; Disease Models, Animal; Estradiol; Estrous Cycle; Female; Humans; Leptin; Memory Disorders; Rats; Rats, Wistar | 2016 |
Adult NG2-Glia Are Required for Median Eminence-Mediated Leptin Sensing and Body Weight Control.
While leptin is a well-known regulator of body fat mass, it remains unclear how circulating leptin is sensed centrally to maintain energy homeostasis. Here we show that genetic and pharmacological ablation of adult NG2-glia (also known as oligodendrocyte precursors), but not microglia, leads to primary leptin resistance and obesity in mice. We reveal that NG2-glia contact the dendritic processes of arcuate nucleus leptin receptor (LepR) neurons in the median eminence (ME) and that these processes degenerate upon NG2-glia elimination, which explains the consequential attenuation of these neurons' molecular and electrical responses to leptin. Our data therefore indicate that LepR dendrites in the ME represent the principal conduits of leptin's anorexigenic action and that NG2-glia are essential for their maintenance. Given that ME-directed X-irradiation confirmed the pharmacological and genetically mediated ablation effects on body weight, our findings provide a rationale for the known obesity risk associated with cranial radiation therapy. Topics: Aging; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Body Weight; Cell Proliferation; Cytarabine; Dendrites; Electrophysiological Phenomena; Female; Gene Deletion; Leptin; Male; Median Eminence; Mice; Microglia; Mitosis; Neuroglia; Obesity; Phenotype; Receptors, Leptin; Signal Transduction; Weight Gain | 2016 |
Long-Term High Fat Diet Has a Profound Effect on Body Weight, Hormone Levels, and Estrous Cycle in Mice.
BACKGROUND Obesity causes several health complications along with disruption of the reproductive system. The aim of the current study was to determine how long-term intake of very high fat diet (VHFD) changes the hormonal milieu, affecting the cellular morphology and reproductive cycle in female mice. MATERIAL AND METHODS Mice were fed on normal diet (ND) and VHFD for 2 weeks, 12 weeks, and 25-27 weeks. We assessed changes in body weight, food consumption, energy intake, cellular and tissue morphology, hormonal levels (leptin, insulin, and estradiol), and vaginal smears were performed at various time points to determine the length and cellularity at each stage of the estrous cycle. RESULTS Mice fed on VHFD showed a significant increase in weight gain, reduction in food intake, and increase in energy intake compared to animals fed on ND, indicating that the caloric density of the diet is responsible for the differences in weight gain. Hormonal analysis showed hyperleptinemia, hyperinsulinemia, and increases in estrogen levels, along with increases in size of the islet of Langerhans and adipocytes. After 25-27 weeks, all animals fed on VHFD showed complete acyclicity; elongation of phases (e.g., diestrous), skipping of phases (e.g., metestrous), or a combination of both, indicating disruption in the reproductive cycle. Quantitative analysis showed that in the diestrous phase there was a 70% increase in cell count in VHFD compared to animals fed on ND. CONCLUSIONS The above results show that morphological and hormonal changes caused by VHFD probably act via negative feedback to the hypothalamic-pituitary axis to shut down reproduction, which has a direct effect on the estrous cycle, causing acyclicity in mice. Topics: Adipocytes; Animals; Body Weight; Diet, High-Fat; Eating; Energy Intake; Estradiol; Estrous Cycle; Female; Hormones; Insulin; Leptin; Mice; Mice, Inbred C57BL; Obesity; Weight Gain | 2016 |
Cord blood leptin levels in relation to child growth trajectories.
Leptin represents a potential modulator of developmental programming of childhood obesity. We investigated the association of cord blood leptin with growth trajectories from birth to early childhood.. We used data from the prospective mother-child cohort "Rhea", Crete, Greece. Cord blood samples from 642 neonates were collected. 578 (90%) children had complete follow up data from birth to 4years. We measured child weight, height, waist circumference, skinfold thicknesses, blood pressure, and serum lipids, leptin, adiponectin and C-reactive protein in early childhood (median 4.2years). We estimated growth trajectories from 3months up to 4years using random-effects linear-spline models. Multivariable logistic and linear regression models were used adjusting for confounders.. Mean cord blood leptin levels were 7.3ng/mL (standard deviation: 6.3). Children with high cord blood leptin (>90th percentile) exhibited lower weight, height and body mass index from 6months to early childhood. Each SD increase in cord blood leptin was associated with lower weight at the age of 4 by 242g (95% CI: -416, -69). In a stratified analysis, the reverse association was observed in children born small for gestational age (p for interaction=0.001), and in those exhibiting rapid infant growth during the first 3months of life (p for interaction=0.002). Cord blood leptin levels were not associated with cardiometabolic risk factors at 4years.. Long term programming effects of in utero exposure to leptin extends beyond infancy into early childhood. Further studies are needed to explore potential effect modification by intrauterine and early infancy growth patterns. Topics: Adiponectin; Body Height; Body Weight; Child Development; Child, Preschool; Female; Fetal Blood; Greece; Humans; Infant; Infant, Newborn; Leptin; Lipids; Male; Waist Circumference | 2016 |
Time-restricted feeding reduces adiposity in mice fed a high-fat diet.
Disruption of the circadian rhythm contributes to obesity. This study tested the hypothesis that time-restricted feeding (TRF) reduces high-fat diet-induced increase in adiposity. Male C57BL/6 mice were fed the AIN93G or the high-fat diet ad libitum (ad lib); TRF of the high-fat diet for 12 or 8hours during the dark cycle was initiated when high-fat diet-fed mice exhibited significant increases in body weight. Energy intake of the TRF 12-hour group was not different from that of the high-fat ad lib group, although that of the TRF 8-hour group was slightly but significantly lower. Restricted feeding of the high-fat diet reduced body fat mass and body weight compared with mice fed the high-fat diet ad lib. There were no differences in respiratory exchange ratio (RER) among TRF and high-fat ad lib groups, but the RER of these groups was lower than that of the AIN93G group. Energy expenditure of the TRF groups was slightly but significantly lower than that of the high-fat ad lib group. Plasma concentrations of ghrelin were increased in TRF groups compared with both AIN93G and high-fat ad lib groups. Elevations of plasma concentrations of insulin, leptin, monocyte chemoattractant protein-1, and tissue inhibitor metalloproteinase-1 by high-fat ad lib feeding were reduced by TRF to the levels of mice fed the AIN93G diet. In conclusion, TRF during the dark cycle reduces high-fat diet-induced increases in adiposity and proinflammatory cytokines. These results indicate that circadian timing of food intake may prevent obesity and abate obesity-related metabolic disturbance. Topics: Adiposity; Animals; Body Weight; Chemokine CCL2; Circadian Rhythm; Diet, High-Fat; Disease Models, Animal; Energy Metabolism; Ghrelin; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Time Factors; Tissue Inhibitor of Metalloproteinase-1 | 2016 |
Morning and Evening Blue-Enriched Light Exposure Alters Metabolic Function in Normal Weight Adults.
Increasing evidence points to associations between light-dark exposure patterns, feeding behavior, and metabolism. This study aimed to determine the acute effects of 3 hours of morning versus evening blue-enriched light exposure compared to dim light on hunger, metabolic function, and physiological arousal. Nineteen healthy adults completed this 4-day inpatient protocol under dim light conditions (<20lux). Participants were randomized to 3 hours of blue-enriched light exposure on Day 3 starting either 0.5 hours after wake (n = 9; morning group) or 10.5 hours after wake (n = 10; evening group). All participants remained in dim light on Day 2 to serve as their baseline. Subjective hunger and sleepiness scales were collected hourly. Blood was sampled at 30-minute intervals for 4 hours in association with the light exposure period for glucose, insulin, cortisol, leptin, and ghrelin. Homeostatic model assessment of insulin resistance (HOMA-IR) and area under the curve (AUC) for insulin, glucose, HOMA-IR and cortisol were calculated. Comparisons relative to baseline were done using t-tests and repeated measures ANOVAs. In both the morning and evening groups, insulin total area, HOMA-IR, and HOMA-IR AUC were increased and subjective sleepiness was reduced with blue-enriched light compared to dim light. The evening group, but not the morning group, had significantly higher glucose peak value during blue-enriched light exposure compared to dim light. There were no other significant differences between the morning or the evening groups in response to blue-enriched light exposure. Blue-enriched light exposure acutely alters glucose metabolism and sleepiness, however the mechanisms behind this relationship and its impacts on hunger and appetite regulation remain unclear. These results provide further support for a role of environmental light exposure in the regulation of metabolism. Topics: Adolescent; Adult; Arousal; Body Weight; Darkness; Energy Metabolism; Environmental Exposure; Female; Ghrelin; Humans; Hunger; Hydrocortisone; Leptin; Light; Male; Middle Aged; Sleep; Young Adult | 2016 |
Cluster Differentiating 36 (CD36) Deficiency Attenuates Obesity-Associated Oxidative Stress in the Heart.
Obesity is often associated with a state of oxidative stress and increased lipid deposition in the heart. More importantly, obesity increases lipid influx into the heart and induces excessive production of reactive oxygen species (ROS) leading to cell toxicity and metabolic dysfunction. Cluster differentiating 36 (CD36) protein is highly expressed in the heart and regulates lipid utilization but its role in obesity-associated oxidative stress is still not clear.. The aim of this study was to determine the impact of CD36 deficiency on cardiac steatosis, oxidative stress and lipotoxicity associated with obesity.. Studies were conducted in control (Lean), obese leptin-deficient (Lepob/ob) and leptin-CD36 double null (Lepob/obCD36-/-) mice. Compared to lean mice, cardiac steatosis, and fatty acid (FA) uptake and oxidation were increased in Lepob/ob mice, while glucose uptake and oxidation was reduced. Moreover, insulin resistance, oxidative stress markers and NADPH oxidase-dependent ROS production were markedly enhanced. This was associated with the induction of NADPH oxidase expression, and increased membrane-associated p47phox, p67phox and protein kinase C. Silencing CD36 in Lepob/ob mice prevented cardiac steatosis, increased insulin sensitivity and glucose utilization, but reduced FA uptake and oxidation. Moreover, CD36 deficiency reduced NADPH oxidase activity and decreased NADPH oxidase-dependent ROS production. In isolated cardiomyocytes, CD36 deficiency reduced palmitate-induced ROS production and normalized NADPH oxidase activity.. CD36 deficiency prevented obesity-associated cardiac steatosis and insulin resistance, and reduced NADPH oxidase-dependent ROS production. The study demonstrates that CD36 regulates NADPH oxidase activity and mediates FA-induced oxidative stress. Topics: Animals; Blood Platelet Disorders; Body Weight; CD36 Antigens; Fatty Acids; Female; Genetic Diseases, Inborn; Glucose Tolerance Test; Heart; Heterozygote; Homozygote; Insulin; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Microsomes; Myocytes, Cardiac; NADPH Oxidases; Obesity; Organ Size; Oxidative Stress; Oxygen; Palmitates; Phenotype; Reactive Oxygen Species | 2016 |
FTO rs 9939609 SNP Is Associated With Adiponectin and Leptin Levels and the Risk of Obesity in a Cohort of Romanian Children Population.
Obesity is a disorder with increasing frequency in children and adolescents, directly linked with various diseases. Variants in the FTO (fat mass and obesity-related) gene have been associated with body mass index and waist and hip circumferences in widespread populations.The aim of this case-control study was to assess if there is any association between FTO gene variants rs9939609, respectively, rs17817449 with anthropometric and metabolic biomarkers (fasting glucose, TC, HDL-cholesterol, LDL-cholesterol, triglycerides) and adipokines (adiponectin and leptin), in Romanian obese children.A total of 387 children, 201 obese and 186 nonobese individuals, were included in this prospective study. Genotyping of the FTO gene polymorphisms for all subjects was performed using the restriction fragment length polymorphism (PCR-RFLP) method.Significant associations were found between FTO rs9939609 single nucleotide polymorphism (SNP) and obesity. AA genotype carriers have a 2.02 times higher risk for obesity compared with AT+TT genotype carriers. Risk allele carriers of rs17817449 SNP had somewhat higher values of weight, body mass index, waist and hip circumference, total cholesterol, triglycerides, adiponectin, and fasting glucose.This study revealed the genetic association between rs9939609 SNP of FTO and obesity in a Romanian population, and to the authors' knowledge, this is the first study to investigate this association in a Romanian population. This study also established that combined variant genotypes (AA/GG) of FTO rs9939609 /rs17817449 are strongly associated with several measures of adiposity (weight, BMI-SD, mid-upper arm circumference, tricipital skinfold thicknesses) and are also associated with total cholesterol, triglyceride, and LDL-cholesterol levels. Topics: Adiponectin; Adolescent; Alleles; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Blood Glucose; Body Mass Index; Body Weight; Case-Control Studies; Child; Child, Preschool; Cholesterol; Female; Genotype; Humans; Infant; Leptin; Male; Obesity; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; Romania; Triglycerides; Waist Circumference | 2016 |
Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance.
Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NES(Cre)/PPARγ-P467L) or selectively in POMC neurons (POMC(Cre)/PPARγ-P467L). Whereas POMC(Cre)/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMC(Cre)/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMC(Cre)/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMC(Cre)/PPARγ-WT, but not POMC(Cre)/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions. Topics: 3T3 Cells; Adipogenesis; Animals; Body Weight; Brain; Cell Line; Diet, High-Fat; Energy Metabolism; Female; HEK293 Cells; Homeostasis; Humans; Leptin; Male; Mice; Neurons; Obesity; PPAR gamma; Pro-Opiomelanocortin; Rosiglitazone; Thiazolidinediones; Weight Gain | 2016 |
Non-hematopoietic effects of endogenous erythropoietin on lean mass and body weight regulation.
To investigate the concurrent relationships between human plasma erythropoietin concentrations and energy expenditure (EE), body composition, plasma leptin concentrations, and associations with weight change.. Plasma to measure erythropoietin and leptin; data for body composition; 24-h EE measured in a whole-room calorimeter; and 75 g oral glucose tolerance testing were available from 109 full-heritage Pima Indians (55% male) from a larger study designed to understand the causes of obesity. Seventy-nine subjects had data for weight at a later visit (mean follow-up = 4.3 ± 1.9 years) to calculate percent weight change per year.. Erythropoietin, adjusted for covariates, correlated with 24-h EE (r = 0.26, P = 0.007), sleeping EE (r = 0.29, P = 0.003), fat-free mass (r = 0.19, P = 0.05), and fat mass (r = 0.27, P = 0.005), but not insulin or glucose measures. The association of erythropoietin with 24-h EE was fully mediated by fat-free mass. Erythropoietin associated with leptin in women (ρ = 0.36, P = 0.01), but not in men (P = 0.9), independently from fat mass. The association of erythropoietin with percent weight change per year was in opposing directions (interaction: P = 0.002) in males (r = -0.35, P = 0.02) versus females (r = 0.37, P = 0.02).. Non-hematopoietic endogenous erythropoietin action may be involved in body weight regulation in opposing directions in men and women, i.e., weight loss in men and weight gain in women. Topics: Adolescent; Adult; Body Composition; Body Weight; Energy Metabolism; Erythropoietin; Female; Glucose Tolerance Test; Humans; Indians, North American; Insulin; Leptin; Male; Middle Aged; Obesity; Sex Factors; Young Adult | 2016 |
Effect of intermittent hypoxia on arcuate nucleus in the leptin-deficient rat.
Intermittent hypoxia (IH) is a major pathophysiological consequence of obstructive sleep apnea. Recently, it has been shown that IH results in changes in body energy balance, leptin secretion and concomitant alterations in arcuate nucleus (ARC). In this study, the role of leptin on these changes was investigated in leptin-deficient rats exposed to IH or normoxic control conditions. Body weights, consumatory and locomotor behaviours, and protein signaling in ARC were assessed immediately after IH exposure. Compared to normoxia, IH altered body weight, food intake, locomotor pattern, and the plasma concentration of leptin and angiotensin II in the wild-type rat. However, these changes were not observed in the leptin-deficient rat. Within ARC of wild-type animals, IH increased phosphorylated signal transducer and activator of transcription 3 and pro-opiomelanocortin protein expression, but not in the leptin-deficient rat. The long-form leptin receptor protein expression was not altered following IH in either rat strain. These data suggest that leptin is involved in mediating the alterations to body energy balance and ARC activity following IH. Topics: Angiotensin II; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Drinking; Eating; Hypoxia; Leptin; Locomotion; Male; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor | 2016 |
Cardiometabolic risk markers of normal weight and excess body weight in Brazilian adolescents.
Excess body weight leads to a variety of metabolic changes and increases the risk for cardiovascular diseases (CVD) in adulthood. The objective of this study was to investigate the presence of risk markers for CVD among Brazilian adolescents of normal weight and with excess body weight. The markers included blood pressure, C-reactive protein, homocysteine, tumor necrosis factor alpha, fibrinogen, fasting insulin and glucose, homeostasis model assessment of insulin resistance (HOMA-IR), leptin, total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triglycerides. We calculated odds ratios (OR) using logistic regression and adjusted for potential confounders such as age, sex, physical activity, and socioeconomic background. Compared with normal weight subjects, overweight/obese adolescents were more likely to have higher systolic blood pressure (OR = 3.49, p < 0.001), fasting insulin (OR = 8.03, p < 0.001), HOMA-IR (OR = 8.03, p < 0.001), leptin (OR = 5.55, p < 0.001), and LDL-c (OR = 5.50, p < 0.001) and lower serum HDL-c concentrations (OR = 2.76, p = 0.004). After adjustment for confounders, the estimates did not change substantially, except for leptin for which the risk associated with overweight increased to 11.09 (95% CI: 4.05-30.35). In conclusion, excess body weight in adolescents exhibits strong associations with several markers that are established as causes of CVD in adults. This observation stresses the importance of primary prevention and of maintaining a healthy body weight throughout adolescence to reduce the global burden of CVD. Topics: Adolescent; Biomarkers; Blood Glucose; Blood Pressure; Body Weight; Brazil; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Cross-Sectional Studies; Exercise; Female; Fibrinogen; Homocysteine; Humans; Insulin; Insulin Resistance; Leptin; Logistic Models; Male; Metabolic Syndrome; Overweight; Risk Factors; Socioeconomic Factors; Triglycerides; Tumor Necrosis Factor-alpha | 2016 |
Central leptin resistance and hypothalamic inflammation are involved in letrozole-induced polycystic ovary syndrome rats.
Accumulating evidence indicates that leptin acts as an important mediator in energy homeostasis and reproduction. Since dysfunction of reproduction and metabolism are major characteristics of polycystic ovarian syndrome (PCOS), the role of leptin in pathogenesis of PCOS needs further research. Many studies have shown that central leptin resistance existed in obesity rats through leptin intracerebroventricular (icv) injection; however, central leptin resistance in PCOS rats has not been reported. This study aimed to investigate whether there was a state of central leptin resistance in PCOS rats, as well as explore the possible association of hypothalamic inflammation with central leptin resistance. First, letrozole was used to induce the PCOS model, 24 h food intake, 24 h body weight changes and the expression of p-STAT3 were determined following leptin or artificial cerebrospinal fluid (aCSF) icv injection in rats. Second, we further evaluated the expressions of IL-1β, IL-6, TNF-α, p-IKKβ, NF-κB, p-NF-κB, IκBα, p-IκBα and SOCS3 in hypothalamus. The results showed that 24 h food intake and body weight were decreased, while the expression of p-STAT3 was increased in control group rats following leptin icv injection compared with aCSF icv injection; however, both of them showed no significant difference in PCOS rats. Furthermore, inflammatory markers were upregulated in the hypothalami of PCOS rats. Taken together, our data indicated that there was a state of chronic low-grade inflammation in hypothalamus which might be the possible mechanism for central leptin resistance in PCOS rats. Topics: Animals; Body Weight; Eating; Female; Hypothalamus; Inflammation; Leptin; Letrozole; Nitriles; Ovary; Polycystic Ovary Syndrome; Rats, Sprague-Dawley; Suppressor of Cytokine Signaling 3 Protein; Triazoles | 2016 |
Leptin serum concentrations are associated with weight gain during lithium augmentation.
Meta-analytical data show lithium augmentation (LA) as an effective treatment strategy in major depression. Weight-gain is a common side effect of LA. The proteohormone leptin is discussed to be involved in the pathophysiology of weight gain induced by psychopharmacological treatment. The purpose of our study was to investigate the association of leptin and body mass index (BMI) during LA in a prospective cohort study.. Leptin serum concentrations and body mass index (BMI) were measured in a total of 89 acute depressive patients before and then after four weeks of LA.. In a linear mixed model analysis the following variables had a significant positive effect on BMI: time (equal with "treatment effect of LA"; F1.83=6.05; p=0.016) and leptin (F1.111=13.83; p=0.0003) as well as the covariates male gender (F1.89=5.08; p=0.027) and adiposity (F1.85=105.13; p<0.0001).. If the reported effect of leptin on BMI is specific to LA remains unclear without a control group.. Leptin signalling might be involved in lithium-induced weight-gain. Topics: Adult; Aged; Body Mass Index; Body Weight; Cohort Studies; Depressive Disorder, Major; Female; Humans; Leptin; Lithium; Male; Middle Aged; Obesity; Prospective Studies; Weight Gain | 2016 |
Leptin promoter variant G2548A is associated with serum leptin and HDL-C levels in a case control observational study in association with obesity in a Pakistani cohort.
Leptin is a protein hormone synthesized by adipocytes and is involved in the regulation of food intake and energy expenditure. We hypothesized that any change in the promoter sequence can affect the expression of the gene and hence leptin protein levels in the serum. The aim of the current study was to investigate the relationship of such a promoter variant of the leptin gene, G-2548A polymorphism, with obesity and its effect on various anthropometric and metabolic parameters in a Pakistani cohort consisting of 250 obese and 225 non-obese control subjects. Body weight, height, waist circumference (WC), hip circumference (HC) and blood pressure (BP) were measured by standard methods and levels of fasting blood glucose (FBG), total cholesterol, triglycerides, HDLC, LDLC, and leptin were determined. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that the LEP G-2548A polymorphism showed significant association with obesity in Pakistan. In addition, the polymorphism showed association with weight, height, BMI, WC, HDLC and serum leptin levels. The findings suggest that the leptin promoter G-2548A variant may play its part in the progression to obesity by not only affecting the body's fat distribution but also by changing the serum leptin and HDLC levels. Topics: Adolescent; Adult; Aged; Body Weight; Child; Cholesterol, HDL; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Male; Middle Aged; Obesity; Pakistan; Polymorphism, Single Nucleotide; Promoter Regions, Genetic | 2016 |
Effects of postnatal bromocriptine injection on thyroid function and prolactinemia of rats at adulthood.
Previously, we demonstrated that maternal prolactin inhibition at the end of lactation, using bromocriptine (BRO), leads to an increase in leptin transfer via milk and induces the adult progeny to present hypothyroidism, leptin resistance and metabolic syndrome (obesity, hyperglycemia, hypertriglyceridemia, lower HDL). To test if these alterations are due to direct BRO action on the pups, in the present study we evaluated the long-term effects of direct injection of BRO (0.1μg/once daily) in male Wistar rats from postnatal (PN) day 1 to 10 (early treatment) or from PN11 to 20 (late treatment) on: food intake, body mass, cardiovascular parameters, hormone profile, hypothalamic leptin signaling, glucose homeostasis and thyroid hormone-dependent proteins. The respective controls were injected with methanol-saline. Offspring were killed at adulthood (PN180). Adult PN1-10 BRO-treated animals had lower food intake, hypoprolactinemia, lower leptin action (lower OBR-b, STAT-3 and SOCS-3 mRNA levels in the arcuate nucleus), lower TRH-TSH-thyroid axis as well as lower thyroid hormone markers. On the other hand, adult animals that were BRO-treated during the PN11-20 period showed hyperphagia, higher blood pressure, higher prolactinemia and OBR-b, higher TRH and plasma T3, hypercorticosteronemia as well as higher Dio2 and UCP1 mRNA expression in the brown adipose tissue. Glucose homeostasis was not changed treatment in either period. Our data show that early and late dopamine overexposure during lactation induces diverse metabolic disturbances later in life, increasing the risk of thyroid dysfunction and, consequently, changes in prolactinemia. Topics: Animals; Animals, Newborn; Blood Pressure; Body Weight; Bromocriptine; Eating; Heart Rate; Hypothalamus; Leptin; Male; Prolactin; Rats; Rats, Wistar; Thyroid Gland; Thyroid Hormones | 2016 |
Serum Leptin as a Nutritional Biomarker in Children with Cerebral Palsy.
Adequate nutrition is crucial for children with cerebral palsy (CCP). However, conventional nutritional assessments may be inadequate for defining undernourished CCP. Leptin, an adipocyte hormone controlling energy expenditure, could be a useful marker. Objectives of this cross-sectional analytic study were to explore correlations between serum leptin level and nutritional status, anthropometric measurements, and biochemical parameters in 86 CCP (aged 9 ± 2 years). Subscapular (SST) and triceps (TST) skinfold thicknesses, weight, and calculated height were obtained. Body mass index and weight-for-height (WH) Z-scores were calculated. Complete blood count and serum levels of leptin and albumin were collected. CCP were classified as undernourished if their WHZ was < -2 according to the World Health Organization criteria. Correlations between anthropometric measurements, biochemical data, and serum leptin levels were evaluated. From 86 CCP, 11 (12%) children were undernourished, and SST, hemoglobin, and hematocrit were significantly lower. Serum leptin levels of nourished and undernourished CCP were 5.4 ± 6.2 and 2.9 ± 1.6 ng/mL (p < 0.001), while the reported value from normal children was 4.9 ng/mL. Serum leptin levels demonstrated a significant correlation with SST and TST (r = 0.83 and 0.72; p < 0.001). Serum leptin was the only marker significantly correlated with WHZ (r = 0.45, p < 0.001) while adjusting for covariates. A serum leptin level of 2.2 ng/mL was the optimal cutoff point for defining adequate nutritional status (WHZ ≥ -2). The measurement of serum leptin should be included in a care scheme of CCP especially during surgical evaluation. Topics: Biomarkers; Body Height; Body Weight; Cerebral Palsy; Child; Demography; Female; Humans; Leptin; Male; ROC Curve; Skinfold Thickness | 2016 |
High-fat diet-induced hypertension and autonomic imbalance are associated with an upregulation of CART in the dorsomedial hypothalamus of mice.
We evaluated herein whether diet-induced obesity alters sympathovagal balance, blood pressure, and neuropeptides levels at the hypothalamus and brainstem of mice. Male C57BL6J mice fed with a high-fat (HFD) or a high-fat high-sucrose (HFHSu), or a regular chow diet (C) for 8 weeks were evaluated for metabolic parameters and blood pressure, the latter being performed in conscious freely moving mice. Spectral analysis from the records of systolic blood pressure (SBP) and cardiac pulse intervals (PI) was performed to analyse the autonomic balance in the cardiovascular system. HFD-fed mice developed two distinct hemodynamic phenotypes: hypertensive mice (HFD-H) with high systolic and diastolic BP levels and hypertension-resistant mice (HFD-R) whose BP levels were similar to C group. Spectral analysis of SBP and PI variabilities indicate that the low-frequency (LF)/high-frequency (HF) ratio, which is an index of sympathovagal balance, is higher in HFD-H compared to HFD-R. Along with hypertension and higher LF/HF ratio, HFD-H mice presented increased hypothalamic mRNA levels of cocaine- and amphetamine-regulated transcript (CART), and increased CART-positive neurones in the dorsomedial hypothalamus (DMH) by high-fat diet when compared to C group. Despite developing obesity to similar levels than HFD feeding, intake of a HFHSu was not associated with hypertension in mice neither CART levels increase. Collectively, our main findings indicate that high-fat diet induced-hypertension and autonomic imbalance are associated to an upregulation of CART levels in the DMH of mice. Topics: Animals; Autonomic Nervous System Diseases; Blood Pressure; Body Weight; Diet, High-Fat; Dorsomedial Hypothalamic Nucleus; Hypertension; Insulin; Interleukin-6; Leptin; Male; Mice; Nerve Tissue Proteins; Obesity; Resistin; Up-Regulation | 2016 |
Identifying factors contributing to slow growth in pigs.
Pigs that grow slower than their contemporaries can cause complications for animal welfare and profitability. This study was conducted to investigate factors that may contribute to slow growth of pigs. Pigs ( = 440) farrowed by 65 sows were monitored from birth to market. Pigs were categorized as slow, average, and fast growers based on market weight adjusted to 170 d of age (slow growers were <105 kg, average growers were between 105 and 125 kg, and fast growers were >125 kg). Blood samples were collected from 48 focal pigs at 9 and 21 wk of age and analyzed for hormone and free AA concentrations. Data were analyzed using the Mixed and Logistic procedures of SAS. Slow-growing pigs accounted for 10% of pigs marketed, average growers accounted for 49% of pigs marketed, and fast growers accounted for 41% of pigs marketed. Compared with fast growers, slow growers were lighter at birth ( < 0.01), at weaning ( < 0.01), and at nursery exit ( < 0.01) and had less backfat ( < 0.01) and smaller loin muscle area ( < 0.01) at marketing at 21 wk of age. Slow growers had lower plasma concentrations of IGF-1 ( = 0.03) and insulin ( < 0.001) during the nursery period and lower concentrations of leptin ( < 0.001) and insulin ( < 0.001) during the finishing period compared with average and fast growers. Serum concentrations of several essential, nonessential, and total free AA were less for slow growers during both the nursery and finishing periods compared with average and fast growers. Gilts were more likely to become slow growers than barrows (odds ratio = 2.17, 95% confidence interval = 1.19 to 3.96, = 0.01). Litter size and parity of the pigs' dam were not associated with slow growth. These results suggest that low concentrations of IGF-1, insulin, leptin, and AA may contribute to or be associated with slow growth in pigs. Topics: Amino Acids; Animals; Body Composition; Body Weight; Female; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Sex Factors; Swine; Weaning | 2016 |
Adult exposure to tributyltin affects hypothalamic neuropeptide Y, Y1 receptor distribution, and circulating leptin in mice.
Tributyltin (TBT), a pesticide used in antifouling paints, is toxic for aquatic invertebrates. In vertebrates, TBT may act in obesogen- inducing adipogenetic gene transcription for adipocyte differentiation. In a previous study, we demonstrated that acute administration of TBT induces c-fos expression in the arcuate nucleus. Therefore, in this study, we tested the hypothesis that adult exposure to TBT may alter a part of the nervous pathways controlling animal food intake. In particular, we investigated the expression of neuropeptide Y (NPY) immunoreactivity. This neuropeptide forms neural circuits dedicated to food assumption and its action is mediated by Y1 receptors that are widely expressed in the hypothalamic nuclei responsible for the regulation of food intake and energy homeostasis. To this purpose, TBT was orally administered at a dose of 0.025 mg/kg/day/body weight to adult animals [male and female C57BL/6 (Y1-LacZ transgenic mice] for 4 weeks. No differences were found in body weight and fat deposition, but we observed a significant increase in feed efficiency in TBT-treated male mice and a significant decrease in circulating leptin in both sexes. Computerized quantitative analysis of NPY immunoreactivity and Y1-related β-galactosidase activity demonstrated a statistically significant reduction in NPY and Y1 transgene expression in the hypothalamic circuit controlling food intake of treated male mice in comparison with controls. In conclusion, the present results indicate that adult exposure to TBT is profoundly interfering with the nervous circuits involved in the stimulation of food intake. Topics: Animals; Body Composition; Body Weight; Eating; Female; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Pesticides; Receptors, Neuropeptide Y; Trialkyltin Compounds | 2016 |
An allosteric antibody to the leptin receptor reduces body weight and reverses the diabetic phenotype in the Lep(ob) /Lep(ob) mouse.
Leptin (LEP) deficiency results in major metabolic perturbations, including obesity, dyslipidemia, and diabetes. Although LEP deficiency can be treated with daily injections of a recombinant LEP, generation of an antibody activating the LEP receptor (LEPR) that has both an intrinsically long half-life and low immunogenicity could be useful in the treatment of this condition.. Phage display technology coupled with flow cytometry and cell-based in vitro assays were employed to identify an allosteric agonist of the mouse LEPR. LEP-deficient Lep(ob) /Lep(ob) mice were used to compare in vivo effects of LEP to antibody administration. To evaluate hypothalamic effects of treatment, changes in mRNA levels of neuropeptide Y and proopiomelanocortin were measured.. XPA.80.037 is a monoclonal antibody that demonstrates allosteric agonism of the mouse LEPR. Treatment of Lep(ob) /Lep(ob) mice with XPA.80.037 markedly reduced hyperphagia and body weight, normalized blood glucose and plasma insulin levels, and corrected dyslipidemia. These metabolic alterations correlated with changes in mRNA levels of neuropeptide Y and proopiomelanocortin, suggesting that XPA.80.037 had hypothalamic effects.. Agonist allosteric monoclonal antibodies to the LEPR can correct metabolic effects associated with LEP deficiency in vivo and thereby have the potential to treat conditions of LEP deficiency. Topics: Allosteric Regulation; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Half-Life; Hypothalamus; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Obesity; Phenotype; Pro-Opiomelanocortin; Receptors, Leptin | 2016 |
Metabolic syndrome and selenium in fetal programming: gender differences.
Since Selenium (Se) forms part of glutathione peroxidase (GPx), which appears to have a dual role in Metabolic Syndrome (MS), this study evaluates the implication of Se in the transmission of this pathology to the progeny.. Se body distribution, glucose, triglycerides, cholesterol, insulin and metabolic hormones [glucagon, leptin, gastric inhibitory polypeptide (GIP), and triiodothyronine (T3)], growth factors, receptor activator of nuclear factor kappa-B ligand (RANK-L) and osteopontin, as well as oxidative hepatic balance in the offspring of dams exposed to a fructose-rich diet (65%) with normal Se content (0.01 ppm) during gestation and lactation, were measured according to sex.. Fructose pups had lower body weight; however, male pups had a lower body mass index and growth indicators in serum. Fructose pups, especially females, had lower levels of serum insulin and HOMA-IR. With regard to Se homeostasis, fructose pups presented a depletion of Se in heart and muscle, and repletion in kidneys, pancreas and thyroid, although only female pups showed a repletion of Se in the liver. Fructose pups presented lower superoxide dismutase activity and only female fructose pups had higher GPx activity, which provoked hepatic oxidation.. Se balance and Se tissue deposits in MS pups during lactation are altered by gender. This difference is focused on hepatic Se deposits that affect GPx activity, which could be related to a disruption in the insulin-signaling cascade in females. Furthermore, although female fructose pups had greater metabolic disorders, only the males' growth and development were affected. Particularly relevant is the depletion of Se found in the heart of fructose pups, as this element is essential for correct heart function. Topics: Animals; Animals, Newborn; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; Cholesterol; Female; Fetal Development; Fructose; Gastric Inhibitory Polypeptide; Glucagon; Glutathione Peroxidase; Homeostasis; Insulin; Leptin; Liver; Male; Metabolic Syndrome; Osteopontin; Oxidative Stress; RANK Ligand; Rats; Rats, Wistar; Selenium; Sex Factors; Triglycerides; Triiodothyronine | 2016 |
Mother and Infant Body Mass Index, Breast Milk Leptin and Their Serum Leptin Values.
This study investigates correlations between mother and infant Body Mass Index (BMI), their serum leptin values and breast milk leptin concentration in early infancy.. We determined serum leptin values in 58 healthy infants and leptin values in their mothers' breast milk, using radioimmunoassay (RIA). Infant and maternal anthropometrics were measured.. Median leptin concentration was 3.9 ng/mL (interquartile range (IQR): 2.75) in infant serum, 4.27 ng/mL (IQR: 5.62) in maternal serum and 0.89 ng/mL (IQR: 1.32) in breast milk. Median maternal BMI and weight were 24 kg/m² (IQR: 4.41) and 64 kg (IQR: 15). Median infant BMI was 15.80 kg/cm² (IQR: 4.02), while average weight was 5.130 kg (IQR: 1.627). Infants serum leptin values positively correlated with infants' BMI (p = 0.001; r = 0.213) and breast milk leptin (p = 0.03; r = 0.285). Maternal serum leptin values positively correlated with maternal BMI (p = 0.000, r = 0.449) and breast milk leptin ones (p = 0.026; r = 0.322).. Breast milk leptin and maternal BMI could influence infant serum leptin values. Further studies are needed to better elucidate the role of genetics and environment on infant leptin production and risk of obesity later in life. Topics: Adult; Birth Weight; Body Mass Index; Body Weight; Female; Follow-Up Studies; Humans; Infant; Leptin; Male; Middle Aged; Milk, Human; Mothers; Radioimmunoassay | 2016 |
Deletion of Suppressor of Cytokine Signaling 3 from Forebrain Neurons Delays Infertility and Onset of Hypothalamic Leptin Resistance in Response to a High Caloric Diet.
The cellular processes that cause high caloric diet (HCD)-induced infertility are poorly understood but may involve upregulation of suppressor of cytokine signaling (SOCS-3) proteins that are associated with hypothalamic leptin resistance. Deletion of SOCS-3 from brain cells is known to protect mice from diet-induced obesity, but the effects on HCD-induced infertility are unknown. We used neuron-specific SOCS3 knock-out mice to elucidate this and the effects on regional hypothalamic leptin resistance. As expected, male and female neuron-specific SOCS3 knock-out mice were protected from HCD-induced obesity. While female wild-type mice became infertile after 4 months of HCD feeding, infertility onset in knock-out females was delayed by 4 weeks. Similarly, knock-out mice had delayed leptin resistance development in the medial preoptic area and anteroventral periventricular nucleus, regions important for generation of the surge of GnRH and LH that induces ovulation. We therefore tested whether the suppressive effects of HCD on the estradiol-induced GnRH/LH surge were overcome by neuron-specific SOCS3 knock-out. Although only 20% of control HCD-mice experienced a preovulatory-like LH surge, LH surges could be induced in almost all neuron-specific SOCS3 knock-out mice on this diet. In contrast to females, HCD-fed male mice did not exhibit any fertility decline compared with low caloric diet-fed males despite their resistance to the satiety effects of leptin. These data show that deletion of SOCS3 delays the onset of leptin resistance and infertility in HCD-fed female mice, but given continued HCD feeding this state does eventually occur, presumably in response to other mechanisms inhibiting leptin signal transduction.. Obesity is commonly associated with infertility in humans and other animals. Treatments for human infertility show a decreased success rate with increasing body mass index. A hallmark of obesity is an increase in circulating leptin levels; despite this, the brain responds as if there were low levels of leptin, leading to increased appetite and suppressed fertility. Here we show that leptin resistant infertility is caused in part by the leptin signaling molecule SOCS3. Deletion of SOCS3 from brain neurons delays the onset of diet-induced infertility. Topics: Age Factors; Animals; Body Weight; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Diet, High-Fat; Disease Models, Animal; Estrous Cycle; Female; Gene Expression Regulation; Hypothalamus; Infertility; Leptin; Luteinizing Hormone; Male; Mice; Mice, Inbred DBA; Mice, Transgenic; Neurons; Obesity; Prosencephalon; Suppressor of Cytokine Signaling 3 Protein | 2016 |
Effects of random food deprivation and refeeding on energy metabolism, behavior and hypothalamic neuropeptide expression in Apodemus chevrieri.
Maintaining adaptive control of behavior and physiology is the main strategy used by animals in responding to changes of food resources. To investigate the effects of random food deprivation (FD) and refeeding on energy metabolism and behavior in Apodemus chevrieri, we acclimated adult males to FD for 4weeks, then refed them ad libitum for 4weeks (FD-Re group). During the period of FD, animals were fed ad libitum for 4 randomly assigned days each week, and deprived of food the other 3days. A control group was fed ad libitum for 8weeks. At 4 and 8weeks we measured body mass, thermogenesis, serum leptin levels, body composition, gastrointestinal tract morphology, behavior and hypothalamic neuropeptide expression. At 4weeks, food intake, gastrointestinal mass, neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expressions increased and thermogenesis, leptin levels, pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) expressions decreased in FD compared with controls. FD also showed more resting behavior and less activity than the controls on ad libitum day. There were no differences between FD-Re and controls at 8weeks, indicating significant plasticity. These results suggested that animals can compensate for unpredictable reduction in food availability by increasing food intake and reducing energy expended through thermogenesis and activity. Leptin levels, NPY, AgRP, POMC, and CART mRNA levels may also regulate energy metabolism. Significant plasticity in energy metabolism and behavior was shown by A. chevrieri over a short timescale, allowing them to adapt to food shortages in nutritionally unpredictable environments. Topics: Agouti-Related Protein; Animals; Basal Metabolism; Behavior, Animal; Body Composition; Body Weight; Eating; Energy Metabolism; Food Deprivation; Hypothalamus; Leptin; Male; Murinae; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Pro-Opiomelanocortin; RNA, Messenger; Thermogenesis | 2016 |
Bardoxolone methyl prevents obesity and hypothalamic dysfunction.
High-fat (HF) diet-induced obesity is associated with hypothalamic leptin resistance and low grade chronic inflammation, which largely impairs the neuroregulation of negative energy balance. Neuroregulation of negative energy balance is largely controlled by the mediobasal and paraventricular nuclei regions of the hypothalamus via leptin signal transduction. Recently, a derivative of oleanolic acid, bardoxolone methyl (BM), has been shown to have anti-inflammatory effects. We tested the hypothesis that BM would prevent HF diet-induced obesity, hypothalamic leptin resistance, and inflammation in mice fed a HF diet. Oral administration of BM via drinking water (10 mg/kg daily) for 21 weeks significantly prevented an increase in body weight, energy intake, hyperleptinemia, and peripheral fat accumulation in mice fed a HF diet. Furthermore, BM treatment prevented HF diet-induced decreases in the anorexigenic effects of peripheral leptin administration. In the mediobasal and paraventricular nuclei regions of the hypothalamus, BM administration prevented HF diet-induced impairments of the downstream protein kinase b (Akt) pathway of hypothalamic leptin signalling. BM treatment also prevented an increase in inflammatory cytokines, tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) in these two hypothalamic regions. These results identify a potential novel neuropharmacological application for BM in preventing HF diet-induced obesity, hypothalamic leptin resistance, and inflammation. Topics: Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Energy Intake; Energy Metabolism; Hypothalamus; Inflammation; Leptin; Male; Mice, Inbred C57BL; Obesity; Oleanolic Acid; Signal Transduction | 2016 |
The combined action of omega-3 polyunsaturated fatty acids and grape proanthocyanidins on a rat model of diet-induced metabolic alterations.
It has been suggested that food components such as ω-3 polyunsaturated fatty acids (ω-3 PUFAs) and (poly)phenols counteract diet-induced metabolic alterations by common or complementary mechanisms. To examine the effects of a combination of ω-3 PUFAs and (poly)phenols on such alterations, adult Wistar-Kyoto rats were fed an obesogenic high-fat high-sucrose diet supplemented, or not, for 24 weeks with: eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) 1 : 1 (16.6 g kg(-1) feed); proanthocyanidin-rich grape seed extract (GSE, 0.8 g kg(-1) feed); or EPA/DHA 1 : 1 + GSE. Body weight, feed intake, and plasma glucose were evaluated every 6 weeks, while adipose tissue weight, insulin, glucagon, ghrelin, leptin, adiponectin, cholesterol, and triglycerides were evaluated at the end of the experiment. ω-3 PUFAs reduced plasma leptin and cholesterol levels, but did not modify diet-induced perigonadal fat or plasma insulin levels; while GSE increased plasma triglyceride levels. The combined action of ω-3 PUFAs and the proanthocyanidins reduced plasma insulin and leptin, as well as partially prevented perigonadal fat accumulation. While separate supplementation with ω-3 PUFAs or grape proanthocyanidins may not counteract all the key metabolic changes induced by a high-energy-dense diet, the combination of both supplements reverts altered insulin, leptin and triglyceride levels to normal. Topics: Adiponectin; Adiposity; Animals; Blood Glucose; Body Weight; Cholesterol; Diet; Dietary Supplements; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; Ghrelin; Glucagon; Insulin; Leptin; Metabolic Syndrome; Proanthocyanidins; Rats; Rats, Inbred WKY; Triglycerides; Vitis | 2016 |
Response to the Commentary: "Methodological Considerations for Analysing the Relation of Physical Activity with Leptin Levels in Children: Comment on the Study by Cicchella et al. (2013)" by David Jiménez-Pavon.
This is a response to commentary by Jiménez-Pavon (2015) on the relationships of leptin levels with children's physical activity. The present response suggests actigraphs are superior to questionnaires for measuring children's physical activity. Cicchella, Stefanelli, Jurimae, Saar and Purge (2013) pointed out some interesting methodological issues related to the relationships of leptin and physical activity in normal weight children. The questions dealt with the reliability of the questionnaires in assessing physical activity in children, choices of the cut-off points for considering levels of physical activity as moderate or intense, and the association of leptin with PA levels. Some considerations in Jiménez-Pavon (2015) remain unclear. Topics: Body Weight; Child; Exercise; Humans; Leptin; Motor Activity; Reproducibility of Results; Surveys and Questionnaires | 2016 |
Estimation of umbilical cord blood leptin and insulin based on anthropometric data by means of artificial neural network approach: identifying key maternal and neonatal factors.
Leptin and insulin levels are key factors regulating fetal and neonatal energy homeostasis, development and growth. Both biomarkers are used as predictors of weight gain and obesity during infancy. There are currently no prediction algorithms for cord blood (UCB) hormone levels using Artificial Neural Networks (ANN) that have been directly trained with anthropometric maternal and neonatal data, from neonates exposed to distinct metabolic environments during pregnancy (obese with or without gestational diabetes mellitus or lean women). The aims were: 1) to develop ANN models that simulate leptin and insulin concentrations in UCB based on maternal and neonatal data (ANN perinatal model) or from only maternal data during early gestation (ANN prenatal model); 2) To evaluate the biological relevance of each parameter (maternal and neonatal anthropometric variables).. We collected maternal and neonatal anthropometric data (n = 49) in normoglycemic healthy lean, obese or obese with gestational diabetes mellitus women, as well as determined UCB leptin and insulin concentrations by ELISA. The ANN perinatal model consisted of an input layer of 12 variables (maternal and neonatal anthropometric and biochemical data from early gestation and at term) while the ANN prenatal model used only 6 variables (maternal anthropometric from early gestation) in the input layer. For both networks, the output layer contained 1 variable to UCB leptin or to UCB insulin concentration.. The best architectures for the ANN perinatal models estimating leptin and insulin were 12-5-1 while for the ANN prenatal models, 6-5-1 and 6-4-1 were found for leptin and insulin, respectively. ANN models presented an excellent agreement between experimental and simulated values. Interestingly, the use of only prenatal maternal anthropometric data was sufficient to estimate UCB leptin and insulin values. Maternal BMI, weight and age as well as neonatal birth were the most influential parameters for leptin while maternal morbidity was the most significant factor for insulin prediction.. Low error percentage and short computing time makes these ANN models interesting in a translational research setting, to be applied for the prediction of neonatal leptin and insulin values from maternal anthropometric data, and possibly the on-line estimation during pregnancy. Topics: Adult; Anthropometry; Biomarkers; Body Mass Index; Body Weight; Computer Simulation; Diabetes, Gestational; Female; Fetal Blood; Humans; Insulin; Leptin; Maternal Age; Neural Networks, Computer; Obesity; Pregnancy; Young Adult | 2016 |
Astragaloside IV improves lipid metabolism in obese mice by alleviation of leptin resistance and regulation of thermogenic network.
Obesity is a worldwide threat to public health in modern society, which may result from leptin resistance and disorder of thermogenesis. The present study investigated whether astragaloside IV (ASI) could prevent obesity in high-fat diet (HFD)-fed and db/db mice. In HFD-fed mice, ASI prevented body weight gain, lowered serum triglyceride and total cholesterol levels, mitigated liver lipid accumulation, reduced fat tissues and decreased the enlargement of adipose cells. In metabolic chambers, ASI lessened appetite of the mice, decreased their respiratory exchange ratio and elevated VCO2 and VO2 without altering circadian motor activity. Moreover, ASI modulated thermogenesis associated gene expressions in liver and brawn fat tissues, as well as leptin resistance evidenced by altered expressions of leptin, leptin receptor (ObR) or appetite associated genes. In SH-SY5Y cells, ASI enhanced leptin signaling transduction. However, in db/db mice, ASI did not change body weight gain and appetite associated genes. But it decreased serum triglyceride and total cholesterol levels as well as liver triglyceride. Meanwhile, it significantly modulated gene expressions of PPARα, PGC1-α, UCP2, ACC, SCD1, LPL, AP2, CD36 and SREBP-1c. Collectively, our study suggested that ASI could efficiently improve lipid metabolism in obese mice probably through enhancing leptin sensitivity and modulating thermogenic network. Topics: Adipose Tissue; Animals; Body Weight; Cell Line; Diet, High-Fat; Gene Expression; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Receptors, Leptin; Saponins; Thermogenesis; Triglycerides; Triterpenes; Weight Gain | 2016 |
[Change in plasma nesfatin-1 concentration within high-fat diet induced nonalcoholic fatty liver disease rat models].
To investigate the change of plasma nesfatin-1 concentration in a nonalcoholic fatty liver disease rat model induced by high-fat diet, and explore its effect on the dysfunction of glucose and lipid metabolism.. The nonalcoholic fatty liver disease rat model was established through introduction of a high-fat diet, and four weeks later, the intraperitoneal glucose tolerance test was conducted. Serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), total cholesterol (TC) triglyceride (TG), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were detected using chemiluminescence technique. The plasma levels of nesfatin-1, leptin, and insulin (INS) were measured via enzyme-linked immunosorbent assay (ELISA), the histological changes of the liver was observed via HE staining, and the protein expressions of beta-catenin, p-beta-catenin and cyclin D1 in the liver were detected using western blot and compared with beta-actin.. The bodyweight, liver weight, liver index, and area under the curve of the intraperitoneal glucose tolerance test were all higher in the model rats than those in the controls. Compared with the control, serum concentrations of ALT, TBIL, IBIL, TC and LDL-C in the model rats were all increased. The plasma nesfatin-1 level was increased in model rats while the plasma concentrations of leptin and insulin were decreased, and a negative correlation was found between the plasma concentration of nesfatin-1 and leptin. Inflammation and hepatocyte steatosis were detected in the livers of model rats, and the protein expression of cyclinD1 was upregulated while the phosphorylation of beta-catenin was decreased in the livers of the model rats.. Post-creation of nonalcoholic fatty liver disease rat models through high fat diets, changes were observed in plasma nesfatin-1 concentration, perhaps a vital part of glucose and lipid metabolism dysfunction. Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; beta Catenin; Bilirubin; Body Weight; Calcium-Binding Proteins; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cyclin D1; Diet, High-Fat; DNA-Binding Proteins; Enzyme-Linked Immunosorbent Assay; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Nerve Tissue Proteins; Non-alcoholic Fatty Liver Disease; Nucleobindins; Rats; Triglycerides | 2016 |
Differential body weight, blood pressure and placental inflammatory responses to normal versus high-fat diet in melanocortin-4 receptor-deficient pregnant rats.
Although obesity increases the risk for hypertensive disorders of pregnancy, the mechanisms remain unclear. Neural melanocortin-4 receptor (MC4R) deficiency causes hyperphagia and obesity. Effects of MC4R deficiency on body weight, blood pressure (BP) and placental inflammatory responses to high-fat diet (HFD) are unknown. We tested two hypotheses: MC4R deficiency results in higher body weight, BP and placental inflammation under normal-fat diet (NFD) conditions and HFD exaggerates these responses in MC4R-deficient pregnant rats.. MC4R and MC4R rats were maintained on NFD (13% kcal fat) or HFD (40% kcal fat) for ∼15 weeks, then measurements made on gestational day 19.. MC4R pregnant rats had greater body mass and total body fat and visceral adipose tissue weights along with greater circulating total cholesterol (TC) and leptin levels than MC4R rats regardless of diet. On NFD, circulating adiponectin levels were lower and placental TNFα levels and BP (conscious with carotid catheter) were higher in these heavier rats. Circulating adiponectin levels were lower and placental TNFα levels and BP were higher in MC4R rats compared with NFD controls. These parameters were not affected by HFD in the already heavier and hypertensive MC4R pregnant rats.. Obesity in MC4R deficiency and HFD in MC4R rats result in higher BP and placental inflammation during pregnancy. However, HFD did not exaggerate these responses in already obese MC4R pregnant rats. These data suggest that obesity and HFD are independently related to hypertension and placental inflammation in pregnancy. Topics: Adiponectin; Adiposity; Animals; Blood Pressure; Body Weight; Cholesterol; Diet, High-Fat; Female; Hypertension; Inflammation; Intra-Abdominal Fat; Leptin; Obesity; Placenta; Pregnancy; Rats; Receptor, Melanocortin, Type 4; Tumor Necrosis Factor-alpha | 2016 |
Regulation of plasma agouti-related protein and its relationship with hunger in lean and obese men.
Agouti-related protein (AgRP) is an orexigenic (appetite stimulating) neuropeptide suggested to exert tonic control over long-term energy balance. While some have speculated AgRP is not involved in the episodic (i.e. meal to meal energy intake) control, acute decreases in plasma agouti-related protein (AgRP) following a meal have been observed in humans in a role consistent with episodic control for AgRP. Whether changes in plasma AgRP are associated with episodic, and/or tonic changes in appetite has yet to be directly examined. The present study examined the relationship between agouti-related protein (AgRP), leptin and the regulation of appetite following a 48-h fast and an acute meal challenge. Blood samples were obtained from young lean and obese men before and after a 48 h fast (lean n = 10; obese n = 7). Fasting resulted in an increase in AgRP and a decrease in leptin with these changes being greater in lean than obese. In addition, blood samples were obtained from lean men before and 1, 2, 3 and 4 h after a meal (n = 8). Following a meal, AgRP was reduced from 2 to 4 h, a change that was dissociated from both leptin and subjective measures of hunger and satiety. These results demonstrate that AgRP is not associated with changes in hunger or satiety, and can change without corresponding changes in leptin. This suggests that AgRP may not be involved in the episodic control of appetite and the release of AgRP may involve signals other than leptin. Topics: Agouti-Related Protein; Appetite Regulation; Body Mass Index; Body Weight; Energy Metabolism; Humans; Hunger; Leptin; Male; Meals; Obesity; Thinness; Waist Circumference; Young Adult | 2016 |
Diet-Induced Maternal Obesity Alters Insulin Signalling in Male Mice Offspring Rechallenged with a High-Fat Diet in Adulthood.
Modern lifestyle has resulted in an increase in the prevalence of obesity and its comorbidities in pregnant women and the young population. It has been well established that the consumption of a high-fat diet (HFD) has many direct effects on glucose metabolism. However, it is important to assess whether maternal consumption of a HFD during critical periods of development can lead to metabolic changes in the offspring metabolism. This study evaluated the potential effects of metabolic programming on the impairment of insulin signalling in recently weaned offspring from obese dams. Additionally, we investigated if early exposure to an obesogenic environment could exacerbate the impairment of glucose metabolism in adult life in response to a HFD. Swiss female mice were fed with Standard Chow (SC) or a HFD during gestation and lactation and tissues from male offspring were analysed at d28 and d82. Offspring from obese dams had greater weight gain and higher adiposity and food intake than offspring from control dams. Furthermore, they showed impairment in insulin signalling in central and peripheral tissues, which was associated with the activation of inflammatory pathways. Adipose tissue was ultimately the most affected in adult offspring after HFD rechallenge; this may have contributed to the metabolic deregulation observed. Overall, our results suggest that diet-induced maternal obesity leads to increased susceptibility to obesity and impairment of insulin signalling in offspring in early and late life that cannot be reversed by SC consumption, but can be aggravated by HFD re-exposure. Topics: Adiposity; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Female; Glucose Tolerance Test; Glycogen; Hypothalamus; Insulin; Leptin; Liver; Male; Mice; Muscle, Skeletal; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Signal Transduction | 2016 |
Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice.
The increasing global prevalence of obesity and its associated disorders points to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules that have mRNA expression profiles similar to that of celastrol, a naturally occurring compound that we previously identified as a leptin sensitizer. Through this process, we identified another naturally occurring compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin-A treatment of mice with diet-induced obesity (DIO) resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities, including hepatic steatosis. Withaferin-A treatment marginally affected the body weight of ob/ob and db/db mice, both of which are deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism that occur independently of its leptin-sensitizing effect. Our results show that the metabolic abnormalities of DIO can be mitigated by sensitizing animals to endogenous leptin, and they indicate that withaferin A is a potential leptin sensitizer with additional antidiabetic actions. Topics: Animals; Blood Glucose; Blotting, Western; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Fatty Liver; Fluorescent Antibody Technique; Glucose Tolerance Test; Hypothalamus; Immunohistochemistry; Leptin; Liver; Mice; Mice, Obese; Obesity; Pentacyclic Triterpenes; Real-Time Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor; Triterpenes; Withanolides | 2016 |
Decreased basal insulin secretion from pancreatic islets of pups in a rat model of maternal obesity.
Maternal obesity (MO) is a deleterious condition that enhances susceptibility of adult offspring to metabolic diseases such as type 2 diabetes. The objective is to study the effect of MO on in vitro insulin secretion and pancreatic cellular population in offspring. We hypothesize that a harmful antenatal metabolic environment due to MO diminishes the basal glucose-responsive secretory function of pancreatic beta cells in offspring. Mothers were fed a control (C) or high-fat diet from weaning through pregnancy (120 days) and lactation. At postnatal days (PNDs) 36 and 110, pups were killed, peripheral blood was collected and pancreatic islets were isolated. Basal insulin secretion was measured in vitro in islets for 60 min. It was found that blood insulin, glucose and homeostasis model assessment (HOMA) index were unaffected by maternal diet and age in females. However, male MO offspring at PND 110 showed hyperinsulinemia and insulin resistance compared with C. Body weight was not modified by MO, but fat content was higher in MO pups compared with C pups. Triglycerides and leptin concentrations were higher in MO than in C offspring in all groups except in females at PND 36. Pancreatic islet cytoarchitecture was unaffected by MO. At PND 36, islets of male and female C and MO offspring responded similarly to glucose, but at PND 110, male and female MO offspring islets showed a 50% decrease in insulin secretion. It was concluded that MO impairs basal insulin secretion of offspring with a greater impact on males than females, and this effect mainly manifests in adulthood. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Female; Insulin; Insulin Secretion; Insulin-Secreting Cells; Leptin; Male; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Triglycerides | 2016 |
Voluntary running decreases nonexercise activity in lean and diet-induced obese mice.
Determine whether voluntary wheel running triggers compensatory changes in nonexercise activity in lean and high-fat diet fed mice.. C57Bl/6 mice received a control (C) or a high-fat diet (H) and half of them had free access to a running wheel 5days/week (CE and HE, respectively) for 10weeks. Energy intake, nonexercise activity (global activity, distance covered and average speed of displacement in the home cage) and energy expenditure (EE) were evaluated at weeks 5 and 10 during the 2days without the wheels.. High-fat diet increased weight gain in H (110%) and HE (60%) groups compared to C and CE groups, respectively, with no effect of exercise. Wheel running increased energy intake (26% CE, 11% HE in week 5; 7% CE, 45% HE in week 10) and decreased distance covered (26% for both CE and HE in week 5; 35% CE and 13% HE in week 10) and average speed (35% CE and 13% HE in week 5; 45% CE and 18% HE in week 10) compared to the respective nonexercised groups. In week 10 there was an interaction between diet and exercise for global activity, which was reduced nearly 18% in CE, H, and HE groups compared to C. Access to a running wheel increased EE in week 5 (11% CE and 16% HE) but not in week 10, which is consistent with the period of highest running (number of turns: weeks 1-5 nearly 100%>weeks 6-10 for CE and HE groups). EE was reduced in H (19%) and HE (12%) groups compared to C and CE, in week 10.. Voluntary running causes a compensatory decrease in nonexercise activity and an increase in energy intake, both contributing to the lack of effect of exercise on body mass. Topics: Adipose Tissue; Animals; Body Weight; Calorimetry; Diet, High-Fat; Disease Models, Animal; Energy Intake; Energy Metabolism; Leptin; Mice; Mice, Inbred C57BL; Obesity; Physical Conditioning, Animal; Time Factors | 2016 |
Anti-obesity effects of boiled tuna extract in mice with obesity induced by a high-fat diet.
The aim of this study was to examine the anti-obesity effects of boiled tuna extract in C57BL/6N mice with obesity induced by a high-fat diet (HFD). We determined the anti-obesity effects of boiled tuna extract (100, 200, or 400 mg/kg) on the progression of HFD-induced obesity for 10 weeks. The mice were divided into 5 groups as follows: the normal diet (ND) group (n=10); the HFD group (n=10); the mice fed HFD and 100 mg/kg boiled tuna extract group (n=10); those fed a HFD and 200 mg/kg boiled tuna extract group (n=10); and those fed a HFD and 400 mg/kg boiled tuna extract group (n=10). Changes in body weight, fat content, serum lipid levels and lipogenic enzyme levels were measured. The consumption of boiled tuna extract lowered epididymal tissue weight and exerted anti-obesity effects, as reflected by the serum glucose, triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL‑C), low-density lipoprotein cholesterol (LDL-C), insulin and leptin levels. In addition, we demonstrated changes in liver adipogenic- and lipogenic-related protein expression by western blot analysis. Boiled tuna extract downregulated the levels of the CCAAT/enhancer-binding protein α, β and δ (C/EBPα, β, δ), and peroxisome proliferator-activated receptor-γ (PPAR-γ) adipocyte marker genes. Boiled tuna extract also attenuated adipogenic and lipogenic gene expression, namely the levels of fatty acid synthase (FAS), lipoprotein lipase (LPL), acetyl-CoA carboxylase (ACC), glucose transporter type 4 (Glut4) and phosphorylated adenosine monophosphate-activated protein kinase α and β (AMPKα, β) in a dose-dependent manner. Moreover, the consumption of boiled tuna extract restored the levels of superoxide dismutase (SOD), catalase (CAT), glutamic oxaloacetic transaminase (GOT), glutamic-pyruvate transaminase (GPT), aspartate transaminase (AST) and alanine transaminase (ALT) to those of the control group. These results suggest that boiled tuna extract attenuates the progression of obesity by stimulating fatty acid oxidation through the upregulation of AMPK genes, as well as by inhibiting the synthesis of adipogenic and lipogenic enzymes. These characteristics of boiled tuna extract highlight its potential anti-obesity effects. Topics: Adipogenesis; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Catalase; Complex Mixtures; Diet, High-Fat; Gene Expression Regulation; Hot Temperature; Insulin; Leptin; Lipogenesis; Liver; Male; Mice, Inbred C57BL; Obesity; Organ Size; Superoxide Dismutase; Transaminases; Triglycerides; Tuna | 2016 |
Obesity alters immune and metabolic profiles: New insight from obese-resistant mice on high-fat diet.
Diet-induced obesity has been shown to alter immune function in mice, but distinguishing the effects of obesity from changes in diet composition is complicated. It was hypothesized that immunological differences would exist between diet-induced obese (DIO) and obese-resistant (OB-Res) mice fed the same high-fat diet (HFD).. BALB/c mice were fed either standard chow or HFD to generate lean or DIO and OB-Res mice, respectively. Resulting mice were analyzed for serum immunologic and metabolic profiles and cellular immune parameters.. BALB/c mice on HFD were categorized as DIO or OB-Res, based on body weight versus lean controls. DIO mice were physiologically distinct from OB-Res mice, whose serum insulin, leptin, gastric inhibitory polypeptide, and eotaxin concentrations remained similar to lean controls. DIO mice had increased macrophage(+) crown-like structures in white adipose tissue, although macrophage percentages were unchanged from OB-Res and lean mice. DIO mice also had decreased splenic CD4(+) T cells, elevated serum GM-CSF, and increased splenic CD11c(+) dendritic cells, but impaired dendritic cell stimulatory capacity (P < 0.05 vs. lean controls). These parameters were unaltered in OB-Res mice versus lean controls.. Diet-induced obesity results in alterations in immune and metabolic profiles that are distinct from effects caused by HFD alone. Topics: Animals; Body Weight; CD4-Positive T-Lymphocytes; Chemokine CCL11; Diet, High-Fat; Female; Insulin; Leptin; Male; Metabolome; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Obese; Obesity; Spleen | 2016 |
Cord blood leptin and gains in body weight and fat mass during infancy.
Low early-life leptin concentrations may promote faster weight gain in infancy. We aimed to examine the associations between cord blood leptin concentrations and changes in weight and body composition during infancy.. Serum leptin was measured at 15 weeks gestation, in umbilical cord blood collected at delivery and at 2 years in 334 children from the Cork Baseline Birth Cohort Study. Body composition was measured at 2 days and 2 months using air displacement plethysmography. Conditional change in weight standard deviation scores over a number of age intervals in the first 2 years and conditional change in fat mass index (FMI) and fat-free mass index (FFMI) (kg/(length)m(2)) between birth and 2 months were calculated and associations with cord blood leptin were examined using linear regression.. At birth, cord blood leptin was positively correlated with FMI (r = 0.48, P < 0.001) and showed a weaker correlation with FFMI (r = 0.12, P = 0.05). After adjustment for confounders, higher cord blood leptin (per ng/mL) was associated with slower conditional weight gain between birth and 2 months (β (95% CI): -0.024 (-0.035, -0.013), P < 0.001) but not over subsequent age intervals. Cord blood leptin was also inversely associated with conditional change in FMI (-0.021 (-0.034, -0.007, P = 0.003) but not FFMI between birth and 2 months.. These are the first data to show that associations between higher cord blood leptin and slower weight gain during infancy are driven by lower increases in adiposity, at least in early infancy. Topics: Adipose Tissue; Birth Weight; Body Composition; Body Mass Index; Body Weight; Female; Fetal Blood; Gestational Age; Humans; Infant; Infant, Newborn; Leptin; Male; Plethysmography; Weight Gain | 2016 |
Restricting feeding to the active phase in middle-aged mice attenuates adverse metabolic effects of a high-fat diet.
Time-restricted feeding ameliorates the deleterious effects of a high-fat diet on body weight and metabolism in young adult mice. Because obesity is highly prevalent in the middle-aged population, this study tested the hypothesis that time-restricted feeding alleviates the adverse effects of a high-fat diet in male middle-aged (12months) mice. C57BL6/J mice were fed one of three diets for 21-25weeks: 1) high-fat diet (60% total calories from fat) ad-libitum (HFD-AL), 2) HFD, time-restricted feeding (HFD-TRF), and 3) low-fat diet (10% total calories from fat) ad-libitum (LFD-AL) (n=15 each). HFD-TRF mice only had food access for 8h/day during their active period. HFD-TRF mice gained significantly less weight than HFD-AL mice (~20% vs 55% of initial weight, respectively). Caloric intake differed between these groups only during the first 8weeks and accounted for most but not all of their body weight difference during this time. TRF of a HFD lowered glucose tolerance in terms of incremental area under the curve (iAUC) (p<0.02) to that of LFD-AL mice. TRF of a HFD lowered liver weight (p<0.0001), but not retroperitoneal or epididymal fat pad weight, to that of LFD-AL mice. Neither HFD-AL nor HFD-TRF had any effect on performance in the novel object recognition or object location memory tests. Circulating corticosterone levels either before or after restraint stress were not affected by diet. In conclusion, TRF without caloric restriction is an effective strategy in middle-aged mice for alleviating the negative effects of a HFD on body weight, liver weight, and glucose tolerance. Topics: Activities of Daily Living; Analysis of Variance; Animals; Blood Glucose; Body Weight; Corticosterone; Diet, High-Fat; Disease Models, Animal; Eating; Energy Intake; Exploratory Behavior; Feeding Behavior; Food Deprivation; Glucose Tolerance Test; Insulin; Leptin; Liver; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Recognition, Psychology; Stress, Physiological | 2016 |
Perinatal Nicotine Exposure Increases Obesity Susceptibility in Adult Male Rat Offspring by Altering Early Adipogenesis.
The present study aims to evaluate whether perinatal nicotine (NIC) exposure increases obesity susceptibility in adult male rat offspring by altering early adipogenesis. NIC was sc administered (2.0 mg/kg per day) to pregnant rats from gestational day 9 to the time of weaning (postnatal day 28). At weaning, NIC-exposed male pups had an increased body weight and inguinal sc fat mass and a decreased average cell area of adipocyte, which was accompanied by an overexpression of adipogenic and lipogenic genes in the epididymal white adipose tissue. Additionally, the hepatic lipogenic gene levels from NIC-exposed male pups were also affected. At 12 and 26 weeks of age, body weight and fat mass were increased, whereas there was no change in food intake in NIC-exposed male offspring. Adipogenic and lipogenic genes, glucose transporter 4, and leptin mRNA levels were increased, whereas adiponectin mRNA levels were decreased in the epididymal white adipose tissue of NIC-exposed males. The hepatic lipogenic gene expression of NIC-exposed males was increased. NIC-exposed male offspring showed normal glycemia and a higher serum insulin level, homeostasis model assessment of insulin resistance, and homeostasis model assessment of β-cell function. Furthermore, the NIC-exposed male offspring showed higher serum lipids and Castelli index I and lower nonesterified fatty acid. At 26 weeks, in the ip glucose and insulin tolerance tests, the glucose clearance was delayed, and the area under the curve was higher in the NIC-exposed male offspring. In conclusion, perinatal NIC exposure increased obesity susceptibility in adult male rat offspring by altering early adipogenesis. Topics: Adipogenesis; Adiponectin; Animals; Blood Glucose; Body Weight; Female; Glucose Transporter Type 4; Insulin; Insulin Resistance; Leptin; Lipogenesis; Male; Nicotine; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; RNA, Messenger | 2016 |
The effect of dietary intervention on the metabolic and behavioural impairments generated by short term high fat feeding in the rat.
Previous studies have shown that rats fed a high calorie diet rich in saturated fat for 12weeks exhibit peripheral insulin resistance and impairments of behavioural flexibility when switched from an operant delayed matching to place (DMTP) schedule to a delayed non-matching to place (DNMTP) schedule. However, the metabolic changes evoked by feeding a high fat (HF) diet can be observed within two weeks of commencing the diet. The current study has confirmed that 4weeks exposure to an HF diet resulted in increased body weight, peripheral insulin resistance and plasma leptin. Studies performed during weeks 3 and 4 on the HF diet revealed suppressed lever pressing rates and impaired behavioural flexibility in the operant DMTP/DNMTP task. When animals fed the HF diet were then returned to a standard chow (SC) diet for 5weeks their weight and blood biochemistry no longer differed from those measured in animals that had never been exposed to the HF diet. The animals restored to the SC diet exhibited a clear ability to acquire the DNMTP schedule of reinforcement although these animals continued to lever press at a lower rate when compared with animals that received the SC diet throughout. The data suggest that exposure to an HF diet diminishes the motivation to respond for a reward and, thus, the capacity to adapt behavioural performance. This deficit was ameliorated, but not totally reversed, by the dietary intervention. If also true for humans, the results suggest that deficits in behavioural flexibility develop after only a short period on a high calorie diet but may be largely reversible through simple dietary intervention, at least in the early stages of deficit development. However, the putative effects of short-term exposure to an HF diet on behavioural motivation may persist for some time after switching to a healthier low fat diet and remain a problem for those seeking to adopt a healthier diet. Topics: Analysis of Variance; Animals; Blood Glucose; Body Weight; Conditioning, Operant; Diet, High-Fat; Disease Models, Animal; Fasting; Insulin; Leptin; Male; Mental Disorders; Metabolic Diseases; Rats; Rats, Wistar; Reinforcement, Psychology; Time Factors | 2016 |
Unaltered Hypothalamic Metabolic Gene Expression in Kiss1r Knockout Mice Despite Obesity and Reduced Energy Expenditure.
Kisspeptin controls reproduction by stimulating gonadotrophin-releasing hormone neurones via its receptor Kiss1r. Kiss1r is also expressed other brain areas and in peripheral tissues, suggesting additional nonreproductive roles. We recently determined that Kiss1r knockout (KO) mice develop an obese and diabetic phenotype. In the present study, we investigated whether Kiss1r KOs develop this metabolic phenotype as a result of alterations in the expression of metabolic genes involved in the appetite regulating system of the hypothalamus, including neuropeptide Y (Npy) and pro-opiomelanocortin (Pomc), as well as leptin receptor (Lepr), ghrelin receptor (Ghsr), and melanocortin receptors 3 and 4 (Mc3r, Mc4r). Body weights, leptin levels and hypothalamic gene expression were measured in both gonad-intact and gonadectomised (GNX) mice at 8 and 20 weeks of age that had received either normal chow or a high-fat diet. We detected significant increases in Pomc expression in gonad-intact Kiss1r KO mice at 8 and 20 weeks, although there were no alterations in the other metabolic-related genes. However, the Pomc increases appeared to reflect genotype differences in circulating sex steroids, because GNX wild-type and Kiss1r KO mice exhibited similar Pomc levels, along with similar Npy levels. The altered Pomc gene expression in gonad-intact Kiss1r KO mice is consistent with previous reports of reduced food intake in these mice and may serve to increase the anorexigenic drive, perhaps compensating for the obese state. However, the surprising overall lack of changes in any of the hypothalamic metabolic genes in GNX KO mice suggests that the aetiology of obesity in the absence of kisspeptin signalling may reflect peripheral rather than central metabolic impairments. Topics: Animals; Appetite; Body Weight; Energy Metabolism; Female; Gene Expression; Gonads; Hypothalamus; Leptin; Male; Mice; Mice, Knockout; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Ghrelin; Receptors, Kisspeptin-1 | 2016 |
Early postnatal amylin treatment enhances hypothalamic leptin signaling and neural development in the selectively bred diet-induced obese rat.
Selectively bred diet-induced obese (DIO) rats become obese on a high-fat diet and are leptin resistant before becoming obese. Compared with diet-resistant (DR) neonates, DIO neonates have impaired leptin-dependent arcuate (ARC) neuropeptide Y/agouti-related peptide (NPY/AgRP) and α-melanocyte-stimulating hormone (α-MSH; from proopiomelanocortin (POMC) neurons) axon outgrowth to the paraventricular nucleus (PVN). Using phosphorylation of STAT3 (pSTAT3) as a surrogate, we show that reduced DIO ARC leptin signaling develops by postnatal day 7 (P7) and is reduced within POMC but not NPY/AgRP neurons. Since amylin increases leptin signaling in adult rats, we treated DIO neonates with amylin during postnatal hypothalamic development and assessed leptin signaling, leptin-dependent ARC-PVN pathway development, and metabolic changes. DIO neonates treated with amylin from P0-6 and from P0-16 increased ARC leptin signaling and both AgRP and α-MSH ARC-PVN pathway development, but increased only POMC neuron number. Despite ARC-PVN pathway correction, P0-16 amylin-induced reductions in body weight did not persist beyond treatment cessation. Since amylin enhances adult DIO ARC signaling via an IL-6-dependent mechanism, we assessed ARC-PVN pathway competency in IL-6 knockout mice and found that the AgRP, but not the α-MSH, ARC-PVN pathway was reduced. These results suggest that both leptin and amylin are important neurotrophic factors for the postnatal development of the ARC-PVN pathway. Amylin might act as a direct neurotrophic factor in DIO rats to enhance both the number of POMC neurons and their α-MSH ARC-PVN pathway development. This suggests important and selective roles for amylin during ARC hypothalamic development. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Diet, High-Fat; Dietary Fats; Female; Hypothalamus; Islet Amyloid Polypeptide; Leptin; Male; Neurogenesis; Obesity; Paraventricular Hypothalamic Nucleus; Postnatal Care; Rats; Treatment Outcome | 2016 |
Lack of Association between Serum Adiponectin/Leptin Levels and Medullary Thyroid Cancer.
Adipokines are bioactive proteins that mediate metabolism, inflammation and angiogenesis. Changes in the secretion of key serum adipokines - adiponectin and letpin - may be associated with obesity, cancer and metabolic disorders. Thyroid cancer is one of the most important types of endocrine cancer. Therefore, investigating the association between serum levels of adiponectin and leptin and thyroid cancer might be important. The purpose of this study was to assess adiponectin and leptin levels in medullary thyroid carcinoma (MTC) cases in order to identify novel tumor markers.. This research was based on a case-control study, including 45 patients with medullary thyroid cancer (21 men and 24 women) and 45 healthy controls (24 males and 21 females). Adiponectin and leptin levels were measured by ELISA in both groups. Height and weight were measured and body mass index (kg/m2) was calculated.. Adiponectin and leptin levels were not significantly different between medullary thyroid carcinomas and the control group. Also, there was no correlation among age and body mass index and the disease.. These results suggest that changes in serum adiponectin and leptin levels do not play an important role in the diagnosis or could act as as biomarkers for medullary thyroid cancer. Topics: Adiponectin; Adult; Biomarkers, Tumor; Body Mass Index; Body Weight; Carcinoma, Neuroendocrine; Case-Control Studies; Female; Humans; Leptin; Male; Thyroid Neoplasms; Young Adult | 2016 |
Metabolism and Energy Expenditure, But Not Feeding or Glucose Tolerance, Are Impaired in Young Kiss1r KO Female Mice.
Kisspeptin regulates reproduction via signaling through the receptor, Kiss1r, in GnRH neurons. However, both kisspeptin and Kiss1r are produced in several peripheral tissues, and recent studies have highlighted a role for kisspeptin signaling in metabolism and glucose homeostasis. We recently reported that Kiss1r knockout (KO) mice display a sexually dimorphic metabolic phenotype, with KO females displaying obesity, impaired metabolism, and glucose intolerance at 4-5 months of age. However, it remains unclear when this metabolic phenotype first emerges in development, or which aspects of the pleiotropic phenotype underlie the metabolic defects and which are secondary to the obesity. Here, we studied Kiss1r KO females at different ages, including several weeks before the emergence of body weight (BW) differences and later when obesity is present. We determined that at young adult ages (6 wk old), KO females already exhibit altered adiposity, leptin levels, metabolism, and energy expenditure, despite having normal BWs at this time. In contrast, food intake, water intake, and glucose tolerance are normal at young ages and only show impairments at older adult ages, suggesting that these impairments may be secondary to earlier alterations in metabolism and adiposity. We also demonstrate that, in addition to BW, all other facets of the adult metabolic phenotype persist even when gonadal sex steroids are similar between genotypes. Collectively, these data highlight the developmental emergence of a metabolic phenotype induced by disrupted kisspeptin signaling and reveal that multiple, but not all, aspects of this phenotype are already disrupted before detectable changes in BW. Topics: Adiposity; Animals; Body Composition; Body Weight; Eating; Energy Metabolism; Female; Glucose Intolerance; Glucose Tolerance Test; Leptin; Male; Mice; Mice, Knockout; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Signal Transduction | 2016 |
Body fat distribution in Parkinson's disease: An MRI-based body fat quantification study.
There is some evidence that Parkinson's Disease (PD) patients have lower body weight and lower fat mass when compared to healthy subjects and that lower body weight and fat mass influence disease risk and progression. It remains unclear, however, if weight loss of fat mass loss occurs only in a subgroup of patients and whether fat distribution is altered during PD. The aim of this study was to prospectively investigate adipose tissue content and distribution in PD patients.. The body fat composition of PD patients (N = 54) was compared with age matched healthy controls (N = 55) using a magnetic resonance imaging (MRI)-based method. A longitudinal MRI scan was acquired in 25 PD patients after a mean follow up period of 12 months.. The volume of total body fat as well as of visceral fat showed no difference between PD patients and healthy controls at baseline or at follow up. However, PD patients displayed decreased subcutaneous fat tissue (p = 0.01) and a higher visceral to subcutaneous fat ratio as compared to controls (p = 0.004). After follow up, 16 PD patients did not lose weight, while 9 PD patients lost between 0.5 and 10 kg.. Fat distribution is altered in PD patients, with an increased ratio of visceral to subcutaneous fat. Topics: Adipose Tissue; Body Fat Distribution; Body Mass Index; Body Weight; Case-Control Studies; Female; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Leptin; Magnetic Resonance Imaging; Male; Parkinson Disease; Statistics as Topic; Statistics, Nonparametric | 2016 |
Differences in body condition of gilts that are maintained from mating to the end of gestation affect mammary development.
The goal of this project was to determine if different body conditions in late gestation that are due to varying body conditions at mating affect mammary development and mammary gene expression of gilts. Gilts that were fed ad libitum in the growing period were selected based on their backfat depths to form 3 groups at mating, namely, low backfat (LBF; 12-15 mm; = 14), medium backfat (MBF; 17-19 mm; = 15), and high backfat (HBF; 22-26 mm; = 16). During gestation, LBF, MBF, and HBF gilts were fed approximately 1.25, 1.43, and 1.63 times maintenance requirements to maintain their differences in body condition. Feed intake was increased by 1 kg in the last 10 d of gestation. Backfat depths of gilts were ultrasonically measured at mating and on d 30, 50, 70, 100, and 109 of gestation. Blood samples were obtained at mating and on d 109 of gestation to measure concentrations of IGF-1, glucose, insulin, estradiol, urea, free fatty acids, leptin, and adiponectin. Gilts were slaughtered on d 110 of gestation to collect mammary glands for compositional analyses. Mammary extraparenchymal tissue weight was lesser in LBF and MBF gilts than in HBF gilts (1,259.3, 1,402.7, and 1,951.5 ± 70.4 g, respectively; < 0.01). The weight of parenchymal tissue was not affected by treatment ( > 0.10), but its composition was altered. Concentrations of DNA and RNA decreased as backfat depth increased ( < 0.05), whereas percent fat and DM increased ( < 0.05). Circulating concentrations of leptin tended to be lower at mating ( < 0.10) and were lower on d 109 of gestation ( < 0.05) in LBF gilts than in HBF gilts. On d 109 of gestation, concentrations of insulin ( < 0.01) and IGF-1 ( < 0.05) were lower in LBF and MBF gilts than in HBF gilts, whereas those of urea were greater ( < 0.05). The mRNA abundance in parenchymal tissue for all genes studied was not affected by treatments ( > 0.10) with the exception of , which had a greater expression level in LBF gilts than in MFB or HBF gilts ( < 0.05). Percent of Ki-67-positive cells, used to assess mammary cell proliferation rate, was greater in HBF gilts than in LBF gilts ( < 0.05). When differences in body conditions of gilts that were present at mating were maintained throughout gestation, it had an impact on mammary development. Extraparenchymal tissue mass was affected and, more importantly, composition of parenchymal tissue was altered, indicating a beneficial effect of gilts being in the thinner treatment groups at mating. Topics: Animals; Body Composition; Body Weight; Estradiol; Fatty Acids, Nonesterified; Female; Insulin; Insulin-Like Growth Factor I; Leptin; Mammary Glands, Animal; Pregnancy; RNA; Swine | 2016 |
Antiobesity Effects of Salvia plebeia R. Br. Extract in High-Fat Diet-Induced Obese Mice.
This study was designed to investigate the antiobesity effects of Salvia plebeia R. Br. ethanolic extracts (SPE) in mice fed high-fat diets (HFD). Male C57BL/6J mice were randomly assigned to four groups: normal diet (Chow), high-fat diet (HFD, 45% fat), HFD+SPE 200 (200 mg/kg b.w.), and HFD+SPE 400 (400 mg/kg b.w.). Extracts were administered orally every day for 8 weeks. Increases in body/fat weight and feed efficiency ratio were monitored in all mice. In addition, obesity resulting from feeding HFD to the mice was confirmed by the increase of glucose level, aspartate transaminase, alanine transaminase, triglyceride (TG), high-density lipoprotein cholesterol, very low-density lipoprotein-c, leptin, and adiponectin in blood. The SPE-treated mice gained less body and mesenteric/subcutaneous adipose tissues weights and had lower TG, very low-density lipoprotein cholesterol, leptin, and glucose level in serum, compared to the HFD group. Moreover, histopathological examinations revealed that the size of adipocytes in liver and adipose tissue was significantly decreased by SPE, compared to the HFD group. The expression of adipogenesis transcription factors (e.g., peroxisome proliferator activated receptor γ and CCAAT/enhancer binding protein α) and lipogenesis-related target genes (adipocyte fatty acid-binding protein 2, lipoprotein lipase, fatty acid synthase, and sterol regulatory element-binding transcription factor 1c) in HFD-induced obese mice was decreased by SPE treatment. These results suggest that SPE attenuates the fat accumulation in HFD-induced obese mice by suppressing the expressions of genes related to adipogenesis and lipogenesis activity. Therefore, SPE could be developed as a potential therapy for reduction of body weight and antiobesity intervention. Topics: Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Cell Differentiation; Diet, High-Fat; Disease Models, Animal; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Organ Size; Plant Extracts; Random Allocation; Salvia | 2016 |
Association of polymorphisms in growth hormone and leptin candidate genes with live weight traits of Brahman cattle.
Polymorphisms in candidate genes can produce significant and favorable changes in the phenotype, and therefore are useful for the identification of the best combination of favorable variants for marker-assisted selection. In the present study, an assessment to evaluate the effect of 11 single nucleotide polymorphisms (SNPs) in candidate genes on live weight traits of registered Brahman cattle was performed. Data from purebred bulls were used in this assessment. The dataset included birth (BW), weaning (WW), and yearling (YW) weights. A panel of 11 SNP markers, selected by their formerly reported or apparent direct and indirect association with live weight traits, was included in an assessment previously confirming their minimum allele frequency (<0.05). Live weights were adjusted BW (aBW), WW (aWW), and YW (aYW) using a generalized linear model, which included the fixed effects of herd and season of birth and the random effect of the sire and year of birth. An SNP in a growth hormone gene (GH4.1) was significantly related to aWW (P = 0.035) with an estimate substitution effect of 3.97 kg (P = 0.0210). In addition, a leptin SNP (LEPg.978) was significantly associated with aYW (P = 0.003) with an estimate substitution effect of 9.57 kg (P = 0.0007). The results suggest that markers GH4.1 and LEPg.978 can be considered as candidate loci for assisted genetic improvement programs in Mexican Brahman cattle. Topics: Alleles; Animals; Body Weight; Breeding; Cattle; Female; Gene Expression; Gene Frequency; Genetic Loci; Genetic Markers; Growth Hormone; Leptin; Linear Models; Male; Mexico; Models, Genetic; Polymorphism, Single Nucleotide; Quantitative Trait, Heritable | 2016 |
Changes in plasma ghrelin and leptin levels in patients with peptic ulcer and gastritis following eradication of Helicobacter pylori infection.
Helicobacter pylori (H. pylori) infection and eradication therapy have been known to influence gastric ghrelin and leptin secretion, which may lead to weight gain. However, the exact relationship between plasma ghrelin/leptin levels and H. pylori infection has remained controversial. The aim of this study was to investigate plasma ghrelin and leptin levels in H. pylori-positive and -negative patients, to compare the two levels of the hormones before and after H. pylori eradication, and to examine the correlation between body mass index (BMI) and active ghrelin or leptin levels, as well as that between atrophic pattern and active ghrelin or leptin levels.. Seventy-two H. pylori-positive patients who underwent upper gastrointestinal endoscopy, 46 diagnosed as having peptic ulcer and 26 as atrophic gastritis, were enrolled. Control samples were obtained from 15 healthy H. pylori-negative volunteers. The extent of atrophic change of the gastric mucosa was assessed endoscopically. Body weight was measured and blood was collected before and 12 weeks after H. pylori eradication therapy. Blood samples were taken between 8 and 10 AM after an overnight fast.. Plasma ghrelin levels were significantly lower in H. pylori-positive patients than in H. pylori-negative patients. In particular, plasma active ghrelin levels were significantly lower in patients with gastritis compared with patients with peptic ulcer. Plasma ghrelin levels decreased after H. pylori eradication in both peptic ulcer and gastritis patients, while plasma leptin levels increased only in peptic ulcer patients. Plasma leptin levels and BMI were positively correlated, and active ghrelin levels and atrophic pattern were weakly negatively correlated in peptic ulcer patients.. H. pylori infection and eradication therapy may affect circulating ghrelin/leptin levels. This finding suggests a relationship between gastric mucosal injury induced by H. pylori infection and changes in plasma ghrelin and leptin levels. Topics: Adult; Aged; Amoxicillin; Anti-Bacterial Agents; Anti-Ulcer Agents; Biopsy; Body Mass Index; Body Weight; Case-Control Studies; Clarithromycin; Drug Therapy, Combination; Endoscopy, Digestive System; Female; Gastric Mucosa; Gastritis, Atrophic; Ghrelin; Helicobacter Infections; Helicobacter pylori; Humans; Lansoprazole; Leptin; Male; Middle Aged; Peptic Ulcer | 2016 |
Age-related changes in acute central leptin effects on energy balance are promoted by obesity.
Leptin is a key catabolic regulator of food intake (FI) and energy expenditure. Both aging and obesity have been shown to induce leptin-resistance. The present study aimed to analyze age-related changes in the anorexigenic and hypermetabolic responsiveness to acute intracerebroventricular leptin administration in different age-groups of normally fed male Wistar rats (adult and old rats from 3 to 24months of age, NF3 to NF24, respectively). The expressions of the long form of the leptin receptor (Ob-Rb) and inhibitory SOCS3 genes were also assessed by quantitative RT-PCR in the arcuate nucleus (ARC). The influence of high-fat diet-induced obesity (HF) on the anorexigenic leptin effects were also tested in younger and older middle-aged groups (HF6 and HF12). Leptin-induced anorexia varied with age: leptin suppressed re-feeding FI (following 48-h fasting) strongly in young adult (NF3), but not in younger or older middle-aged (NF6 or NF12) or in aging (NF18) rats. However, anorexigenic leptin effects reached statistical significance again in old NF24 rats. Leptin-induced hypermetabolism, on the other hand, showed monotonous age-related decline and disappeared by old age. Ob-Rb expression declined until 12months of age followed by a partial recovery in NF18 and NF24 groups. On the other hand, SOCS3 expression was high in NF6 and NF18 and to some extent in NF24 rats. Age-related alterations of Ob-Rb and SOCS3 expression in the ARC may partly contribute to the explanation of age-related variations in anorexigenic but not hypermetabolic leptin effects. High-fat diet-induced obesity was associated with resistance to leptin-induced anorexia in HF6, similar to that seen in NF6. However, instead of the expected leptin-resistance in HF12, a strong leptin-induced suppression of re-feeding was detected in these obese middle-aged rats. Our results suggest that acute central effects of leptin on anorexia and hypermetabolism change in disparate ways during aging, implying separate mechanisms (e.g. signal transduction pathways) of different leptin actions. The age-related pattern shown by leptin-induced anorexia may contribute to the explanation of middle-aged obesity, and partly to that of aging anorexia. Our findings concerning obese rats are in accord with previous observations on anorexigenic effects of peripherally administered cholecystokinin: diet-induced obesity appeared to accelerate the development of age-related regulatory alterations. Similarly, our present data Topics: Aging; Animals; Anorexia; Body Temperature; Body Weight; Diet, High-Fat; Eating; Energy Metabolism; Feeding Behavior; Gene Expression; Leptin; Male; Obesity; Rats; Rats, Wistar; Receptors, Leptin; Suppressor of Cytokine Signaling 3 Protein | 2016 |
The role of dietary fat in obesity-induced insulin resistance.
Consumption of excess calories results in obesity and insulin resistance and has been intensively studied in mice and humans. The objective of this study was to determine the specific contribution of dietary fat rather than total caloric intake to the development of obesity-associated insulin resistance. We used an intragastric feeding method to overfeed excess calories from a low-fat diet (and an isocalorically matched high-fat diet) through a surgically implanted gastric feeding tube to generate obesity in wild-type mice followed by hyperinsulinemic-euglycemic clamp studies to assess the development of insulin resistance. We show that overfeeding a low-fat diet results in levels of obesity similar to high-fat diet feeding in mice. However, despite a similar body weight, obese high-fat diet-fed mice are more insulin resistant than mice fed an isocaloric low-fat diet. Therefore, increased proportion of calories from dietary fat further potentiates insulin resistance in the obese state. Furthermore, crossover diet studies revealed that reduction in dietary fat composition improves glucose tolerance in obesity. In the context of the current obesity and diabetes epidemic, it is particularly important to fully understand the role of dietary macronutrients in the potentiation and amelioration of disease. Topics: Adipose Tissue; Animals; Body Weight; Chemokine CCL2; Cross-Over Studies; Diet, Fat-Restricted; Diet, High-Fat; Dietary Fats; Energy Intake; Enteral Nutrition; Fatty Acids, Nonesterified; Glucose Clamp Technique; Glucose Tolerance Test; Insulin Resistance; Interleukin-6; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Real-Time Polymerase Chain Reaction; Resistin; Serpin E2; Tumor Necrosis Factor-alpha | 2016 |
Daesiho-Tang Is an Effective Herbal Formulation in Attenuation of Obesity in Mice through Alteration of Gene Expression and Modulation of Intestinal Microbiota.
Obesity has become a major global health challenge due to its increasing prevalence, and the associated health risk. It is the main cause of various metabolic diseases including diabetes, hypertension, cardiovascular disease, stroke and certain forms of cancer.. In the present study we evaluated the anti-obesity property of Daesiho-tang (DSHT), an herbal medicine, using high fat diet (HFD)-induced obese mice as a model. Our results showed that DSHT ameliorated body weight gain, decreased total body fat, regulated expression of leptin and adiponectin genes of adipose tissue and exerted an anti-diabetic effect by attenuating fasting glucose level and serum insulin level in HFD-fed animals. In addition, DSHT-treatment significantly reduced total cholesterol (TC), triglycerides (TG) and increased high density lipoprotein-cholesterol (HDL), glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) levels in serum and reduced deposition of fat droplets in liver. DSHT treatment resulted in significantly increased relative abundance of bacteria including Bacteroidetes, Bacteroidetes/Firmicutes ratio, Akkermansia Bifidobacterium., Lactobacillus, and decreased the level of Firmicutes. Using RT2 profiler PCR array, 39 (46%) genes were found to be differentially expressed in HFD-fed mice compared to normal control. However, normal gene expressions were restored in 36 (92%) genes of HFD-fed mice, when co-exposed to DSHT.. The results of this study demonstrated that DSHT is an effective herbal formulation in attenuation of obesity in HFD-fed mice through alteration of gene expressions and modulation of intestinal microbiota. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Cholesterol; Diet, High-Fat; Drug Compounding; Gastrointestinal Microbiome; Gene Expression Regulation; Glucose; Homeostasis; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Plant Extracts | 2016 |
A Novel Selective Inhibitor of Delta-5 Desaturase Lowers Insulin Resistance and Reduces Body Weight in Diet-Induced Obese C57BL/6J Mice.
Obesity is now recognized as a state of chronic low-grade inflammation and is called as metabolic inflammation. Delta-5 desaturase (D5D) is an enzyme that metabolizes dihomo-γ-linolenic acid (DGLA) to arachidonic acid (AA). Thus, D5D inhibition increases DGLA (precursor to anti-inflammatory eicosanoids) while decreasing AA (precursor to pro-inflammatory eicosanoids), and could result in synergistic improvement in the low-grade inflammatory state. Here, we demonstrate reduced insulin resistance and the anti-obesity effect of a D5D selective inhibitor (compound-326), an orally active small-molecule, in a high-fat diet-induced obese (DIO) mouse model. In vivo D5D inhibition was confirmed by determining changes in blood AA/DGLA profiles. In DIO mice, chronic treatment with compound-326 lowered insulin resistance and caused body weight loss without significant impact on cumulative calorie intake. Decreased macrophage infiltration into adipose tissue was expected from mRNA analysis. Increased daily energy expenditure was also observed following administration of compound-326, in line with sustained body weight loss. These data indicate that the novel D5D selective inhibitor, compound-326, will be a new class of drug for the treatment of obese and diabetic patients. Topics: 8,11,14-Eicosatrienoic Acid; Adiponectin; Adipose Tissue; Animals; Arachidonic Acid; Body Weight; Delta-5 Fatty Acid Desaturase; Diet, High-Fat; Energy Metabolism; Enzyme Inhibitors; Fatty Acid Desaturases; Gene Expression; Hep G2 Cells; Humans; Inflammation; Insulin Resistance; Leptin; Macrophages; Male; Mice, Inbred C57BL; Obesity; Pyrimidinones; Pyrrolidinones; Reverse Transcriptase Polymerase Chain Reaction; Weight Loss | 2016 |
Effects of High-Fat Diet on Stress Response in Male and Female Wildtype and Prolactin Knockout Mice.
Prolactin (PRL) is well characterized for its roles in initiation and maintenance of lactation, and it also suppresses stress-induced responses. Feeding a high-fat diet (HFD) disrupts activity of the hypothalamic-pituitary-adrenal (HPA) axis. Whether PRL regulates HPA axis activation under HFD feeding is not clear. Male and female wildtype (WT) and PRL knockout (KO) mice were fed either a standard low-fat diet (LFD) or HFD for 12 weeks. Circulating corticosterone (CORT) levels were measured before, during, and after mice were subjected to an acute restraint stress or remained in their home cages as no stress controls. HFD feeding increased leptin levels, but the increase was lower in KO than in WT mice. All stressed female groups and only LFD-fed stressed males had elevated CORT levels compared to their no stress same-sex counterparts regardless of genotype. These results indicated that HFD consumption blunted the HPA axis response to acute stress in males but not females. Additionally, basal hypothalamic CRH content was lower in HFD than LFD males, but was similar among female groups. Furthermore, although basal CORT levels were similar among KO and WT groups, CORT levels were higher in KO mice than their WT counterparts during stress, suggesting that loss of PRL led to greater HPA axis activation. Basal PRL receptor mRNA levels in the choroid plexus were higher in HFD than LFD same-sex counterparts, suggesting activation of central PRL's action by HFD feeding in both males and females. Current results confirmed PRL's roles in suppression of the stress-induced HPA axis activation. Although HFD feeding activated central PRL's action in both sexes, only the male HPA axis was dampened by HFD feeding. Topics: Animals; Body Composition; Body Weight; Choroid Plexus; Corticosterone; Diet, Fat-Restricted; Diet, High-Fat; Energy Intake; Female; Hypothalamus; Leptin; Male; Mice; Mice, Knockout; Prolactin; Receptors, Prolactin; RNA, Messenger; Stress, Physiological | 2016 |
Neuroendocrine Inflammatory Responses in Overweight/Obese Infants.
Childhood obesity is related to a cascade of neuroendocrine inflammatory changes. However, there remains a gap in the current literature regarding the possible occurrence of these changes in overweight/obese infants. The objective of this study was to evaluate adipokines, cortisol, brain-derived neurotrophic factor (BDNF) and redox status in overweight/obese infants versus normal-weight peers. A cross-sectional study was conducted with 50 infants (25 in the overweight/obese group and 25 in the normal-weight group) between 6 and 24 months. Plasma levels of leptin, adiponectin, resistin, soluble tumor necrosis factor (TNF) receptors, chemokines, BDNF, serum cortisol and redox status were measured. Unpaired Student's t-test was used to analyze the results and a probability of p<0.05 was acceptable for rejection of the null hypothesis. The Pearson correlation was used to verify the association between the biomarkers analyzed in each group. Plasma levels of leptin (p = 0.0001), adiponectin (p = 0.0007) and BDNF (p = 0.003), and serum cortisol (p = 0.048) were significantly higher in overweight/obese infants than normal-weight infants. In contrast, the concentration of thiobarbituric acid reactive substances (TBARS) (p = 0.004), and catalase (p = 0.045) and superoxide dismutase activity (p = 0.02) were lower in overweight/obese infants than normal-weight peers. All the results together indicate neuroendocrine inflammatory response changes in overweight/obese infants between 6 and 24 months. Although there is already an environment that predisposes for a subsequent pro-inflammatory response, neuroendocrine secretion changes that permit the control of the inflammatory process in this age interval can be observed. Topics: Adipokines; Adiponectin; Biomarkers; Body Composition; Body Weight; Brain-Derived Neurotrophic Factor; Cross-Sectional Studies; Humans; Hydrocortisone; Infant; Inflammation; Leptin; Neurosecretory Systems; Obesity; Overweight; Oxidation-Reduction | 2016 |
The effect of combined inositol hexakisphosphate and inositol supplement in streptozotocin-induced type 2 diabetic rats.
Inositol hexakisphosphate (IP6) and inositol both regulate insulin secretion, but their combined use in the management of diabetes deserves investigation. The combined effects of IP6 and inositol supplementation were investigated in streptozotocin-induced type 2 diabetic rats. The following groups of rats were studied for 8 weeks: non-diabetic control, non-diabetic high-fat diet control, diabetic untreated, diabetic rats treated with the combination of IP6 and inositol (650 mg/kg bw) and diabetic rats treated with glibenclamide (10 mg/kg bw). High-fat diet and streptozotocin were used to induce type 2 diabetes mellitus in Sprague-Dawley rats. Body weight, blood glucose, glycated haemoglobin, insulin, serum leptin, HOMA-insulin resistance scores, intestinal amylase activity, serum and faecal lipids and food and fluid consumption were measured. Treatment with the combination significantly reduced blood glucose (306 ± 53 mg/dl) and insulin resistance score (1.93 ± 0.45) compared with diabetic controls (522 ± 24 mg/dl and 5.1 ± 0.69 respectively). Serum leptin (2.8 ± 0.6 ng/dl) and faecal triglycerides (108 ± 8 mg/dl) were significantly increased in rats treated with the combination compared with the diabetic control (1.8 ± 0.06 ng/dl and 86 ± 4 mg/dl). Serum triglyceride (47 ± 5.1 mg/dl), total cholesterol (98 ± 3.2 mg/dl) and food intake (26 ± 0.3 g) were significantly reduced by 45%, 25% and 25%, respectively, in rats treated with the combination compared with the diabetic control. Inositol and IP6 combined supplementation may be effective in the management of type 2 diabetes mellitus and related metabolic disorders by regulating some aspects of lipid and carbohydrate metabolism. Topics: Amylases; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Supplements; Drinking; Drug Evaluation, Preclinical; Drug Therapy, Combination; Eating; Feces; Hypoglycemic Agents; Inositol; Intestines; Leptin; Lipid Metabolism; Lipids; Male; Phytic Acid; Rats, Sprague-Dawley | 2016 |
Anti-Hyperglycemic Effect of a Kudzu (Pueraria lobata) Vine Extract in Ovariectomized Mice.
Postmenopausal diabetes is exacerbated by estrogen deficiency. Ovariectomized (OVX) animal models can be used to develop strategies for preventing or treating postmenopausal symptoms. We previously found that a diet containing kudzu (Pueraria lobata) vine ethanol extract (PVEE) suppressed weight gain in OVX mice. Therefore, this study further elucidated how PVEE affected OVX mice. Ten-week-old OVX or sham-operated mice were fed diets containing either no PVEE (control) or 20 mg•kg Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Disease Models, Animal; Female; Hypoglycemic Agents; Insulin; Isoflavones; Leptin; Mice; Organ Size; Ovariectomy; Phytotherapy; Plant Extracts; Postmenopause; Pueraria; Triglycerides; Uterus; Weight Gain | 2016 |
High Thyroid-stimulating Hormone Levels Increase Proinflammatory and Cardiovascular Markers in Patients with Extreme Obesity.
Obesity is an important health problem worldwide and many studies have suggested a relationship between obesity and thyroid function, with controversial results. Interestingly, high TSH levels have been involved with the presence of inflammatory state and risk for developing cardiovascular diseases in hypothyroid and obese patients. The aim in this work was to determine the prevalence of hypothyroidism in patients with extreme obesity and to determine whether their TSH levels were related to increased serum levels of inflammatory and cardiovascular markers.. A cross-sectional study in 101 patients with extreme obesity (BMI ≥40) was performed. Anthropometric (weight, height and waist circumference) and biochemical (fasting glucose, glycosylated hemoglobin, triglycerides, total cholesterol, LDL-C, HDL-C and insulin) parameters were measured. TSH and FT4 levels as well as clinical exploration for diagnosis of hypothyroidism were carried out. Serum concentration of IL-10, IL-6, adiponectin, resistin, leptin, ICAM-1, VCAM-1 and E-selectin were determined.. A high prevalence for diabetes (37.6%), prediabetes (50.5%), dyslipidemia (74.3%), hypertension (61.4%) and hypothyroidism (48.5%) was observed in patients with extreme obesity. The presence of hypothyroidism increased serum concentration of proinflammatory cytokines IL-6 and leptin and decreased the antiinflammatory cytokine adiponectin. In addition, serum TSH levels showed a correlation for waist circumference, weight, BMI, A1c, insulin, IL-6, leptin, ICAM-1 and E-selectin.. There is a high prevalence for hypothyroidism in patients with extreme obesity. High levels of TSH contribute to elevate proinflammatory and cardiovascular risk markers, increasing the risk for development of cardiovascular diseases. Topics: Adiponectin; Adult; Biomarkers; Body Weight; Cardiovascular Diseases; Cross-Sectional Studies; E-Selectin; Female; Humans; Hypothyroidism; Inflammation; Insulin; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-6; Leptin; Male; Middle Aged; Obesity, Morbid; Prevalence; Resistin; Risk Factors; Thyrotropin; Triglycerides; Vascular Cell Adhesion Molecule-1; Waist Circumference | 2016 |
Higher Leptin but Not Human Milk Macronutrient Concentration Distinguishes Normal-Weight from Obese Mothers at 1-Month Postpartum.
Exclusively breastfed infants born to obese mothers have previously been shown to gain less weight by 1-month postpartum than infants of normal-weight mothers. Our hypothesis is that human milk composition and volume may differ between obese and normal-weight mothers.. To compare human milk leptin, macronutrient concentration, and volume in obese and normal-weight mothers. Mother and infant characteristics were studied as secondary aims.. This cross-sectional observational study compared 50 obese mothers matched for age, parity, ethnic origin, and educational level with 50 normal-weight mothers. Leptin, macronutrient human milk concentration, and milk volume were determined at 1 month in exclusively breastfed infants. Mother characteristics and infant growth were recorded.. Human milk leptin concentration was higher in obese mothers than normal-weight mothers (4.8±2.7 vs. 2.5±1.5 ng.mL-1, p<0.001). No difference was observed between obese and normal-weight mothers in protein, lipid, carbohydrate content, and volume, nor in infant weight gain.. Leptin concentration was higher in the milk of obese mothers than that of normal-weight mothers, but macronutrient concentration was not. It remains to be established whether the higher leptin content impacts on infant growth beyond the 1-month of the study period. Topics: Adult; Body Weight; Breast Feeding; Carbohydrates; Case-Control Studies; Child Development; Cross-Sectional Studies; Female; Humans; Infant; Infant, Newborn; Leptin; Lipids; Male; Milk, Human; Mothers; Obesity; Postpartum Period; Pregnancy; Proteins; Weight Gain | 2016 |
Time Course of Leptin in Patients with Anorexia Nervosa during Inpatient Treatment: Longitudinal Relationships to BMI and Psychological Factors.
Leptin, a hormone secreted by adipose tissue, appears to play a major role in the homeostasis of body weight and psychobiological processes associated with anorexia nervosa (AN). However, there is scarce data on its exact influence on this disorder, in particular data over time.. The present study addresses whether leptin changes during inpatient treatment play a role for treatment outcome and psychological factors in underweight AN patients.. In order to understand whether leptin's role differs in relation to AN severity, data were assessed from 11 patients with a very low BMI and a higher chronicity (high severity group; HSS; mean BMI at the beginning of the study = 13.6; mean duration of illness = 5.1 years) vs. nine with less severe symptoms (LSS; mean BMI = 16.2; mean duration of illness = 3.7 years). During the course of treatment, serum leptin concentrations were assessed weekly while weight (BMI) was assessed twice per week. Concomitantly, psychological variables were obtained by means of electronic diaries. Unconditional linear growth models were calculated to evaluate the temporal course of leptin in relation to BMI. For HSS patients, two phases of treatment (BMI < 16 and BMI ≥ 16 kg/m2) were investigated.. Leptin increased significantly with BMI in both groups of patients. For HSS patients, the increase of leptin in the first treatment phase did not predict later increases in BMI. Furthermore, the relationship of leptin and psychological factors was modulated by symptom severity. In HSS patients, higher leptin levels were associated with greater feelings of depression, anxiety, and stress whereas in LSS patients a higher leptin level showed the trend to be associated with lower psychological symptom burden.. Our results suggest that leptin changes are differently associated with weight gain and psychological symptoms depending on the severity of starvation. Topics: Adolescent; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Case-Control Studies; Depression; Female; Humans; Inpatients; Leptin; Longitudinal Studies; Male; Middle Aged; Patient Discharge; Young Adult | 2016 |
A Single Bout of Fasting (24 h) Reduces Basal Cytokine Expression and Minimally Impacts the Sterile Inflammatory Response in the White Adipose Tissue of Normal Weight F344 Rats.
Sterile inflammation occurs when inflammatory proteins are increased in blood and tissues by nonpathogenic states and is a double-edged sword depending on its cause (stress, injury, or disease), duration (transient versus chronic), and inflammatory milieu. Short-term fasting can exert a host of health benefits through unknown mechanisms. The following experiment tested if a 24 h fast would modulate basal and stress-evoked sterile inflammation in plasma and adipose. Adult male F344 rats were either randomized to Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Corticosterone; Cytokines; Fatty Acids, Nonesterified; Food Deprivation; Inflammation; Insulin; Interleukin-10; Interleukin-1beta; Interleukin-6; Leptin; Male; Random Allocation; Rats; Rats, Inbred F344; Tumor Necrosis Factor-alpha | 2016 |
Relation of the rs6923761 gene variant in glucagon-like peptide 1 receptor with weight, cardiovascular risk factor, and serum adipokine levels in obese female subjects.
Studies of the glucagon-like peptide 1 (GLP-1) receptor have been directed at identifying polymorphisms in the GLP-1 receptor gene that may be a contributing factor in the pathogenesis of diabetes mellitus and cardiovascular risk factors. Nevertheless, the role of GLP-1 variants on body weight, cardiovascular risk factors, and adipokines remains unclear in obese patients.. Our aim was to analyze the effects of rs6923761 GLP-1 receptor polymorphism on body weight, cardiovascular risk factors, and serum adipokine levels in nondiabetic obese females.. A sample of 645 obese nondiabetic Caucasian females was enrolled in a prospective way. Basal fasting glucose, c-reactive protein (CRP), insulin, insulin resistance (homeostasis model assessment (HOMA)), total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides concentration, and adipokines were measured. Weights, body mass index (BMI), waist circumference, fat mass by bioimpedance, and blood pressure measures were measured.. Three hundred and twenty-seven participants (50.7%) had the genotype GG and 318 (49.3%) study subjects had the next genotypes; GA (270 study subjects, 41.9%) or AA (48 study subjects, 7.4%) (second group). In wild group (GG genotype), BMI (1.8 ± 2.3 kg/m(2) ; P < 0.05), weight (3.1 ± 1.3 kg; P < 0.05), fat mass (2.4 ± 1.1 kg; P < 0.05), waist circumference (2.7 ± 1.9 cm; P < 0.05), triglyceride levels (10.4 ± 5.3 mg/dl; P < 0.05), interleukin 6 (IL-6) (1.5 ± 0.9 ng/dl; P < 0.05), resistin (1.1 ± 0.3 ng/dl; P < 0.05), and leptin (30.1 ± 10.3 ng/dl; P < 0.05) levels were higher than mutant group (GA + AA).. Data from our study revealed an association with decreased metabolic and cardiovascular markers in obese females. BMI weight, fat mass, waist circumference, triglycerides, leptin, resistin, and IL-6 serum levels were lower in subjects with A allele than non-A allele subjects. Topics: Adipokines; Adult; Body Composition; Body Mass Index; Body Weight; Cardiovascular Diseases; Female; Genotype; Glucagon-Like Peptide-1 Receptor; Humans; Interleukin-6; Leptin; Middle Aged; Obesity; Polymorphism, Genetic; Prospective Studies; Receptors, Glucagon; Resistin; Risk Factors; Triglycerides; Waist Circumference; White People | 2015 |
Factors associated with prospective leptin concentrations throughout pregnancy in pregestational normal weight, overweight and obese women.
Leptin concentrations increase throughout pregnancy but little is known about factors that influence this physiological change and whether they differ according to pregestational body mass index (BMI).. To assess whether longitudinal trends of leptin in pregnancy are influenced by biochemical, anthropometric and lifestyle factors in women with normal weight (NW), overweight (OW) or obese (OB) pregestational BMI.. Prospective cohort of 232 pregnant women followed at 5-13th, 20-26th and 30-36th gestational weeks. The effect of selected variables on longitudinal behaviour of plasma leptin concentrations, stratifying for NW (18·5-24·9 kg/m(2) ), OW (25-29·9 kg/m(2) ) and OB (≥30·0 kg/m(2) ) pregestational BMI was assessed through longitudinal linear mixed-effects models.. The multiple regression model for women with NW revealed associations of maternal body weight (β = 0·714, CI = 0·491 to 0·937), serum HDL-cholesterol (β = 0·239, CI =0·089 to 0·388) and C-reactive protein (CRP) (β = -0·138, CI = -0·272 to -0·004) with plasma leptin concentrations. Maternal body weight (β = -0·871, CI = 0·475 to 1·267) and serum HDL-cholesterol concentrations (β = 0·315, CI = -0·022 to 0·651) were also associated with leptin in OW women. In OB women, serum HDL-cholesterol (β = 0·722, CI = 0·219 to 1·226), maternal body weight (β = 0·666, CI = 0·187 to 1·145), triglycerides concentrations (β = -0·130, CI = -0·241 to -0·020) and dietary carbohydrate (β = 0·075, CI = 0·023 to 0·126) were significantly associated with plasma leptin.. Maternal body weight and serum concentrations of HDL-cholesterol were associated with leptin changes independent of pregestational BMI. Serum CRP concentrations were associated with leptin only in NW women and serum triglycerides concentrations and dietary carbohydrate only in OB. These results indicate that factors that influence leptin concentrations differ according to pregestational BMI. Topics: Adult; Body Weight; Female; Gestational Age; Humans; Leptin; Obesity; Overweight; Pregnancy; Prospective Studies; Young Adult | 2015 |
Relationship between leptin and adiponectin concentrations in plasma and femoral and spinal bone mineral density in spinal cord-injured individuals.
Previously, the associations between leptin and adiponectin levels with bone mineral density (BMD) have been reported in different populations, and occasionally, controversial results have been demonstrated. Until now, these relationships in spinal cord-injured individuals have not yet been described.. We tried to investigate the correlation between leptin and adiponectin concentrations in plasma and BMD in Iranian patients with spinal cord injury (SCI).. Cross-sectional investigation.. Referred patients with SCI who did not meet our exclusion criteria such as pregnancy, lactation, amputation, history of diabetes, cancer, endocrinology disease, and use of special medications entered the study.. Bone mineral density of femoral neck, trochanter, intertrochanteric zone, total hip, and lumbar vertebrae assessed by dual-energy X-ray absorptiometry and serum leptin and adiponectin levels measured by blood sample analysis using immunoassay techniques.. Patient demographic characteristics were measured during face-to-face visits. Injury level and Spinal cord Injury Association (ASIA) score were assessed by clinical examination and were confirmed by imaging aids. Measured levels of leptin and adiponectin and dual-energy X-ray absorptiometry results were analyzed with partial correlation analysis method after adjustment for weight, body mass index (BMI), and age.. Total of 104 patients (19 females and 85 males) entered this investigation. Higher leptin concentration was significantly associated with higher BMD in femoral neck (p=.006, r=0.73), femoral intertrochanteric zone (p=.001, r=0.83), and hip (p=.001, r=0.81) only in female patients, whereas no such association was detected in male participants after adjusting for BMI and age. Leptin and adiponectin levels were not associated with lumbar spine BMD in both genders. Neither injury level nor ASIA score and plegia type (paraplegia or tetraplegia) influenced on leptin and adiponectin concentrations.. We found no association between leptin concentration and BMD in male individuals, whereas a positive correlation between leptin and BMD of femoral neck, intertrochanter, and hip was observed in female patients that shows a sexual polymorphism in this relationship. However, by considering the low number of female participants, these results should be interpreted cautiously. Lumbar spine BMD was associated with neither leptin nor adiponectin level in both genders. Topics: Absorptiometry, Photon; Adiponectin; Adult; Aged; Body Mass Index; Body Weight; Bone Density; Cross-Sectional Studies; Female; Femur; Hip Joint; Humans; Iran; Leptin; Lumbar Vertebrae; Male; Middle Aged; Pregnancy; Spinal Cord Injuries | 2015 |
Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury.
The mechanisms linking obesity and osteoarthritis (OA) are not fully understood and have been generally attributed to increased weight, rather than metabolic or inflammatory factors. Here, we examined the influence of fatty acids, adipokines, and body weight on OA following joint injury in an obese mouse model.. Mice were fed high-fat diets rich in various fatty acids (FA) including saturated FAs (SFAs), ω-6 polyunsaturated FAs (PUFAs), and ω-3 PUFAs. OA was induced by destabilising the medial meniscus. Wound healing was evaluated using an ear punch. OA, synovitis and wound healing were determined histologically, while bone changes were measured using microCT. Activity levels and serum cytokines were measured at various time-points. Multivariate models were performed to elucidate the associations of dietary, metabolic and mechanical factors with OA and wound healing.. Using weight-matched mice and multivariate models, we found that OA was significantly associated with dietary fatty acid content and serum adipokine levels, but not with body weight. Furthermore, spontaneous activity of the mice was independent of OA development. Small amounts of ω-3 PUFAs (8% by kcal) in a high-fat diet were sufficient to mitigate injury-induced OA, decreasing leptin and resistin levels. ω-3 PUFAs significantly enhanced wound repair, SFAs or ω-6 PUFAs independently increased OA severity, heterotopic ossification and scar tissue formation.. Our results indicate that with obesity, dietary FA content regulates wound healing and OA severity following joint injury, independent of body weight, supporting the need for further studies of dietary FA supplements as a potential therapeutic approach for OA. Topics: Animals; Body Weight; Bone and Bones; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Ear Auricle; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Femur; Leg Injuries; Leptin; Mice; Obesity; Osteoarthritis; Osteoarthritis, Knee; Resistin; Stifle; Synovitis; Tibia; Tibial Meniscus Injuries; Wound Healing; X-Ray Microtomography | 2015 |
Effects of scaling and root planing on clinical response and serum levels of adipocytokines in patients with obesity and chronic periodontitis.
Despite several investigations suggesting that obesity is a risk indicator for periodontitis, little is known about the effect of obesity on periodontal treatment response. The aim of this study is to evaluate the effects of scaling and root planing (SRP) on clinical parameters and circulating levels of leptin and adiponectin in patients with obesity with chronic periodontitis (CP).. Twenty-four patients with obesity and CP and 24 patients without obesity with CP were submitted to SRP. Clinical parameters were assessed at baseline and 3 and 6 months after therapy. Serum levels of leptin and adiponectin were evaluated at all time points, using enzyme-linked immunosorbent assay.. SRP improved the clinical parameters of both groups at 3 and 6 months (P < 0.05). Nonetheless, the patients without obesity presented a lower mean probing depth (PD) at 6 months after therapy and a greater reduction in PD from baseline to 6 months in the full-mouth analysis (primary outcome variable) and in initially deep sites (P < 0.05). Leptin serum levels were higher in patients with obesity than in patients without obesity at all time points (P < 0.05). No changes in the serum levels of leptin and adiponectin were observed in groups with and without obesity after therapy (P > 0.05).. Patients with obesity and CP presented lower reductions in PD than patients without obesity with CP at 6 months after SRP. Furthermore, the treatment did not affect the circulating levels of leptin and adiponectin in any group. Topics: Adiponectin; Adult; Aged; Blood Glucose; Body Height; Body Mass Index; Body Weight; Chronic Periodontitis; Dental Plaque; Dental Scaling; Female; Follow-Up Studies; Humans; Leptin; Male; Middle Aged; Obesity; Oral Hygiene; Periodontal Attachment Loss; Periodontal Pocket; Root Planing; Waist Circumference; Waist-Hip Ratio | 2015 |
Dietary fiber intake and its association with indicators of adiposity and serum biomarkers in European adolescents: the HELENA study.
To evaluate total, energy-adjusted dietary fiber (DF), water-soluble fiber (WSF), and water-insoluble fiber (WIF) intakes in European adolescents and to investigate their association with indicators of adiposity and serum biomarkers.. This study, conducted from 2006 to 2007, included 1804 adolescents aged 12.5-17.5 years (47% males) from eight European cities completing two non-consecutive computerized 24-h dietary recalls. GLM multivariate analysis was used to investigate associations.. Mean DF intake (20 g/day) of the sample met the European Food Safety Authority recommendation, but was below those of the World Health Organization and of the Institute of Medicine. Total DF, WSF and WIF intakes were higher in males (P < 0.001), but following energy-adjustments significantly higher intakes were observed among females (P < 0.001). Bread and cereals contributed most to total DF, WSF and WIF intakes, followed by potatoes and grains, energy-dense but low-nutritious foods, fruits and vegetables. Moreover, energy-adjusted WSF and WIF were positively associated with body fat percentage (BF%), waist to height ratio and low-density lipoprotein cholesterol, while energy-adjusted WSF was inversely associated with serum fasting glucose (β = -0. 010, P = 0.020).. Total DF intakes are rather low in European adolescents. An inverse association with serum fasting glucose might indicate a possible beneficial role of DF in preventing insulin resistance and its concomitant diseases, even though DF intakes were positively associated with adolescents' BF%. Therefore, further longitudinal studies should elaborate on these potential beneficial effects of DF intake in the prevention of obesity and related chronic diseases. Topics: Adiposity; Adolescent; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Child; Cholesterol, HDL; Cholesterol, LDL; Cross-Sectional Studies; Dietary Fiber; Energy Intake; Female; Fruit; Humans; Insulin; Leptin; Male; Mental Recall; Nutrition Assessment; Obesity; Triglycerides; Vegetables; Waist-Hip Ratio; White People | 2015 |
The relationship between moderate-to-vigorous intensity physical activity and insulin resistance, insulin-like growth factor (IGF-1)-system 1, leptin and weight change in healthy women during pregnancy and after delivery.
Childbearing is considered to be a significant risk factor for developing overweight and obesity. Physical activity might influence weight change via hormonal changes.. To test the hypothesis that higher levels of moderate-to-vigorous intensity physical activity (MVPA) are positively associated with maternal insulin sensitivity and reduce IGF-1, IGFBP-3, leptin levels, bodyweight gain/retention and birth weight.. In healthy nulliparous women, weight measurements were carried out and blood was collected during pregnancy in the 15th, 25th and 35th week, and after delivery at 6, 26 and 52 weeks. At 15 and 35 weeks of pregnancy and 26 weeks postpartum, MVPA was measured using accelerometers. In linear regression models, the relationship between MVPA below or above the median with metabolic and weight outcomes was assessed, adjusted for maternal BMI, age and smoking.. Moderate-to-vigorous intensity physical activity (MVPA) decreased significantly during pregnancy, but was very low already in early pregnancy. Insulin resistance and leptin levels increased during pregnancy and decreased significantly after delivery (all P < 0·05). After adjustment, insulin, IGFBP-3 and BMI were significantly lower at 15 weeks of pregnancy in women with MVPA above the median compared to those with MVPA below the median. After 15 weeks of pregnancy, no significant associations were observed between hormonal levels and MVPA. MVPA was neither related to weight retention, nor to birth weight.. Except in early pregnancy, MPVA was not related to metabolic outcomes. In addition, MVPA during pregnancy was not related to weight retention or birth weight. Topics: Adult; Body Mass Index; Body Weight; Exercise; Female; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Postpartum Period; Pregnancy; Randomized Controlled Trials as Topic; Young Adult | 2015 |
Onset of exercise and diet program in obese women: metabolic and anorexigenic responses related to weight loss and physical capacities.
Perturbations of energy balance induce compensatory processes that may alter expected weight loss. In obese patients, our aim was to investigate the relationships that occurred between fasting plasma concentrations of anorexigenic peptides and metabolic parameters, appetite, physical capacity, and weight loss in the 5 first days of a program associating exercise and caloric reduction. Thirteen obese women were monitored from day 1 to day 5 with 2 exercise sessions in day 2 and day 4. We measured, in a fasted state, changes in body weight, hunger ratings, and plasma concentrations of fatty acids, triglycerides, leptin, insulin, amylin, peptide YY, and insulin-resistance index. Physical performance was assessed by a 6-min walking test. The program resulted in significantly reduced body weight (0.75±0.4 kg; p=0.001), of plasma concentrations of triglycerides, insulin, amylin, peptide YY, and the insulin-resistance index, and also increased fatty acids (p<0.05). Hunger ratings were increased (p<0.05). Program-induced changes in fatty acids, leptin, and insulin concentrations were related to physical performance (r(2)=0.45, 0.59, and 0.52; p<0.05, respectively) and to weight loss (r(2)=0.65, 0.57, 0.55; p<0.05, respectively). Five days of diet and exercise induced weight loss, improved lipid profile, and decreased insulin resistance while hunger ratings increased. Subjects with higher physical capacity lost more weight, presented higher increases in fatty acids and lower changes of leptin and insulin concentrations suggesting a better metabolic flexibility. To reduce the compensatory responses that can occur with energy imbalances, our study supports to account for individual activity level before prescribing weight-loss program associating diet and exercise. Topics: Adult; Body Weight; Diet, Reducing; Exercise; Female; Humans; Hunger; Insulin; Insulin Resistance; Leptin; Lipids; Middle Aged; Obesity; Weight Loss | 2015 |
Hippocampal GSK3β as a Molecular Link Between Obesity and Depression.
Obesity is considered as a risk factor for mood disorders including depression. Nevertheless, the mechanisms underlying this association are not clearly understood. To address this issue, we investigated the impact of high-fat (HF)-diet-induced obesity on depressive-like behavior and on serotonin (5-HT)-dependent Akt/glycogen synthase kinase 3β (GSK3β) signaling in the dentate gyrus (DG) of the hippocampus, which has been associated with mood regulation. We first showed that a HF diet induced significant overweight and hyperglycemia as well as a depressive-like behavior in adult Wistar rats. By using an ex vivo approach on brain slices, we demonstrated that 5-HT activates the Akt/GSK3β cascade in the DG of control chow (C) diet-fed animals and that a 16-week HF diet feeding abolishes this activation, concurrently with a desensitization of leptin and insulin signaling in the same region. Furthermore, depressive-like behavior inversely correlated with 5-HT-induced phosphorylation of GSK3β in the subgranular neurons of the DG. Interestingly, a substitution of HF with C diet for 6 weeks induced a total loss of depressive symptoms, whereas body weight and glycemia remained significantly higher compared to control rats. In addition, food restoration led to a recovery of the Akt/GSK3β signaling pathway activation in the DG. In parallel, we observed a negative correlation between body weight and cell proliferation in the subgranular zone of the DG. To conclude, we provide evidence for a desensitization of 5-HT-induced Akt/GSK3β signaling and an impaired cell proliferation in the DG by HF diet, suggesting novel molecular mechanisms linking obesity to depression. Topics: Animals; Body Weight; Cell Proliferation; Dentate Gyrus; Depression; Diet, High-Fat; Energy Intake; Feeding Behavior; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Immunohistochemistry; Insulin; Leptin; Male; Motor Activity; Neurons; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Wistar; Serotonin | 2015 |
Activation of the brain melanocortin system is required for leptin-induced modulation of chemorespiratory function.
Melanocortin receptors (MC3/4R) mediate most of the metabolic and cardiovascular actions of leptin.. Here, we tested if MC4R also contributes to leptin's effects on respiratory function.. After control measurements, male Holtzman rats received daily microinjections of leptin, SHU9119 (MC3/4R antagonist) or SHU9119 combined with leptin infused into the brain lateral ventricle for 7 days. On the 6th day of treatment, tidal volume (VT ), respiratory frequency (fR ) and pulmonary ventilation (VE ) were measured by whole-body plethysmography during normocapnia or hypercapnia (7% CO2 ). Baseline mean arterial pressure (MAP), heart rate (HR) and metabolic rate were also measured. VE , VT and fR were also measured in mice with leptin receptor deletion in the entire central nervous system (LepR/Nestin-cre) or only in proopiomelanocortin neurones (LepR/POMC-cre) and in MC4R knockout (MC4R(-/-) ) and wild-type mice.. Leptin (5 μg day(-1) ) reduced body weight (~17%) and increased ventilatory response to hypercapnia, whereas SHU9119 (0.6 nmol day(-1) ) increased body weight (~18%) and reduced ventilatory responses compared with control-PBS group (Lep: 2119 ± 90 mL min(-1) kg(-1) and SHU9119: 997 ± 67 mL min(-1) kg(-1) , vs. PBS: 1379 ± 91 mL min(-1) kg(-1) ). MAP increased after leptin treatment (130 ± 2 mmHg) compared to PBS (106 ± 3 mmHg) or SHU9119 alone (109 ± 3 mmHg). SHU9119 prevented the effects of leptin on body weight, MAP (102 ± 3 mmHg) and ventilatory response to hypercapnia (1391 ± 137 mL min(-1) kg(-1) ). The ventilatory response to hypercapnia was attenuated in the LepR/Nestin-cre, LepR/POMC-cre and MC4R(-/-) mice.. These results suggest that central MC4R mediate the effects of leptin on respiratory response to hypercapnia. Topics: Animals; Body Weight; Carbon Dioxide; Gene Expression Regulation; Hypercapnia; Leptin; Male; Melanocortins; Melanocyte-Stimulating Hormones; Mice; Mice, Knockout; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Respiratory Physiological Phenomena | 2015 |
The effects of parity, litter size, physiological state, and milking frequency on the metabolic profile of Lacaune dairy ewes.
Effects of parity (primiparous, PRIM vs multiparous, MULT) and litter size (singletons, SING vs twins, TWIN) on metabolic profiles from 1 wk before lambing to the end of lactation were studied in 48 Lacaune dairy ewes reared in confinement during most of the year and grazed on improved pastures at the end of lactation (summer). Another group of 48 ewes was incorporated during the milking period (ie, from 1 wk after weaning), to measure the effects of milking frequency (1 vs 2 milkings per day) on intake, milk production and composition, and body energy usage. Thus, in a 2 × 2 × 2 factorial design, ewes (n = 96) were allocated to homogeneous groups according to body weight (BW) and body condition score (BCS) and were monitored from late pregnancy to late lactation as a function of parity (PRIM, n = 48; MULT, n = 48), litter size (LSi) (SING, n = 40; TWIN, n = 56) and daily milking frequency (FREQ; milked once, ONE; n = 48; or twice, TWO; n = 48). Individual BW, BCS, plasma metabolites, and metabolic hormones were measured regularly (ie, 9 consecutive sampling dates). The BW was higher in MULT but no differences because of LSi or FREQ were detected at the intra-parity group level. The BCS was higher in MULT and in ewes with SING throughout the experiment. The latter was related to the demands for body reserves mobilization, as expressed by higher nonesterified fatty acids and β-hydroxybutyrate concentrations in ewes with TWIN from late pregnancy to weaning (35 d postpartum) in both PRIM and MULT ewes. This was consistent with higher insulin in MULT and higher triiodothyronine, leptin and insulin-like growth factor 1 in ewes with SING during this period. Differences in energy balance because of FREQ were evident after interpretation of plasma nonesterified fatty acids, glucose, insulin, and leptin concentration during the milking period. At similar feed intakes, ewes in ONE were in positive balance with regard to TWO. Overall, clear effects of parity, LSi, physiological states, and FREQ on metabolic profiles were found because of differences in nutrient partitioning when combining these experimental factors. Without considering FREQ, changes in metabolic measures in milking period were marginal compared with the periparturient adjustments performed until weaning to compensate energy deficiencies. Topics: Animal Husbandry; Animals; Body Composition; Body Weight; Diffuse Axonal Injury; Eating; Female; Lactation; Leptin; Litter Size; Milk; Parity; Pregnancy; Sheep; Triiodothyronine | 2015 |
Sex-related differences in the effects of high-fat diets on DHEA-treated rats.
Several studies have investigated the beneficial effects of dehydroepiandrosterone (DHEA) on lipid and glucose metabolism. However, many of these studies are inconclusive about the effects of DHEA administration on metabolic disorders, and there appear to be sex-related differences in the effects of DHEA treatment. Few animal studies have addressed the effects of DHEA on diet-induced metabolic disorders. The present study sought to ascertain whether sex differences exist in the effects of a high-fat diet (HFD) on weight gain, adiposity, and biochemical and hormonal parameters in DHEA-treated rats. Rats were fed a HFD for 4 weeks and simultaneously received treatment with DHEA (10 mg/kg by subcutaneous injection) once weekly. Body weight, retroperitoneal fat depot weight, serum glucose, insulin, and leptin levels, and hepatic lipids were measured. HFD exposure increased the adiposity index in both sexes, the hepatic triglyceride content in both sexes, and the hepatic total cholesterol level in males. Moreover, the HFD induced an increase in blood glucose levels in both sexes, and hyperinsulinemia in males. In this experimental model, DHEA treatment reduced hepatic triglyceride levels only in females, regardless of HFD exposure. Exposure to a HFD, even if it does not cause obesity, may enhance risk factors for metabolic disorders, and males are more sensitive to this effect. DHEA treatment can help prevent metabolic derangements, but its effect varies with sex. Topics: Animals; Blood Glucose; Body Weight; Dehydroepiandrosterone; Diet, High-Fat; Female; Hyperinsulinism; Insulin; Leptin; Lipid Metabolism; Lipids; Liver; Male; Obesity; Rats; Rats, Wistar; Risk Factors; Sex Factors | 2015 |
The mediating effect of leptin on the relationship between body weight and knee osteoarthritis in older adults.
Obesity is associated with an increased risk of osteoarthritis (OA) of the knee. Emerging evidence suggests that adipokines, substances produced by adipose tissue, may play a role in the development of knee OA. The aim of this study was to determine whether the inflammatory adipokine leptin partially mediates the relationship between body mass index (BMI) and knee OA.. We used baseline data from 653 participants who were 70 years of age or older in the population-based Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly Boston Study. Height and weight were measured, and participants were assessed for knee OA using clinical criteria. Serum leptin was measured using a microsphere-based assay.. The average BMI and the average serum leptin level were 27.5 kg/m(2) and 589 pM, respectively; the prevalence of knee OA was 24.7%. In regression models adjusted for covariates, we found that a 5-kg/m(2) increase in BMI was associated with 32% increased odds of knee OA (odds ratio [OR] 1.32, 95% confidence interval [95% CI] 1.10, 1.58); a 200-pM increase in serum leptin levels was associated with 11% increased odds of knee OA (OR 1.11, 95% CI 1.05, 1.17). The ratio of the standardized coefficients for the indirect:total effect calculated using the product-of-coefficients method was 0.49, suggesting that approximately half of the total effect of BMI on knee OA may be mediated by serum leptin. The estimated 95% CIs for the mediated effect suggest that this effect is statistically significant. Similarly, mediation analysis using a counterfactual approach suggested that the effect of leptin mediation was statistically significant.. We found that almost half of the association between elevated BMI and knee OA could be explained by the inflammatory adipokine leptin. Topics: Age Factors; Aged; Aged, 80 and over; Biomarkers; Body Mass Index; Body Weight; Female; Humans; Leptin; Male; Obesity; Osteoarthritis, Knee; Postural Balance; Prevalence; Regression Analysis; Risk Factors | 2015 |
Timing of fat and liquid sugar intake alters substrate oxidation and food efficiency in male Wistar rats.
In addition to the amount of ingested calories, both timing of food intake and meal composition are determinants of body weight gain. However, at present, it is unknown if the inappropriate timing of diet components is responsible for body weight gain. In the present study, we therefore studied a time-dependent effect of the diet composition on energy homeostasis. Male Wistar rats were subjected to chow ad libitum (chow group) or a choice diet with saturated fat, a 30% sugar solution, chow and tap water. The choice diet was provided either with all components ad libitum (AL), with ad libitum access to chow, tap water and a 30% sugar solution, but with access to saturated fat only during the light period (LF), or with ad libitum access to chow, tap water and saturated fat, but access to a 30% sugar solution only during the light period (LS). Caloric intake and body weight gain were monitored during 31 days. Energy expenditure was measured in the third week in calorimetric cages. All rats on a choice diet showed hyperphagia and gained more body weight compared to the chow group. Within the choice diet groups, rats on the LS diet were most food efficient (i.e. gained most body weight per ingested calorie) and showed a lower respiratory exchange ratio (RER) with an anti-phasic pattern, whereas no differences in locomotor activity or heat production were found. Collectively these data indicate that the timing of the diet composition affects food efficiency, most likely due to a shifted oxidation pattern, which can predispose for obesity. Further studies are underway to assess putative mechanisms involved in this dysregulation. Topics: Animals; Body Composition; Body Weight; Calorimetry; Circadian Rhythm; Diabetes Mellitus, Type 2; Diet; Dietary Fats; Dietary Sucrose; Disease Models, Animal; Eating; Energy Intake; Feeding Behavior; Homeostasis; Leptin; Light; Male; Obesity; Oxygen; Rats; Rats, Wistar; Time Factors; Weight Gain | 2015 |
Sex dimorphism in late gestational sleep fragmentation and metabolic dysfunction in offspring mice.
Excessive sleep fragmentation (SF) is common in pregnant women. Adult-onset metabolic disorders may begin during early development and exhibit substantial sex dimorphism. We hypothesized that metabolic dysfunction induced by gestational SF in male mice would not be apparent in female littermates.. Body weight and food consumption were measured weekly in male and female offspring after late gestational SF or control sleep (SC). At 20 weeks, plasma leptin, adiponectin, lipid profiles, and insulin and glucose tolerance tests were assessed. Leptin and adiponectin, M1, and M2 macrophage messenger RNA expression and polarity were examined. Adiponectin gene promoter methylation levels in several tissues were assessed.. Food intake, body weight, visceral fat mass, and insulin resistance were higher, and adiponectin levels lower in male but not female offspring exposed to gestational SF. However, dyslipidemia was apparent in both male and female offspring exposed to SF, albeit of lesser magnitude. In visceral fat, leptin messenger RNA expression was selectively increased and adiponectin expression was decreased in male offspring exposed to gestational SF, but adiponectin was increased in exposed female offspring. Differences in adipokine expression also emerged in liver, subcutaneous fat, and muscle. Increased M1 macrophage markers were present in male offspring exposed to SF (SFOM) while increased M2 markers emerged in SF in female offspring (SFOF). Similarly, significant differences emerged in the methylation patterns of adiponectin promoter in SFOM and SFOF.. Gestational sleep fragmentation increases the susceptibility to obesity and metabolic syndrome in male but not in female offspring, most likely via epigenetic changes. Thus, sleep perturbations impose long-term detrimental effects to the fetus manifesting as sex dimorphic metabolic dysfunction in adulthood. Topics: Adiponectin; Animals; Body Weight; Disease Susceptibility; DNA Methylation; Eating; Epigenesis, Genetic; Female; Glucose Tolerance Test; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lipids; Liver; Macrophages; Male; Metabolic Syndrome; Mice; Muscles; Obesity; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Promoter Regions, Genetic; Sex Characteristics; Sleep; Sleep Deprivation; Subcutaneous Fat | 2015 |
Polydatin supplementation ameliorates diet-induced development of insulin resistance and hepatic steatosis in rats.
The pathophysiology of non-alcoholic fatty liver disease remains to be elucidated, and the currently available treatments are not entirely effective. Polydatin, a stilbenoid compound derived from the rhizome of Polygonum cuspidatum, has previously been demonstrated to possess hepatoprotective effects. The present study aimed to determine the effects of polydatin supplementation on hepatic fat accumulation and injury in rats fed a high-fat diet. In addition, the mechanisms underlying the protective effects of polydatin were examined. Male Sprague Dawley rats were randomly divided into four groups and received one of four treatment regimes for 12 weeks: Control diet, control diet supplemented with polydatin, high-fat diet, or high-fat diet supplemented with polydatin. Polydatin was supplemented in the drinking water at a concentration of 0.3% (wt/vol). The results of the present study showed that long-term high-fat feeding resulted in fatty liver in rats, which was manifested by excessive hepatic neutral fat accumulation and elevated plasma alanine aminotransferase and aspartate aminotransferase levels. Polydatin supplementation alleviated the hepatic pathological changes, and attenuated the insulin resistance, as shown by an improved homeostasis model assessment of basal insulin resistance values and a glucose tolerance test. Polydatin supplementation also corrected abnormal leptin and adiponectin levels. Specifically, polydatin supplementation enhanced insulin sensitivity in the liver, as shown by improved insulin receptor substrate 2 expression levels and Akt phosphorylation in the rat liver, following high-fat diet feeding. The results of the present study suggest that polydatin protects rats against high-fat feeding-induced insulin resistance and hepatic steatosis. Polydatin may be an effective hepatoprotective agent and a potential candidate for the prevention of fatty liver disease and insulin resistance. Topics: Adiponectin; Animals; Body Weight; Diet; Dietary Supplements; Disease Models, Animal; Fatty Liver; Gene Expression; Glucose Tolerance Test; Glucosides; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Liver; Male; Rats; Stilbenes | 2015 |
Comparative measurement of ghrelin, leptin, adiponectin, EGF and IGF-1 in breast milk of mothers with overweight/obese and normal-weight infants.
Obese infants are more susceptible to develop adulthood obesity and its related comorbidities. Previous studies have shown the presence of hormones and growth factors in maternal breast milk that may influence infant adiposity. The aim of this study was to investigate differences in concentrations of three hormones and two growth factors in the breast milk of mothers with obese and non-obese infants.. In this cross-sectional study, 40 mothers with overweight or obese infants (weight for length percentile >97) and 40 age-matched mothers with normal-weight infant (-10 < weight for length percentile < 85) who were between 2 and 5 months of age were enrolled. Anthropometric indices of infants and mothers were measured by routine methods. Breast milk concentrations of ghrelin and adiponectin, leptin, epithelial growth factor (EGF) and insulin-like growth factor-1 (IGF-1) were measured using enzyme-linked immunosorbent assay methods.. The mean breast milk concentration of ghrelin was higher in mothers with normal-weight infants, 137.50 pg/ml, than in mothers with obese infants, 132.00 pg/ml (P=0.001). This was also true regarding the concentration of EGF in mothers with (0/04 ng/ml) and without (0/038 ng/ml) normal-weight infants (P=0.01). No significant differences were observed in concentrations of leptin, adiponectin and IGF-1 between two groups (P > 0.05). There was also a significant positive correlation between EGF and ghrelin in both groups.. This study revealed that there was a correlation between ghrelin and EGF level in breast milk of mothers with obese and non-obese infants, suggesting a possible regulatory effect of these two hormones on weight in infants. Topics: Adiponectin; Adult; Body Weight; Breast Feeding; Case-Control Studies; Child Development; Cross-Sectional Studies; Epidermal Growth Factor; Female; Ghrelin; Humans; Infant; Infant Nutritional Physiological Phenomena; Insulin-Like Growth Factor I; Leptin; Milk, Human; Mothers; Obesity; Overweight; Pregnancy; Young Adult | 2015 |
Maternal prolactin inhibition causes changes in leptin at 22- and 30-day-old pups.
Breastfeeding is associated with obesity prevention. We showed previously that prolactin inhibition at the end of lactation causes hyperleptinemia at weaning (PN21) and programs for obesity, insulin resistance, dyslipidemia, and leptin resistance (PN180). Here, we evaluate the source of neonatal hyperleptinemia and how it develops during the nutritional transition from milk through solid food. Lactating rats were treated with bromocriptine (BRO), a prolactin inhibitor, 0.5 mg twice a day, or saline (CON) for the last 3 days of lactation. All parameters were studied at PN22 and PN30. At PN22, BRO-treated rats showed lower food intake, body mass, and body length. At PN30, only body length and mesenteric fat mass were lower. Despite normal plasma leptin levels at PN22, the adipose tissue leptin mRNA expression was lower, while plasma leptin was higher in PN30, possibly due to a higher adipose mesenteric tissue production. At PN22, the hypothalamus seems to be more sensitive to leptin, since OBR and STAT3 are higher. Conversely, at PN30 leptin signaling pathway is suggestive of leptin resistance with lower STAT3 and higher SOCS3 in hypothalamus and consequently higher NPY. Glycemia was lower at PN22 and higher at PN30, without changes in plasma insulin levels. At PN30, BRO-treated rats had other metabolic changes such as higher plasma cholesterol, lower HDL-c, higher hepatic cholesterol and AST, suggesting a liver dysfunction. Our data show that milk supply can exert a crucial role in the imprinting of a second leptin peak, which is important for survival adaptation to adverse nutritional conditions. Topics: Animals; Body Weight; Bromocriptine; Eating; Female; Hormone Antagonists; Hypothalamus; Lactation; Leptin; Prolactin; Rats; Receptors, Leptin; STAT3 Transcription Factor; Weaning | 2015 |
Novel polymorphisms in porcine 3'UTR of the leptin gene, including a rare variant within target sequence for MIR-9 gene in Duroc breed, not associated with production traits.
The leptin gene (LEP) is considered as a functional candidate for production traits in livestock due to its crucial role in energy homeostasis. Because polymorphisms in regulatory sequences may affect gene expression, we searched for them in the 3'UTR of LEP and analyzed their association with production traits. Four breeds and a composite line were studied. In the Polish Landrace and Polish Large White breeds, 8 SNPs and 1 indel were observed; whereas, in the Duroc breed, 9 specific SNPs were found. Pietrain and Line 990 were monomorphic. One SNP (g.+168C>T), observed in the Duroc breed only, was located within a target site for microRNA (miR-9). Association studies showed a weak association between one SNP (c.+846C>T) and abdominal fat weight in the Polish Landrace only. Thus, we concluded that contribution of polymorphisms in the 3'UTR to phenotypic variability of pig production traits is marginal. Moreover, we presented an overview of known polymorphisms (128) in the pig leptin gene. Topics: 3' Untranslated Regions; Animals; Body Composition; Body Weight; Female; Genetic Association Studies; Leptin; MicroRNAs; Poland; Polymorphism, Genetic; Swine | 2015 |
Umbilical cord blood adipokines and newborn weight change.
To ascertain the association between umbilical cord levels of adiponectin, leptin and resistin, and birth weight (BW) and newborn weight change (NWC) in the first 96 h of life.. 392 full-term singletons were recruited, in 2005/2006, at the five public units providing obstetrical and neonatal care in Porto. Information was collected by face-to-face interview and additionally from clinical records. Umbilical cord blood adipokines levels were determined and categorized using the 10th and 90th percentiles. Anthropometrics were obtained by trained examiners and NWC estimated as (weight - BW)/BW × 100, adjusted for newborn's age. Regression coefficients and 95% confidence intervals were calculated.. Low leptin levels (≤5.6 ng/ml) were associated with lower BW (β = -137.3 g 95%CI -268.6 g, -6.1 g) and high leptin levels (≥30.7 ng/ml) were associated with higher BW (β = 276.3 g 95%CI 145.8 g, 406.8 g) and higher NWC (β = 1.10% 95% CI 0.29%, 1.92%), comparing to newborns with normal leptin levels. Adiponectin and resistin were not associated with BW or NWC.. High umbilical cord blood leptin levels predicted higher BW and lower weight loss in the immediate postnatal period. Topics: Adipokines; Adiponectin; Birth Weight; Body Weight; Female; Fetal Blood; Humans; Infant, Low Birth Weight; Infant, Newborn; Leptin; Male; Resistin; Weight Loss | 2015 |
Mitigating or exacerbating effects of maternal-fetal programming of female mice through the food choice environment.
Humans live, eat, and become overweight/obese in complex surroundings where there are many available food choices. Prenatal exposure to poor food choices predisposes offspring to increased negative health risks, including obesity. Many animal experiments have analyzed intergenerational body weight parameters in an environment without food choices, which may not be directly translatable to the human food environment. In this study, offspring from mothers with a defined high-fat diet (HFD) or low-fat diet (LFD) were arbitrarily assigned to either an exclusively LFD or HFD or to a diet where they have a choice between LFD and HFD (choice diet). Offspring displayed negative outcomes of increased body weight, body fat, serum leptin, and blood glucose levels when given the choice diet compared with offspring on the LFD. Conversely, improved energy expenditure was found for offspring given the choice diet compared with offspring from HFD dams given LFD. In addition, maternal diet-specific influences on offspring metabolic parameters were identified, especially in offspring from HFD dams, including positive outcomes of reduced leptin in LFD offspring, reduced corticosterone and cholesterol levels in HFD offspring, and increased exercise levels in choice offspring, as well as the negative outcome of increased calorie intake in LFD offspring from HFD dams. This defined model can now be used as the basis for future studies to characterize the cycle of inter- and intragenerational obesity and whether more realistic diet environments, especially those including choice, can mitigate phenotype. Topics: Alopecia; Animal Feed; Animals; Body Composition; Body Weight; Corticosterone; Dietary Fats; Dose-Response Relationship, Drug; Eating; Energy Intake; Energy Metabolism; Female; Food Preferences; Glucose Tolerance Test; Insulin; Leptin; Lipids; Maternal-Fetal Relations; Mice; Mice, Inbred C57BL; Motor Activity; Pregnancy | 2015 |
Growth hormone receptor antagonist transgenic mice are protected from hyperinsulinemia and glucose intolerance despite obesity when placed on a HF diet.
Reduced GH levels have been associated with improved glucose metabolism and increased longevity despite obesity in multiple mouse lines. However, one mouse line, the GH receptor antagonist (GHA) transgenic mouse, defies this trend because it has reduced GH action and increased adiposity, but glucose metabolism and life span are similar to controls. Slight differences in glucose metabolism and adiposity profiles can become exaggerated on a high-fat (HF) diet. Thus, in this study, male and female GHA and wild-type (WT) mice in a C57BL/6 background were placed on HF and low-fat (LF) diets for 11 weeks, starting at 10 weeks of age, to assess how GHA mice respond to additional metabolic stress of HF feeding. On a HF diet, all mice showed significant weight gain, although GHA gained weight more dramatically than WT mice, with males gaining more than females. Most of this weight gain was due to an increase in fat mass with WT mice increasing primarily in the white adipose tissue perigonadal depots, whereas GHA mice gained in both the sc and perigonadal white adipose tissue regions. Notably, GHA mice were somewhat protected from detrimental glucose metabolism changes on a HF diet because they had only modest increases in serum glucose levels, remained glucose tolerant, and did not develop hyperinsulinemia. Sex differences were observed in many measures with males reacting more dramatically to both a reduction in GH action and HF diet. In conclusion, our findings show that GHA mice, which are already obese, are susceptible to further adipose tissue expansion with HF feeding while remaining resilient to alterations in glucose homeostasis. Topics: Adipocytes; Adiposity; Animals; Body Weight; Cattle; Diet, High-Fat; Disease Models, Animal; Eating; Female; Glucose; Glucose Intolerance; Hyperinsulinism; Insulin; Leptin; Liver; Male; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Receptors, Somatotropin; Triglycerides; Weight Gain | 2015 |
Dose-dependent effects of isoflavone exposure during early lifetime on the rat mammary gland: Studies on estrogen sensitivity, isoflavone metabolism, and DNA methylation.
Isoflavone (ISO) exposure during adolescence modulates 17β-estradiol (E2) sensitivity of the adult mammary gland. The present study investigated the dose dependency of these effects focusing on proliferation, estrogen receptor dependent and independent gene expression, as well as DNA methylation and ISO metabolism.. Female Wistar rats were lifelong exposed to an ISO-depleted diet or to diets enriched with a soy ISO extract (ISO-rich diet (IRD)) causing plasma concentrations as observed minimally (IRDlow) and maximally (IRDhigh) in Asian women. The extract was characterized by both phytochemical analysis and E-Screen. Rats were ovariectomized at postnatal day (PND) 80 and treated with E2 from PND94 to 97. In contrast to uterine response, body weight and visceral fat mass were affected by ISO. In the mammary gland, both E2-induced proliferation (proliferating cell nuclear antigen staining) and estrogen receptor activation (progesterone receptor staining) were significantly reduced by IRDhigh but not by IRDlow, which however attenuated Gdf15 mRNA expression. DNA methylation analysis revealed significant differences in the promoter regions of Aldhl1, Extl1, and WAP between IRDhigh and ISO-depleted diet.. Lifelong exposure to ISO results in dose-dependent differential effects on proliferation, gene expression, and DNA methylation in rat mammary glands. Yet, a decrease in estrogen responsiveness was only achieved by IRDhigh. Topics: Animals; Body Weight; Cell Proliferation; DNA Methylation; Dose-Response Relationship, Drug; Estrogens; Female; Glycine max; Humans; Isoflavones; Leptin; Mammary Glands, Animal; MCF-7 Cells; Rats; Rats, Wistar; Receptors, Estrogen; Uterus | 2015 |
Social overcrowding as a chronic stress model that increases adiposity in mice.
Stress is a widely recognized risk factor for psychiatric and metabolic disorders. A number of animal models utilizing various stressors have been developed to facilitate our understanding in the pathophysiology of stress-related dysfunctions. The most commonly used chronic stress paradigms include the unpredictable chronic mild stress paradigm, the social defeat paradigm and the social deprivation paradigm. Here we assess the potential of social crowding as an alternative chronic stress model to study the effects on affective behaviors and metabolic disturbances. Ten-week-old male C57BL/6 mice were housed in groups of four (control) or eight (social crowding; SC) in standard cage for 9 weeks. Exploration, anxiety- and depressive-like behaviors were assessed in the open field test, the elevated T-maze, the novelty-suppressed feeding test and the forced swim test. SC mice exhibited a modest anxiety-like phenotype without change in depressive-like behaviors. Nine weeks of social crowding did not affect the body weight, but robustly increased adiposity as determined by increased mass of fat depots. Consistent with the increased fat content, serum leptin was markedly elevated in the SC mice. Specific changes in gene expression were also observed in the hypothalamus and the white adipose tissue following SC housing. Our study demonstrates the potential of social crowding as an alternative model for the study of stress-related metabolic and behavioral dysfunctions. Topics: Adiponectin; Adiposity; Animals; Anxiety; Behavior, Animal; Body Weight; Corticosterone; Crowding; Depression; Disease Models, Animal; Eating; Environment; Exploratory Behavior; Housing, Animal; Insulin-Like Growth Factor I; Leptin; Male; Mice; Motor Activity; Stress, Psychological | 2015 |
Liraglutide, leptin and their combined effects on feeding: additive intake reduction through common intracellular signalling mechanisms.
To investigate the behavioural and intracellular mechanisms by which the glucagon like peptide-1 (GLP-1) receptor agonist, liraglutide, and leptin in combination enhance the food intake inhibitory and weight loss effects of either treatment alone.. We examined the effects of liraglutide (a long-acting GLP-1 analogue) and leptin co-treatment, delivered in low or moderate doses subcutaneously (s.c.) or to the third ventricle, respectively, on cumulative intake, meal patterns and hypothalamic expression of intracellular signalling proteins [phosphorylated signal transducer and activator of transcription-3 (pSTAT3) and protein tyrosine phosphatase-1B (PTP1B)] in lean rats.. A low-dose combination of liraglutide (25 µg/kg) and leptin (0.75 µg) additively reduced cumulative food intake and body weight, a result mediated predominantly through a significant reduction in meal frequency that was not present with either drug alone. Liraglutide treatment alone also reduced meal size; an effect not enhanced with leptin co-administration. Moderate doses of liraglutide (75 µg/kg) and leptin (4 µg), examined separately, each reduced meal frequency, cumulative food intake and body weight; only liraglutide reduced meal size. In combination these doses did not further enhance the anorexigenic effects of either treatment alone. Ex vivo immunoblot analysis showed elevated pSTAT3 in the hypothalamic tissue after liraglutide-leptin co-treatment, an effect which was greater than that of leptin treatment alone. In addition, s.c. liraglutide reduced the expression of PTP1B (a negative regulator of leptin receptor signalling), revealing a potential mechanism for the enhanced pSTAT3 response after liraglutide-leptin co-administration.. Collectively, these results show novel behavioural and molecular mechanisms underlying the additive reduction in food intake and body weight after liraglutide-leptin combination treatment. Topics: Animals; Appetite Depressants; Body Weight; Drug Therapy, Combination; Eating; Glucagon-Like Peptide 1; Hypothalamus; Incretins; Leptin; Liraglutide; Male; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Weight Loss | 2015 |
Role of FAT/CD36 in fatty acid sensing, energy, and glucose homeostasis regulation in DIO and DR rats.
Hypothalamic fatty acid (FA) sensing neurons alter their activity utilizing the FA translocator/receptor, FAT/CD36. Depletion of ventromedial hypothalamus (VMH) CD36 with adeno-associated viral vector expressing CD36 shRNA (AAV CD36 shRNA) leads to redistribution of adipose stores and insulin resistance in outbred rats. This study assessed the requirement of VMH CD36-mediated FA sensing for the regulation of energy and glucose homeostasis in postnatal day 5 (P5) and P21 selectively bred diet-induced obese (DIO) and diet-resistant (DR) rats using VMH AAV CD36 shRNA injections. P5 CD36 depletion altered VMH neuronal FA sensing predominantly in DIO rats. After 10 wk on a 45% fat diet, DIO rats injected with VMH AAV CD36 shRNA at P21 ate more and gained more weight than DIO AAV controls, while DR AAV CD36 shRNA-injected rats gained less weight than DR AAV controls. VMH CD36 depletion increased inguinal fat pad weights and leptin levels in DIO and DR rats. Although DR AAV CD36 shRNA-injected rats became as obese as DIO AAV controls, only DIO control and CD36 depleted rats became insulin-resistant on a 45% fat diet. VMH CD36 depletion stunted linear growth in DIO and DR rats. DIO rats injected with AAV CD36 shRNA at P5 had increased fat mass, mostly due to a 45% increase in subcutaneous fat. They were also insulin-resistant with an associated 71% increase of liver triglycerides. These results demonstrate that VMH CD36-mediated FA sensing is a critical factor in the regulation of energy and glucose homeostasis and fat deposition in DIO and DR rats. Topics: Adipose Tissue; Animal Feed; Animals; Blood Glucose; Body Weight; CD36 Antigens; Disease Models, Animal; Energy Intake; Fatty Acids; Homeostasis; Insulin; Leptin; Male; Obesity; Rats | 2015 |
Intermittent access to liquid sucrose differentially modulates energy intake and related central pathways in control or high-fat fed mice.
Intake of sodas has been shown to increase energy intake and to contribute to obesity in humans and in animal models, although the magnitude and importance of these effects are still debated. Moreover, intake of sugar sweetened beverages is often associated with high-fat food consumption in humans. We studied two different accesses to a sucrose-sweetened water (SSW, 12.3%, a concentration similar to that usually found in sugar sweetened beverages) in C57BL/6 mice fed a normal-fat (NF) or a high-fat (HF) diet in a scheduled access (7.5h). NF-fed and HF-fed mice received during 5weeks access to water, to SSW continuously for 7.5h (SSW), or to water plus SSW for 2h (randomly-chosen time slot for only 5 random days/week) (SSW-2h). Mouse preference for SSW was greater in HF-fed mice than NF-fed mice. Continuous SSW access induced weight gain whatever the diet and led to greater caloric intake than mice drinking water in NF-fed mice and in the first three weeks in HF-fed mice. In HF-fed mice, 2h-intermittent access to SSW induced a greater body weight gain than mice drinking water, and led to hyperphagia on the HF diet when SSW was accessible compared to days without SSW 2h-access (leading to greater overall caloric intake), possibly through inactivation of the anorexigenic neuropeptide POMC in the hypothalamus. This was not observed in NF-fed mice, but 2h-intermittent access to SSW stimulated the expression of dopamine, opioid and endocannabinoid receptors in the nucleus accumbens compared to water-access. In conclusion, in mice, a sucrose solution provided 2h-intermittently and a high-fat diet have combined effects on peripheral and central homeostatic systems involved in food intake regulation, a finding which has significant implications for human obesity. Topics: Animals; Body Composition; Body Weight; Brain; Cholecystokinin; Diet, High-Fat; Drinking Behavior; Eating; Energy Intake; Feeding Behavior; Food Deprivation; Gene Expression Regulation; Ghrelin; Leptin; Male; Mice; Mice, Inbred C57BL; Peptide YY; Sucrose; Sweetening Agents; Time Factors | 2015 |
Maternal dietary protein supplement confers long-term sex-specific beneficial consequences of obesity resistance and glucose tolerance to the offspring in Brandt's voles.
Maternal under- or over-nutrition not only alters neonatal body mass but also increases the risk of metabolic disorders in adulthood. Little is known about how maternal dietary protein affects offspring fitness in wild rodents. The present study was conducted to test the hypothesis that maternal dietary protein supplement has a long-term beneficial effect on offspring fitness in Brandt's vole (Lasiopodomys brandtii), a herbivorous rodent model. The vole dams were fed either a control (18% protein) or high-protein (36% protein) diet throughout pregnancy and lactation. After weaning, all offspring received a control diet till 14 weeks old. Energetic parameters, serum leptin concentration and glucose tolerance were measured. The adult offspring were fed high-fat diet for 8 weeks, and body weight and food intake were measured. No difference was observed in litter size, litter mass or pup mass before weaning. Maternal protein supplement increased body mass and the mass of reproductive organ but decreased digestibility and fat deposition and alleviated HFD-induced obesity especially in the males. Glucose tolerance was elevated in the offspring from maternal protein supplement, especially in the females. The accelerated growth may be associated with high serum leptin concentration at weaning, a state of leptin resistance, and the low digestibility may predispose obesity resistance especially in male offspring from maternal high-protein diet. These data demonstrate that maternal protein supplement confers the long-term sex-specific beneficial consequences of accelerated growth and improved obesity resistance and glucose tolerance of their offspring. Topics: Animals; Arvicolinae; Body Composition; Body Weight; Diet, High-Fat; Dietary Proteins; Dietary Supplements; Eating; Female; Glucose Intolerance; Lactation; Leptin; Male; Obesity; Pregnancy; Pregnancy, Animal | 2015 |
Maternal high-fat diet feeding during pregnancy and lactation augments lung inflammation and remodeling in the offspring.
Accumulating evidence suggests that maternal obesity increases the risk of their offspring developing noncommunicable diseases later in life, but the potential mechanisms, especially those resulting in abnormal respiratory conditions, are not thoroughly understood. Here, we used maternal high-fat diet (HFD) feeding during premating, pregnancy, and lactation to investigate the effect of maternal HFD on offspring lung development. Offspring birth weight and body weight and composition were measured. Serum leptin levels were measured by ELISA. Hematoxylin-eosin (H&E) and Masson's staining were used in paraffin-embedded lung sections. Levels of transfer growth factor-β (TGF-β) and α-smooth muscle actin (α-SMA) were examined by immunohistochemistry and western blot, respectively. Maternal HFD feeding during pregnancy and lactation lead to higher birth weight, final body weight, fat accumulation and hyperleptinemia in offspring. Maternal HFD feeding aggravated lung inflammatory response in the offspring, resulting in inflammatory cell infiltration and collagen deposition potentially via the enhanced expression of TGF-β and α-SMA in the offspring. Topics: Actins; Animals; Birth Weight; Body Composition; Body Weight; Diet, High-Fat; Enzyme-Linked Immunosorbent Assay; Female; Lactation; Leptin; Lung; Male; Pneumonia; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Sprague-Dawley; Transforming Growth Factor beta | 2015 |
Lactobacillus rhamnosus LA68 and Lactobacillus plantarum WCFS1 differently influence metabolic and immunological parameters in high fat diet-induced hypercholesterolemia and hepatic steatosis.
In this study, two Lactobacillus strains (L. rhamnosus LA68 and L. plantarum WCFS1) were evaluated for their effects on high fat diet induced pathology in mice. The aim was to determine whether the administration of lactic acid bacteria had beneficial effects on ameliorating pathology. C57BL/6 mice fed a high fat diet were orally administered with the Lactobacillus strains. Both the metabolic and immunological parameters were analyzed. The administration of both of the strains had beneficial effects on mouse weight, serum cholesterol, TNF-α levels and liver histology. LA68 lowered the total cholesterol and HDL levels more prominently, whereas WCFS1 was more potent in lowering the TG and LDL levels. Leptin and adiponectin levels were increased in all experimental groups to different extents. The administration of L. plantarum WCFS1 led to a marked increase in leptin levels, as well as an increase in CD3+CD4+ and CD3+CD8+ cells, and a decrease of CD25+ cells, and had a lowering effect on IL-6 production and cell metabolic activity. In conclusion, active administration of both Lactobacillus strains had a positive effect on HFD-induced pathology. Although both of the tested strains had beneficial effects, oral administration of WCFS1 increased leptin levels and had a more prominent immunomodulatory effect, which should be taken into consideration in case of humane usage. Topics: Adiponectin; Animals; Aspartate Aminotransferases; Body Weight; CD13 Antigens; Cholesterol, HDL; Cholesterol, LDL; Diet, High-Fat; Fatty Liver; Hypercholesterolemia; Interleukin-6; Lacticaseibacillus rhamnosus; Lactobacillus plantarum; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Probiotics; Triglycerides; Tumor Necrosis Factor-alpha | 2015 |
Prolonged REM sleep restriction induces metabolic syndrome-related changes: Mediation by pro-inflammatory cytokines.
Chronic sleep restriction in human beings results in metabolic abnormalities, including changes in the control of glucose homeostasis, increased body mass and risk of cardiovascular disease. In rats, 96h of REM sleep deprivation increases caloric intake, but retards body weight gain. Moreover, this procedure increases the expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which may be involved with the molecular mechanism proposed to mediate insulin resistance. The goal of the present study was to assess the effects of a chronic protocol of sleep restriction on parameters of energy balance (food intake and body weight), leptin plasma levels and its hypothalamic receptors and mediators of the immune system in the retroperitoneal adipose tissue (RPAT). Thirty-four Wistar rats were distributed in control (CTL) and sleep restriction groups; the latter was kept onto individual narrow platforms immersed in water for 18h/day (from 16:00h to 10:00h), for 21days (SR21). Food intake was assessed daily, after each sleep restriction period and body weight was measured daily, after the animals were taken from the sleep deprivation chambers. At the end of the 21day of sleep restriction, rats were decapitated and RPAT was obtained for morphological and immune functional assays and expression of insulin receptor substrate 1 (IRS-1) was assessed in skeletal muscle. Another subset of animals was used to evaluate blood glucose clearance. The results replicated previous findings on energy balance, e.g., increased food intake and reduced body weight gain. There was a significant reduction of RPAT mass (p<0.001), of leptin plasma levels and hypothalamic leptin receptors. Conversely, increased levels of TNF-α and IL-6 and expression of phosphorylated NFκ-β in the RPAT of SR21 compared to CTL rats (p<0.01, for all parameters). SR21 rats also displayed reduced glucose clearance and IRS-1 expression than CTL rats (p<0.01). The present results indicated that 21days of sleep restriction by the platform method induced metabolic syndrome-related alterations that may be mediated by inflammation of the RPAT. Topics: Adipose Tissue; Animals; Body Weight; Cytokines; Eating; Hypothalamus; Inflammation; Insulin Receptor Substrate Proteins; Leptin; Male; Metabolic Syndrome; Muscle, Skeletal; Phosphorylation; Rats; Rats, Wistar; Receptors, Leptin; Sleep Deprivation | 2015 |
Immunohistochemical distribution of leptin in kidney tissues of melatonin treated diabetic rats.
We examined using immunohistochemistry the distribution of leptin in kidney tissues of melatonin treated, streptozotocin (STZ) diabetic rats. The animals were divided into five groups: control, sham, melatonin-treated, diabetic and melatonin-treated diabetic. Kidney sections were prepared and stained with hematoxylin and eosin, and Crossman's triple staining for histological examination. The immunohistochemical localization of leptin in the kidney tissue was determined using the streptavidin-biotin-peroxidase method. We determined that on days 7 and 14, the leptin immunoreactivity of the diabetic and melatonin-treated diabetic groups was weaker than for the other groups. Weak immunoreactivity was found in the proximal and distal tubules of the kidney in the diabetic and melatonin-treated diabetic groups on days 7 and 14, and strong immunoreactivity was found in the control, sham and melatonin groups. Melatonin application had no significant effect on leptin production in the kidney tissues of diabetic rats. Topics: Animals; Antioxidants; Body Weight; Diabetes Mellitus, Experimental; Immunohistochemistry; Kidney; Leptin; Melatonin; Organ Size; Rats; Streptozocin | 2015 |
Effect of leptin on the relationship between body weight and knee osteoarthritis--a methodologic approach: comment on the article by Fowler-Brown et al.
Topics: Body Weight; Female; Humans; Leptin; Male; Obesity; Osteoarthritis, Knee | 2015 |
Reply: To PMID 25302634.
Topics: Body Weight; Female; Humans; Leptin; Male; Obesity; Osteoarthritis, Knee | 2015 |
Impact of cow size on dry matter intake, residual feed intake, metabolic response, and cow performance.
Thirty-eight Angus-cross beef cows were used to evaluate differences in DMI, residual feed intake (RFI), and endocrine markers on the basis of cow size and RFI ranking during 2 stages of production. Cows housed in individual pens (2.2 × 9.1 m) were fed, over a 70-d feeding period, 30% Bermuda grass hay and 70% ryegrass baleage diet during lactation (LACT) and a 100% ryegrass hay diet during postweaning (NOLACT). Individual daily feed intake, BW, and BCS were recorded, and hip height was used to determine frame score (FS). Feed intake was used to calculate RFI for each cow, and cow was the experimental unit. Blood samples were obtained on d 0 and 70 and were analyzed for glucose, insulin, leptin, triiodothyronine (T3), and thyroxine (T4). Cows were assigned to a light (LIT) or heavy (HEV) BW groups on the basis of mean BW at the beginning of the LACT period. On the basis of RFI values for each feeding period, cows were placed into a negative (NEG; RFI < 0.00) or positive (POS; RFI > 0.00) RFI group and into a low (LOW; ≤0.2 SD mean RFI), medium (MED; within ±0.19 SD), or high (HI; ≥0.2 SD mean RFI) RFI group. During LACT, DMI was 4.8% greater (P = 0.03) and FS was greater (P < 0.01; 6.4 and 5.5 ± 0.16) for the HEV compared with LIT BW cows. No RFI by day interaction or RFI group main effect occurred for endocrine markers during LACT; however, a negative relationship (P = 0.04) existed between BW group and combined T3 data, and a positive relationship (P = 0.04) existed between RFI and combined insulin data. For both LACT and NOLACT, RFI was similar (P > 0.05) among BW groups; however, DMI was 6.5% and 8.9% greater (P < 0.01) for POS compared with NEG RFI in the LACT and NOLACT periods. In LACT, DMI was greater (P < 0.01) for HI and MED RFI compared with LOW RFI, and in NOLACT, DMI was greater (P < 0.01) for the HI compared with MED and LOW RFI cows and MED compared with LOW RFI cows. During NOLACT, DMI was 8.9% greater (P < 0.01) for the HEV (12.4 ± 0.22 kg) compared with LIT (11.3 ± 0.19 kg) BW cows. Change in BCS was greater (P ≤ 0.03) in higher RFI cows in both RFI groups only in the NOLACT period. Differences in T3 and T4 on d 0 and 70 were 25% and 15% greater (P ≤ 0.04) for the LIT BW group compared with the HEV BW group. A negative correlation existed (P ≤ 0.04) between BW group and T3 and T4, as well as leptin and RFI (P = 0.03). Although cow BW was independent of RFI and T3 and T4 levels tended to be greater in lighter BW cows, DMI was consistently Topics: Animal Feed; Animals; Body Size; Body Weight; Cattle; Cynodon; Diet; Digestion; Eating; Energy Metabolism; Feeding Behavior; Female; Lactation; Leptin; Lolium; Thyroid Hormones | 2015 |
Localization of resistin and its possible roles in the ovary of a vespertilionid bat, Scotophilus heathi.
The aim of the present study was to evaluate the expression and effect of resistin on ovarian activities of Scotophilus heathi. Immunohistochemical study showed marked variation in resistin immunostaining during different reproductive phases. Most intense immunostaining of resistin was noticed in thecal-interstitial cells in ovary during the period of delayed ovulation, the period of increased androgen synthesis and suppressed ovulation. The changes in ovarian resistin level also correlated positively with circulating leptin level and body white adipose tissue accumulation. The in vitro study showed that resistin alone preferentially stimulated progesterone synthesis, but with luteinizing hormone (LH) stimulated androgen secretion. Resistin alone dose-dependently increased expression of LH-receptor, steroidogenic acute regulatory protein and insulin receptor proteins in the ovary, whereas together with LH showed dose-dependent stimulatory effect on expression of androgen receptor and insulin receptor proteins in the ovary. In conclusion, during the period of fat accumulation increased ovarian resistin level may be responsible for increased androgen synthesis through insulin receptor mediated pathways in the ovary of S. heathi. Topics: Adiponectin; Androgens; Androstenedione; Animals; Body Weight; Chiroptera; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Insulin; Leptin; Luteinizing Hormone; Ovary; Receptor, Insulin; Receptors, LH; Reproduction; Resistin; Seasons | 2015 |
A cross-over experiment to investigate possible mechanisms for lower BMIs in people who habitually eat breakfast.
The body mass index (BMI) of breakfast eaters is frequently reported to be lower compared with that of breakfast skippers. This is not explained by differences in energy intakes, indicating there may be other mechanisms serving to drive this paradoxical association between breakfast and BMI. This study aimed to investigate the effect of eating breakfast versus morning fasting on measures predominantly of metabolism in lean and overweight participants who habitually eat or skip breakfast.. Participants (n=37) were recruited into four groups on the basis of BMI (lean and overweight) and breakfast habit (breakfast eater and breakfast skipper). Participants were randomly assigned to a breakfast experimental condition, breakfast eating or no breakfast, for 7 days and then completed the alternative condition. At the end of each breakfast experimental condition, measurements were made before and after a high carbohydrate breakfast of 2274 ± 777 kJ or a rest period. Resting metabolic rate, thermic effect of food (TEF), blood glucose, insulin and leptin levels were recorded. Hunger and 'morningness' were assessed and pedometers worn.. Lean participants had lower fasting insulin levels (P=0.045) and higher insulin concentrations following breakfast (P=0.001). BMI and breakfast habit did not interact with the experimental breakfast condition, with the exception of hunger ratings; breakfast eaters were hungrier in the mornings compared with breakfast skippers in the no breakfast condition (P=0.001).. There is little evidence from this study for a metabolic-based mechanism to explain lower BMIs in breakfast eaters. Topics: Adult; Blood Glucose; Body Mass Index; Body Weight; Breakfast; Cross-Over Studies; Fasting; Feeding Behavior; Female; Humans; Insulin; Leptin; Male; Overweight; Random Allocation; Thinness; Young Adult | 2015 |
Increased prepubertal body weight enhances leptin sensitivity in proopiomelanocortin and neuropeptide y neurons before puberty onset in female rats.
Pubertal onset may be advanced by obesity, with leptin potentially acting as a permissive factor. We hypothesized that having increased body weight (BW) prepubertally affects the ability of leptin to activate intracellular signaling pathways and modulate the expression of hypothalamic neuropeptides involved in reproduction and metabolism. Because being raised in small litters (SLs) tends to increase BW at weaning, female rats were raised in litters of 4 or large litters (LLs) of 12 pups. Leptin (3 μg/g BW) or vehicle (saline) was injected sc at postnatal day (PND) 21 and 30. Rats raised in SLs weighed more at both ages, but relative visceral and subcutaneous fat was increased only on PND21. Serum leptin levels were not different at PND21 or PND30. At PND21, key elements of intracellular leptin signaling (phosphorylated signal transducer and activator of transcription 3 and phosphorylated Akt [p-Akt]) were lower in SL than in LL rats. Leptin injection stimulated phosphorylated signal transducer and activator of transcription 3 in both groups, with a greater increase in LL, whereas p-Akt rose only in SL rats. At PND30, basal leptin signaling did not differ between LL and SL rats. Leptin activation of Akt was similar at 45 minutes, but at 2 hours p-AKT levels were higher in SL than in LL rats, as was the decrease in neuropeptide Y mRNA and increase in pro-opiomelanocortin mRNA levels. No change in the reproductive axis was found. Thus, being raised in SLs increases BW and visceral body fat content, fails to increase plasma leptin concentrations, and increases the leptin responsiveness of both neuropeptide Y and pro-opiomelanocortin cells in the prepubertal hypothalamus. Topics: Animals; Body Weight; Female; Hypothalamus; Leptin; Neurons; Neuropeptide Y; Phosphorylation; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-akt; Rats; Receptors, Leptin; Sexual Maturation; Signal Transduction; STAT3 Transcription Factor | 2015 |
Anti-obesity effect of total phenylpropanoid glycosides from Ligustrum robustum Blume in fatty diet-fed mice via up-regulating leptin.
In Chinese folk medicine, the leaves of Ligustrum robustum Blume (LR) were commonly used in the treatment of obesity and hyperlipidemia. This study aimed to evaluate the anti-obesity effect and mechanisms of total phenylpropanoid glycosides from Ligustrum robustum Blume (LRTPG) in fatty diet-fed C57BL/6J mice.. C57BL/6J mice were divided randomly into 6 groups, i.e., control, model, positive (Orlistat 0.12g/kg), and LRTPG at three dosages (0.3, 0.6 or 1.2g/kg), respectively. Control mice were fed with standard diet; the others were fed with fatty diet. After 4 weeks׳ modeling, therapy mice were intragastrically administrated with positive drug or LRTPG for 5 weeks, respectively. Pharmacodynamic effects including body weight, fat weight, Lee׳s index, serum lipid levels, morphological changes and adipocyte area ratio were evaluated. The mechanisms were explored as the factors related to lipids metabolism in gene expressions by real-time PCR, and assured as the protein level of differential gene by Western blotting.. The anti-obesity effects of LRTPG in all treated mice were shown as decreased body weight, fat mass, Lee׳s index, total cholesterol (TC) level, and adipocyte area. The mechanisms were demonstrated as elevated mRNA and protein levels of adipose leptin, and consequently decreasing mRNA of adipose acyl coenzyme A: diacylglycerol acyltransferase (DGAT) with increasing mRNA of hepatic cholesterol 7α-hydroxylase (CYP7A1), which led to inhibition of triglyceride (TG) synthesis and promotion of cholesterol catabolism.. The anti-obesity effect of LRTPG in fatty diet-fed mice was related to the up-regulation of leptin, which may provide scientific evidence supporting the traditional usage of LR on obesity in China. Topics: Acyl Coenzyme A; Adipocytes; Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Cholesterol 7-alpha-Hydroxylase; Diacylglycerol O-Acyltransferase; Dietary Fats; Dose-Response Relationship, Drug; Glycosides; Leptin; Ligustrum; Lipid Metabolism; Male; Mice; Obesity; Phytotherapy; Plant Extracts; Plant Leaves; Up-Regulation | 2015 |
Loss of Atg12, but not Atg5, in pro-opiomelanocortin neurons exacerbates diet-induced obesity.
The autophagy-related proteins ATG12 and ATG5 form a covalent complex essential for autophagy. Here, we demonstrate that ATG12 has distinct functions from ATG5 in pro-opiomelanocortin (POMC)-expressing neurons. Upon high-fat diet (HFD) consumption, mice lacking Atg12 in POMC-positive neurons exhibit accelerated weight gain, adiposity, and glucose intolerance, which is associated with increased food intake, reduced ambulation, and decreased LEP/leptin sensitivity. Importantly, although genetic deletion of either Atg12 or Atg5 renders POMC neurons autophagy-deficient, mice lacking Atg5 in POMC neurons do not exhibit these phenotypes. Hence, we propose nonautophagic functions for ATG12 in POMC neurons that counteract excessive weight gain in response to HFD consumption. Topics: Adiposity; Animals; Animals, Newborn; Autophagy-Related Protein 12; Autophagy-Related Protein 5; Body Weight; Diet, High-Fat; Energy Metabolism; Feeding Behavior; Gene Deletion; Gene Targeting; Integrases; Leptin; Mice, Inbred C57BL; Microtubule-Associated Proteins; Neurons; Obesity; Pro-Opiomelanocortin; Proteins | 2015 |
Helichrysum and Grapefruit Extracts Boost Weight Loss in Overweight Rats Reducing Inflammation.
Obesity is characterized by an increased production of inflammatory markers. High levels of circulating free fatty acids and chronic inflammation lead to increased oxidative stress, contributing to the development of insulin resistance (IR). Recent studies have focused on the potential use of flavonoids for obesity management due to their antioxidant and anti-inflammatory properties. This study was designed to investigate the antioxidant and anti-inflammatory effects of helichrysum and grapefruit extracts in overweight insulin-resistant rats. Thirty-eight male Wistar rats were randomly distributed in two groups: control group (n=8) and high-fat sucrose (HFS) group (n=30). After 22 days of ad libitum water and food access, the rats fed HFS diet changed to standard diet and were reassigned into three groups (n=10 each group): nonsupplemented, helichrysum extract (2 g/kg bw), and grapefruit extract (1 g/kg bw) administered for 5 weeks. Rats supplemented with both extracts gained less body weight during the 5-week period of treatment, showed lower serum insulin levels and liver TBARS levels. Leptin/adiponectin ratio, as an indicator of IR, was lower in both extract-administered groups. These results were accompanied by a reduction in TNFα gene expression in epididymal adipose tissue and intestinal mucosa, and TLR2 expression in intestinal mucosa. Helichrysum and grapefruit extracts might be used as complement hypocaloric diets in weight loss treatment. Both extracts helped to reduce weight gain, hyperinsulinemia, and IR, improved inflammation markers, and decreased the HFS diet-induced oxidative stress in insulin-resistant rats. Topics: Adiponectin; Animals; Antioxidants; Blood Glucose; Body Weight; Citrus paradisi; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Helichrysum; Inflammation; Insulin; Insulin Resistance; Leptin; Male; Overweight; Plant Extracts; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Treatment Outcome; Weight Loss | 2015 |
Implications of diet modification on sympathoinhibitory mechanisms and hypertension in obesity.
We have previously demonstrated that a number of rats fed a moderately high-fat diet (MHFD) become obese and hypertensive and had compromised sympathoinhibitory and vasodilator responses to the gut hormones cholecystokinin (CCK) and gastric leptin. This has implications for increased resistance in vascular beds that attract a large proportion of cardiac output after a meal and may be an important mechanism underlying the development of hypertension in obesity in which food consumption is greatly increased. The aim of this study was to determine whether swapping a MHFD for a low-fat diet (LFD) would induce weight loss in obese animals, reverse the signs of hypertension and restore sympathoinhibitory reflexes. Male Sprague-Dawley rats were placed on a LFD (controls; n = 8) or a MHFD (n = 24) for 11 weeks after which the latter displayed either an obesity-prone (OP) or obesity-resistant (OR) phenotype. All animals were fed a LFD for a further 6 weeks after which they were anaesthetised with isoflurane and artificially ventilated for evaluation of resting arterial pressure (AP) and renal sympathetic nerve responses to CCK (0.1-4 μg/kg) and leptin (15 μg/kg). Weight gain in OP animals remained higher than OR or controls following diet switch (P < 0.05 for both). Resting AP was not significantly different between OP (103 ± 4 mmHg), OR (102 ± 3 mmHg) or control (104 ± 3 mmHg) animals and sympathoinhibitory responses to CCK or leptin were not different between the groups (P > 0.05). These results demonstrate that diet modification can have beneficial effects on sympathetic function and restore normotension without the need for weight reduction. Topics: Animals; Arterial Pressure; Autonomic Agents; Body Weight; Cholecystokinin; Diet, Fat-Restricted; Diet, High-Fat; Disease Models, Animal; Gastrointestinal Agents; Genetic Predisposition to Disease; Hypertension; Leptin; Male; Obesity; Rats, Sprague-Dawley; Sympathetic Nervous System | 2015 |
Endocrine and metabolic function in male Carioca High-conditioned Freezing rats.
The aim of this study was to characterize Carioca High-conditioned Freezing rats (CHF) regarding their endocrine and metabolic backgrounds. We found an increase in serum corticosterone (CTRL: 96.7 ± 21.65 vs CHF: 292.0 ± 4 0.71 ng/ml) and leptin (CTRL: 9.5 ± 1.51 vs CHF: 19.2 ± 4.32 ng/ml). Serum testosterone (CTRL: 3.3 ± 0.29 vs CHF: 2.0 ± 0.28 ng/ml) and T3 (CTRL: 52.4 ± 2.74 vs CHF: 42.7 ± 2.94 ng/dl) were decreased in the CHF group, but serum TSH and T4 were unaffected. Body weight and food intake were unchanged, nevertheless retroperitoneal fat (CTRL: 2.2 ± 0.24 vs CHF: 4.8 ± 0.64 g) and epididymal fat (CTRL: 2.6 ± 0.20 vs CHF: 4.8 ± 0.37 g) depot weights were around 2-fold higher in CHF animals. BAT weight was similar in both groups. Serum triglycerides (CTRL: 41.4 ± 6.03 vs CHF: 83.2 ± 17.09 mg/dl) and total cholesterol (CTRL: 181.6 ± 5.61 vs CHF: 226.4 ± 13.04 mg/dl) were higher in the CHF group. Fasting glycemia (CTRL: 68.7 ± 3.04 vs CHF: 82.3 ± 2.99 mg/dl) was also higher in the CHF group, however glucose tolerance test response and serum insulin levels were similar between the groups. Oxygen consumption (CTRL: 10.5 ± 0.40 vs CHF: 7.9 ± 0.58 VO2ml/min/kg(0.75)) and BAT D2 activity (CTRL: 0.7 ± 0.17 vs CHF: 0.3 ± 0.04 fmolT4/min/mg ptn) were lower in the CHF group. Our data show that anxiety could impair endocrine and metabolic functions and may contribute to the development of metabolic diseases. Topics: Adipose Tissue, Brown; Animals; Anxiety Disorders; Body Weight; CD3 Complex; CD4 Antigens; Cholesterol; Corticosterone; Disease Models, Animal; Fasting; Insulin; Intra-Abdominal Fat; Leptin; Male; Oxygen Consumption; Rats, Wistar; Species Specificity; Testosterone; Thyrotropin; Triglycerides | 2015 |
Perivascular adipose tissue and vascular responses in healthy trained rats.
Topics: Adiponectin; Adipose Tissue; Animals; Aorta; Blood Glucose; Body Weight; Eating; Leptin; Lipids; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Physical Conditioning, Animal; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Vasoconstriction | 2015 |
Meal-induced insulin sensitization is preserved after acute olanzapine administration in female Sprague-Dawley rats.
Olanzapine, an atypical antipsychotic, can acutely induce fasting insulin resistance, but we do not know whether it is able to modulate the meal-induced insulin sensitization (MIS). Two main experimental groups (control and olanzapine-treated) were created with two subgroups (fasted and re-fed) within each. After oral vehicle/olanzapine administration, the first meal size and duration and the total amount of consumed food was recorded in conscious rats. Then, under anaesthesia, the carotid artery and jugular vein was prepared and cannulated to obtain samples for blood glucose and hormone determination as well as for insulin/glucose infusion, respectively. Basal insulin sensitivity and MIS was determined by homeostasis model assessment (HOMA) calculation and by rapid insulin sensitivity test, respectively. In fasted animals, olanzapine increased blood glucose and plasma insulin and reduced basal insulin sensitivity, but it failed to modify other hormone levels. Postprandial leptin and glucose-dependent insulinotropic polypeptide (GIP) levels increased, and ghrelin level decreased significantly (p < 0.05) both in vehicle- and olanzapine-treated groups, but plasma insulin increased only in vehicle-treated animals. Furthermore, decrement in ghrelin level was attenuated in olanzapine-treated animals compared to controls. There was no significant change in the first meal size and duration or in the total amount of food consumed. Olanzapine had no effect on the MIS. We demonstrated that olanzapine can induce insulin resistance without weight gain in healthy rats. Furthermore, the MIS was preserved after acute olanzapine treatment. The blunted postprandial ghrelin and insulin response could contribute to the effect of olanzapine on feeding behaviour. Pharmacological induction of MIS may improve the olanzapine-induced insulin resistance. Topics: Animals; Benzodiazepines; Blood Glucose; Body Weight; Energy Intake; Fasting; Feeding Behavior; Female; Ghrelin; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Olanzapine; Postprandial Period; Rats, Sprague-Dawley | 2015 |
Association between dietary patterns and serum leptin-to-adiponectin ratio in apparently healthy adults.
Dietary patterns reflect diet and nutritional habits of individuals in a society. Various dietary patterns could influence leptin and adiponectin secretion from adipose tissue. These hormones are associated with metabolic diseases. It is suggested that the leptin-to-adiponectin (L/A) ratio might be a more useful diagnostic marker in predicting chronic diseases than leptin and adiponectin separately. The aim of this study was to investigate the association between various dietary patterns and L/A ratio in Iranian adults.. This cross-sectional study was conducted on 150 apparently healthy subjects aged 25-50 years in Tabriz, Iran. Dietary patterns were determined using 132-item semiquantitative food frequency questionnaire on a 5-point scale. Weight, height, waist circumference (WC), as well as fasting serum leptin and adiponectin levels were measured to assess the association between dietary patterns and L/A ratio.. Four major dietary patterns were identified using a factor analysis approach: Western, healthy, mixed, and traditional dietary patterns. Linear regression analysis showed that a Western dietary pattern was negatively associated with serum adiponectin concentration, even after adjusting for the confounders (r = -0.19, p = 0.02). No statistically significant associations were found between any dietary pattern and leptin (r = -0.14, p = 0.06) or L/A ratio (r = -0.10, p = 0.09).. Our findings indicate an inverse association between a Western dietary pattern and serum adiponectin levels but not for serum leptin or L/A ratio. Topics: Adiponectin; Adult; Body Height; Body Weight; Cross-Sectional Studies; Diet; Fasting; Feeding Behavior; Female; Health Status; Humans; Iran; Leptin; Male; Middle Aged; Waist Circumference | 2015 |
Endogenous hormones, inflammation, and body size in premenopausal Mexican women: results from the Mexican Teachers' Cohort (MTC, ESMaestras).
Obesity is a major risk factor for several cancers, including female cancers. Endogenous hormones and inflammatory factors may mediate the association between anthropometric measures and cancer risk, although these associations have been studied mainly in Caucasians. The aim of the current study was to explore the association of circulating hormones, adipokines, and inflammatory factors with obesity and overweight in premenopausal Mexican women.. We conducted a cross-sectional analysis of 504 premenopausal women from the large Mexican Teachers' Cohort (MTC, ESMaestras) study to determine the association of insulin-like growth factor I (IGF-I), its major circulating binding protein (IGFBP-3), leptin, adiponectin, C-peptide, and C-reactive protein with comprehensive measures of body size. Biomarkers were measured by immunoassays. Multivariate regression analyses were performed to compare geometric mean biomarker concentrations with measured markers of body size and adiposity.. Mean IGF-I and IGFBP-3 concentrations significantly increased with increasing height and leg length. Concentrations of IGF-I, adiponectin, and the IGF-I/IGFBP-3 ratio strongly decreased with increasing BMI, weight, waist and hip circumferences, waist-to-hip ratio (WHpR), and waist-to-height ratio (WHtR), while CRP, leptin, C-peptide concentrations, and the leptin/adiponectin ratio strongly increased. Adiponectin and the leptin/adiponectin ratio remained significantly related to measures of central adiposity (waist circumference, WHpR, and WHtR) after adjustment by body mass index.. The results of our study suggest a strong relation between biomarkers and body size in this study population and suggest that different fat depots may have different metabolic properties. Topics: Adiposity; Adult; Biomarkers; Body Mass Index; Body Size; Body Weight; C-Peptide; C-Reactive Protein; Cohort Studies; Cross-Sectional Studies; Female; Humans; Immunoassay; Inflammation; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Mexico; Middle Aged; Multivariate Analysis; Obesity; Overweight; Premenopause; Waist Circumference; Waist-Hip Ratio | 2015 |
Role of hindbrain melanocortin-4 receptor activity in controlling cardiovascular and metabolic functions in spontaneously hypertensive rats.
Although we previously demonstrated that activation of central nervous system (CNS) melanocortin3/4 receptors (MC3/4R) play a key role in blood pressure (BP) regulation, especially in spontaneously hypertensive rats (SHRs), the importance of hindbrain MC4R is still unclear.. In the present study, we examined the cardiovascular and metabolic effects of chronic inhibition of MC3/4R in the hindbrain of SHRs and normotensive Wistar-Kyoto (WKY) rats. Male WKY rats (n = 6) and SHRs (n = 7) were implanted with telemetry probes to measure BP and heart rate (HR) 24 h/day, and an intracerebroventricular cannula was placed into the fourth ventricle. After 10 days of recovery and 5 days of control measurements, the MC3/4R antagonist (SHU-9119) was infused into the fourth ventricle (1 nmol/h) to antagonize hindbrain MC4R for 10 days, followed by a 5-day recovery period.. Chronic hindbrain MC3/4R antagonism significantly increased food intake and body weight in WKY rats (17 ± 1 to 35 ± 2 g/day and 280 ± 8 to 353 ± 8 g) and SHRs (19 ± 2 to 35 ± 2 g/day and 323 ± 7 to 371 ± 11 g), and markedly increased fasting insulin and leptin levels while causing no changes in blood glucose levels (99 ± 4 to 87 ± 4 and 89 ± 5 to 89 ± 4 mg/dl, respectively, for WKY rats and SHRs). Chronic SHU-9119 infusion reduced mean arterial pressure and HR similarly in WKY rats (-8 ± 1 mmHg and -47 ± 3 b.p.m.) and SHRs (-11 ± 3 mmHg and -44 ± 3 b.p.m.).. These results suggest that although hindbrain MC4R activity contributes to appetite and HR regulation, it does not play a major role in mediating the elevated BP in SHRs. Topics: Animals; Appetite; Blood Pressure; Body Weight; Eating; Heart Rate; Hypertension; Insulin; Leptin; Male; Melanocyte-Stimulating Hormones; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Rhombencephalon | 2015 |
Seasonal changes in body mass, serum leptin levels and hypothalamic neuropeptide gene expression in male Eothenomys olitor.
The present study examined seasonal changes in body mass and energy metabolism in the Chaotung vole (Eothenomys olitor) and the physiological mechanisms underpinning these changes. Seasonal changes in the following parameters were measured in male E. olitor, body mass, food intake, thermogenesis, enzyme activity, masses of tissues and organs, hormone concentrations and expression of hypothalamic arcuate nucleus energy balance genes including neuropeptide Y (NPY), agouti-related protein (AgRP), pro-opiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART). Body mass was constant over the year, but the masses of tissues and organs differed significantly between seasons. There were significant changes in body fat mass and serum leptin levels over the four seasons. E. olitor showed significant seasonal changes in food intake and thermogenesis, uncoupling protein 1 (UCP1) content, enzyme activity, and serum tri-iodothyronine (T3) and thyroxine (T4) levels. Moreover, mRNA expression in the hypothalamus showed significant seasonal changes. All of our results suggested that E. olitor had constant body mass over the year, which was inconsistent with the prediction of the 'set-point' hypothesis. However, body fat mass and serum leptin levels were significantly different among the four seasons, providing support for the 'set-point' hypothesis. The changes in leptin, NPY, AgRP, POMC, and CART mRNA levels may play a role in the regulation of energy intake in E. olitor. Furthermore, the role of leptin and hypothalamic neuropeptide gene in the regulation of energy metabolism and body mass may be different in animals that are acclimated to different seasons. Topics: Animals; Arvicolinae; Body Weight; Hypothalamus; Leptin; Male; Neuropeptides; RNA, Messenger; Seasons | 2015 |
Sex differences in serum leptin and its relation to markers of cardiometabolic risk in middle-aged adults: evidence from a population-based study.
At elevated concentrations, circulating leptin has been associated with metabolic disturbances, namely insulin resistance, elevated blood pressure, inflammation, and endothelial dysfunction. Because women have higher leptin concentrations than men, it is possible that the effects of leptin on the metabolic profile are different between the sexes. The aim of this study was to investigate whether leptin is one of the key hormones to sex affect differences in the pathophysiology of cardiometabolic risk.. Participants were 178 men and 284 women (average age: 53.9 y), evaluated in a cross-sectional, population-based study performed in Brazil. A structural equation model was used to test a theoretic pathway for the relationship between serum leptin, obesity indicators (body weight and waist circumference), and cardiometabolic risk factors (high-sensitivity C-reactive protein; blood pressure; atherogenic dyslipidemia-total cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio and triacylglycerol /HDL-C ratio; and fasting plasma glucose) stratified by sex.. In men, increasing 1 SD in serum leptin predicted an increase in 0.731 SD in body weight and in 0.123 SD in C-reactive protein. Serum leptin had positive and significant indirect effects on men's ratios of total cholesterol to HDL-C (β = 0.215) and triacylglycerol to HDL-C (β = 0.209), as well as fasting glucose (β = 0.173). In women, serum leptin predicted an increase of 0.675 SD in body weight and had positive indirect effects on all cardiometabolic risk factors evaluated.. Serum leptin was indirectly related to cardiometabolic risk factors and its relation was modest and different between sexes. The effects of leptin through mediation of body weight and waist circumference highlight the importance of weight control to prevent cardiometabolic disorders in middle-aged adults. Topics: Aged; Biomarkers; Blood Glucose; Body Weight; Brazil; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL; Cross-Sectional Studies; Female; Humans; Leptin; Lipids; Male; Middle Aged; Obesity; Sex Factors; Triglycerides | 2015 |
Voluntary exercise prevents colonic inflammation in high-fat diet-induced obese mice by up-regulating PPAR-γ activity.
Obesity is associated with increased colonic inflammation, which elevates the risk of colon cancer. Although exercise exerts anti-inflammatory actions in multiple chronic diseases associated with inflammation, it is unknown whether this strategy prevents colonic inflammation in obesity. We hypothesized that voluntary exercise would suppress colonic inflammation in high-fat diet (HFD)-induced obesity by modulation of peroxisome proliferator-activated receptor (PPAR)-γ. Male C57Bl/6J mice fed either a control diet (6.5% fat, CON) or a high-fat diet (24% fat, HFD) were divided into sedentary, voluntary exercise or voluntary exercise with PPAR-γ antagonist GW9662 (10 mg/kg/day). All interventions took place for 12 weeks. Compared with CON-sedentary group, HFD-sedentary mice gained significantly more body weight and exhibited metabolic disorders. Molecular studies revealed that HFD-sedentary mice had increased expression of inflammatory mediators and activation of nuclear factor (NF)-κB in the colons, which were associated with decreased expression and activity of PPAR-γ. Voluntary exercise markedly attenuated body weight gain, improved metabolic disorders, and normalized the expression of inflammatory mediators and activation of NF-κB in the colons in HFD-mice while having no effects in CON-animals. Moreover, voluntary exercise significantly increased expression and activity of PPAR-γ in the colons in both HFD- and CON-animals. However, all of these beneficial effects induced by voluntary exercise were abolished by GW9662, which inhibited expression and activity of PPAR-γ. The results suggest that decreased PPAR-γ activity in the colon of HFD-induced obesity may facilitate the inflammatory response and colon carcinogenesis. Voluntary exercise prevents colonic inflammation in HFD-induced obesity by up-regulating PPAR-γ activity. Topics: Adiponectin; Anilides; Animals; Body Weight; Colitis; Colon; Diet, High-Fat; Eating; Glucose Tolerance Test; Inflammation Mediators; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Obesity; Physical Exertion; PPAR gamma; Up-Regulation | 2015 |
The expression of leptin, hypothalamic neuropeptides and UCP1 before, during and after fattening in the Daurian ground squirrel (Spermophilus dauricus).
The Daurian ground squirrel (Spermophilus dauricus) accumulates large amounts of body fat during pre-hibernation fattening. Leptin, an adipose-derived hormone, plays important roles in energy balance and thermogenesis. We predicted that body fat accumulation would lead to the elevation of leptin concentration while its effect on satiety would be suppressed in hypothalamus during fattening. In addition, the uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) would increase and correlated positively with leptin concentration before hibernation. Here, we measured serum leptin concentration and leptin mRNA in white adipose tissue (WAT), hypothalamic neuropeptides involved in energy regulation and UCP1 in BAT before, during and after fattening in squirrels. The fat mass gradually increased during fattening but serum leptin increased mainly in the late phase of fattening, which was consistent with leptin mRNA expression in WAT. During fattening, the mRNA of hypothalamic leptin receptor was up-regulated and correlated positively with serum leptin. Orexigenic neuropeptide Y mRNA increased by 67%; however agouti-related peptide remained unchanged before hibernation. There was no significant change in anorexigenic neuropeptide mRNA. No change in suppressor of cytokine signaling-3 and protein tyrosine phosphatase-1B was detected. UCP1 mRNA expression and protein content in BAT increased significantly after fattening. These changes were independent of environmental conditions and serum leptin concentration. Our results suggest that the dissociation of leptin production and adiposity during fattening may facilitate fat accumulation. No evidence of suppressed leptin signal was found in fattening squirrels. The UCP1 recruitment in post-fattening squirrels could occur without winter-like acclimation and increased leptin. Topics: Animals; Body Composition; Body Weight; Hypothalamus; Ion Channels; Leptin; Mitochondrial Proteins; Neuropeptides; RNA, Messenger; Sciuridae; Uncoupling Protein 1 | 2015 |
The effects of prenatal undernutrition and postnatal high-fat diet on hypothalamic Kiss1 mRNA and serum leptin levels.
Prenatal undernutrition and postnatal overnutrition increase the risk of some metabolic disorders in adulthood, and hypothalamic leptin resistance makes an important contribution to these effects. Leptin plays important roles in the maintenance of reproductive function, and its actions might be partially mediated by kisspeptin, which is a potent positive regulator of gonadotropin-releasing hormone. In this study, the effects of prenatal undernutrition and postnatal overnutrition on reproductive parameters and sexual maturation during the peripubertal period were evaluated. Rats subjected to prenatal undernutrition (IUGR) and fed a postnatal high-fat diet (HFD) (n = 7) exhibited 40% higher serum leptin levels and 30% lower hypothalamic Kiss1 (the gene encoding kisspeptin) mRNA levels than those subjected to prenatal undernutrition (IUGR) and fed a normal diet (n = 7). No such HFD-induced postnatal alterations were observed in the rats fed a normal diet during the prenatal period (control) (n = 7 per group). Although the consumption of the HFD did not affect the serum luteinizing hormone levels or body weight of the IUGR or control rats, it did promote vaginal opening in both groups (evaluated in 14 rats per group). These findings indicate that hypothalamic leptin resistance might occur in IUGR-HFD rats, but these changes do not influence downstream effectors of the reproductive endocrinological system. They also suggest that the relationships between nutritional conditions, body weight, reproductive factors, and sexual maturation are complex. Topics: Animals; Animals, Newborn; Body Weight; Female; Gonadotropin-Releasing Hormone; Hypothalamus; Kisspeptins; Leptin; Male; Malnutrition; Neuropeptides; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Receptors, Neuropeptide; RNA, Messenger | 2015 |
Leptin signaling is required for adaptive changes in food intake, but not energy expenditure, in response to different thermal conditions.
Survival of free-living animals depends on the ability to maintain core body temperature in the face of rapid and dramatic changes in their thermal environment. If food intake is not adjusted to meet the changing energy demands associated with changes of ambient temperature, a serious challenge to body energy stores can occur. To more fully understand the coupling of thermoregulation to energy homeostasis in normal animals and to investigate the role of the adipose hormone leptin to this process, comprehensive measures of energy homeostasis and core temperature were obtained in leptin-deficient ob/ob mice and their wild-type (WT) littermate controls when housed under cool (14°C), usual (22°C) or ∼ thermoneutral (30°C) conditions. Our findings extend previous evidence that WT mice robustly defend normothermia in response to either a lowering (14°C) or an increase (30°C) of ambient temperature without changes in body weight or body composition. In contrast, leptin-deficient, ob/ob mice fail to defend normothermia at ambient temperatures lower than thermoneutrality and exhibit marked losses of both body fat and lean mass when exposed to cooler environments (14°C). Our findings further demonstrate a strong inverse relationship between ambient temperature and energy expenditure in WT mice, a relationship that is preserved in ob/ob mice. However, thermal conductance analysis indicates defective heat retention in ob/ob mice, irrespective of temperature. While a negative relationship between ambient temperature and energy intake also exists in WT mice, this relationship is disrupted in ob/ob mice. Thus, to meet the thermoregulatory demands of different ambient temperatures, leptin signaling is required for adaptive changes in both energy intake and thermal conductance. A better understanding of the mechanisms coupling thermoregulation to energy homeostasis may lead to the development of new approaches for the treatment of obesity. Topics: Animals; Appetite Regulation; Body Composition; Body Temperature; Body Temperature Regulation; Body Weight; Eating; Energy Intake; Energy Metabolism; Leptin; Male; Mice, Inbred C57BL; Mice, Obese; Signal Transduction | 2015 |
Chronic hyperleptinemia results in the development of hypertension in pregnant rats.
Despite the fact that obesity is a major risk factor for preeclampsia (PE), the pathophysiological mechanisms whereby obesity and metabolic factors such as leptin increase this risk are unclear. While human data have shown that hyperleptinemia is associated with PE, the long-term effect of hyperleptinemia on blood pressure during pregnancy is unknown. Thus we tested the hypothesis whether chronic circulating leptin elevations in pregnant rats increase blood pressure and placental factors known to play a role in PE. On gestational day (GD)14, rats were assigned to the normal pregnant group with food intake ad libitum (control), leptin-treated (0.5 μg·kg(-1)·min(-1) ip) pregnant group with food intake ad libitum (pregnant+LEP), and normal pregnant group with food intake adjusted to the food intake of pregnant+LEP rats (pregnant-FR). On GD19, mean arterial pressure (MAP) was assessed and tissues were collected. Serum leptin concentration was elevated in pregnant+LEP compared with control and pregnant-FR (18.0 ± 2.8 vs. 0.8 ± 0.1 vs. 0.3 ± 0.1 ng/ml; P < 0.05), which was associated with increased MAP (121.3 ± 8.1 vs. 102.4 ± 2.4 vs. 101.3 ± 1.8 mmHg; P < 0.05). Food intake and body weight were reduced in pregnant+LEP and pregnant-FR by the end of gestation. Additionally, placentas and fetuses of these groups were lighter than those of control. However, placental expression of tumor necrosis factor-α was significantly greater in pregnant+LEP compared with controls (1.6 ± 0.1 vs. 1.1 ± 0.1 pg/mg; P < 0.05). In conclusion, leptin increases blood pressure and placental tumor necrosis factor-α during pregnancy despite its effect of reducing food intake and body weight, and represents a mechanism whereby obesity can promote the development of hypertension in PE. Topics: Animals; Blood Pressure; Body Weight; Eating; Female; Hypertension; Leptin; Organ Size; Placenta; Pregnancy; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha | 2015 |
Obesity alters gene expression for GH/IGF-I axis in mouse mammary fat pads: differential role of cortistatin and somatostatin.
Locally produced growth hormone (GH) and IGF-I are key factors in the regulation of mammary gland (MG) development and may be important in breast cancer development/progression. Somatostatin (SST) and cortistatin (CORT) regulate GH/IGF-I axis at various levels, but their role in regulating GH/IGF-I in MGs remains unknown. Since obesity alters the expression of these systems in different tissues and is associated to MG (patho) physiology, we sought to investigate the role of SST/CORT in regulating GH/IGF-I system in the MGs of lean and obese mice. Therefore, we analyzed GH/IGF-I as well as SST/CORT and ghrelin systems expression in the mammary fat pads (MFPs) of SST- or CORT-knockout (KO) mice and their respective littermate-controls fed a low-fat (LF) or a high-fat (HF) diet for 16 wks. Our results demonstrate that the majority of the components of GH/IGF-I, SST/CORT and ghrelin systems are locally expressed in mouse MFP. Expression of elements of the GH/IGF-I axis was significantly increased in MFPs of HF-fed control mice while lack of endogenous SST partially suppressed, and lack of CORT completely blunted, the up-regulation observed in obese WT-controls. Since SST/CORT are known to exert an inhibitory role on the GH/IGFI axis, the increase in SST/CORT-receptor sst2 expression in MFPs of HF-fed CORT- and SST-KOs together with an elevation on circulating SST in CORT-KOs could explain the differences observed. These results offer new information on the factors (GH/IGF-I axis) involved in the endocrine/metabolic dysregulation of MFPs in obesity, and suggest that CORT is not a mere SST sibling in regulating MG physiology. Topics: Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Female; Ghrelin; Growth Hormone; Insulin-Like Growth Factor I; Leptin; Mammary Glands, Animal; Mice; Mice, Knockout; Mice, Obese; Neuropeptides; Obesity; Real-Time Polymerase Chain Reaction; Receptors, Somatostatin; Somatostatin; Up-Regulation | 2015 |
Meta-chlorophenylpiperazine enhances leptin sensitivity in diet-induced obese mice.
Most forms of human obesity are characterized by impaired leptin sensitivity and, therefore, the effectiveness of anti-obesity leptin therapy in these leptin-resistant obese patients is marginal. Hence, the development of strategies to increase leptin sensitivity is of high priority in the field of obesity research.. We first examined the effects of co-administration of leptin and meta-chlorophenylpiperazine (mCPP), an agonist of 5-HT2C and 5-HT1B receptors, on energy balance in leptin-resistant diet-induced obese (DIO) mice. We further assessed leptin-induced phosphorylation of the STAT-3 (pSTAT3) in various brain regions of DIO mice pretreated with mCPP or in mice genetically lacking 5-HT2C receptors.. Co-administration of mCPP with leptin had an additive effect on reducing body weight in DIO mice. Furthermore, mCPP pretreatment in DIO mice enhanced leptin-induced pSTAT3 in the arcuate nucleus, the ventromedial hypothalamic nucleus, and the ventral premammillary nucleus. Finally, deletion of 5-HT2C receptors significantly blunted leptin-induced pSTAT3 in these same hypothalamic regions.. Our study provides evidence that drugs, which activate 5-HT2C receptors, could function as leptin sensitizers and be used in combination with leptin to provide additional weight loss in DIO. Topics: Animals; Body Weight; Diet; Dose-Response Relationship, Drug; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phosphorylation; Piperazines; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; STAT3 Transcription Factor; Structure-Activity Relationship | 2015 |
Irisin levels before and after physical activity among school-age children with different BMI: a direct relation with leptin.
Irisin is a novel myokine that seems to mediate the beneficial effects of exercise. Levels of circulating irisin before and after an 8-month physical activity program (PAP) in school-age children were evaluated.. Irisin and leptin were measured at baseline and at follow-up among 85 children with different BMI.. Of the 85 children (mean age 8.9; 47% female), 25 children had normal weight, 23 were overweight, and 37 had obesity. We observed no significant difference in irisin serum levels between boys and girls. Irisin was positively associated with BMI before and after the PAP (r(before) = 0.42; r(after) = 0.37, P < 0.001), with the highest levels in children with obesity. There was a slight decrease of circulating irisin after PAP, but this decrease was not of statistical significance. We observed a high and positive association between irisin and leptin levels before and after the PAP (r(before) = 0.78; r(after) = 0.82, P < 0.001). Moreover, changes in leptin correlated with changes in irisin (r = 0.72, P < 0.001).. Circulating irisin is positively linked to BMI and leptin in school-age children, supporting the notion that that irisin is produced by adipose tissue. As in previous reports, this study failed to observe changes in irisin levels after exercise, likely because higher irisin levels are produced only during exercise. Topics: Biomarkers; Body Mass Index; Body Weight; Child; Exercise; Female; Fibronectins; Follow-Up Studies; Humans; Leptin; Male; Pediatric Obesity | 2015 |
Piceatannol lowers the blood glucose level in diabetic mice.
We previously found that passion fruit (Passiflora edulis) seeds contained a high amount of piceatannol (3,5,3',4'-trans-tetrahydroxystilbene), a natural analog of resveratrol (3,5,4'-trans-trihydroxystilbene). Resveratrol has been proposed as a potential anti-metabolic disorder compound, by its activation of sirtuin and AMP-activated protein kinase. Many reports show that resveratrol ameliorates diet-induced obesity and insulin resistance. However, it is not known whether piceatannol also affects diet-induced obesity. We explored the effect of piceatannol on high fat diet-fed mice. The results showed that piceatannol did not affect high fat diet-induced body weight gain or visceral fat gain in mice. However, piceatannol did reduce fasting blood glucose levels. Furthermore, to explore the potential of passion fruit seed extract containing piceatannol as a functional food, passion fruit seed extract was administered in a genetic diabetic mouse model (db/db mice). Single administration of passion fruit seed extract, as well as piceatannol reduced the blood glucose levels of these db/db mice. These results suggest that piceatannol and passion fruit seed extract may have potential application in the prevention of diabetes. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diet, High-Fat; Eating; Hypoglycemic Agents; Leptin; Male; Mice, Inbred C57BL; Passiflora; Plant Extracts; Seeds; Stilbenes | 2015 |
The Effects of High-Fat Diet Exposure In Utero on the Obesogenic and Diabetogenic Traits Through Epigenetic Changes in Adiponectin and Leptin Gene Expression for Multiple Generations in Female Mice.
Recent studies demonstrate that epigenetic changes under malnutrition in utero might play important roles in transgenerational links with metabolic diseases. We have previously shown that exposure to a high-fat diet (HFD) in utero may cause a metabolic syndrome-like phenomenon through epigenetic modifications of Adiponectin and Leptin genes. Because an association of obesity between mother and offspring endured in multiple generations, we examined whether HFD exposure in utero might affect the metabolic status of female offspring through multigenerational epigenetic changes of Adiponectin and Leptin genes and whether a normal diet in utero for multiple generations might abolish such epigenetic changes after exposure to a HFD in utero using ICR mice. We observed that the effect of maternal HFD on offspring over multiple generations in metabolic syndrome-like phenomenon such as weight and fat mass gain, glucose intolerance, hypertriglyceridemia, abnormal adiponectin and leptin levels, and hypertension, were accumulated with expression and epigenetic changes in Adiponectin and Leptin genes. A normal diet in utero in the subsequent generations after HFD exposure in utero diminished, and a normal diet in utero for 3 generations completely abolished, the effect of HFD in utero on weight and fat mass gain, insulin resistance, serum triglyceride, adiponectin, and leptin levels, with epigenetic changes of Adiponectin and Leptin genes. Exposure to a HFD in utero might affect glucose and lipid metabolism of female offspring through epigenetic modifications to Adiponectin and Leptin genes for multiple generations. Obesogenic and diabetogenic traits were abolished after a maternal normal diet for 3 generations. Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Epigenesis, Genetic; Female; Gene Expression; Glucose Intolerance; Glucose Tolerance Test; Hypertriglyceridemia; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Mice; Mice, Inbred ICR; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Real-Time Polymerase Chain Reaction; RNA, Messenger; Triglycerides | 2015 |
Blockage of the Neonatal Leptin Surge Affects the Gene Expression of Growth Factors, Glial Proteins, and Neuropeptides Involved in the Control of Metabolism and Reproduction in Peripubertal Male and Female Rats.
Leptin (Lep) is important in the development of neuroendocrine circuits involved in metabolic control. Because both Lep and metabolism influence pubertal development, we hypothesized that early changes in Lep signaling could also modulate hypothalamic (HT) systems involved in reproduction. We previously demonstrated that a single injection of a Lep antagonist (Antag) on postnatal day (PND)9, coincident with the neonatal Lep peak, induced sexually dimorphic modifications in trophic factors and markers of cell turnover and neuronal maturation in the HT on PND13. Here, our aim was to investigate whether the alterations induced by Lep antagonism persist into puberty. Accordingly, male and female rats were treated with a pegylated super Lep Antag from PND5 to PND9 and killed just before the normal appearance of external signs of puberty (PND33 in females and PND43 in males). There was no effect on body weight, but in males food intake increased, subcutaneous adipose tissue decreased and HT neuropeptide Y and Agouti-related peptide mRNA levels were reduced, with no effect in females. In both sexes, the Antag increased HT mRNA levels of the kisspeptin receptor, G protein-coupled recepter 54 (Gpr54). Expression of the Lep receptor, trophic factors, and glial markers were differently affected in the HT of peripubertal males and females. Lep production in adipose tissue was decreased in Antag-treated rats of both sexes, with production of other cytokines being differentially regulated between sexes. In conclusion, in addition to the long-term effects on metabolism, changes in neonatal Lep levels modifies factors involved in reproduction that could possibly affect sexual maturation. Topics: Adipose Tissue; Agouti-Related Protein; Animals; Animals, Newborn; Body Weight; Brain-Derived Neurotrophic Factor; Cytokines; Eating; Female; Follicle Stimulating Hormone; Gene Expression Profiling; Glial Fibrillary Acidic Protein; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Luteinizing Hormone; Male; Neuropeptide Y; Neuropeptides; Rats; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sex Factors; Sexual Maturation; Subcutaneous Fat; Vimentin | 2015 |
Improvement in metabolic effects by dietary intervention is dependent on the precise nature of the developmental programming challenge.
Predisposition to offspring metabolic dysfunction due to poor maternal nutrition differs with the developmental stage at exposure. Post-weaning nutrition also influences offspring phenotype in either adverse or beneficial ways. We studied a well-established rat maternal protein-restriction model to determine whether post-weaning dietary intervention improves adverse outcomes produced by a deficient maternal nutritional environment in pregnancy. Pregnant rats were fed a controlled diet (C, 20% casein) during pregnancy and lactation (CC) or were fed a restricted diet (R, 10% casein isocaloric diet) during pregnancy and C diet during lactation (RC). After weaning, the offspring were fed the C diet. At postnatal day (PND) 70 (young adulthood), female offspring either continued with the C diet (CCC and RCC) or were fed commercial Chow Purina 5001 (I) to further divide the animals into dietary intervention groups CCI and RCI. Another group of mothers and offspring were fed I throughout (III). Offspring food intake was averaged between PND 95-110 and 235-250 and carcass and liver compositions were measured at PND 25 and 250. Leptin (PND 110 and 250) and serum glucose, triglycerides and cholesterol (PND 250) levels were measured. Statistical analysis was carried out using ANOVA. At PND 25, body and liver weights were similar between groups; however, CCC and RCC carcass protein:fat ratios were lower compared with III diet. At PND 110 and 250, offspring CCC and RCC had higher body weight, food intake and serum leptin compared with CCI and RCI. CCI had lower carcass fat and increased protein compared with CCC and improved fasting glucose and triglycerides. Adult dietary intervention partially overcomes adverse effects of programming. Further studies are needed to determine the mechanisms involved. Topics: Animals; Body Weight; Diet; Diet Therapy; Dietary Proteins; Female; Lactation; Leptin; Liver; Male; Malnutrition; Pregnancy; Prenatal Nutritional Physiological Phenomena; Random Allocation; Rats, Wistar | 2015 |
Negative Regulation of Leptin-induced Reactive Oxygen Species (ROS) Formation by Cannabinoid CB1 Receptor Activation in Hypothalamic Neurons.
The adipocyte-derived, anorectic hormone leptin was recently shown to owe part of its regulatory effects on appetite-regulating hypothalamic neuropeptides to the elevation of reactive oxygen species (ROS) levels in arcuate nucleus (ARC) neurons. Leptin is also known to exert a negative regulation on hypothalamic endocannabinoid levels and hence on cannabinoid CB1 receptor activity. Here we investigated the possibility of a negative regulation by CB1 receptors of leptin-mediated ROS formation in the ARC. Through pharmacological and molecular biology experiments we report data showing that leptin-induced ROS accumulation is 1) blunted by arachidonyl-2'-chloroethylamide (ACEA) in a CB1-dependent manner in both the mouse hypothalamic cell line mHypoE-N41 and ARC neuron primary cultures, 2) likewise blocked by a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, troglitazone, in a manner inhibited by T0070907, a PPAR-γ antagonist that also inhibited the ACEA effect on leptin, 3) blunted under conditions of increased endocannabinoid tone due to either pharmacological or genetic inhibition of endocannabinoid degradation in mHypoE-N41 and primary ARC neuronal cultures from MAGL(-/-) mice, respectively, and 4) associated with reduction of both PPAR-γ and catalase activity, which are reversed by both ACEA and troglitazone. We conclude that CB1 activation reverses leptin-induced ROS formation and hence possibly some of the ROS-mediated effects of the hormone by preventing PPAR-γ inhibition by leptin, with subsequent increase of catalase activity. This mechanism might underlie in part CB1 orexigenic actions under physiopathological conditions accompanied by elevated hypothalamic endocannabinoid levels. Topics: Adipocytes; Animals; Animals, Newborn; Arachidonic Acids; Benzamides; Body Weight; Cannabinoids; Catalase; Cells, Cultured; Chromans; Endocannabinoids; Gene Expression Regulation; Gene Silencing; Hydrolysis; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Neurons; PPAR alpha; PPAR gamma; Pyridines; Reactive Oxygen Species; Receptor, Cannabinoid, CB1; RNA, Small Interfering; Thiazolidinediones; Troglitazone | 2015 |
Exercise training and calorie restriction influence the metabolic parameters in ovariectomized female rats.
The estrogen deficiency after menopause leads to overweight or obesity, and physical exercise is one of the important modulators of this body weight gain. Female Wistar rats underwent ovariectomy surgery (OVX) or sham operation (SO). OVX and SO groups were randomized into new groups based on the voluntary physical activity (with or without running) and the type of diet for 12 weeks. Rats were fed standard chow (CTRL), high triglyceride diet (HT), or restricted diet (CR). The metabolic syndrome was assessed by measuring the body weight gain, the glucose sensitivity, and the levels of insulin, triglyceride, leptin, and aspartate aminotransferase transaminase (AST) and alanine aminotransferase (ALT). The exercise training combined with the CR resulted in improvements in the glucose tolerance and the insulin sensitivity. Plasma TG, AST, and ALT levels were significantly higher in OVX rats fed with HT but these high values were suppressed by exercise and CR. Compared to SO animals, estrogen deprivation with HT caused a significant increase in leptin level. Our data provide evidence that CR combined with voluntary physical exercise can be a very effective strategy to prevent the development of a metabolic syndrome induced by high calorie diet. Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Glucose; Body Weight; Caloric Restriction; Diet; Female; Insulin; Leptin; Obesity; Ovariectomy; Physical Conditioning, Animal; Rats; Rats, Wistar; Triglycerides | 2015 |
Serum levels of adipocytokines in psoriasis patients receiving tumor necrosis factor-α inhibitors: results of a retrospective analysis.
Adipocytokines are bioactive molecules that are deeply involved in the occurrence of atherosclerosis, obesity, and autoimmune inflammatory diseases.. This study was conducted to evaluate the effects of tumor necrosis factor-α (TNF-α) inhibitors on serum levels of adipocytokines in patients with chronic plaque psoriasis.. Serum levels of adiponectin, resistin, visfatin, leptin, TNF-α, and interleukin-6 (IL-6) were evaluated in sera obtained from 47 patients with psoriasis, both at baseline and after they had received TNF-α inhibitors for 24 weeks. Equivalent data were obtained for 39 control subjects matched by age, sex, body mass index, waist : hip ratio, geographical origin, Mediterranean dietary habits, and smoking habits.. At baseline, mean serum levels of TNF-α, IL-6, leptin, resistin, and visfatin were higher in the psoriasis group than in healthy controls; these differences were statistically significant (P < 0.05). Conversely, mean serum levels of adiponectin were significantly lower in patients with psoriasis than in controls (P < 0.0001). Serum levels of adipocytokines did not linearly correlate with anthropometric indices in psoriasis patients (P > 0.05), except in the case of leptin, for which serum levels were related to waist : hip ratio in both men and women (P < 0.05). After 24 weeks of treatment, although serum levels of proinflammatory adipocytokines were decreased, only that of leptin showed a statistically significant reduction (P = 0.0003). Serum levels of adiponectin, an anti-inflammatory adipocytokine, were only mildly increased and persisted at a significantly lower level than in healthy controls (P > 0.005).. Patients with psoriasis show an imbalance between pro- and anti-inflammatory adipocytokines, which is reduced but not normalized after administration of TNF-α inhibitors for 24 weeks. This partial rebalancing seems to be mainly related to a reduction in proinflammatory adipocytokines, rather than an increase in anti-inflammatory adipocytokines. Topics: Adalimumab; Adipokines; Adiponectin; Adult; Anti-Inflammatory Agents, Non-Steroidal; Body Mass Index; Body Weight; Case-Control Studies; Etanercept; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Psoriasis; Resistin; Retrospective Studies; Severity of Illness Index; Tumor Necrosis Factor-alpha; Waist-Hip Ratio | 2015 |
Evaluation of anti-obesity activities of ethanolic extract of Terminalia paniculata bark on high fat diet-induced obese rats.
The prevalence and severity of obesity and associated co-morbidities are rapidly increasing across the world. Natural products-based drug intervention has been proposed as one of the crucial strategies for management of obesity ailments. This study was designed to investigate the anti-obesity activities of ethanolic extract of Terminalia paniculata bark (TPEE) on high fat diet-induced obese rats.. LC-MS/MS analysis was done for ethanolic extract of T. paniculata bark. Male Sprague-Dawley (SD) rats were randomly divided into six groups of six each, normal diet fed (NC), high fat diet-fed (HFD), HFD+ orlistat (standard drug control) administered, and remaining three groups were fed with HFD + TPEE in different doses (100,150 and 200 mg/kg b. wt). For induction of obesity rats were initially fed with HFD for 9 weeks, then, (TPEE) was supplemented along with HFD for 42 days. Changes in body weight, body composition, blood glucose, insulin, tissue and serum lipid profiles, atherogenic index, liver markers, and expression of adipogenesis-related genes such as leptin, adiponectin, FAS, PPARgamma, AMPK-1alpha and SREBP-1c, were studied in experimental rats. Also, histopathological examination of adipose tissue was carried out.. Supplementation of TPEE reduced significantly (P < 0.05) body weight, total fat, fat percentage, atherogenic index, blood glucose, insulin, lipid profiles and liver markers in HFD-fed groups, in a dose-dependent manner. The expression of adipogenesis-related genes such as Leptin, FAS, PPARgamma, and SREBP-1c were down regulated while Adiponectin and AMPK-1alpha were up regulated in TPEE + HFD-fed rats. Furthermore, histopathological examination of adipose tissue revealed the alleviating effect of TPEE which is evident by reduced size of adipocytes.. Together, the biochemical, histological and molecular studies unambiguously demonstrate the potential anti adipogenic and anti obesity activities of TPEE promoting it as a formidable candidate to develop anti obesity drug. Topics: Adipocytes; Adipogenesis; Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Diet, High-Fat; Dietary Fats; Insulin; Leptin; Liver; Male; Obesity; Phytotherapy; Plant Bark; Plant Extracts; PPAR gamma; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Terminalia | 2015 |
Exendin-4 improves thermogenic capacity by regulating fat metabolism on brown adipose tissue in mice with diet-induced obesity.
This study aimed to investigate the benefits of exendin-4 treatment on brown adipose tissue (BAT) in C57BL/6J mice with high-fat diet (HFD)-induced obesity.. We examined the effects of exendin-4 on body adiposity and the level of genes associated with adipogenesis, glucose/lipid uptake, lipolysis, and thermogenesis in mice with diet-induced obesity.. Exendin-4 treatment deceased body weight, serum-free fatty acid, and triglyceride levels in HFD-induced obese C57BL/6J mice. Exendin-4 treatment increased the expression of genes associated with adipogenesis, glucose/lipid uptake, lipolysis, and thermogenesis in BAT. Compared with HFD-fed mice, exendin-4 treatment also exhibited elevated energy expenditure and reduced respiratory quotient, but showed similar food intake and locomotor activity.. Exendin-4 treatment reduced high-fat-induced obesity by decreasing adiposity and increasing thermogenesis. This result suggests that GLP-1 agonist may be a new approach to combat obesity by shifting the energy balance from obesogenesis to thermogenesis. Topics: Adipogenesis; Adiponectin; Adipose Tissue, Brown; Animals; Body Weight; Diet, High-Fat; Energy Metabolism; Exenatide; Fasting; Fatty Acids; Feeding Behavior; Gene Expression Regulation; Glucose; Leptin; Lipid Metabolism; Mice, Inbred C57BL; Motor Activity; Obesity; Peptides; Thermogenesis; Triglycerides; Venoms | 2015 |
Cooperative interaction between leptin and amylin signaling in the ventral tegmental area for the control of food intake.
Peripheral coadministration of amylin and leptin produces enhanced suppression of food intake and body weight, but the central nuclei mediating these effects remain unclear. Because each of these peptides controls feeding via actions at the ventral tegmental area (VTA), we tested the hypothesis that the VTA is a site of action for the cooperative effects of leptin and amylin on energy balance control. First, we show that intra-VTA injection of amylin and leptin at doses of each peptide that are effective in reducing food intake and body weight when administered separately produces an enhanced suppression of feeding when administered in combination. We also demonstrate that subthreshold doses of both amylin and leptin cause significant hypophagia and body weight loss when coadministered into the VTA. Additionally, we provide evidence that VTA amylin receptor blockade significantly attenuates the ability of intra-VTA leptin to reduce feeding and body weight gain. Together, these data provide the first evidence that the VTA mediates the interaction of amylin and leptin to cooperatively promote negative energy balance. Topics: Animals; Appetite Regulation; Body Weight; Energy Metabolism; Islet Amyloid Polypeptide; Leptin; Male; Rats; Rats, Sprague-Dawley; Signal Transduction; Ventral Tegmental Area; Weight Loss | 2015 |
Anti-obesity effect of Triticum aestivum sprout extract in high-fat-diet-induced obese mice.
Obesity is a common disease worldwide that often results in serious conditions including hypertension, diabetes, and hyperlipidemia. Many herbal medicines have been examined with regard to ameliorating obesity. We investigated the anti-obesity effects of 50% EtOH extract of Triticum aestivum sprout (TAEE) in high-fat-diet (HFD)-induced obese mice. TAEE administration (10, 50, or 200 mg/kg) for 6 weeks significantly decreased the body weights, serum total cholesterol (TC), and low-density lipoprotein cholesterol levels in HFD-fed mice. TAEE treatment reduced lipid accumulation in epididymal white adipose tissue (EWAT) and liver. Moreover, TC and lipid levels were decreased by TAEE treatment in liver. Serum leptin and adiponectin concentrations were reduced by TAEE treatment. TAEE-treated mice showed decreases in peroxisome proliferator-activated receptor γ (PPARγ) and fatty acid synthase expression in EWAT. Furthermore, TAEE administration elevated levels of PPARα protein in the liver of HFD-induced obese mice. These results suggest that TAEE supplementation might be beneficial for the treatment and prevention of obesity and related diseases. Topics: Adiponectin; Adipose Tissue, White; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Diet, High-Fat; Dietary Supplements; Eating; Leptin; Lipids; Liver; Male; Mice, Inbred C57BL; Obesity; Plant Extracts; Triticum | 2015 |
Expression of Selenoprotein Genes Is Affected by Obesity of Pigs Fed a High-Fat Diet.
Relations of the 25 mammalian selenoprotein genes with obesity and the associated inflammation remain unclear.. This study explored impacts of high-fat diet-induced obesity on inflammation and expressions of selenoprotein and obesity-related genes in 10 tissues of pigs.. Plasma and 10 tissues were collected from pigs (n = 10) fed a corn-soy-based control diet or that diet containing 3-7% lard from weanling to finishing (180 d). Plasma concentrations (n = 8) of cytokines and thyroid hormones and tissue mRNA abundance (n = 4) of 25 selenoprotein genes and 16 obesity-related genes were compared between the pigs fed the control and high-fat diets. Stepwise regression was applied to analyze correlations among all these measures, including the previously reported body physical and plasma biochemical variables.. The high-fat diet elevated (P < 0.05) plasma concentrations of tumor necrosis factor α, interleukin-6, leptin, and leptin receptor by 29-42% and affected (P < 0.05-0.1) tissue mRNA levels of the selenoprotein and obesity-related genes in 3 patterns. Specifically, the high-fat diet up-regulated 12 selenoprotein genes in 6 tissues, down-regulated 13 selenoprotein genes in 7 tissues, and exerted no effect on 5 genes in any tissue. Body weights and plasma triglyceride concentrations of pigs showed the strongest regressions to tissue mRNA abundances of selenoprotein and obesity-related genes. Among the selenoprotein genes, selenoprotein V and I were ranked as the strongest independent variables for the regression of phenotypic and plasma measures. Meanwhile, agouti signaling protein, adiponectin, and resistin genes represented the strongest independent variables of the obesity-related genes for the regression of tissue selenoprotein mRNA.. The high-fat diet induced inflammation in pigs and affected their gene expression of selenoproteins associated with thioredoxin and oxidoreductase systems, local tissue thyroid hormone activity, endoplasmic reticulum protein degradation, and phosphorylation of lipids. This porcine model may be used to study interactive mechanisms between excess fat intake and selenoprotein function. Topics: Adiponectin; Agouti Signaling Protein; Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Inflammation; Interleukin-6; Leptin; Obesity; Receptors, Leptin; Resistin; RNA, Messenger; Selenoproteins; Swine; Thyroid Hormones; Tumor Necrosis Factor-alpha; Up-Regulation | 2015 |
Diet-induced obese mice retain endogenous leptin action.
Obesity is characterized by hyperleptinemia and decreased response to exogenous leptin. This has been widely attributed to the development of leptin resistance, a state of impaired leptin signaling proposed to contribute to the development and persistence of obesity. To directly determine endogenous leptin activity in obesity, we treated lean and obese mice with a leptin receptor antagonist. The antagonist increased feeding and body weight (BW) in lean mice, but not in obese models of leptin, leptin receptor, or melanocortin-4 receptor deficiency. In contrast, the antagonist increased feeding and BW comparably in lean and diet-induced obese (DIO) mice, an increase associated with decreased hypothalamic expression of Socs3, a primary target of leptin. These findings demonstrate that hyperleptinemic DIO mice retain leptin suppression of feeding comparable to lean mice and counter the view that resistance to endogenous leptin contributes to the persistence of DIO in mice. Topics: Animals; Body Weight; Diet; Hyperlipidemias; Leptin; Mice; Mice, Knockout; Mice, Obese; Obesity; Receptor, Melanocortin, Type 4; Receptors, Leptin; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins | 2015 |
Beneficial Effects of Supplementation of the Rare Sugar "D-allulose" Against Hepatic Steatosis and Severe Obesity in Lep(ob)/Lep(ob) Mice.
A rare sugar, D-allulose (also called D-psicose), has recently been applied as a food supplement in view of controlling diabetes and obesity in Japan. D-allulose has been proven to have unique effects against hyperglycemia and hyperlipidemia in a number of studies using several species of rats and mice. However, the antiobesity effects of D-allulose have not yet been assessed in Lep(ob)/Lep(ob) (ob/ob) mice. Therefore, this study explored the dietary supplemental effects of this sugar in leptin-deficient ob/ob mice. Consequently, the subchronic ingestion of D-allulose in ob/ob mice for 15 wk significantly decreased the body and liver weights, and the loss of body weight was involved in the reduction of the total fat mass, including abdominal visceral fat, and not fat-free body mass, including muscle. Furthermore, D-allulose improved hepatic steatosis, as evaluated using hepatic histological studies and MRI. In the normal mice, none of these parameters were influenced by the single or long-term ingestion of D-allulose. These results indicate that dietary supplementation of D-allulose especially influences postprandial hyperglycemia and obesity-related hepatic steatosis, without exercise therapy or dietary restriction. Therefore, D-allulose may be useful as a supplement for preventing and improving obesity and obesity-related disorders. Topics: 3T3-L1 Cells; Adipose Tissue; Animals; Body Composition; Body Weight; Cell Differentiation; Dietary Supplements; Fatty Liver; Fructose; Leptin; Liver; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Organ Size | 2015 |
Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels.
Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice. Topics: Adipokines; Adiponectin; Animals; Bilirubin; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; Disease Models, Animal; Glucose Tolerance Test; Insulin Resistance; Leptin; Lipid Metabolism; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; PPAR gamma; Receptor, Insulin; Sterol Regulatory Element Binding Protein 1 | 2015 |
Differences in mitochondrial DNA inheritance and function align with body conformation in genetically lean and fat sheep.
Body weight and adiposity are determined by the balance between energy intake, energy expenditure, and nutrient deposition. We have identified differences in appetite-regulating peptides in sheep selectively bred to be either lean or fat, wherein gene expression for orexin and melanin-concentrating hormone are elevated in the lean group. Despite this, the underlying mechanisms leading to differences in body composition in the lean and fat lines remains unknown. We measured postprandial temperature in adipose tissue and muscle to ascertain whether a difference in thermogenesis is associated with the difference in body composition in genetically lean (n = 8) and fat (n = 12) ewes. Body weight was higher (P < 0.01) but percent fat mass was lower (P < 0.001) in the lean group. The percent lean mass was similar in lean and fat groups. Animals received intracerebroventricular cannulae and temperature probes implanted into the retroperitoneal fat and the hind-limb skeletal muscle (vastus lateralis). Animals were meal fed (1100-1600 h) to entrain postprandial thermogenesis. Food intake was similar between lean and fat animals. Postprandial thermogenesis was greater (P < 0.05) in the retroperitoneal adipose tissue of lean animals but not in skeletal muscle. Intracerebroventricular infusion of leptin reduced (P< 0.05) food intake by an equal extent in both groups. Postprandial expression of UCP1 mRNA was greater (P < 0.05) in retroperitoneal fat of lean animals, with similar UCP3 expression in skeletal muscle. Mitochondrial genome sequencing indicated haplotypic clustering in lean and fat animals within both the encoding and nonencoding regions. This demonstrates that differences in body composition may be underpinned by differences in thermogenesis, specifically within adipose tissue. Furthermore, thermogenic differences may be associated with specific mitochondrial DNA haplotypes, suggesting a strong genetic component inherited through the maternal lineage. Topics: Adiposity; Animals; Appetite; Body Composition; Body Temperature; Body Weight; DNA, Mitochondrial; Eating; Energy Intake; Energy Metabolism; Female; Hypothalamic Hormones; Intra-Abdominal Fat; Leptin; Melanins; Pituitary Hormones; Postprandial Period; Sheep; Sheep, Domestic; Thermogenesis | 2015 |
KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration.
KBP-042 is a synthetic peptide dual amylin- and calcitonin-receptor agonist (DACRA) developed to treat type 2 diabetes by inducing a significant weight loss while improving glucose homeostasis. In this study the aim was to compare two different formulations: An oral formulation (1mg/kg) to subcutaneous formulations of KBP-042 (2.5μg/kg, 5.0μg/kg and 7.5μg/kg) with comparable pharmacokinetic profiles. Furthermore to examine if differences in mode of action between the two different routes of administration in high-fat fed Sprague-Dawley rats were present. It was established that the subcutaneous administrations of KBP-042 were able to dose-dependently cause a significant weight-loss, reduce food intake, and improve glucose homeostasis without increasing insulin secretion, effects comparable to those observed with oral administration. At the same time, s.c. KBP-042 suppressed the inappropriate glucagon response better than the oral formulation. Furthermore, KBP-042 was found to reduce incretins GLP-1 and GIP and considerably, improve gastric emptying, and to alleviate leptin resistance, as well as insulin resistance. In conclusion, the subcutaneous route of administration was found to have the same beneficial effects on blood glucose homeostasis and weight loss as well as resistance towards important insulin and leptin, albeit with a markedly lower variation in both exposure and biological responses. These data support the application of subcutaneously delivered peptide for mechanistic studies, and highlight the potential of developing s.c. KBP-042 as a therapy for T2D. Topics: Adiposity; Animals; Blood Glucose; Body Weight; Calcitonin; Diet, High-Fat; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Insulin Resistance; Intra-Abdominal Fat; Islet Amyloid Polypeptide; Leptin; Male; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Calcitonin | 2015 |
Mexico City normal weight children exposed to high concentrations of ambient PM2.5 show high blood leptin and endothelin-1, vitamin D deficiency, and food reward hormone dysregulation versus low pollution controls. Relevance for obesity and Alzheimer dise
Millions of Mexico, US and across the world children are overweight and obese. Exposure to fossil-fuel combustion sources increases the risk for obesity and diabetes, while long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with increased risk of Alzheimer's disease (AD). Mexico City Metropolitan Area children are chronically exposed to PM2.5 and O3 concentrations above the standards and exhibit systemic, brain and intrathecal inflammation, cognitive deficits, and Alzheimer disease neuropathology. We investigated adipokines, food reward hormones, endothelial dysfunction, vitamin D and apolipoprotein E (APOE) relationships in 80 healthy, normal weight 11.1±3.2 year olds matched by age, gender, BMI and SES, low (n: 26) versus high (n:54) PM2.5 exposures. Mexico City children had higher leptin and endothelin-1 (p<0.01 and p<0.000), and decreases in glucagon-like peptide-1 (GLP 1), ghrelin, and glucagon (<0.02) versus controls. BMI and leptin relationships were significantly different in low versus high PM2.5 exposed children. Mexico City APOE 4 versus 3 children had higher glucose (p=0.009). Serum 25-hydroxyvitamin D<30 ng/mL was documented in 87% of Mexico City children. Leptin is strongly positively associated to PM 2.5 cumulative exposures. Residing in a high PM2.5 and O3 environment is associated with 12h fasting hyperleptinemia, altered appetite-regulating peptides, vitamin D deficiency, and increases in ET-1 in clinically healthy children. These changes could signal the future trajectory of urban children towards the development of insulin resistance, obesity, type II diabetes, premature cardiovascular disease, addiction-like behavior, cognitive impairment and Alzheimer's disease. Increased efforts should be made to decrease pediatric PM2.5 exposures, to deliver health interventions prior to the development of obesity and to identify and mitigate environmental factors influencing obesity and Alzheimer disease. Topics: Adolescent; Alzheimer Disease; Body Weight; Case-Control Studies; Child; Cohort Studies; Endothelin-1; Hormones; Humans; Leptin; Mexico; Obesity; Particulate Matter; Vitamin D Deficiency | 2015 |
Effects of early-onset voluntary exercise on adult physical activity and associated phenotypes in mice.
The purpose of this study was to evaluate the effects of early-life exercise on adult physical activity (wheel running, home-cage activity), body mass, food consumption, and circulating leptin levels in males from four replicate lines of mice selectively bred for high voluntary wheel running (High Runner or HR) and their four non-selected control (C) lines. Half of the mice were given wheel access shortly after weaning for three consecutive weeks. Wheel access was then removed for 52 days, followed by two weeks of adult wheel access for all mice. A blood sample taken prior to adult wheel testing was analyzed for circulating leptin concentration. Early-life wheel access significantly increased adult voluntary exercise on wheels during the first week of the second period of wheel access, for both HR and C mice, and HR ran more than C mice. During this same time period, activity in the home cages was not affected by early-age wheel access, and did not differ statistically between HR and C mice. Throughout the study, all mice with early wheel access had lower body masses than their sedentary counterparts, and HR mice had lower body masses than C mice. With wheel access, HR mice also ate significantly more than C mice. Early-life wheel access increased plasma leptin levels (adjusted statistically for fat-pad mass as a covariate) in C mice, but decreased them in HR mice. At sacrifice, early-life exercise had no statistically significant effects on visceral fat pad, heart (ventricle), liver or spleen masses (all adjusted statistically for variation in body mass). Results support the hypothesis that early-age exercise in mice can have at least transitory positive effects on adult levels of voluntary exercise, in addition to reducing body mass, and may be relevant for the public policy debates concerning the importance of physical education for children. Topics: Animals; Body Mass Index; Body Weight; Eating; Leptin; Male; Mice; Motor Activity; Phenotype; Physical Conditioning, Animal; Time Factors | 2015 |
Overexpression of insulin receptor partially improves obese and diabetic phenotypes in db/db mice.
Type 2 diabetes mellitus (T2DM) is one of the major health concern among the world. Several treatment options for T2DM are in clinical use, including injecting insulin, promoting insulin secretion by insulin secretagogues, and improving insulin sensitivity by insulin sensitizers. However, increasing the amount of insulin receptor in insulin-target tissues has not been explored. In order to test the efficacy of insulin receptor overexpression for improving glucose control, we established a transgenic mouse line expressing human insulin receptor (INSR). We analyzed, growth, energy balance, and glucose control of INSR-overexpressing db/db mice (INSR; db/db), which we produced by mating INSR transgenic mice with db/db mice, a genetic model of obesity due to insufficient leptin signaling. Compared to db/db mice, INSR; db/db mice were rescued from hyperphagia and obesity, leading to improved blood glucose levels. Unexpectedly, however, INSR; db/db mice presented with stunted growth, accompanied by decreased plasma levels of free IGF1 and IGFBP-3, indicating the down-regulation of GH/IGF1 axis. These phenotypes were observed in INSR; db/db mice but not in INSR littermates. Meanwhile, bone defects observed in db/db male mice were not rescued. Moreover, improved blood glucose was not accompanied by improved insulin sensitivity. Therefore, overexpression of insulin receptor improves obese and diabetic phenotypes in db/db mice, with consequences on growth. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Energy Metabolism; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Transgenic; Obesity; Phenotype; Receptor, Insulin | 2015 |
A mathematical model of leptin resistance.
Obesity is often associated with leptin resistance, which leads to a physiological system with high leptin concentration but unable to respond to leptin signals and to regulate food intake. We propose a mathematical model of the leptin-leptin receptors system, based on the assumption that leptin is a regulator of its own receptor activity, and investigate its qualitative behavior. Based on current knowledge and previous models developed for body weight dynamics in rodents, the model includes the dynamics of leptin, leptin receptors and the regulation of food intake and body weight. It displays two stable equilibria, one representing a healthy state and the other one an obese and leptin resistant state. We show that a constant leptin injection can lead to leptin resistance and that a temporal variation in some parameter values influencing food intake can induce a change of equilibrium and a pathway to leptin resistance and obesity. Topics: Animals; Body Weight; Drug Resistance; Eating; Humans; Leptin; Mathematical Concepts; Models, Biological; Obesity; Receptors, Leptin | 2015 |
Leptin and leptin receptor gene polymorphisms are correlated with production performance in the Arctic fox.
The polymerase chain reaction-single-strand conformation polymorphism technique was employed to measure mononucleotide diversity in the coding region of the leptin and leptin receptor genes in the Arctic fox. The relationships between specific genetic mutations and reproductive performance in Arctic foxes were determined to im-prove breeding strategies. We found that a leptin gene polymorphism was significantly associated with body weight (P < 0.01), abdominal circumference (P < 0.01), and fur length (P < 0.01). Furthermore, a polymorphism in the leptin receptor gene was associated with carcass weight and guard hair length (P < 0.01). Leptin and leptin receptor gene combinatorial genotypes were significantly associated with abdominal circumference, fur length (P < 0.01), and body weight (P < 0.05). The leptin gene is thus a key gene affecting body weight, abdominal circumference, and fur length in Arctic foxes, whereas variations in the leptin receptor mainly affect carcass weight and guard hair. The marker loci identified in this study can be used to assist in the selection of Arctic foxes for breeding to raise the production performance of this species. Topics: Animals; Body Weight; Breeding; Foxes; Genotype; Hair; Leptin; Polymorphism, Single Nucleotide; Receptors, Leptin | 2015 |
D-Fagomine attenuates metabolic alterations induced by a high-energy-dense diet in rats.
d-Fagomine is a natural iminosugar that counteracts the short-term effects of a high-energy-dense diet on body weight, fasting blood glucose levels and the proportion of gut Enterobacteriales. This suggests that supplementation with d-fagomine for longer periods may delay the onset of other factors related to metabolic syndrome. Here we evaluate the effects of d-fagomine dietary supplementation on relevant metabolic hormones and lipid peroxidation. Adult Sprague-Dawley rats were fed a high-fat high-sucrose diet supplemented or not with d-fagomine (0.065% w/w) for 9 weeks. Weight gain, plasma triglycerides, glucose, insulin, glucagon, ghrelin, leptin, and urine F2-isoprostanes were evaluated. d-Fagomine attenuated the changes induced by the high-energy-dense diet in triglycerides and all the hormones tested. These results suggest that d-fagomine may help to avert the complications associated with unhealthy eating by counteracting the effects of high-energy-dense diets during the early stages of the development of metabolic disorders. Topics: Animals; Blood Glucose; Body Weight; Diet, High-Fat; Humans; Imino Pyranoses; Insulin; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Triglycerides | 2015 |
Beneficial Effects of Red Yeast Rice on High-Fat Diet-Induced Obesity, Hyperlipidemia, and Fatty Liver in Mice.
Obesity is a common cause of hyperlipidemia, which is a major coronary risk factor. Previous studies have shown red yeast rice (RYR) effectiveness in lowering low-density lipoprotein cholesterol. The aim of this study was to investigate the effects of RYR on obesity and hyperlipidemia. Mice were randomly separated into five groups: the control group with a normal diet, the high-fat diet (HFD) group fed a HFD without any treatment, and HFD-fed groups supplemented with RYR (1 g/kg/day for 8 weeks, 1 g/kg/day for 12 weeks, and 2.5 g/kg/day for 8 weeks). Body weight was recorded twice and food intake thrice weekly. Liver and fat pads were surgically removed and weighed. The levels of lipid parameters, liver enzymes, and leptin levels were measured. The HFD feeding resulted in obesity, which was associated with increases in body weight, liver weight, fat pad weight, liver enzymes, and plasma leptin levels with the development of hyperlipidemia. RYR prevented weight gain and fat pad weight in mice fed a HFD. RYR alleviated blood lipid parameters, liver enzymes, and leptin levels, and improved atherogenic index. These findings suggest that RYR has therapeutic potential in treating obesity and hyperlipidemia. Topics: Adipose Tissue; Alanine Transaminase; Animals; Aspartate Aminotransferases; Biological Products; Body Weight; Diet; Diet, High-Fat; Hyperlipidemias; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Organ Size | 2015 |
Effects of estradiol, estrogen receptor subtype-selective agonists and genistein on glucose metabolism in leptin resistant female Zucker diabetic fatty (ZDF) rats.
The leptin resistant Zucker diabetic fatty (ZDF) rats are hyperphagic and become obese, but whereas the males develop type 2 diabetes mellitus (T2DM), the females remain euglycaemic. As estrogen deficiency is known to increase the risk of developing T2DM, we evaluated the role of ER subtypes alpha and beta in the development of glucose tolerance in leptin resistant ovariectomized (OVX) ZDF rats. At least six rats per group were treated with either vehicle (OVX), 17β-estradiol (E2), ER subtype-selective agonists (Alpha and Beta), or genistein (Gen) for 17 weeks. At the end of the treatment period a glucose tolerance assay was performed and the metabolic flux of (13)C-glucose for the E2 group was investigated. OVX ZDF rats treated with E2, Alpha, Beta, and Gen tolerated the glucose significantly better than untreated controls. E2 treatment increased absorbance/flux of (13)C-glucose to metabolic relevant tissues such liver, adipose tissue, gastrocnemius, and soleus muscle. Moreover, whereas Alpha treatment markedly increased mRNA expression of GLUT4 in gastrocnemius muscle, Beta treatment resulted in the largest fiber sizes of the soleus muscle. Treatment with Gen increased both the mRNA expression of GLUT 4 and the fiber sizes in the skeletal muscle. In addition, E2 and Alpha treatment decreased food intake and body weight gain. In summary, estrogen-improved glucose absorption is mediated via different molecular mechanisms: while activation of ER alpha seems to stimulate muscular GLUT4 functionality, activation of ER beta results in a hypertrophy of muscle fibers. In addition, selective activation of ER alpha decreased food intake and body weight gain. Our data further indicate that ER subtype-selective agonists and genistein improve systemic glucose tolerance also in the absence of a functional leptin signaling pathway. Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus, Experimental; Estradiol; Female; Genistein; Glucose; Glucose Tolerance Test; Glucose Transporter Type 4; Leptin; Liver; Muscle, Skeletal; Obesity; Organ Size; Rats; Rats, Zucker; Receptors, Estrogen; Uterus | 2015 |
Behavioural and physiological responses of wood mice (Apodemus sylvaticus) to experimental manipulations of predation and starvation risk.
Body weight and the levels of stored body fat have fitness consequences. Greater levels of fat may provide protection against catastrophic failures in the food supply, but they may also increase the risk of predation. Animals may therefore regulate their fatness according to their perceived risks of predation and starvation: the starvation-predation trade-off model. We tested the predictions of this model in wood mice (Apodemus sylvaticus) by experimentally manipulating predation risk and starvation risk. We predicted that under increased predation risk individuals would lose weight and under increased starvation risk they would gain it. We simulated increased predation risk by playing the calls made by predatory birds (owls: Tyto alba and Bubo bubo) to the mice. Control groups included exposure to calls of a non-predatory bird (blackbird: Turdus merula) or silence. Mice exposed to owl calls at night lost weight relative to the silence group, mediated via reduced food intake, but exposure to owl calls in the day had no significant effect. Exposure to blackbird calls at night also resulted in weight loss, but blackbird calls in the day had no effect. Mice seemed to have a generalised response to bird calls at night irrespective of their actual source. This could be because in the wild any bird calling at night will be a predation risk, and any bird calling in the day would not be, because at that time the mice would normally be resting, and hence not exposed to avian predators. Consequently, mice have not evolved to distinguish different types of call but only to respond to the time of day that they occur. Mice exposed to stochastic 24h starvation events altered their behaviour (reduced activity) during the refeeding days that followed the deprivation periods to regain the lost mass. However, they only marginally elevated their food intake and consequently had reduced body weight/fat storage compared to that of the control unstarved group. This response may have been constrained by physiological factors (alimentary tract absorption capacity) or behavioural factors (perceived risk of predation). Overall the responses of the mice appeared to provide limited support for the starvation-predation trade-off model, and suggest that wood mice are much more sensitive to predation risk than they are to starvation risk. Topics: Acoustic Stimulation; Analysis of Variance; Animals; Body Mass Index; Body Weight; Corticosterone; Eating; Fasting; Hyperphagia; Leptin; Models, Animal; Murinae; Oxygen Consumption; Predatory Behavior; Risk Factors; Starvation; Time Factors | 2015 |
Effects of Estrogen on Insulin Sensitivity and Adipokines in Mice.
To study the potential mechanisms via which estrogen exerts its effects on the insulin sensitivity in mice.. Totally 36 female C57BL/6J mice aged 6 weeks were randomly divided into six groups:normal diet (NOR) group, normal diet with ovariectomy (NOR+OVX) group, normal diet with ovariectomy and estrogen replacement (NOR+OVX+E2) group,high-fat diet (HF) group, high-fat diet with ovariectomy (HF+OVX) group, and high-fat diet with ovariectomy and estrogen replacement (HF+OVX+E2) group. There were six mice in each group. After the ovariectomy based on the grouping, the mice were given normal diet or high-fat diet for 20 weeks. The intervention groups were given estrogen (5 μg/d,subcutaneous injection) for 20 days. Then,the body weight,visceral fat weight,oral glucose tolerance and insulin sensitivity (by euglycemic hyperinsulinemic clamp test), and serum leptin, adiponectin,and resistin levels were compared among these six groups.. Compared with HF group, the HF+OVX group had significantly higher body weight and visceral fat weight and lower glucose tolerance, which were significantly improved after estrogen replacement therapy (all P<0.05). However, these indicators showed no significant differences among groups with normal diets (all P>0.05). The insulin sensitivity of ovariectomized mice was significantly decreased in both high-fat and normal diet groups and was also improved significantly after estrogen replacement (P<0.05). The serum leptin was increased and adiponectin was decreased significantly in ovariectomized mice, and the improvements of these two adipokines were also statistically significant after estrogen therapy (P<0.05): however,the serum resistin level was not significantly different among these 6 groups (P>0.05).. Estrogen replacement therapy can improve insulin resistance by lowering body weight. In addition, it can exert its effect directly on adipose tissue,improve the levels of adipokines,reduce the amount of visceral fat, and improve insulin sensitivity in mice. Topics: Adipokines; Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Estrogens; Female; Insulin Resistance; Intra-Abdominal Fat; Leptin; Mice; Mice, Inbred C57BL; Ovariectomy | 2015 |
Reanalysis of parabiosis of obesity mutants in the age of leptin.
In this study we set out to explain the differing effects of parabiosis with genetically diabetic (db) mice versus administration of recombinant leptin. Parabiosis of db mutant, which overexpress leptin, to wildtype (WT) or genetically obese (ob) mice has been reported to cause death by starvation, whereas leptin infusions do not produce lethality at any dose or mode of delivery tested. Leptin is not posttranslationally modified other than a single disulphide bond, raising the possibility that it might require additional factor(s) to exert the maximal appetite-suppressing effect. We reconfirmed the lethal effect of parabiosis of db mutant on WT mice and further showed that this lethality could not be rescued by administration of ghrelin or growth hormone. We then initiated a biochemical fractionation of a high-molecular-weight leptin complex from human plasma and identified clusterin as a major component of this leptin-containing complex. However, in contrast to previous reports, we failed to observe a leptin-potentiating effect of either exogenous or endogenous clusterin, and parabiosis of db clusterin(-/-) double-mutant to WT mice still caused lethality. Intriguingly, in parabiotic pairs of two WT mice, leptin infusion into one of the mice led to an enhanced starvation response during calorie restriction as evidenced by increased plasma ghrelin and growth-hormone levels. Moreover, leptin treatment resulted in death of the parabiotic pairs. These data suggest that the appetite suppression in WT mice after parabiosis to db mutants is the result of induced hyperleptinemia combined with the stress or other aspect(s) of the parabiosis procedure. Topics: Animals; Body Weight; Clusterin; Diabetes Mellitus, Experimental; Feeding Behavior; Gene Expression Profiling; Humans; Leptin; Mice, Inbred C57BL; Mice, Obese; Molecular Weight; Mutation; Neurons; Obesity; Parabiosis; Receptors, Leptin; STAT3 Transcription Factor | 2015 |
Adulthood dietary exposure to a common pesticide leads to an obese-like phenotype and a diabetic profile in apoE3 mice.
Increasing evidence links the widespread exposure to organophosphate (OP) pesticides to the global epidemics of type 2 diabetes and obesity. Our recent data highlighted gene×environment interactions: mice expressing the human apolipoprotein E3 (apoE3) isoform were more prone to develop obesity than those expressing apoE2 or apoE4 upon dietary challenge with chlorpyrifos (CPF), the most used OP worldwide. Thus, we aimed to further explore the contribution of the APOE3 genotype on the emergence of obesity and related metabolic dysfunctions upon subchronic exposure to CPF. Seven-month-old targeted replacement apoE3 and C57BL/6N male mice were orally exposed to CPF at 0 or 2mg/kg body weight/day for 8 consecutive weeks. We examined body weight status, food and water intake, lipid and glucose homeostasis, metabolic biomarkers concentrations, insulin levels and insulin resistance, and leptin and ghrelin profiles. CPF exposure generally increased food ingestion, glucose and total cholesterol concentrations, and tended to elevate acyl ghrelin levels. Nonetheless, excess weight gain and increased leptin levels were inherent to apoE3 mice. Moreover, the propensity towards a diabetic profile was markedly higher in these animals than in C57BL/6N, as they showed a higher homeostatic model assessment for insulin resistance index and higher insulin levels. Although both genotypes were metabolically affected by CPF, the results of the present investigation revealed that apoE3 mice were the most vulnerable to developing obesity and related disturbances following CPF administration through the diet. Since the APOE3 genotype is the most prevalent worldwide, current findings have particular implications for human health. Topics: Animals; Apolipoprotein E3; Blood Glucose; Body Weight; Chlorpyrifos; Cholesterol; Cholinesterases; Diabetes Mellitus; Diet; Eating; Ghrelin; Insecticides; Insulin; Insulin Resistance; Leptin; Male; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Phenotype; Triglycerides | 2015 |
Circadian Dysfunction Induces Leptin Resistance in Mice.
Circadian disruption is associated with obesity, implicating the central clock in body weight control. Our comprehensive screen of wild-type and three circadian mutant mouse models, with or without chronic jet lag, shows that distinct genetic and physiologic interventions differentially disrupt overall energy homeostasis and Leptin signaling. We found that BMAL1/CLOCK generates circadian rhythm of C/EBPα-mediated leptin transcription in adipose. Per and Cry mutant mice show similar disruption of peripheral clock and deregulation of leptin in fat, but opposite body weight and composition phenotypes that correlate with their distinct patterns of POMC neuron deregulation in the arcuate nucleus. Chronic jet lag is sufficient to disrupt the endogenous adipose clock and also induce central Leptin resistance in wild-type mice. Thus, coupling of the central and peripheral clocks controls Leptin endocrine feedback homeostasis. We propose that Leptin resistance, a hallmark of obesity in humans, plays a key role in circadian dysfunction-induced obesity and metabolic syndromes. Topics: Adipose Tissue; Animals; Base Sequence; Body Weight; Circadian Clocks; Circadian Rhythm; CLOCK Proteins; Energy Metabolism; Leptin; Melanocortins; Mice; Mice, Inbred C57BL; Obesity; Signal Transduction; Transcriptional Activation | 2015 |
A Hyperlipidic Diet Combined with Short-Term Ovariectomy Increases Adiposity and Hyperleptinemia and Decreases Cytokine Content in Mesenteric Adipose Tissue.
Four-week-old female Wistar rats were divided into two groups and fed a control diet (C) or a hyperlipidic diet (H) for 4 weeks. Rats from each group underwent ovariectomy (OVX) or sham surgery (SHAM). They received C or H for the next four weeks. The body weight gain (BW), food efficiency (FE), and carcass lipid content were higher in the OVX H than in the SHAM H. The OVX H exhibited a higher serum leptin level than other groups. IL-6, TNF-α, and IL-10 content of mesenteric (MES) adipose tissue was lower in the OVX H than in the OVX C. IL-6, TNF-α, and IL-10 content of retroperitoneal (RET) adipose tissue was lower in the SHAM H than in the SHAM C. The SHAM H showed decreased TG relative to the SHAM C. Similar results were obtained in relation to IL-6Rα, TNFR1, TLR-4, and MyD88 contents in the MES and RET white adipose tissue among the groups. A hyperlipidic diet for 8 weeks combined with short-term ovariectomy decreases the cytokine content of MES adipose tissues but increases BW, enhancing FE and elevating serum leptin levels. These suggest that the absence of estrogens promotes metabolic changes that may contribute to installation of a proinflammatory process induced by a hyperlipidic diet. Topics: Adipose Tissue; Adiposity; Animals; Blood Glucose; Body Weight; Cytokines; Diet; Female; Hyperlipidemias; Insulin; Leptin; Mesentery; Ovariectomy; Rats; Rats, Wistar | 2015 |
Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene.
Congenital leptin deficiency is a very rare cause of severe early-onset obesity. We recently characterized a mutation in the leptin gene (p.D100Y), which was associated with detectable leptin levels and bioinactivity of the hormone.. We now describe two siblings, a 9-year-old girl and a 6-year-old boy with severe early-onset obesity and hyperphagia, both homozygous for a c.309C>A substitution in the leptin gene leading to a p.N103K amino acid exchange in the protein and detectable circulating levels of leptin. In vitro experiments in a heterologous cell system demonstrated that the mutated protein was biologically inactive. Treatment with sc recombinant human leptin led to rapid improvement of eating behavior and weight loss.. Sequencing of the leptin gene may need to be considered in hyperphagic, severely obese children with detectable levels of circulating leptin. Topics: Body Weight; Child; Female; Humans; Hyperphagia; Leptin; Male; Mutation; Obesity | 2015 |
Ondansetron attenuates co-morbid depression and anxiety associated with obesity by inhibiting the biochemical alterations and improving serotonergic neurotransmission.
In our earlier study we reported the antidepressant activity of ondansetron in obese mice. The present study investigates the effect of ondansetron on depression and anxiety associated with obesity in experimental mice with biochemical evidences. Male Swiss albino mice were fed with high fat diet (HFD) for 14weeks to induce obesity. Then the subsequent treatment with ondansetron (0.5 and 1mg/kg, p.o.), classical antidepressant escitalopram (ESC) (10mg/kg, p.o.) and vehicle (distilled water 10ml/kg, p.o.) was given once daily for 28days. Behavioral assay for depression including sucrose preference test, forced swim test (FST) and anxiety such as light dark test (LDT) and hole board test (HBT) were performed in obese mice. Furthermore, in biochemical estimations oral glucose tolerance test (OGTT), plasma leptin, insulin, corticosterone, brain oxidative stress marker malonaldehyde (MDA), antioxidant reduced glutathione (GSH) and serotonin assays were performed. Results indicated that HFD fed obese mice showed severe depressive and anxiety-like behaviors. Chronic treatment with ondansetron inhibited the co-morbid depression and anxiety in obese mice by increasing sucrose consumption in sucrose preference test and reducing the immobility time in FST, increasing time and transitions of light chamber in LDT, improving head dip and crossing scores in HBT compared to HFD control mice. Ondansetron in obese mice inhibited glucose sensitivity in OGTT, improved plasma leptin and insulin sensitivity, reversed hypothalamic pituitary adrenal (HPA) axis hyperactivity by reducing the corticosterone concentration, restored brain pro-oxidant/anti-oxidant balance by inhibiting MDA and elevating GSH concentrations and facilitated serotonergic neurotransmission. In conclusion, ondansetron reversed the co-morbid depression and anxiety associated with obesity in experimental mice by attenuating the behavioral and biochemical abnormalities. Topics: Animals; Anxiety; Behavior, Animal; Body Weight; Brain; Citalopram; Corticosterone; Depression; Diet, High-Fat; Glucose Tolerance Test; Glutathione; Insulin; Leptin; Male; Malondialdehyde; Mice; Mice, Obese; Obesity; Ondansetron; Oxidative Stress; Serotonin; Synaptic Transmission | 2015 |
Weight suppression in bulimia nervosa: Associations with biology and behavior.
Bulimia nervosa (BN) is a serious eating disorder that can persist for years and contribute to medical complications and increased mortality, underscoring the need to better understand factors maintaining this disorder. Higher levels of weight suppression (WS) have been found to predict both the onset and maintenance of BN; however, no studies have examined mechanisms that may account for the effects of WS on BN. We hypothesized that high WS would lead to reduced leptin levels, which may increase risk of binge eating by modulating reward responses to food. The current study examined the relationship between WS, leptin levels, and the reinforcing value of food in women with BN (n = 32) and noneating disorder controls (n = 30). Participants provided information on WS, completed a fasting blood draw to obtain serum leptin, and completed a progressive ratio task to measure the reinforcing value of food. Individuals with BN had greater WS (p < .01) and reinforcing food value (p < .05) compared with controls. Additionally, higher WS was associated with both lower leptin (p < .05) and increased reinforcing value of food (p < .05). Contrary to hypotheses, BN and control participants did not differ on leptin levels, and leptin levels were not significantly associated with the reinforcing value of food. Findings support that efforts to conform to the thin ideal may alter drive to consume rewarding foods and leave women vulnerable to binge episodes. However, mechanisms through which WS contributes to food reward and binge eating remain unknown. Topics: Adolescent; Adult; Body Mass Index; Body Weight; Bulimia Nervosa; Female; Humans; Leptin; Reward; Young Adult | 2015 |
Role of Enhanced Central Leptin Activity in a Scoliosis Model Created in Bipedal Amputated Mice.
An experimental study to investigate the role of enhanced central leptin activity in a bipedal mouse scoliosis model.. To investigate the influence of enhanced central leptin activity on the development of scoliosis in mice, and to support Burwell's hypothesis that central leptin dysfunction is involved in the etiopathogenesis of idiopathic scoliosis.. Significantly lower level of circulating leptin and higher level of soluble leptin receptor have been reported in adolescent idiopathic scoliosis compared with healthy adolescents, suggesting possible association between abnormal central leptin level and dysfunction.. Amputation of forelimbs and tail was performed on 50 male C3H/HeJ mice at the age of 3 weeks. Then, the mice were randomly divided into 2 groups: Group A consisted of 25 mice treated with injection into the hypothalamus with lentivirus vectors that overexpressed leptin; and Group B involved the remaining 25 mice receiving intracerebral injection with the control vectors. Radiographs were obtained at 20th week to determine the presence of spinal deformity. The incidence of scoliosis and curve magnitude were compared between groups.. The body weight was initially found to be slightly lower in mice of Group A when compared with Group B. Significantly higher peripheral serum leptin level was found in leptin-overexpressing mice than control mice. Scoliosis developed in 23 mice of Group A (92%), with an average Cobb angle of 30.2°, and in 13 of Group B (52%), with an average Cobb angle of 18.4°, respectively. A higher incidence (P = 0.002) and more severe curve (P <0.001) were observed in Group A.. In this bipedal mouse scoliosis model, enhanced central leptin activity might not only increase the risk of developing a scoliosis, but also contribute to the progression of scoliosis.. N/A. Topics: Amputation, Surgical; Animals; Body Weight; Disease Models, Animal; Disease Progression; Leptin; Male; Mice; Mice, Inbred C3H; Receptors, Leptin; Risk; Scoliosis | 2015 |
Replacing SNAP-25b with SNAP-25a expression results in metabolic disease.
Synaptosomal-associated protein of 25 kDa (SNAP-25) is a key molecule in the soluble N-ethylmaleimide-sensitive factor attachment protein (SNARE) complex mediating fast Ca(2+)-triggered release of hormones and neurotransmitters, and both splice variants, SNAP-25a and SNAP-25b, can participate in this process. Here we explore the hypothesis that minor alterations in the machinery mediating regulated membrane fusion can increase the susceptibility for metabolic disease and precede obesity and type 2 diabetes. Thus, we used a mouse mutant engineered to express normal levels of SNAP-25 but only SNAP-25a. These SNAP-25b-deficient mice were exposed to either a control or a high-fat/high-sucrose diet. Monitoring of food intake, body weight, hypothalamic function, and lipid and glucose homeostases showed that SNAP-25b-deficient mice fed with control diet developed hyperglycemia, liver steatosis, and adipocyte hypertrophy, conditions dramatically exacerbated when combined with the high-fat/high-sucrose diet. Thus, modified SNARE function regulating stimulus-dependent exocytosis can increase the vulnerability to and even provoke metabolic disease. When combined with a high-fat/high-sucrose diet, this vulnerability resulted in diabesity. Our SNAP-25b-deficient mouse may represent a diabesity model. Topics: Adipocytes; Adipose Tissue, White; Adiposity; Animals; Blood Glucose; Body Weight; Dyslipidemias; Energy Intake; Energy Metabolism; Feeding Behavior; Female; Homeostasis; Hypertrophy; Hypothalamus; Insulin; Insulin Secretion; Leptin; Liver; Male; Metabolic Diseases; Mice, Obese; Phenotype; Receptors, Leptin; Synaptosomal-Associated Protein 25 | 2015 |
Hyperleptinemia During Pregnancy Decreases Adult Weight of Offspring and Is Associated With Increased Offspring Locomotor Activity in Mice.
Pregnant women who are obese or have gestational diabetes mellitus have elevated leptin levels and their children have an increased risk for child and adult obesity. The goals of this study were to determine whether offspring weights are altered by maternal hyperleptinemia, and whether this occurs via behavioral changes that influence energy balance. We used 2 hyperleptinemic mouse models. The first was females heterozygous for a leptin receptor mutation (DB/+), which were severely hyperleptinemic, and that were compared with wild-type females. The second model was wild-type females infused with leptin (LEP), which were moderately hyperleptinemic, and were compared with wild-type females infused with saline (SAL). Total food consumption, food preference, locomotor activity, coordinated motor skills, and anxiety-like behaviors were assessed in wild-type offspring from each maternal group at 3 postnatal ages: 4-6, 11-13, and 19-21 weeks. Half the offspring from each group were then placed on a high-fat diet, and behaviors were reassessed. Adult offspring from both groups of hyperleptinemic dams weighed less than their respective controls beginning at 23 weeks of age, independent of diet or sex. Weight differences were not explained by food consumption or preference, because female offspring from hyperleptinemic dams tended to consume more food and had reduced preference for palatable, high-fat and sugar, food compared with controls. Offspring from DB/+ dams were more active than offspring of controls, as were female offspring of LEP dams. Maternal hyperleptinemia during pregnancy did not predispose offspring to obesity, and in fact, reduced weight gain. Topics: Animals; Body Weight; Diet, High-Fat; Eating; Exploratory Behavior; Female; Gene Expression; Leptin; Male; Metabolic Diseases; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Mutation; Obesity; Pregnancy; Pregnancy Complications; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Time Factors | 2015 |
Pectin supplementation in rats mitigates age-related impairment in insulin and leptin sensitivity independently of reducing food intake.
This study investigates whether pectin supplementation in adult rats can ameliorate age-associated disturbances in peripheral insulin and leptin actions.. Seven-month-old male Wistar rats were divided into three groups: control (rats fed ad libitum a standard-diet), pectin (rats fed ad libitum a standard-diet supplemented with 10% pectin), and pair-fed (rats pair-fed to the pectin group). They were sacrificed after 1 month. Pectin and pair-fed rats showed lower body weight gain and food intake than controls and underwent a decrease in leptin levels and an increase in adiponectin levels. Pectin-treated animals, but not pair-fed ones, showed lower body-fat content and HOMA-IR index after dietary intervention. Compared to controls, pectin-treated rats showed a decline in the expression of genes related to energy uptake (WAT) and lipogenesis (WAT and liver), and increased expression levels of lipolysis- and fatty-acid oxidation-related genes (liver). Some of the changes were not evidenced in the pair-fed group. These effects appear to be associated with improved leptin signaling.. Ten percent pectin supplementation for 1 month in adult rats decreases body-fat content and ameliorates age-related insulin and leptin resistance more intensely than what could be attributed to the decrease in energy intake, overall contributing to better metabolic health. Topics: Adipose Tissue, White; Aging; Animals; Body Composition; Body Weight; Dietary Fiber; Dietary Supplements; Eating; Gene Expression Regulation; Insulin Resistance; Leptin; Liver; Male; Pectins; Proteins; Rats, Wistar; Stomach | 2015 |
Concentrating carbohydrates before sleep improves feeding regulation and metabolic and inflammatory parameters in mice.
New evidance highlights the importance of food timing. Recently, we showed that a low-calorie diet with carbohydrates eaten mostly at dinner changed diurnal hormone secretion and led to greater weight loss and improved metabolic status in obese people. Herein, we set out to test whether concentrated-carbohydrates diet (CCD), in which carbohydrates are fed only before sleep, leads to an improved metabolic status in mouse hypothalamus and peripheral tissues. Diet-induced obese mice were given concentrated or distributed carbohydrate diet for 6 weeks. Obese mice fed CCD ate 8.3% less, were 9.3% leaner and had 39.7% less fat mass. Leptin, ghrelin and adiponectin displayed altered secretion. In addition, these mice exhibited an improved biochemical and inflammatory status. In the hypothalamus, anorexigenic signals were up-regulated and orexigenic signals were down-regulated. In peripheral tissues, CCD promoted adiponectin signaling, repressed gluconeogenesis, enhanced lipid oxidation and lowered inflammation, thus ameliorating the major risk factors of obesity. Topics: Adiponectin; Animals; Appetite Regulation; Body Weight; Dietary Carbohydrates; Disease Models, Animal; Feeding Behavior; Gene Expression Regulation; Ghrelin; Gluconeogenesis; Hypothalamus; Inflammation; Leptin; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Obesity; Sleep | 2015 |
Effects of prepartum fat supplementation on plasma concentrations of glucagon-like peptide-1, peptide YY, adropin, insulin, and leptin in periparturient dairy cows.
Dietary fat supplementation during the periparturient period is one strategy to increase energy intake and attenuate the degree of negative energy balance during early lactation; however, little is known of the underlying hormonal and metabolic adaptations. We evaluated the effects of prepartum fat supplementation on energy-balance parameters and plasma concentrations of glucagon-like peptide-1, peptide tyrosine-tyrosine (PYY), adropin, insulin, leptin, glucose, nonesterified fatty acid, and β-hydroxybutyric acid in dairy cows. Twenty-four pregnant dairy cows were randomized to diets containing either rolled canola or sunflower seed at 8% of dry matter, or no oilseed supplementation, during the last 5 wk of gestation and then assigned to a common lactation diet postpartum. Blood samples were collected at -2, +2, and +14 h relative to feeding, at 2 wk after the initiation of the diets, and at 2 wk postpartum. Dietary canola and sunflower supplementation alone did not affect energy balance, body weight, and plasma concentrations of glucagon-like peptide-1, PYY, adropin, insulin, leptin, nonesterified fatty acid, and β-hydroxybutyric acid; however, canola decreased and sunflower tended to decrease dry matter intake. We also observed that the physiological stage had a significant, but divergent, effect on circulating hormones and metabolite concentrations. Plasma glucagon-like peptide-1, PYY, adropin, nonesterified fatty acid, and β-hydroxybutyric acid concentrations were greater postpartum than prepartum, whereas glucose, insulin, leptin, body weight, and energy balance were greater prepartum than postpartum. Furthermore, the interaction of treatment and stage was significant for leptin and adropin, and tended toward significance for PYY and insulin; only insulin exhibited an apparent postprandial increase. Postpartum PYY concentrations exhibited a strong negative correlation with body weight, suggesting that PYY may be associated with body weight regulation during the transition period. These novel findings demonstrate that the transition from pregnancy to lactation is a stronger determinant of circulating gut hormone concentrations than dietary lipid in transition dairy cows. Topics: 3-Hydroxybutyric Acid; Animals; Blood Proteins; Body Weight; Cattle; Diet; Dietary Fats; Dietary Supplements; Dipeptides; Energy Intake; Energy Metabolism; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Hormones; Insulin; Lactation; Leptin; Peptide YY; Postpartum Period; Pregnancy; Random Allocation | 2015 |
The adipokine leptin mediates muscle- and liver-derived IGF-1 in aged mice.
Muscle- and liver-derived IGF-1 play important roles in muscle anabolism throughout growth and aging. Yet, prolonged food restriction is thought to increase longevity in part by lowering levels of IGF-1, which in turn reduces the risk for developing various cancers. The dietary factors that modulate IGF-1 levels are, however, poorly understood. We tested the hypothesis that the adipokine leptin, which is elevated with food intake and suppressed during fasting, is a key mediator of IGF-1 levels with aging and food restriction. First, leptin levels in peripheral tissues were measured in young mice fed ad libitum, aged mice fed ad libitum, and aged calorie-restricted (CR) mice. A group of aged CR mice were also treated with recombinant leptin for 10 days. Later, aged mice fed ad libitum were treated with saline (VEH) or with a novel leptin receptor antagonist peptide (Allo-aca) and tissue-specific levels of IGF-1 were determined. On one hand, recombinant leptin induced a three-fold increase in liver-derived IGF-1 and a two-fold increase in muscle-derived IGF-1 in aged, CR mice. Leptin also significantly increased serum growth hormone levels in the aged, CR mice. On the other, the leptin receptor antagonist Allo-aca did not alter body weight or muscle mass in treated mice compared to VEH mice. Allo-aca did, however, produce a significant (20%) decline in liver-derived IGF-1 as well as an even more pronounced (>50%) decrease in muscle-derived IGF-1 compared to VEH-treated mice. The reduced IGF-1 levels in Allo-aca treated mice were not accompanied by any significant change in growth hormone levels compared to VEH mice. These findings suggest that leptin receptor antagonists may represent novel therapeutic agents for attenuating IGF-1 signaling associated with aging, and could potentially mimic some of the positive effects of calorie restriction on longevity. Topics: Aging; Animals; Body Weight; Caloric Restriction; Eating; Growth Hormone; Insulin-Like Growth Factor I; Leptin; Liver; Longevity; Mice; Muscle, Skeletal; Peptides; Receptors, Leptin; Recombinant Proteins | 2015 |
Maternal obesity regulates gene expression in the hearts of offspring.
Growing evidence suggests maternal obesity leads to adverse outcomes for offspring, including increased cardiovascular disease (CVD). Alterations in taste preferences of offspring from mothers consuming a high fat diet (HFD) have also been reported. Given recent reports describing cardiac taste receptors, we examined whether the expression of umami and bitter taste receptors is modulated by maternal obesity, and compared this with the physiological challenge of maternal exercise.. Female Sprague-Dawley rats were fed chow (C) or HFD (F) and half of each were provided with a running wheel to enable voluntary exercise (CE or FE), the others remaining sedentary (CS or FS). Two pups from each mother were killed at postnatal day 19. Both lean and obese dams undertook similar amounts of exercise (8.1 ± 2.4 vs 5.1 ± 1.5 km). Maternal obesity increased offspring body weight, adiposity, net and weight-corrected heart ventricle weight, with no effect of exercise. Maternal obesity also increased offspring plasma leptin concentrations, which were normalised by maternal exercise. Cardiac ventricle mRNA expression of bitter taste receptors, β-adrenoceptor (Adrbk1) and angiotensin II receptor type 1a (Agtr1a) were significantly decreased in response to maternal obesity, with maternal exercise decreasing Agtr1a in FE offspring. No changes in umami receptors were observed. FTO mRNA expression was down-regulated by maternal HFD with an up-regulation in offspring of CE mothers.. Maternal obesity affected the expression of bitter taste receptors and other genes in the heart ventricle, potentially implicating these genes in the development of CVD associated with maternal obesity. Topics: Adiposity; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Body Weight; Diet; Diet, High-Fat; Down-Regulation; Female; Gene Expression; Heart Ventricles; Leptin; Maternal Nutritional Physiological Phenomena; Obesity; Physical Conditioning, Animal; Pregnancy; Proteins; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; RNA, Messenger; Up-Regulation | 2015 |
Gene expression profiling of hormonal regulation related to the residual feed intake of Holstein cattle.
An accumulation of over a decade of research in cattle has shown that genetic selection for decreased residual feed intake (RFI), defined as the difference between an animal's actual feed intake and its expected feed intake, is a viable option for improving feed efficiency and reducing the feed requirements of herds, thereby improving the profitability of cattle producers. Hormonal regulation is one of the most important factors in feed intake. To determine the relationship between hormones and feed efficiency, we performed gene expression profiling of jugular vein serum on hormonal regulation of Chinese Holstein cattle with low and high RFI coefficients. 857 differential expression genes (from 24683 genes) were found. Among these, 415 genes were up-regulated and 442 genes were down-regulated in the low RFI group. The gene ontology (GO) search revealed 6 significant terms and 64 genes associated with hormonal regulation, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) selected the adipocytokine signaling pathway, insulin signaling pathway. In conclusion, the study indicated that the molecular expression of genes associated with hormonal regulation differs in dairy cows, depending on their RFI coefficients, and that these differences may be related to the molecular regulation of the leptin-NPY and insulin signaling pathways. Topics: Adipokines; Animal Feed; Animals; Appetite Regulation; Body Weight; Cattle; Dairying; Eating; Female; Gene Expression Profiling; Gene Expression Regulation; Insulin; Leptin; Molecular Sequence Annotation; Neuropeptide Y; Signal Transduction | 2015 |
Cinnamon extract improves the body composition and attenuates lipogenic processes in the liver and adipose tissue of rats.
In models of metabolic disorders, cinnamon improves glucose and lipid metabolism. This study explores the effect of chronic supplementation with aqueous cinnamon extract (CE) on the lipid metabolism of rats. Male adult Wistar rats were separated into a control group (CTR) receiving water and a CE Group receiving aqueous cinnamon extract (400 mg of cinnamon per kg body mass per day) by gavage for 25 consecutive days. Cinnamon supplementation did not change the food intake or the serum lipid profile but promoted the following changes: lower body mass gain (P = 0.008), lower relative mass of white adipose tissue (WAT) compartments (P = 0.045) and higher protein content (percentage of the carcass) (P = 0.049). The CE group showed lower leptin mRNA expression in the WAT (P = 0.0017) and an important tendency for reduced serum leptin levels (P = 0.059). Cinnamon supplementation induced lower mRNA expression of SREBP1c (sterol regulatory element-binding protein 1c) in the WAT (P = 0.001) and liver (P = 0.013) and lower mRNA expression of SREBP2 (P = 0.002), HMGCoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase) (P = 0.0003), ACAT1 (acetyl-CoA acetyltransferase 1) (P = 0.032) and DGAT2 (diacylglycerol O-acyltransferase 2) (P = 0.03) in the liver. These changes could be associated with the reduced esterified cholesterol and triacylglycerol content detected in this tissue. Our results suggest that chronic ingestion of aqueous cinnamon extract attenuates lipogenic processes, regulating the expression of key enzymes and transcriptional factors and their target genes, which are directly involved in lipogenesis. These molecular changes possibly promote adaptations that would prevent an increase in circulating cholesterol and triacylglycerol levels and prevent lipid accumulation in tissues, such as liver and WAT. Therefore, we speculate that cinnamon may also be useful for preventing or retarding the development of lipid disorders. Topics: Acetyl-CoA C-Acetyltransferase; Adipose Tissue; Animals; Body Composition; Body Mass Index; Body Weight; Cholesterol; Cinnamomum zeylanicum; Diacylglycerol O-Acyltransferase; Hydroxymethylglutaryl CoA Reductases; Leptin; Lipogenesis; Liver; Male; Plant Extracts; Rats; Rats, Wistar; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Proteins; Triglycerides | 2015 |
The Gut Microbiota of Wild Mice.
The gut microbiota profoundly affects the biology of its host. The composition of the microbiota is dynamic and is affected by both host genetic and many environmental effects. The gut microbiota of laboratory mice has been studied extensively, which has uncovered many of the effects that the microbiota can have. This work has also shown that the environments of different research institutions can affect the mouse microbiota. There has been relatively limited study of the microbiota of wild mice, but this has shown that it typically differs from that of laboratory mice (and that maintaining wild caught mice in the laboratory can quite quickly alter the microbiota). There is also inter-individual variation in the microbiota of wild mice, with this principally explained by geographical location. In this study we have characterised the gut (both the caecum and rectum) microbiota of wild caught Mus musculus domesticus at three UK sites and have investigated how the microbiota varies depending on host location and host characteristics. We find that the microbiota of these mice are generally consistent with those described from other wild mice. The rectal and caecal microbiotas of individual mice are generally more similar to each other, than they are to the microbiota of other individuals. We found significant differences in the diversity of the microbiotas among mice from different sample sites. There were significant correlations of microbiota diversity and body weight, a measure of age, body-mass index, serum concentration of leptin, and virus, nematode and mite infection. Topics: Animals; Bacteroidetes; Body Weight; Cecum; Computational Biology; DNA, Bacterial; England; Female; Firmicutes; Gastrointestinal Microbiome; Geography; Intestine, Large; Intestines; Leptin; Male; Mice; Mites; Nematoda; Phylogeny; Viruses | 2015 |
A 72-hour high fat diet increases transcript levels of the neuropeptide galanin in the dorsal hippocampus of the rat.
Recent evidence identifies the hippocampus, a brain structure commonly associated with learning and memory, as key to the regulation of food intake and the development and consequences of obesity. Intake of a high fat diet (HFD) results in altered consumptive behavior, hippocampal damage, and cognitive deficits. While many studies report the effects of HFD after chronic consumption and in the instance of obesity, few examine the events that occur following acute HFD consumption. In this study, male rats were fed either a control diet (10% fat by kcal) or HFD (45% fat by kcal) for 72 h. At the end of the 72-h period, serum and tissues were collected and weighed. Brains were rapidly frozen or formalin-fixed in preparation for qRT-PCR or immunohistochemistry, respectively.. Acute intake of HFD resulted in higher serum levels of leptin and cholesterol, with no significant changes in final body weight or adipose tissue mass. In the dorsal hippocampus, transcription of the neuroprotective peptide galanin was significantly upregulated along with a trend for an increase in brain-derived neurotrophic factor and histone deacetylase 2 in the rats fed HFD. In the ventral hippocampus, there was a significant increase in histone deacetylase 4 and a decrease in galanin receptor 1 in this group. Results from immunohistochemistry validate strong presence of the galanin peptide in the CA1/CA2 region of the dorsal hippocampus.. These results provide evidence for a distinct response in specific functional regions of the hippocampus following acute HFD intake. Topics: Adipose Tissue; Animals; Body Weight; Cholesterol; Diet, High-Fat; Eating; Enzyme-Linked Immunosorbent Assay; Galanin; Gene Expression; Hippocampus; Immunohistochemistry; Leptin; Male; Organ Size; Rats, Long-Evans; Real-Time Polymerase Chain Reaction; Time Factors | 2015 |
High dietary protein decreases fat deposition induced by high-fat and high-sucrose diet in rats.
High-protein diets are known to reduce adiposity in the context of high carbohydrate and Western diets. However, few studies have investigated the specific high-protein effect on lipogenesis induced by a high-sucrose (HS) diet or fat deposition induced by high-fat feeding. We aimed to determine the effects of high protein intake on the development of fat deposition and partitioning in response to high-fat and/or HS feeding. A total of thirty adult male Wistar rats were assigned to one of the six dietary regimens with low and high protein, sucrose and fat contents for 5 weeks. Body weight (BW) and food intake were measured weekly. Oral glucose tolerance tests and meal tolerance tests were performed after 4th and 5th weeks of the regimen, respectively. At the end of the study, the rats were killed 2 h after ingestion of a calibrated meal. Blood, tissues and organs were collected for analysis of circulating metabolites and hormones, body composition and mRNA expression in the liver and adipose tissues. No changes were observed in cumulative energy intake and BW gain after 5 weeks of dietary treatment. However, high-protein diets reduced by 20 % the adiposity gain induced by HS and high-sucrose high-fat (HS-HF) diets. Gene expression and transcriptomic analysis suggested that high protein intake reduced liver capacity for lipogenesis by reducing mRNA expressions of fatty acid synthase (fasn), acetyl-CoA carboxylase a and b (Acaca and Acacb) and sterol regulatory element binding transcription factor 1c (Srebf-1c). Moreover, ketogenesis, as indicated by plasma β-hydroxybutyrate levels, was higher in HS-HF-fed mice that were also fed high protein levels. Taken together, these results suggest that high-protein diets may reduce adiposity by inhibiting lipogenesis and stimulating ketogenesis in the liver. Topics: 3-Hydroxybutyric Acid; Acetyl-CoA Carboxylase; Adipose Tissue; Adiposity; Animals; Blood Glucose; Body Composition; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Diet, High-Fat; Dietary Fats; Dietary Proteins; Dietary Sucrose; Energy Intake; Fatty Acid Synthases; Ghrelin; Glucose Tolerance Test; Hypothalamus; Leptin; Lipogenesis; Liver; Male; Muscle, Skeletal; Rats; Rats, Wistar; Sterol Regulatory Element Binding Protein 1; Triglycerides | 2015 |
Short term exendin-4 treatment reduces markers of metabolic disorders in female offspring of obese rat dams.
Maternal obesity imposes significant health risks in the offspring including diabetes and dyslipidemia. We previously showed that the hypoglycaemic agent exendin-4 (Ex-4) administered from weaning can reverse the maternal impact of 'transmitted disorders' in such offspring. However daily injection for six-weeks was required and the beneficial effect may lapse upon drug withdrawal. This study aimed to investigate whether short term Ex-4 treatment during suckling period in a rodent model can reverse transmitted metabolic disorders due to maternal obesity.. Maternal obesity was induced in female Sprague Dawley rats by high-fat diet feeding for 6 weeks, throughout gestation and lactation. Female offspring were treated with Ex-4 (5μg/kg/day) between postnatal day (P) 4 and 14. Female offspring were harvested at weaning (P20). Lipid and glucose metabolic markers were measured in the liver and fat. Appetite regulators were measured in the plasma and hypothalamus.. Maternal obesity significantly increased body weight, fat mass, and liver weight in the offspring. There was an associated inhibition of peroxisomal proliferator activated receptor gamma coactivator 1α (PGC1α), increased fatty acid synthase (FASN) expression in the liver, and reduced adipocyte triglyceride lipase (ATGL) expression. It also increased the plasma gut hormone ghrelin and reduced glucagon-like peptide-1. Ex-4 treatment partially reversed the maternal impact on adiposity and impaired lipid metabolism in the offspring, with increased liver PGC1α and inhibition of FASN mRNA expression. Ex-4 treatment also increased the expression of a novel fat depletion gene a2-zinc-glycoprotein 1 in the fat tissue.. Short term Ex-4 treatment during the suckling period significantly improved the metabolic profile in the offspring from the obese mothers at weaning. Long-term studies are needed to follow such offspring to adulthood to examine the sustained effects of Ex-4 in preventing the development of metabolic disease. Topics: Age Factors; Animals; Animals, Newborn; Biomarkers; Body Weight; Brain; Diet, High-Fat; Exenatide; Female; Gene Expression Regulation; Hypoglycemic Agents; Leptin; Liver; Male; Maternal Nutritional Physiological Phenomena; Metabolic Diseases; Obesity; Peptides; Pregnancy; Pregnancy Complications; Rats; Rats, Sprague-Dawley; Venoms | 2015 |
Lactation and appetite-regulating hormones: increased maternal plasma peptide YY concentrations 3-6 months postpartum.
Breast-feeding is associated with maternal hormonal and metabolic changes ensuring adequate milk production. In this study, we investigate the impact of breast-feeding on the profile of changes in maternal appetite-regulating hormones 3-6 months postpartum. Study participants were age- and BMI-matched lactating mothers (n 10), non-lactating mothers (n 9) and women without any history of pregnancy or breast-feeding in the previous 12 months (control group, n 10). During study sessions, young mothers breast-fed or bottle-fed their babies, and maternal blood samples were collected at five time points during 90 min: before, during and after feeding the babies. Outcome parameters were plasma concentrations of ghrelin, peptide YY (PYY), leptin, adiponectin, prolactin, cortisol, insulin, glucose and lipid values. At baseline, circulating PYY concentrations were significantly increased in lactating mothers (100·3 (se 6·7) pg/ml) v. non-lactating mothers (73·6 (se 4·9) pg/ml, P=0·008) and v. the control group (70·2 (se 9) pg/ml, P=0·021). We found no differences in ghrelin, leptin and adiponectin values. Baseline prolactin concentrations were over 4-fold higher in lactating mothers (P<0·001). Lactating women had reduced TAG levels and LDL-cholesterol:HDL-cholesterol ratio, but increased waist circumference, when compared with non-lactating women. Breast-feeding sessions further elevated circulating prolactin (P<0·001), but induced no acute effects on appetite-regulating hormones. In summary, one single breast-feeding session did not acutely modulate circulating appetite-regulating hormones, but increased baseline PYY concentrations are associated with prolonged lactation. PYY might play a role in the coordination of energy balance during lactation, increasing fat mobilisation from maternal depots and ensuring adequate milk production for the demands of the growing infant. Topics: Adiponectin; Adult; Appetite; Blood Glucose; Body Mass Index; Body Weight; Breast Feeding; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Female; Ghrelin; Humans; Hydrocortisone; Infant; Insulin; Lactation; Leptin; Peptide YY; Postpartum Period; Pregnancy; Prolactin; Triglycerides; Waist Circumference | 2015 |
Ameliorative effect of vanadyl(IV)-ascorbate complex on high-fat high-sucrose diet-induced hyperglycemia, insulin resistance, and oxidative stress in mice.
There is mounting evidence demonstrating causative links between hyperglycemia, oxidative stress, and insulin resistance, the core pathophysiological features of type 2 diabetes mellitus. Using a combinational approach, we synthesized a vanadium-antioxidant (i.e., l-ascorbic acid) complex and examined its effect on insulin resistance and oxidative stress. This study was designed to examine whether vanadyl(IV)-ascorbate complex (VOAsc) would reduce oxidative stress, hyperglycemia, and insulin resistance in high-fat high-sucrose diet (HFSD)-induced type 2 diabetes in mice. Male C57BL/6J mice were fed a HFSD for 12 weeks to induce insulin resistance, rendering them diabetic. Diabetic mice were treated with rosiglitazone, sodium l-ascorbate, or VOAsc. At the end of treatment, fasting blood glucose, fasting serum insulin, homeostasis model assessment-insulin resistance index, and serum adipocytokine levels were measured. Serum levels of nitric oxide (NO) parameters were also determined. The liver was isolated and used for determination of malondialdehyde, reduced glutathione, and catalase levels, and superoxide dismutase and glutathione peroxidase activities. VOAsc groups exhibited significant reductions in serum adipocytokine and NO levels, and oxidative stress parameters compared to the corresponding values in the untreated diabetic mice. The results indicated that VOAsc is non-toxic. In conclusion, we identified VOAsc as a potentially effective adjunct therapy for the management of type 2 diabetes. Topics: Adiponectin; Adipose Tissue; Animals; Ascorbic Acid; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Feeding Behavior; Glucose Tolerance Test; Homeostasis; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Liver; Male; Malondialdehyde; Mice, Inbred C57BL; Nitric Oxide; Organ Size; Oxidative Stress; Resistin; Sucrose; Tumor Necrosis Factor-alpha; Vanadates | 2015 |
A talk between fat tissue, gut, pancreas and brain to control body weight.
The incidence of obesity and its related disorders are increasing at a rate of pandemic proportions. Understanding the mechanisms behind the maintenance of energy balance is fundamental in developing treatments for clinical syndromes including obesity and diabetes. A neural network located in the nucleus of the solitary tract-area postrema complex in the hindbrain and the hypothalamus in the forebrain has long been implicated in the control of energy balance. In the hypothalamus this central neuronal network consists of small populations of nuclei with distinct functions such as the arcuate nucleus (ARH), the paraventricular nuclei of the hypothalamus (PVH), the dorsomedial (DMH), the ventromedial (VMH) and the lateral hypothalamus (LH). These hypothalamic areas form interconnected neuronal circuits that respond to fluctuations in energy status by altering the expression of neuropeptides, leading to changes in energy intake and expenditure. Regulation of these hypothalamic nuclei involves the actions of orexigenic peptides (ie ghrelin), which act to stimulate energy intake and decrease energy expenditure, and anorexigenic peptides (ie. leptin and insulin), which act to reduce energy intake and stimulate energy expenditure. Here we review the role of the ARH, DMH and PVH in the control of energy homeostasis and how recent advances in research technologies (Cre-loxP technology, optogenetics and pharmacogenetics) have shed light on the role of these hypothalamic nuclei in the control of energy balance. Such novel findings include the implication of ARH POMC and AgRP neurons in the browning of white adipose tissue to regulate energy expenditure as well as the likely existence of divergent hypothalamic pathways in the DMH and PVH in the control of food intake and energy expenditure. Topics: Adipose Tissue; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Brain; Dorsomedial Hypothalamic Nucleus; Energy Intake; Energy Metabolism; Humans; Hypothalamus; Leptin; Pancreas; Paraventricular Hypothalamic Nucleus | 2015 |
Role of leptin G-2548A polymorphism in age- and gender-specific development of obesity.
Leptin is involved in the regulation of food intake and energy expenditure, and therefore, is central to adipositysensing pathway. We examined the relationship of the leptin G-2548A polymorphism with obesity and obesityrelated anthropometric and metabolic parameters in a total of 394 (239 obese and 155 non-obese) subjects between 5 and 45 years of age. Body weight, height, waist circumference (WC), hip circumference (HC) and blood pressure (BP) were measured. Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated. Levels of fasting blood glucose (FBG), insulin, leptin and leptin receptor were determined, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The LEP G-2548A polymorphism showed association with obesity in children and adolescents (less than or equal to 18 years of age) but not in adults. However, analysis by gender stratification revealed association with obesity in girls only. In addition, G-2548A polymorphism showed association with BMI, WC, HC, fasting blood glucose and serum leptin levels. This suggests that G-2548A polymorphism may influence the susceptibility to metabolic disturbances and obesity at an early life. Further investigation with a larger sample size is required to validate the effect of LEP G-2548A polymorphism in obese Pakistani girls. Topics: Adolescent; Adult; Age Factors; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Receptors, Leptin; Sex Factors; Waist-Hip Ratio; Young Adult | 2015 |
Leptin Suppresses the Rewarding Effects of Running via STAT3 Signaling in Dopamine Neurons.
The adipose hormone leptin potently influences physical activity. Leptin can decrease locomotion and running, yet the mechanisms involved and the influence of leptin on the rewarding effects of running ("runner's high") are unknown. Leptin receptor (LepR) signaling involves activation of signal transducer and activator of transcription-3 (STAT3), including in dopamine neurons of the ventral tegmental area (VTA) that are essential for reward-relevant behavior. We found that mice lacking STAT3 in dopamine neurons exhibit greater voluntary running, an effect reversed by viral-mediated STAT3 restoration. STAT3 deletion increased the rewarding effects of running whereas intra-VTA leptin blocked it in a STAT3-dependent manner. Finally, STAT3 loss-of-function reduced mesolimbic dopamine overflow and function. Findings suggest that leptin influences the motivational effects of running via LepR-STAT3 modulation of dopamine tone. Falling leptin is hypothesized to increase stamina and the rewarding effects of running as an adaptive means to enhance the pursuit and procurement of food. Topics: Animals; Body Weight; Dopaminergic Neurons; Eating; Immunohistochemistry; Leptin; Mice; Mice, Knockout; Microscopy, Confocal; Motor Activity; Receptors, Leptin; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Ventral Tegmental Area | 2015 |
Effect of long-term olanzapine treatment on meal-induced insulin sensitization and on gastrointestinal peptides in female Sprague-Dawley rats.
Meal-induced insulin sensitization (MIS), an endogenous adaptive mechanism is activated post-prandially. Reduced MIS leads to diabetes, but its activation improves insulin sensitivity. MIS is preserved to single olanzapine administration, therefore we aimed to investigate the chronic effect of olanzapine on fasted-state insulin sensitivity and on MIS in female Sprague-Dawley rats. Daily food and water intake, stool and urine production and body weight were determined. The MIS was characterized by a rapid insulin sensitivity test. Fasting hepatic and peripheral insulin sensitivity were determined by a hyperinsulinaemic euglycaemic glucose clamping supplemented with radiotracer technique. Fasted and post-prandial blood samples were obtained for plasma insulin, leptin, ghrelin, amylin, GLP-1, GIP, PYY and PP determination. Adiposity was characterized by weighing intra-abdominal and inguinal fat pads. Olanzapine caused hepatic insulin resistance and a reduced metabolic clearance rate of insulin, but the MIS retained its function. Body weight and adiposity were enhanced, but olanzapine failed to increase food intake. Fasting insulin and leptin were elevated and the post-prandial reduction in ghrelin level was inhibited by olanzapine.The MIS remained functionally intact after long-term olanzapine treatment. Altered insulin, leptin and ghrelin levels indicate olanzapine-induced metabolic derangements. Pharmacological activation of MIS could potentially be exploited to treat or prevent olanzapine-induced insulin resistance. Topics: Animals; Benzodiazepines; Blood Glucose; Body Weight; Eating; Female; Gastrointestinal Hormones; Ghrelin; Insulin; Insulin Resistance; Leptin; Obesity; Olanzapine; Rats; Rats, Sprague-Dawley | 2015 |
Reduced metabolic disease risk profile by voluntary wheel running accompanying juvenile Western diet in rats bred for high and low voluntary exercise.
Metabolic disease risk is influenced by genetics and modifiable factors, such as physical activity and diet. Beginning at 6 weeks of age, rats selectively bred for high (HVR) versus low voluntary running distance (LVR) behaviors were housed in a complex design with or without voluntary running wheels being fed either a standard or Western (WD, 42% kcal from fat and added sucrose) diet for 8 weeks. Upon intervention completion, percent body fat, leptin, insulin, and mediobasal hypothalamic mRNAs related to appetite control were assessed. Wheel access led to differences in body weight, food intake, and serum leptin and insulin. Intriguingly, percent body fat, leptin, and insulin did not differ between HVR and LVR lines in response to the two levels of voluntary running, regardless of diet, after the 8 wk. experiment despite HVR eating more calories than LVR regardless of diet and voluntarily running 5-7 times further in wheels than LVR. In response to WD, we observed increases in Cart and Lepr mediobasal hypothalamic mRNA in HVR, but no differences in LVR. Npy mRNA was intrinsically greater in LVR than HVR, while wheel access led to greater Pomc and Cart mRNA in LVR versus HVR. These data suggest that despite greater consumption of WD, HVR animals respond similarly to WD as LVR as a result, in part, of their increased wheel running behavior. Furthermore, high physical activity in HVR may offset the deleterious effects of a WD on adiposity despite greater energy intake in this group. Topics: Animals; Animals, Outbred Strains; Body Composition; Body Weight; Diet, Western; Eating; Female; Gene-Environment Interaction; Hypothalamus; Insulin; Leptin; Motor Activity; Physical Conditioning, Animal; Rats, Wistar; RNA, Messenger; Running; Species Specificity; Volition | 2015 |
Paradoxical effects of partial leptin deficiency on bone in growing female mice.
Morbidly obese, leptin-deficient ob/ob mice display low bone mass, mild osteoclast-rich osteopetrosis, and increased bone marrow adiposity. While partial leptin deficiency results in increased weight, the skeletal manifestations of partial leptin deficiency are less well defined. We therefore analyzed femora and lumbar vertebrae in growing (7-week-old) female C57BL/6 wildtype (WT) mice, partial leptin-deficient ob/+ mice, and leptin-deficient ob/ob mice. The bones were evaluated by dual energy absorptiometry, microcomputed tomography and histomorphometry. As expected, ob/+ mice were heavier, had more white adipose tissue, and lower serum leptin than WT mice, but were lighter and had less white adipose tissue than ob/ob mice. With a few exceptions, cancellous bone architecture, cell (osteoblast, osteoclast, and adipocyte), and dynamic measurements did not differ between WT and ob/+ mice. In contrast, compared to WT and ob/+ mice, ob/ob mice had lower cancellous bone volume fraction, and higher bone marrow adiposity in the femur metaphysis, and higher cancellous bone volume fraction in lumbar vertebra. Paradoxically, ob/+ mice had greater femoral bone volume than either WT or ob/ob mice. There was a positive correlation between body weight and femur volume in all three genotypes. However, the positive effect of weight on bone occurred with lower body weight in leptin-producing mice. The paradoxical differences in bone size among WT, ob/+, and ob/ob mice may be explained if leptin, in addition to stimulating bone growth and cancellous bone turnover, acts to lower the set-point at which increased body weight leads to a commensurate increase in bone size. Topics: Adipose Tissue; Animals; Body Weight; Bone Density; Bone Marrow; Female; Femur; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese | 2015 |
Serum Adiponectin and Leptin Concentrations in Relation to Body Fat Distribution, Hematological Indices and Lipid Profile in Humans.
The purpose of the study was to evaluate the relationship between serum adiponectin and leptin concentrations and body composition, hematological indices and lipid profile parameters in adults. The study involved 95 volunteers (BMI from 23.3 to 53 kg/m²). Anthropometric parameters were measured: body weight and height, waist and hip circumference, waist-to-hip ratio, body fat mass (BMF), subcutaneous and visceral fat mass (SFM, VFM), lean body mass (LBM), skeletal muscle mass (SMM). In serum we determined adiponectin and leptin concentrations, extracellular hemoglobin, total bilirubin, as well as lipid metabolism (TCh, HDL-Ch, LDL-Ch, TG). Mean adipokine levels were significantly higher in women (p ≤ 0.01), adiponectin significantly negatively correlated with body height and weight, systolic blood pressure and absolute LBM and SMM values. The same relation was observed for erythroid system indicators and lipid indicators. A positive correlation was exceptionally found between adiponectin and HDL-Ch. LEP negatively correlated with some percentage rates (%LBM, %SMM). Only in women, we observed a positive correlation between LEP and body weight, BMI and WHR. Studies on ADPN and the ADPN/LEP ratio as a valuable complementary diagnostic element in the prediction and prevention of cardiovascular diseases need to be continued. Topics: Adiponectin; Adult; Anthropometry; Blood Pressure; Body Composition; Body Fat Distribution; Body Height; Body Weight; Cardiovascular Diseases; Female; Humans; Leptin; Lipids; Male; Middle Aged; Obesity; Sex Factors; Waist-Hip Ratio; Young Adult | 2015 |
Defense of Elevated Body Weight Setpoint in Diet-Induced Obese Rats on Low Energy Diet Is Mediated by Loss of Melanocortin Sensitivity in the Paraventricular Hypothalamic Nucleus.
Some animals and humans fed a high-energy diet (HED) are diet-resistant (DR), remaining as lean as individuals who were naïve to HED. Other individuals become obese during HED exposure and subsequently defend the obese weight (Diet-Induced Obesity- Defenders, DIO-D) even when subsequently maintained on a low-energy diet. We hypothesized that the body weight setpoint of the DIO-D phenotype resides in the hypothalamic paraventricular nucleus (PVN), where anorexigenic melanocortins, including melanotan II (MTII), increase presynaptic GABA release, and the orexigenic neuropeptide Y (NPY) inhibits it. After prolonged return to low-energy diet, GABA inputs to PVN neurons from DIO-D rats exhibited highly attenuated responses to MTII compared with those from DR and HED-naïve rats. In DIO-D rats, melanocortin-4 receptor expression was significantly reduced in dorsomedial hypothalamus, a major source of GABA input to PVN. Unlike melanocortin responses, NPY actions in PVN of DIO-D rats were unchanged, but were reduced in neurons of the ventromedial hypothalamic nucleus; in PVN of DR rats, NPY responses were paradoxically increased. MTII-sensitivity was restored in DIO-D rats by several weeks' refeeding with HED. The loss of melanocortin sensitivity restricted to PVN of DIO-D animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer-term changes in dietary energy density. These properties are consistent with a mechanism of body weight setpoint. Topics: alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Caloric Restriction; Diet; Dietary Fats; gamma-Aminobutyric Acid; Leptin; Melanocortins; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Ventromedial Hypothalamic Nucleus | 2015 |
Body fat loss induced by calcium in co-supplementation with conjugated linoleic acid is associated with increased expression of bone formation genes in adult mice.
The potential of conjugated linoleic acids (CLA) and calcium in weight management in animal models and human studies has been outlined, as well as their use to prevent bone loss at critical stages. In addition, it has been suggested that bone remodeling and energy metabolism are regulated by shared pathways and involve common hormones such as leptin. We have previously shown that supplementation with CLA and calcium in adult obese mice decreases body weight and body fat. The aim of the present study was to assess the effects of these two compounds on bone and energy metabolism markers on bone. Mice (C57BL/6J) were divided into five groups according to diet and treatment (up to 56 days): control (C), high-fat diet (HF), HF+CLA (CLA), HF+calcium (Ca) and HF with both compounds (CLA+Ca). At the end of treatment, bone formation markers were determined in plasma and expression of selected bone and energy markers was determined in tibia by quantitative polymerase chain reaction. Results show that CLA was associated with decreased tibia weight and minor impact on bone markers, whereas calcium, either alone or co-supplemented with CLA, maintained bone weight and promoted the expression of bone formation genes such as bone gamma-carboxyglutamate protein 2 (Bglap2) and collagen Iα1 (Col1a1). Furthermore, it had a significant effect on key players in energy metabolism, in particular leptin and adiponectin tibia receptors. Overall, in addition to the weight loss promoting properties of calcium, on its own or co-supplemented with CLA, our results support beneficial effects on bone metabolism in mice. Topics: Adiponectin; Adipose Tissue; Animals; Biomarkers; Blood Glucose; Body Weight; Bone and Bones; Calcium; Collagen Type I; Collagen Type I, alpha 1 Chain; Diet, High-Fat; Dietary Supplements; Gene Expression Regulation; Leptin; Linoleic Acids, Conjugated; Male; Mice; Mice, Inbred C57BL; Obesity; Osteocalcin; Osteogenesis; Receptors, Adiponectin; Receptors, Leptin; Tibia | 2015 |
Behavioral, hormonal and central serotonin modulating effects of injected leptin.
Leptin is viewed as an important target for developing novel therapeutics for obesity, depression/anxiety and cognitive dysfunctions. The present study therefore concerns behavioral, hormonal and central serotonin modulating effects of systemically injected leptin. Pharmacological doses (100 and 500 μg/kg) of leptin injected systemically decreased 24h cumulative food intake and body weight in freely feeding rats and improved acquisition and retention of memory in Morris water maze test. Potential anxiety reducing, hormonal and serotonin modulating effects of the peptide hormone were determined in a separate experiment. Animals injected with 100 or 500 μg/kg leptin were tested for anxiety in an elevated plus maze test 1h later. A significant increase in the number of entries and time passed in open arm of the elevated plus maze in leptin injected animals suggested pronounced anxiety reducing effect. Moreover, circulating levels of leptin correlated significantly with anxiety reducing effects of the peptide hormone. Serum serotonin increased and ghrelin decreased in leptin injected animals and correlated, positively and negatively respectively, with circulating leptin. Corticosterone increased at low dose and levels were normal at higher dose. Serotonin metabolism in the hypothalamus and hippocampus decreased only at higher dose of leptin. The results support a role of leptin in the treatment of obesity, anxiety and cognitive dysfunctions. It is suggested that hormonal and serotonin modulating effects of leptin can alter treatment efficacy in particularly comorbid conditions. Topics: Animals; Anxiety; Behavior, Animal; Body Weight; Eating; Ghrelin; Hypothalamus; Injections; Leptin; Male; Memory; Rats; Rats, Wistar; Serotonin | 2015 |
Excessive eccentric exercise leads to transitory hypothalamic inflammation, which may contribute to the low body weight gain and food intake in overtrained mice.
Low body weight gain and food intake are related to exhaustive training and overtraining; however, the molecular mechanisms responsible for these alterations remain unknown. The main aim of this study was to evaluate the effects of running overtraining (OT) protocols performed downhill, uphill and without inclination on the inflammatory pathway in the mouse hypothalamus. The rodents were randomized into the control (C), overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up) and overtrained by running without inclination (OTR) groups. The body weights and food intake were recorded daily. The incremental load, exhaustive, rotarod and grip force tests were used to measure performance. At 36 h after the grip force test was performed at the end of OT protocols (i.e., week eight) and/or after a 2-week total recovery period (i.e., week 10), the hypothalamus and gastrocnemius were extracted for immunoblotting analysis. In addition, the serum was used to determine cytokine and leptin concentrations. From week 0 to week 8, the OTR/down group exhibited decreased body weight and food intake, and the OTR/up group increased their food intake. At week 10, the OTR/down group exhibited increased body weight, while the OTR group decreased their food intake. The OTR/down group exhibited increased IL-1beta, IL-6, TNF-alpha, pSAPK/JNK and SOCS3 levels at week eight. The OTR/down, OTR/up and OTR groups exhibited increased IL-10 levels at week 10. The OTR/up group displayed increased pJAK2 levels at week eight. While the OTR/down group exhibited increased IL-1beta levels, the OTR/down and OTR/up groups exhibited increased IL-6 and TNF-alpha levels, but decreased IL-10 levels in the gastrocnemius at week eight. The three OT protocols increased the IL-1beta and IL-6 levels, but only the OTR/down and OTR/up groups had increased TNF-alpha levels in serum at week eight. The serum leptin levels were lower for the OTR group compared with the CT group at week eight. In conclusion, the OTR/down protocol induced transitory hypothalamic inflammation with concomitant reductions in the body weight and food intake. After the 2-week total recovery period, the OTR/down group had reversed the hypothalamic inflammation, with the concomitant normalization of the body weight and food intake. Topics: Animals; Body Weight; Cytokines; Eating; Hand Strength; Hypothalamus; Inflammation; Leptin; Male; Mice, Inbred C57BL; Motor Activity; Muscle, Skeletal; Random Allocation; Rotarod Performance Test; Running; Sedentary Behavior | 2015 |
Hypothalamic leptin gene therapy reduces body weight without accelerating age-related bone loss.
Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related cancellous bone loss. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature (9 months old) female rats and determined the impact of leptin-induced weight loss on bone mass, density, and microarchitecture, and serum biomarkers of bone turnover (CTx and osteocalcin). Rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either recombinant adeno-associated virus encoding the gene for rat leptin (rAAV-Leptin, n=7) or a control vector encoding green fluorescent protein (rAAV-GFP, n=10) and sacrificed 18 weeks later. A baseline control group (n=7) was sacrificed at vector administration. rAAV-Leptin-treated rats lost weight (-4±2%) while rAAV-GFP-treated rats gained weight (14±2%) during the study. At study termination, rAAV-Leptin-treated rats weighed 17% less than rAAV-GFP-treated rats and had lower abdominal white adipose tissue weight (-80%), serum leptin (-77%), and serum IGF1 (-34%). Cancellous bone volume fraction in distal femur metaphysis and epiphysis, and in lumbar vertebra tended to be lower (P<0.1) in rAAV-GFP-treated rats (13.5 months old) compared to baseline control rats (9 months old). Significant differences in cancellous bone or biomarkers of bone turnover were not detected between rAAV-Leptin and rAAV-GFP rats. In summary, rAAV-Leptin-treated rats maintained a lower body weight compared to baseline and rAAV-GFP-treated rats with minimal effects on bone mass, density, microarchitecture, or biochemical markers of bone turnover. Topics: Animals; Body Weight; Bone Density; Female; Genetic Therapy; Hypothalamus; Insulin-Like Growth Factor I; Leptin; Obesity; Rats; Rats, Sprague-Dawley; Weight Loss | 2015 |
Overweight, hypertension and cardiovascular disease: focus on adipocytokines, insulin, weight changes and natriuretic peptides.
Hypertension is one of the leading causes of cardiovascular disease (CVD) worldwide. Overweight and obesity are major risk factors for hypertension. The mechanisms linking these two diseases are incompletely understood, but abnormalities in several different pathways including insulin and glucose metabolism, inflammation, the sympathetic nervous system and the renin-angiotensin-aldosterone system have been known for decades. Lately, the attention has shifted toward the endocrine function of adipose tissue, which among others secrete adiponectin, leptin and interleukin-6 (IL-6), which stimulates liver CRP production. These substances have all been regarded as candidate intermediates between adiposity and the development of hypertension. Furthermore, the so-called "natriuretic handicap" which characterizes obesity, has also attracted a great deal of attention as a possible pathway. Primary hypotheses: • The adipocytokines, adiponectin, leptin and CRP (used as a surrogate marker of IL-6) are independently associated with prevalent and incident hypertension. • Five-year weight changes associate with BP alterations, even after adjustment for changes in lifestyle risk factors and serum insulin. • NT-proBNP (used as a surrogate marker of active BNP) is positively associated with prevalent hypertension, but negatively associated with incident hypertension. • The adipocytokines, adiponectin, leptin and CRP (used as a surrogate marker of IL-6), are independently associated with incident CVD. . The Inter99 study provided data for this thesis. In brief, Inter99 is a randomized, non-pharmacological intervention study for the prevention of ischemic heart disease. The study included approximately 6,700 participants from the background population, who were thoroughly examined at baseline. Various measurements, including blood samples, were done at baseline and five-year follow-up. Data about cardiovascular events were gathered from national registers. . Paper I: In the prevalent model including leptin, CRP, adiponectin, sex, age, lifestyle risk factors, lipids, insulin, haemoglobin A1c, and in the incident model which also included baseline heart rate and blood pressure, only leptin of the three candidate intermediates was significantly associated with both prevalent and incident hypertension. Paper II: Five-year weight changes were associated with blood pressure alterations and had a substantial impact on both fasting and two-hour post-glucose serum insulin levels. However, in multivariable regression analyses, additional adjustments for insulin values only attenuated the associations between weight changes and blood pressure minimally. Paper III: Higher serum concentrations of NT-proBNP associated with prevalent hypertension whereas lower concentrations associated with incident hypertension. Paper IV: Among 6,502 participants with a mean follow-up time of 11.4 years, 527 participants experienced one or multiple cardio-vascular events. Among adiponectin, leptin and CRP, only CRP were significantly positive associated with CVD in all models. . Regarding the pathophysiology of overweight-related hypertension and CVD, our results indicate that: • Leptin is possibly an independent risk factor for the development of hypertension. • Albeit weight loss improves insulin-profile, the effect of insulin on blood pressure changes seems minimal, indicating that insulin does not play a major direct role in the early development of hypertension. • A deficiency of the natriuretic peptides, resulting in reduced vasodilation and natriuresis, could be involved in the pathogenesis of hypertension in its early stages. • Since adjustment for CRP decreased the BMI-associated CVD risk markedly, our data indirectly suggest that IL-6 originating from fat tissue could play a role in overweight and obesity-related cardiovascular disease. Topics: Adipokines; Adiponectin; Biomarkers; Blood Pressure; Body Weight; C-Reactive Protein; Cardiovascular Diseases; Humans; Hypertension; Insulin; Interleukin-6; Leptin; Natriuretic Peptides; Obesity; Risk Factors | 2015 |
Role of leptin in body temperature regulation and lipid metabolism following splenectomy.
The physiological changes in serum triglycerides and body temperature that are induced by splenectomy are poorly understood. Therefore, the aim of this study was to investigate parameters related to lipid and glucose metabolism, as well as thermoregulation, in splenectomized mice.. Splenectomized and sham-operated WT mice (C57Bl/6) and ob/ob mice were randomly divided and treated with a standard or high fat diet, and several metabolic parameters and the body temperature were investigated.. Splenectomy induced a significant increase in triglyceride levels regardless of the diet. It was found that the splenectomized WT mice showed greater serum leptin and insulin levels compared with the sham-operated mice. Additionally, the body temperatures of the splenectomized WT mice were greater than the body temperatures of the control animals regardless of diet; this result too was observed without any significant change in the temperature of the splenectomized ob/ob animals.. The results suggest that splenectomy interferes with serum triglyceride metabolism and body temperature regardless of the fat content in the diet and that leptin is involved in the regulation of body temperature related to splenectomy. Topics: Adipose Tissue; Animals; Body Temperature Regulation; Body Weight; Diet, High-Fat; Eating; Glucose; Insulin; Leptin; Mice; Mice, Inbred C57BL; Spleen; Splenectomy; Triglycerides | 2015 |
Long-term, calorie-restricted intake of a high-fat diet in rats reduces impulse control and ventral striatal D2 receptor signalling - two markers of addiction vulnerability.
High impulsivity, mediated through ventral striatal dopamine signalling, represents an established risk factor for substance abuse, and may likewise confer vulnerability to pathological overeating. Mechanistically, the assumption is that trait impulsivity facilitates the initiation of maladaptive eating styles or choices. However, whether consumption of appetitive macronutrients themselves causes deficits in impulse control and striatal signalling, thereby contributing to cognitive changes permissive of overeating behaviour, has yet to be considered. We examined the effects of chronic maintenance on restricted equicaloric, but high-fat or high-sugar, diets (48 kcal/day; 60 kcal% fat or sucrose) on rats' performance in the five-choice serial reaction time task, indexing impulsivity and attention. Markers of dopamine signalling in the dorsal and ventral striatum, and plasma insulin and leptin levels, were also assessed. Rats maintained on the high-fat diet (HFD) were more impulsive, whereas the high-sugar diet (HSD) did not alter task performance. Importantly, body weight and hormone levels were similar between groups when behavioural changes were observed. Maintenance on HFD, but not on HSD, reduced the levels of dopamine D2 receptor (D2 R), cAMP response element-binding protein (CREB) and phosphophorylated CREB (Ser133) proteins in the ventral, but not dorsal, striatum. D2 R expression in the ventral striatum also negatively correlated with impulsive responding, independently of diet. These data indicate that chronic exposure to even limited amounts of high-fat foods may weaken impulse control and alter neural signalling in a manner associated with vulnerability to addictions - findings that have serious implications for the propagation of uncontrolled eating behaviour in obesity and binge-eating disorder. Topics: Animals; Attention; Blood Chemical Analysis; Body Weight; Cyclic AMP Response Element-Binding Protein; Diet, High-Fat; Diet, Reducing; Dietary Sucrose; Enzyme-Linked Immunosorbent Assay; Executive Function; Immunoblotting; Impulsive Behavior; Inhibition, Psychological; Insulin; Leptin; Male; Motor Activity; Rats, Long-Evans; Receptors, Dopamine D2; Time Factors; Ventral Striatum | 2015 |
Corn Gluten Hydrolysate Affects the Time-Course of Metabolic Changes Through Appetite Control in High-Fat Diet-Induced Obese Rats.
This study first investigated the effects of corn gluten hydrolysate (CGH) (1.5 g/day) administration for 7 days on appetite-responsive genes in lean Sprague-Dawley (SD) rats. In a second set of experiments, the metabolic changes occurring at multiple time points over 8 weeks in response to CGH (35.33% wt/wt) were observed in high-fat (HF, 60% of energy as fat) diet-fed SD rats. In lean rats, the hypothalamus neuropeptide-Y and proopiomelanocortin mRNA levels of the CGH group were significantly changed in response to CGH administration. In the second part of the study, CGH treatment was found to reduce body weight and perirenal and epididymal fat weight. CGH also prevented an increase in food intake at 2 weeks and lowered plasma leptin and insulin levels in comparison with the HF group. This reduction in the plasma and hepatic lipid levels was followed by improved insulin resistance, and the beneficial metabolic effects of CGH were also partly related to increases in plasma adiponectin levels. The Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR), an index of insulin resistance, was markedly improved in the HF-CGH group compared with the HF group at 6 weeks. According to the microarray results, adipose tissue mRNA expression related to G-protein coupled receptor protein signaling pathway and sensory perception was significantly improved after 8 weeks of CGH administration. In conclusion, the present findings suggest that dietary CGH may be effective for improving hyperglycemia, dyslipidemia and insulin resistance in diet-induced obese rats as well as appetite control in lean rats. Topics: Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Eating; Glutens; Insulin; Leptin; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; Zea mays | 2015 |
Leptin and the Regulation of Food Intake and Body Weight.
Topics: Adipose Tissue; Appetite Regulation; Body Weight; Eating; Humans; Leptin; Obesity | 2015 |
Prawn Shell Chitosan Has Anti-Obesogenic Properties, Influencing Both Nutrient Digestibility and Microbial Populations in a Pig Model.
The potential of natural products to prevent obesity have been investigated, with evidence to suggest that chitosan has anti-obesity effects. The current experiment investigated the anti-obesity potential of prawn shell derived chitosan on a range of variables relevant to obesity in a pig model. The two dietary treatment groups included in this 63 day study were: T1) basal diet and T2) basal diet plus 1000 ppm chitosan (n = 20 gilts per group (70 ± 0.90 kg). The parameter categories which were assessed included: performance, nutrient digestibility, serum leptin concentrations, nutrient transporter and digestive enzyme gene expression and gut microbial populations. Pigs offered chitosan had reduced feed intake and final body weight (P< 0.001), lower ileal digestibility of dry matter (DM), gross energy (GE) (P< 0.05) and reduced coefficient of apparent total tract digestibility (CATTD) of gross energy and nitrogen (P<0.05) when compared to the basal group. Fatty acid binding protein 2 (FABP2) gene expression was down-regulated in pigs offered chitosan (P = 0.05) relative to the basal diet. Serum leptin concentrations increased (P< 0.05) in animals offered the chitosan diet compared to pigs offered the basal diet. Fatness traits, back-fat depth (mm), fat content (kg), were significantly reduced while lean meat (%) was increased (P<0.05) in chitosan supplemented pigs. Pigs offered chitosan had decreased numbers of Firmicutes in the colon (P <0.05), and Lactobacillus spp. in both the caecum (P <0.05) and colon (P <0.001). Bifidobacteria populations were increased in the caecum of animals offered the chitosan diet (P <0.05). In conclusion, these findings suggest that prawn shell chitosan has potent anti-obesity/body weight control effects which are mediated through multiple biological systems in vivo. Topics: Animal Shells; Animals; Body Weight; Chitosan; Dietary Supplements; Disease Models, Animal; Eating; Gastrointestinal Tract; Leptin; Microbiota; Nephropidae; Obesity; Swine | 2015 |
Evidence of male hypogonadism at an early age as a familial risk of type 2 diabetes.
Previous investigations provide evidence of an association of hypogonadism with type 2 diabetes in men, and low testosterone levels have been regarded a risk factor for the disease. Since a strong genetic predisposition to type 2 diabetes has been demonstrated, here we investigate a possible tendency towards hypogonadism in young male offspring of diabetic parents.. The study compares 32 male offspring of diabetic parents with 31 male offspring of nondiabetic parents matched by age. The subjects comprised boys (9-17 years) and young adults (19-25 years). Anthropomorphic measurements were made in all subjects. Fasting blood samples were analyzed for glucose and serum concentrations of testosterone (T), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), insulin and leptin were measured by ELISA. Free testosterone (FT) was calculated using T and SHBG levels.. Serum T, FT and bioavailable T (BAT) levels in offspring of diabetic parents were significantly lower than those of offspring of nondiabetic parents across all age groups. Mean serum LH levels were also lower in offspring of diabetic parents compared to the controls. Although LH levels in young adults with diabetic parents, tended to be lower than those of age-matched controls but the difference was not statistically significant. Serum insulin and leptin, and insulin resistance measured by HOMA-IR were significantly raised in older offspring of diabetic parents but were within the normal range.. Whereas hypogonadism was the only indicator of a possible predisposition to metabolic dysfunction in peripubertal children of diabetic parents, a significant change in other metabolic markers becomes apparent at a more advanced age. Topics: Adolescent; Adult; Blood Glucose; Body Mass Index; Body Weight; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Eunuchism; Family; Fasting; Humans; Insulin; Insulin Resistance; Leptin; Luteinizing Hormone; Male; Prospective Studies; Risk Factors; Sex Hormone-Binding Globulin; Testosterone; Young Adult | 2015 |
[Relationships between serum Ghrelin and body composition and lipid metabolism-related cytokines among 591 adult Chinese from 3 Provinces].
To describe the relationships between serum Ghrelin and body composition and lipid metabolism-related cytokines among Chinese adults.. A total of 591 adults younger than 60 years were selected from urban and rural areas of Liaoning, Henan and Hunan Provinces. Height, body weight, waist circumference, hip circumference, body mass index (BMI), waist-hip ratio (WHR), body fat percentage (% BF), blood lipid, serum leptin, Ghrelin and Ca were measured in all samples.. The mean serum Ghrelin concentration in males was 24.12 μg/L and in females 23.62 μg/L. There were no significant differences between different genders. With the increasing concentration in serum Ghrelin, a significant decreasing trend (P < 0.05) was found in waist circumference, BMI, WHR, overweight/obesity rates, central obesity rates, BF%, TC, TG, LDL-C and serum leptin. A significant increasing trend (P < 0.05) was found in HDL-C and ApoA1/ApoB, and no significant change in hip circumference and serum Ca were found. Correlations showed that there was a significant correlation among serum Ghrelin, BMI, waist circumference, WHR, BF%, TC, LDL-C and leptin (P < 0.05).. Serum Ghrelin level correlates strongly with body composition and lipid metabolism-related cytokines, and can have a more closely associations with BF% and leptin. Topics: Adult; Apolipoprotein A-I; Asian People; Body Composition; Body Mass Index; Body Weight; Cytokines; Female; Ghrelin; Humans; Leptin; Lipid Metabolism; Lipids; Male; Obesity; Waist Circumference; Waist-Hip Ratio | 2015 |
Mimecan, a Hormone Abundantly Expressed in Adipose Tissue, Reduced Food Intake Independently of Leptin Signaling.
Adipokines such as leptin play important roles in the regulation of energy metabolism, particularly in the control of appetite. Here, we describe a hormone, mimecan, which is abundantly expressed in adipose tissue. Mimecan was observed to inhibit food intake and reduce body weight in mice. Intraperitoneal injection of a mimecan-maltose binding protein (-MBP) complex inhibited food intake in C57BL/6J mice, which was attenuated by pretreatment with polyclonal antibody against mimecan. Notably, mimecan-MBP also induced anorexia in A(y)/a and db/db mice. Furthermore, the expression of interleukin (IL)-1β and IL-6 was up-regulated in the hypothalamus by mimecan-MBP, as well as in N9 microglia cells by recombinant mouse mimecan. Taken together, the results suggest that mimecan is a satiety hormone in adipose tissue, and that mimecan inhibits food intake independently of leptin signaling by inducing IL-1β and IL-6 expression in the hypothalamus. Topics: Adipose Tissue; Animals; Body Weight; Eating; Gene Expression; Humans; Hypothalamus; Intercellular Signaling Peptides and Proteins; Interleukin-1beta; Interleukin-6; Leptin; Mice; Mice, Knockout; Microglia; Rats; Signal Transduction | 2015 |
Ficus carica leaf extract modulates the lipid profile of rats fed with a high-fat diet through an increase of HDL-C.
Ficus carica has been traditionally used for the treatment of several metabolic syndrome-related health problems. It was the objective of this study to investigate the preventive effects of a Ficus carica (FC) leaf extract on hyperlipidemia in high fat diet (HFD)-induced obese male rats. Male Sprague-Dawley rats (180-200 g) were fed with a regular diet, HFD or a HFD + oral treatment of either 50 mg/kg or 100 mg/kg of FC or 30 mg/kg pioglitazone for six weeks. A range of parameters was evaluated including body weight development, plasma levels of total cholesterol, triglycerides (TG), low-density-lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), adiponectin, leptin, glucose, insulin, interleukin-6 (IL-6), atherogenic index (AI) and the coronary risk index (CRI). FC significantly lowered TG and IL-6 levels and elevated HDL cholesterol (p < 0.05). The effects of FC on lipid parameters were more pronounced than those of the positive control pioglitazone. FC significantly lowered AI and CRI (p < 0.01) while it had no effect on adiponectin and leptin levels. Our results demonstrate that preventive treatment with FC significantly improved the lipid profile and decreased adipogenic risk factors in HFD rats most likely mediated through an increase in HDL-C levels. Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Diet, High-Fat; Ficus; Hyperlipidemias; Insulin; Interleukin-6; Leptin; Male; Obesity; Pioglitazone; Plant Extracts; Plant Leaves; Rats; Rats, Sprague-Dawley; Thiazolidinediones; Triglycerides | 2014 |
Predictors of body composition and body energy changes in response to chronic overfeeding.
We have previously shown that 24 young lean men (12 pairs of identical twins) subjected to a standardized 353 MJ (84 000 kcal) overfeeding protocol over 100 days exhibited individual differences in body weight and composition gains. The mean (+s.d.) gains in fat mass (FM) and fat-free mass (FFM) were 5.4+1.9 kg and 2.7+1.5 kg for a total body energy (BE) gain of 221+75 MJ, representing 63% of the energy surplus consumed. We report here on the most important baseline correlates of these overfeeding-induced changes with the aim of identifying biomarkers of the response.. Baseline maximal oxygen uptake per kg body mass was negatively correlated with gains in weight, FM and BE (all P<0.05). Enzyme activities indicative of skeletal muscle oxidative potential correlated with gains in FM and BE (all P<0.05). Baseline thyroid-stimulating hormone levels in response to thyrotropin-releasing hormone stimulation correlated positively with changes in FM-to-FFM ratio (P<0.05). Plasma concentrations of androstenediol sulfate, dehydroepiandrosterone and 17-hydroxy pregnenolone were negatively correlated with gains in FM and BE (0.01 Topics: Adiponectin; Adipose Tissue; Adult; Basal Metabolism; Biomarkers; Blood Glucose; Body Composition; Body Mass Index; Body Weight; Energy Intake; Energy Metabolism; Glucose Tolerance Test; Humans; Insulin Resistance; Leptin; Male; Muscle, Skeletal; Overnutrition; Predictive Value of Tests; Sedentary Behavior; Twins, Monozygotic | 2014 |
Hypoadiponectinaemia in nonalcoholic fatty liver disease obese women is associated with infrequent intake of dietary sucrose and fatty foods.
The present study aimed to investigate the relationship between adiponectinaemia and food intake among obese women with nonalcoholic fatty liver disease (NAFLD).. In total, 60 obese women were examined by abdominal ultrasound for liver steatosis and subcutaneous and visceral adiposity. A standard interview (including questions about alcohol intake, medical history and physical activity), a physical examination (including height, weight, body mass index, waist and hip circumferences, waist-to-hip ratio, and body composition) and biochemical and clinical parameters (including serum glucose and insulin, homeostatic model assessment insulin resistance, lipid profile, aminotransferases, C-reactive protein, adiponectin, leptin, resistin, tumour necrosis factor-α, interleukin-6 levels and blood pressure) were performed. Food intake was evaluated by a qualitative food frequency questionnaire.. Twenty-four NAFLD patients and thirty-six controls were analysed. The Mann-Whitney test showed lower adiponectin levels in the liver disease group compared to controls (P < 0.05). The Pearson correlation coefficient indicated that adiponectinaemia was negatively correlated with lipid profile and serum tumour necrosis factor-α (P = 0.05) and was positively associated with adiposity measures and serum leptin (P < 0.05). By simple linear regression, all of these variables predicted serum adiponectin levels. Chi-squared and Fisher's exact tests indicated that, in both groups, food intake showed no differences, although sucrose and fatty foods were associated with lower adiponectin levels in the liver disease group (P < 0.05 and P < 0.05, respectively), as well as in the control group (P = 0.05 and P < 0.05, respectively).. Hypoadiponectinaemia in NAFLD was associated with dietary sucrose and fatty food intake, emphasising the important role of diet in the occurrence of this disease. Topics: Adiponectin; Adult; Blood Glucose; Blood Pressure; Body Composition; Body Height; Body Mass Index; Body Weight; C-Reactive Protein; Dietary Fats; Dietary Sucrose; Female; Humans; Insulin; Insulin Resistance; Interleukin-6; Leptin; Linear Models; Non-alcoholic Fatty Liver Disease; Obesity; Resistin; Transaminases; Tumor Necrosis Factor-alpha; Waist Circumference; Waist-Hip Ratio; Young Adult | 2014 |
The anti-obesity effects of the dietary combination of fermented red ginseng with levan in high fat diet mouse model.
In this study, to evaluate the anti-obesity effects of fermented red ginseng (FG), levan (L), and their combination (FGL), we investigated their effects on the weights of body, liver and white adipose tissue, lipid profiles, and biomarkers for insulin resistance in high fat diet (HFD)-induced obese C57BL/6J male mice. Furthermore, the levels of leptin in the serum were measured. FG (150 mg/kg/d), L (100 mg/kg/d), and FGL (150 mg/kg/d of FG plus 100 mg/kg/d of L) were administered orally to mice daily for 11 weeks. After 11 weeks feeding, FGL showed significantly lower body weight and fat mass with decreasing food efficiency ratio than the HFD control mice. In addition, the FGL group was significantly lower in the levels of total cholesterol and fasting blood glucose and score of the homeostatic model assessment of insulin resistance. Furthermore, FGL decreased serum leptin levels compared to the HFD control group. Taken together, FGL showed a significant anti-obesity effect in HFD-induced obese mice and prevent insulin and leptin resistance. FGL may be potentially useful for the prevention of obesity. Topics: Adipose Tissue, White; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; Disease Models, Animal; Fermentation; Fructans; Hyperlipidemias; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Panax; Plant Extracts | 2014 |
Altered gastric vagal mechanosensitivity in diet-induced obesity persists on return to normal chow and is accompanied by increased food intake.
Gastric vagal afferents convey satiety signals in response to mechanical stimuli. The sensitivity of these afferents is decreased in diet-induced obesity. Leptin, secreted from gastric epithelial cells, potentiates the response of vagal afferents to mechanical stimuli in lean mice, but has an inhibitory effect in high-fat diet (HFD)-induced obese mice. We sought to determine whether changes in vagal afferent function and response to leptin in obesity were reversible by returning obese mice consuming a HFD to standard laboratory chow diet (SLD).. Eight-week-old female C57BL/6 mice were either fed a SLD (N=20) or HFD (N=20) for 24 weeks. A third group was fed a HFD for 12 weeks and then a SLD for a further 12 weeks (RFD, N=18). An in vitro gastro-oesophageal vagal afferent preparation was used to determine the mechanosensitivity of gastric vagal afferents and the modulatory effect of leptin (0.1-10 nM) was examined. Retrograde tracing and quantitative RT-PCR were used to determine the expression of leptin receptor (LepR) messenger RNA (mRNA) in whole nodose and specific cell bodies traced from the stomach.. After 24 weeks, both the HFD and RFD mice had increased body weight, gonadal fat mass, plasma leptin, plasma insulin and daily energy consumption compared with the SLD mice. The HFD and RFD mice had reduced tension receptor mechanosensitivity and leptin further inhibited responses to tension in HFD, RFD but not SLD mice. Mucosal receptors from both the SLD and RFD mice were potentiated by leptin, an effect not seen in HFD mice. LepR expression was unchanged in the whole nodose, but was reduced in the mucosal afferents of the HFD and RFD mice.. Disruption of gastric vagal afferent function by HFD-induced obesity is only partially reversible by dietary change, which provides a potential mechanism preventing maintenance of weight loss. Topics: Afferent Pathways; Animals; Body Weight; Diet, High-Fat; Energy Intake; Feeding Behavior; Female; Gastric Mucosa; Immunohistochemistry; Leptin; Mice; Mice, Inbred C57BL; Obesity; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Thinness; Vagus Nerve; Weight Gain | 2014 |
Leptin and ghrelin levels in colostrum, milk and blood plasma of sows and pig neonates during the first week of lactation.
Radioimmunology was used to determine leptin and ghrelin levels in sow colostrum and milk in relation to those in sow and neonatal pig blood plasma and to the body weight of piglets during the first week of lactation. The highest concentration of leptin was found in colostrum on the second day of lactation (69.3 ± 6.3 ng/mL). Leptin concentrations in sow plasma were significantly lower than in colostrum/milk (2.19 ± 0.9 ng/mL, P = 0.7692) and were stable in the first 7 days of lactation. Total and active ghrelin concentrations in colostrum/milk were stable in the measured time points (6734 ± 261 pg/mL, P = 0.3397; 831 ± 242 pg/mL, P = 0.3988, respectively). Total ghrelin concentrations in sow plasma were lower than in colostrum/milk. These results indicate that pigs follow a unique species-specific pattern of leptin and ghrelin synthesis, release and existence, and that the mammary gland is an important source of leptin and ghrelin contained in colostrum/milk. Topics: Animals; Animals, Newborn; Body Weight; Colostrum; Female; Ghrelin; Lactation; Leptin; Mammary Glands, Animal; Milk; Radioimmunoassay; Species Specificity; Swine | 2014 |
High cortisol responses identify propensity for obesity that is linked to thermogenesis in skeletal muscle.
Subjects characterized as cortisol high responders (HRs) consume more calories after stress, but it is unknown whether cortisol responsiveness predicts a propensity for obesity. Female sheep with either high or low cortisol responses to adrenocorticotropin (ACTH) were identified. Body composition was similar in HRs and cortisol low responders (LRs), but the HRs had greater (P<0.01) adiposity than did the LRs (40.5±0.7 vs. 35.8±1.4%) after high-energy feeding, despite comparable food intake. Postprandial thermogenesis in muscle temperature was 0.8 ± 0.08°C higher in the LRs than in the HRs (P<0.01), whereas feeding-induced changes in fat temperature were similar. Leptin and insulin sensitivity were similar in the HRs and LRs. Feeding lowered (P<0.001) the respiratory control ratio in muscle (HRs 9.2±0.8-5.2±1.2; LRs 8.4±0.5-5.2±0.7), indicative of increased uncoupled respiration. Also in muscle, the feeding-induced increases in uncoupling protein (UCP)-3 (fold increase: HRs, 2.4; LRs, 2.0), ryanodine 1 receptor (RyR1; fold increase: HRs 3.1; LRs 2.1), and sarcoendoplasmic reticulum Ca(2+)-dependent ATPase (fold increase: HRs 1.5; LRs 1.6) were equivalent in the HRs and LRs. Sequencing of mitochondrial DNA revealed no haplotypic differences between the 2 groups. We conclude that predisposition to obesity can be predicted by cortisol responsiveness to an ACTH challenge and that the response is due to innate differences in muscle thermogenesis. Topics: Animals; Blotting, Western; Body Composition; Body Weight; Energy Metabolism; Female; Hydrocortisone; Hypothalamo-Hypophyseal System; Leptin; Muscle, Skeletal; Obesity; Pituitary-Adrenal System; Real-Time Polymerase Chain Reaction; Sheep; Thermogenesis | 2014 |
Dietary linoleic acid elevates the endocannabinoids 2-AG and anandamide and promotes weight gain in mice fed a low fat diet.
Dietary intake of linoleic acid (LNA, 18:2n-6) has increased dramatically during the 20th century and is associated with greater prevalence of obesity. The endocannabinoid system is involved in regulation of energy balance and a sustained hyperactivity of the endocannabinoid system may contribute to obesity. Arachidonic acid (ARA, 20:4n-6) is the precursor for 2-AG and anandamide (AEA), and we sought to determine if low fat diets (LFD) could be made obesogenic by increasing the endocannabinoid precursor pool of ARA, causing excessive endocannabinoid signaling leading to weight gain and a metabolic profile associated with obesity. Mice (C57BL/6j, 6 weeks of age) were fed 1 en% LNA and 8 en% LNA in low fat (12.5 en%) and medium fat diets (MFD, 35 en%) for 16 weeks. We found that increasing dietary LNA from 1 to 8 en% in LFD and MFD significantly increased ARA in phospholipids (ARA-PL), elevated 2-AG and AEA in liver, elevated plasma leptin, and resulted in larger adipocytes and more macrophage infiltration in adipose tissue. In LFD, dietary LNA of 8 en% increased feed efficiency and caused greater weight gain than in an isocaloric reduction to 1 en% LNA. Increasing dietary LNA from 1 to 8 en% elevates liver endocannabinoid levels and increases the risk of developing obesity. Thus a high dietary content of LNA (8 en%) increases the adipogenic properties of a low fat diet. Topics: Adipose Tissue; Analysis of Variance; Animals; Arachidonic Acids; Body Weight; Diet; Diet, Fat-Restricted; Endocannabinoids; Erythrocytes; Fatty Acids; Glycerides; Leptin; Linoleic Acid; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Obesity; Phospholipids; Polyunsaturated Alkamides; Risk Factors; Weight Gain | 2014 |
Obesity induced a leptin-Notch signaling axis in breast cancer.
To investigate whether obesity induces a leptin-Notch signaling axis in breast cancer (BC), leptin-induced Notch was determined in human MCF-7 and MDA-MB231 and mouse E0771 cells and in E0771-BC hosted by syngeneic lean and diet-induced obesity (DIO) C57BL/6J female mice. Lean and DIO mice were treated for 3 weeks with leptin inhibitor (PEG-LPrA2) 1 week after the inoculation of E0771 cells. Leptin induced Notch1, 3 and 4 in BC cells, but Notch2 expression showed opposite pattern in MCF-7 compared to MDA-MB231 cells. Notch loss-of-function (DAPT and dominant negative [R218H] RBP-Jk [CSL/CBF1]) showed that a functional leptin-Notch signaling axis was involved in the proliferation and migration of E0771 cells. E0771-BC onset was affected by obesity (lean mice7/10 [70%] vs. DIO mice: 11/12 [92%]; Pearson χ(2) : p = 0.06]). PEG-LPrA2 significantly reduced BC growth (untreated: 19/42; [45%] vs. treated: 8/42 [19%]; Pearson χ(2) : p = 0.008). PEG-LPrA2 did not influence the caloric intake of mice but increased carcass and/or body weights of lean and DIO mice inoculated with E0771 cells, which could be related to the improvement of health conditions (less aggressive disease). Importantly, BC from obese mice had higher levels of Notch3, JAG1 and survivin than lean mice. Inhibition of leptin signaling reduced protein levels of Notch (NICD1, NICD4, Notch3, JAG1 and survivin) and significantly decreased mRNA expression of Notch receptors, ligands and targets. PEG-LPrA's effects were more prominent in DIO mice. Present data suggest that leptin induces Notch, which could be involved in the reported higher incidence and aggressiveness and, poor prognosis of BC in obese patients. Topics: Animals; Body Weight; Breast Neoplasms; Calcium-Binding Proteins; Cell Growth Processes; Cell Line, Tumor; Cell Movement; Female; Humans; Inhibitor of Apoptosis Proteins; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Leptin; MCF-7 Cells; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Receptors, Notch; Repressor Proteins; Serrate-Jagged Proteins; Signal Transduction; Survivin | 2014 |
Pegylated leptin antagonist with strong orexigenic activity in mice is not effective in chickens.
A chicken gene orthologous to human leptin receptor (LEPR) has been characterized and found to be active in leptin signaling in vitro in response to a variety of recombinant leptins and leptin-containing blood samples. However, the endogenous ligand of chicken LEPR (cLEPR) - the putative chicken leptin - has been reported by us and others to be undetectable at the DNA, mRNA, protein and activity levels. These reports have raised questions as to cLEPR's role. Here we analyzed the effects of a pegylated superactive mouse leptin antagonist (PEG-SMLA) in chicken. We showed that the leptin antagonist efficiently and specifically blocks leptin signaling through the cLEPR in vitro. The effect of the leptin antagonist was then studied in vivo by daily administration of 10 mg kg(-1) for 10 consecutive days to white leghorn female chickens (Gallus gallus) at the age of 2 weeks. Despites the efficient attenuation of the cLEPR in vitro, no effect was observed on body mass, feed intake, feed efficiency or fat accumulation in the treated birds. Because similar treatment in rodents leads to a highly pronounced increase in appetite and body mass that are observed from the first day of treatment, it is concluded that the cLEPR is not implicated in the control of appetite or adipose homeostasis in chickens. Topics: Animals; Body Weight; Chickens; Eating; Fats; Female; HEK293 Cells; Humans; Leptin; Male; Mice; Receptors, Leptin; Signal Transduction | 2014 |
Enteral leptin administration affects intestinal autophagy in suckling piglets.
Leptin has been shown to play an integral role in the endocrine regulation of metabolism. Moreover, a substantial amount of this peptide has been found in colostrum and milk. The aim of the study was to investigate the effects of exogenous leptin, administered intragastrically, on the process of autophagy and the changes in cell hyperplasia and hypertrophy in the small intestine mucosa. Three groups (n = 6) of neonatal piglets were used in the study. The pigs were fed either by their sows (sow-reared piglets) or with only milk formula, or with milk formula together with leptin administered via a stomach tube (10 μg/kg BW) every 8 h for 6 d. We have shown that pure milk formula feeding significantly elevates (P < 0.05) autophagy compared with that observed in sow-reared piglets. Compared with the control group, feeding milk formula supplemented with leptin resulted in a significant decrease (P < 0.05) in immunodetection of microtubule-associated protein 1 light chain 3, as well as significantly accelerated epithelial cell renewal (P < 0.05). We demonstrated that autophagy is involved in the remodeling of the small intestine mucosa and that leptin, when administered enterally, may be an important factor for its regulation. Topics: Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Animals, Suckling; Autophagy; Body Weight; Epithelial Cells; Female; Immunohistochemistry; In Situ Nick-End Labeling; Intestinal Mucosa; Intestine, Small; Leptin; Microscopy, Confocal; Microtubule-Associated Proteins; Random Allocation; Statistics, Nonparametric; Swine | 2014 |
Comparison between placental gene expression of 11β-hydroxysteroid dehydrogenases and infantile growth at 10 months of age.
The local expression of two isoenzymes of 11β-hydroxysteroid dehydrogenase, type 1 (11βHSD-1) and type 2 (11βHSD-2), regulates the access of glucocorticoid hormones to their target cells. Reports on the association between the placental expression of 11βHSD and infantile growth are limited. The aim of the present study was to investigate if the placental gene expression of 11βHSD affects infantile growth at 10 months of age.. Placentas and umbilical venous cord blood were obtained from 42 singleton cases of cesarean deliveries between 31 and 40 weeks of gestation at Hamamatsu University Hospital between March 2009 and June 2010. The gene expression of both 11βHSD-1 and 11βHSD-2 was measured by quantitative reverse transcription polymerase chain reaction. Adiponectin and leptin levels in umbilical cord blood were measured using enzyme-linked immunoassay.. 11βHSD-1 and 11βHSD-2 gene expression in human placentas did not correlate with bodyweight or the ponderal index (PI) at 10 months of age, whereas the gene expression of 11βHSD-1, but not 11βHSD-2, correlated with birthweight as well as PI at birth. Adiponectin levels in umbilical cord blood significantly correlated with the placental gene expression of 11βHSD-1 as well as bodyweight and PI at 10 months of age, although no direct correlation was observed between them.. No direct correlation was observed between the placental gene expression of 11βHSD and infantile growth at 10 months of age. However, the placental gene expression of 11βHSD-1 may be indirectly connected with infantile growth via adiponectin-associated metabolic regulation represented by adiponectin levels in umbilical cord blood. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; Adiponectin; Adult; Body Weight; Child Development; Female; Fetal Blood; Gene Expression; Gestational Age; Humans; Hydrocortisone; Infant; Leptin; Middle Aged; Placenta; Pregnancy; RNA, Messenger; Time Factors; Young Adult | 2014 |
Attenuated pain response of obese mice (B6.Cg-lep(ob)) is affected by aging and leptin but not sex.
Genetically obese mice (B6.Cg-lep(ob)) manifest decreased responses to noxious thermal stimuli (hotplate test) suggesting endogenous analgesia (Roy et al., 1981). To examine further the analgesic response of these mice, we conducted 4 experiments. Experiment 1 assessed the response of ob/ob mice to tail flick, another noxious thermal test. Tail-flick testing was performed on B6.Cg-lep(ob) mice (n=14) and B6.Cg-lep(OB/?) (n=12) across a range of temperatures. Ob/ob mice exhibited longer latencies than control mice at all temperatures tested. In Experiment 2, potential sex differences were examined. Tail-flick latencies in male and female ob/ob mice (n=6/group) did not differ. The final 2 experiments examined factors that could modulate endogenous analgesia. Experiment 3 assessed the effects of aging in ob/ob mice (n=10/group). Older mice displayed longer tail-flick latencies than did younger mice. Experiment 4 examined the effect of leptin administration in the leptin-deficient ob/ob mice. Two groups (n=10/group) of ob/ob mice received osmotic pump implants filled with either leptin or vehicle, and were tail-flick tested at days 7 and 14 post-implantation. Ob/ob mice receiving leptin showed shorter latencies than did vehicle-receiving ob/ob mice. Taken together, these results support earlier reports of heightened analgesia in ob/ob mice and suggest that aging further reduces the already impaired pain response. Furthermore, leptin deficiency partially contributes to decreased pain sensation of ob/ob mice. Topics: Aging; Analysis of Variance; Animals; Body Weight; Drinking; Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pain; Pain Measurement; Reaction Time | 2014 |
Hormones and diet, but not body weight, control hypothalamic microglial activity.
The arcuate nucleus (ARC) of the hypothalamus plays a key role in sensing metabolic feedback and regulating energy homeostasis. Recent studies revealed activation of microglia in mice with high-fat diet (HFD)-induced obesity (DIO), suggesting a potential pathophysiological role for inflammatory processes within the hypothalamus. To further investigate the metabolic causes and molecular underpinnings of such glial activation, we analyzed the microglial activity in wild-type (WT), monogenic obese ob/ob (leptin deficient), db/db (leptin-receptor mutation), and Type-4 melanocortin receptor knockout (MC4R KO) mice on either a HFD or on standardized chow (SC) diet. Following HFD exposure, we observed a significant increase in the total number of ARC microglia, immunoreactivity of ionized calcium binding adaptor molecule 1 (iba1-ir), cluster of differentiation 68 (CD68-ir), and ramification of microglial processes. The ob/ob mice had significantly less iba1-ir and ramifications. Leptin replacement rescued these phenomena. The db/db mice had similar iba1-ir comparable with WT mice but had significantly lower CD68-ir and more ramifications than WT mice. After 2 weeks of HFD, ob/ob mice showed an increase of iba1-ir, and db/db mice showed increase of CD68-ir. Obese MC4R KO mice fed a SC diet had comparable iba1-ir and CD68-ir with WT mice but had significantly more ramifications than WT mice. Intriguingly, treatment of DIO mice with glucagon-like peptide-1 receptor agonists reduced microglial activation independent of body weight. Our results show that diet type, adipokines, and gut signals, but not body weight, affect the presence and activity levels of hypothalamic microglia in obesity. Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Body Weight; Cytokinins; Diet, High-Fat; Disease Models, Animal; Exenatide; Hormones; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Obesity; Peptides; Receptor, Melanocortin, Type 4; Receptors, Interleukin-8A; Receptors, Leptin; Signal Transduction; Supraoptic Nucleus; Venoms | 2014 |
Effect of peripherally administered leptin antagonist on whole body metabolism and bone microarchitecture and biomechanical properties in the mouse.
Leptin's in vivo effect on the rodent skeleton depends on the model used and the mode of administration. Superactive mouse leptin antagonist (SMLA) was produced and then pegylated (PEG) to prolong and enhance its in vivo activity. We blocked leptin signaling by injecting this antagonist peripherally into normal mice at various time points and studied their metabolic and skeletal phenotypes. Subcutaneous PEG-SMLA injections into 4-wk-old female C57BL/6J mice increased weight gain and food consumption significantly after only 1 mo, and the effect lasted for the 3 mo of the experiment, proving its central inhibiting activity. Mice showed a significant increase in serum glucose, cholesterol, triglycerides, insulin, and HOMA-IR throughout the experiment. Quantification of gene expression in "metabolic" tissues also indicated the development of insulin resistance. Bone analyses revealed a significant increase in trabecular and cortical parameters measured in both the lumbar vertebrae and tibiae in PEG-SMLA-treated mice in the 1st and 3rd months as well as a significant increase in tibia biomechanical parameters. Interestingly, 30 days of treatment with the antagonist in older mice (aged 3 and 6 mo) affected body weight and eating behavior, just as they had in the 1-mo-old mice, but had no effect on bone parameters, suggesting that leptin's effect on bones, either directly or through its obesogenic effect, is dependent upon stage of skeletal development. This potent and reversible antagonist enabled us to study leptin's in vivo role in whole body and bone metabolism and holds potential for future therapeutic use in diseases involving leptin signaling. Topics: Animals; Biomechanical Phenomena; Blood Glucose; Body Weight; Bone and Bones; Cholesterol; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Female; Gene Expression; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Metabolism; Mice; Mice, Inbred C57BL; Triglycerides | 2014 |
Effects of smoking cessation on β-cell function, insulin sensitivity, body weight, and appetite.
To stop smoking is commonly associated with significant weight gain, but the mechanisms for this are poorly understood. We assessed the effects of smoking cessation on body weight, insulin sensitivity, β-cell function, and appetite.. Twenty-seven long-term smokers (n=27; nine females/18 males, 28±1 years, 22.9±0.6 kg/m(2)) attending an ambulatory smoking cessation program in a community hospital in Vienna, Austria were examined at baseline (Visit A; still smoking) and after a minimum of 3 months of smoking abstinence (Visit B; n=14); relapsed smokers were not followed up. Participants underwent 3-h oral glucose tolerance tests and body composition measurements at each study visit. Fasting (QUICKI) and dynamic (oral glucose insulin sensitivity (OGIS)) insulin sensitivity and β-cell secretion (insulinogenic index 140 (IGI40)) were calculated. Food intake was quantified with a free choice buffet. Fasting plasma concentrations of neuropeptide-Y (NPY), peptide-YY (PYY), glucagon-like peptide 1 (GLP1), leptin, ghrelin, and visfatin were measured.. AFTER 3 MONTHS' SMOKING ABSTINENCE, BODY WEIGHT, AND FAT MASS WERE INCREASED (+4 AND +22% RESPECTIVELY, P0.05) AND FASTING INSULIN SENSITIVITY DETERIORATED (QUICKI: post, 0.37±0.02 vs baseline, 0.41±0.2; P<0.05), while OGIS remained unchanged throughout. IGI40 increased by 31% after >3 months' smoking abstinence (P<0.01). Carbohydrate ingestion increased after stopping smoking (P<0.05). NPY fasting levels were increased after >3 months (P<0.05), PYY, GLP1, leptin, ghrelin, and visfatin were unchanged.. Smoking cessation is associated with transient metabolic changes including increased β-cell secretion in response to glucose and fasting insulin resistance. These alterations may be associated with or contribute to the body weight gain after smoking cessation. Topics: Adult; Appetite; Body Weight; Eating; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Male; Neuropeptide Y; Peptide YY; Smoking Cessation | 2014 |
Changes in central and peripheral inflammatory responses to lipopolysaccharide in ovariectomized female rats.
Obesity leads to increases in inflammatory responses in a site-specific manner. Ovariectomized animals, usually used as menopause models, exhibit obesity; however, their inflammatory responses have not been fully examined. In the present study, we investigated whether ovariectomy had site-specific effects on inflammatory responses. First, fever and anorectic responses to systemic injections of lipopolysaccharide (LPS) (500μg/kg, i.p.) were compared between ovariectomized rats (OVX) and sham-operated female rats (Sham). Inflammatory cytokines at the central and peripheral levels were also compared under saline-injected and LPS-injected conditions. Body weight in OVX was significantly higher than in Sham. The anorectic responses (reduction of body weight and food intake) to LPS were higher in OVX than in Sham. In the hypothalamus, all of the examined cytokine (IL-1β, TNF-α and IL-6) mRNA levels in OVX were higher than in Sham under the LPS-injected condition. On the other hand, in serum and adipose tissue, only IL-6, not IL-1β and TNF-α, levels in OVX were significantly higher than those in Sham under the LPS-injected condition. Second, responses to central (intracerebroventricular) injections of LPS (500ng) were compared between OVX and Sham. The result was that the fever response in OVX was more evident than in Sham. Finally, responses to systemic injections of LPS (500μg/kg, i.p.) were compared between OVX (OVX-oil) and OVX with estradiol (E) and progesterone (P) supplementation (OVX-EP). The anorectic responses and hypothalamic cytokine mRNA levels under LPS-injected condition were not different between OVX-oil and OVX-EP. These results indicate that ovariectomy enhances inflammatory responses, especially at the central level compared with the peripheral level. As supplementation of E and P could not attenuate the anorectic and cytokine responses to LPS, the deficiency of gonadal steroids might not be directly involved in the increase of inflammatory responses in OVX. Topics: Adipose Tissue; Animals; Body Weight; Estradiol; Female; Inflammation; Interleukin-1beta; Interleukin-6; Leptin; Lipopolysaccharides; Obesity; Ovariectomy; Progesterone; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tumor Necrosis Factor-alpha | 2014 |
Isolation during the prepubertal period associated with chronic access to palatable diets: effects on plasma lipid profile and liver oxidative stress.
Pre-puberty is a critical period for the final maturation of the neural circuits that control energy homeostasis, as external stimuli such as exposure to diets and stress may influence the adaptive responses with long-term repercussions. Our aim is to investigate the effects of isolation stress during early life and of chronic access to palatable diets, rich in sugar or fat, on the metabolic profile (glycemia, plasma lipids, leptin and cholinesterase activity) and oxidative stress parameters in the livers of adult male rats. We observed changes mainly in animals that received the high-fat diet (increased body weight and abdominal fat in adults, as well as increased plasma glucose, and cholinesterase activity), and most of these effects were further increased by exposure to stress. High-fat diet also affected the rats' lipid profile (increased cholesterol, LDL-cholesterol and triglycerides); these effects were more marked in stressed animals. Additionally, exposure to stress led to an oxidative imbalance in the liver, by increasing production of reactive species, as well as the activity of antioxidant enzymes (superoxide dismutase and catalase); these effects were accentuated with the high-fat diet (which also caused a severe reduction in glutathione peroxidase activity). Taken together, these results show that the pre-pubertal period constitutes a critical window for stressful interventions during development, leading to alterations in metabolic parameters and increased oxidative stress during adulthood that may be more pronounced in animals that receive a high-fat diet. Topics: Abdominal Fat; Adrenal Glands; Aging; Animals; Blood Glucose; Body Weight; Catalase; Cholinesterases; Dietary Fats; Dietary Sucrose; Eating; Energy Intake; Free Radicals; Glutathione Peroxidase; Leptin; Lipids; Liver; Male; Organ Size; Oxidative Stress; Rats; Social Isolation; Sulfhydryl Compounds; Superoxide Dismutase | 2014 |
Circannual body reserve dynamics and metabolic profile changes in Romane ewes grazing on rangelands.
Throughout an entire year, 41 Romane ewes reared in an extensive rangeland were used to investigate temporal changes in body reserves (BRs) and profiles of related metabolites and metabolic hormones. Ewes were allocated to homogeneous groups according to BW and BCS and were distributed by parity (primiparous [PRIM], n = 21; multiparous [MULT], n = 20) and litter size (LSi; lambing singletons [SING], n = 21 or TWINS, n = 20). The feeding system was based on rotational grazing of rangeland paddocks and progressive supplementation with hay, silage, and barley at late pregnancy during the winter. Individual BW, BCS, plasma NEFA, β-hydroxybutyrate (β-OHB), glucose, insulin, leptin, and triiodothyronine (T3) were monitored at -56, -12, 8, 49, 76, 107, 156, 195, 216, 246, and 301 d relative to lambing. The BR mobilization was observed from late pregnancy to the end of suckling and varied as a function of the ewe energy balance but also because of transitions from fertilized to native rangeland paddocks and by supplementation. Contrarily, BR accretion occurred from weaning, during the dry-off, and until the start of the next pregnancy. Lipolysis was well reflected by NEFA, β-OHB, and T3 kinetics. Mean BW (but not mean BCS) was affected by parity (MULT > PRIM), whereas both BW and BCS were influenced by LSi (SING > TWINS) but only for MULT. The most drastic BW loss was observed during the mid-suckling period (49 d in milk [DIM]) in all ewes. The lack of effects of LSi in PRIM but not in MULT was also evident in the majority of blood plasma kinetics, which were affected (P < 0.0001) by physiological stage in all ewes. A tendency to ketosis (β-OHB) was found in ewes nursing TWINS around lambing, irrespective of parity. Glucose concentrations were greater during suckling and dry-off, and a peak (0.96 ± 0.05 g/L) was attained at 156 DIM in MULT nursing TWINS. The highest plasma leptin concentration was observed during the start and the middle of the next pregnancy in MULT (107-216 DIM; 9.6 ± 0.44 ng/mL). In all ewes the physiological stage affected T3, which was affected by LSi just in MULT (from late pregnancy, MULT by SING > MULT by TWINS; 99.91 vs 85.52 ng/dL) and during suckling (111.7 ± 4.18 ng/dL). Lamb BW was affected at birth and weaning by parity (MULT > PRIM) and LSi (SING > TWINS). Overall, temporal changes in BR were directly affected by the transition of physiological states and feeding levels, whereas individual responses were predetermined by parity. In Topics: 3-Hydroxybutyric Acid; Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Blood Glucose; Body Weight; Fatty Acids, Nonesterified; Female; Insulin; Least-Squares Analysis; Leptin; Metabolome; Nutritional Status; Pregnancy; Random Allocation; Sheep; Triiodothyronine | 2014 |
Metformin inhibits skin tumor promotion in overweight and obese mice.
In the present study, the ability of metformin to inhibit skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) was analyzed in mice maintained on either an overweight control diet or an obesity-inducing diet. Rapamycin was included for comparison, and a combination of metformin and rapamycin was also evaluated. Metformin (given in the drinking water) and rapamycin (given topically) inhibited development of both papillomas and squamous cell carcinomas in overweight and obese mice in a dose-dependent manner. A low-dose combination of these two compounds displayed an additive inhibitory effect on tumor development. Metformin treatment also reduced the size of papillomas. Interestingly, all treatments seemed to be at least as effective for inhibiting tumor formation in obese mice, and both metformin and rapamycin were more effective at reducing tumor size in obese mice compared with overweight control mice. The effect of metformin on skin tumor development was associated with a significant reduction in TPA-induced epidermal hyperproliferation. Furthermore, treatment with metformin led to activation of epidermal AMP-activated protein kinase (AMPK) and attenuated signaling through mTOR complex (mTORC)-1 and p70S6K. Combinations of metformin and rapamycin were more effective at blocking epidermal mTORC1 signaling induced by TPA consistent with the greater inhibitory effect on skin tumor promotion. Collectively, the current data demonstrate that metformin given in the drinking water effectively inhibited skin tumor promotion in both overweight and obese mice and that the mechanism involves activation of epidermal AMPK and attenuated signaling downstream of mTORC1. Topics: Adenylate Kinase; Adiponectin; Animals; Body Weight; Carcinogenesis; Carcinoma, Squamous Cell; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Insulin; Insulin-Like Growth Factor I; Leptin; Mechanistic Target of Rapamycin Complex 1; Metformin; Mice; Mice, Obese; Multiprotein Complexes; Neoplasms, Experimental; Obesity; Overweight; Papilloma; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Skin Neoplasms; Tetradecanoylphorbol Acetate; TOR Serine-Threonine Kinases | 2014 |
High-fat diet induces site-specific unresponsiveness to LPS-stimulated STAT3 activation in the hypothalamus.
Hypophagia induced by inflammation is associated with Janus kinase (JAK)-2/signal transducer and activator of transcription (STAT) 3 signaling pathway, and leptin-mediated hypophagia is also mediated by JAK2-STAT3 pathway. We have previously reported that lipopolysaccharide (LPS) did not reduce food intake in leptin-resistant high-fat diet (HFD) rats but maintained body weight loss. We investigated whether changes in p-STAT3 expression in the hypothalamus and brain stem could account for the desensitization of hypophagia in HFD animals after a low LPS dose (100 μg/kg). Wistar rats fed standard diet (3.95 kcal/g) or HFD (6.3 kcal/g) for 8 wk were assigned into control diet-saline, control diet-LPS, HFD-saline, and HFD-LPS groups. LPS reduced feeding in the control diet but not HFD. This group showed no p-STAT3 expression in the paraventricular nucleus (PVN) and ventromedial hypothalamic nucleus (VMH), but sustained, though lower than control, p-STAT3 in the nucleus of the solitary tract (NTS) and raphe pallidus (RPa). LPS decreased body weight in HFD rats and increased Fos expression in the NTS. LPS increased body temperature, oxygen consumption, and energy expenditure in both control diet and HFD rats, and this response was more pronounced in HFD-LPS group. Brown adipose tissue (BAT) thermogenesis and increased energy expenditure seem to contribute to body weight loss in HFD-LPS. This response might be related with increased brain stem activation. In conclusion, LPS activates STAT3-mediated pathway in the hypothalamus and brain stem, leading to hypophagia, however, LPS effects on food intake, but not body weight loss, are abolished by leptin resistance induced by HFD. The preserved STAT3 phosphorylation in the brain stem suggests that unresponsiveness to LPS on STAT3 activation under HFD might be selective to the hypothalamus. Topics: Animals; Body Weight; Diet, High-Fat; Dietary Fats; Eating; Hypothalamus; Leptin; Lipopolysaccharides; Male; Rats; Rats, Wistar; Signal Transduction; STAT3 Transcription Factor | 2014 |
The effect of puberty on fat oxidation rates during exercise in overweight and normal-weight girls.
Excess weight is often associated with insulin resistance (IR) and may disrupt fat oxidation during exercise. This effect is further modified by puberty. While studies have shown that maximal fat oxidation rates (FOR) during exercise decrease with puberty in normal-weight (NW) and overweight (OW) boys, the effect of puberty in NW and OW girls is unclear. Thirty-three NW and OW girls ages 8-18 yr old completed a peak aerobic capacity test on a cycle ergometer. FOR were calculated during progressive submaximal exercise. Body composition and Tanner stage were determined. For each participant, a best-fit polynomial curve was constructed using fat oxidation vs. exercise intensity to estimate max FOR. In a subset of the girls, IR derived from an oral glucose tolerance test (n = 20), and leptin and adiponectin levels (n = 11) were assessed in relation to FOR. NW pre-early pubertal girls had higher max FOR [6.9 ± 1.4 mg·kg fat free mass (FFM)(-1)·min(-1)] than NW mid-late pubertal girls (2.2 ± 0.9 mg·kg FFM(-1)·min(-1)) (P = 0.002), OW pre-early pubertal girls (3.8 ± 2.1 mg·kg FFM(-1)·min(-1)), and OW mid-late pubertal girls (3.3 ± 0.9 mg·kg FFM(-1)·min(-1)) (P < 0.05). Bivariable analyses showed positive associations between FOR with homeostatic model assessment of IR (P = 0.001), leptin (P < 0.001), and leptin-to-adiponectin ratio (P = 0.001), independent of percent body fat. Max FOR decreased in NW girls during mid-late puberty; however, this decrease associated with puberty was blunted in OW girls due to lower FOR in pre-early puberty. The presence of IR due to obesity potentially masks the effect of puberty on FOR during exercise in girls. Topics: Adiponectin; Adipose Tissue; Adolescent; Body Composition; Body Weight; Child; Exercise; Female; Humans; Insulin Resistance; Leptin; Obesity; Overweight; Oxidation-Reduction; Puberty; Sexual Maturation | 2014 |
Thermoneutrality results in prominent diet-induced body weight differences in C57BL/6J mice, not paralleled by diet-induced metabolic differences.
Mice are usually housed at 20-24 °C. At thermoneutrality (28 °C) larger diet-induced differences in obesity are seen. We tested whether this leads to large differences in metabolic health parameters.. We performed a 14-wk dietary intervention in C57BL/6J mice at 28 °C and assessed adiposity and metabolic health parameters for a semipurified low fat (10 energy%) diet and a moderate high fat (30 energy%) diet. A large and significant diet-induced differential increase in body weight, adipose tissue mass, adipocyte size, serum leptin level, and, to some extent, cholesterol level was observed. No adipose tissue inflammation was seen. No differential effect of the diets on serum glucose, free fatty acids, triacylglycerides, insulin, adiponectin, resistin, PAI-1, MMP-9, sVCAM-1, sICAM-1, sE-selectin, IL-6, ApoE, fibrinogen levels, or HOMA index was observed. Also in muscle no differential effect on mitochondrial density, mitochondrial respiratory control ratio, or mRNA expression of metabolic genes was found. Finally, in liver no differential effect on weight, triacylglycerides level, aconitase/citrate synthase activity ratio was seen.. Low fat diet and moderate high fat diet induce prominent body weight differences at thermoneutrality, which is not paralleled by metabolic differences. Our data rather suggest that thermoneutrality alters metabolic homeostasis. Topics: Aconitate Hydratase; Adiponectin; Adipose Tissue; Animals; Body Temperature Regulation; Body Weight; Diet, Fat-Restricted; Diet, High-Fat; Energy Metabolism; Fatty Acids; Leptin; Male; Mice, Inbred C57BL; Muscle, Skeletal | 2014 |
Aerobic plus resistance training improves bone metabolism and inflammation in adolescents who are obese.
Obesity is a worldwide epidemic with a high prevalence of comorbidities, including alterations in bone mineral metabolism. The purpose of this yearlong study was to evaluate the role of 2 types of exercise training (aerobic and aerobic plus resistance exercise) on adipokines parameters and bone metabolism in adolescents who are obese. This was a clinical trial study with interdisciplinary weight loss therapy. Forty-two postpubertal adolescents who are obese were subjected to interdisciplinary weight loss therapy with physical exercise, medical monitoring, nutritional intervention, and psychological intervention. Data were collected from serum analyses of leptin, ghrelin, adiponectin, glucose, and insulin. Anthropometric measurements of body composition, bone mineral density, visceral, and subcutaneous fat were also performed. Statistical tests were applied using repeated-measures analysis of variance. Correlations were established using the Pearson test, and dependencies of variables were established using simple linear regression test. Both training types promoted reductions in body mass index, total central, visceral and subcutaneous fat, insulin concentration, and homeostasis model assessment insulin resistance (HOMA-IR) index, but only aerobic plus resistance training showed statistical improvements in the bone mineral content, adiponectin concentration, and lean tissue. Effective reduction in the visceral/subcutaneous ratio, central/peripheral ratio, and leptin concentration was observed. Insulin and the HOMA-IR index were negative predictors of bone mineral content in the combined training group. Moreover, fat distribution was a negative predictor for bone mineral density in both groups. Aerobic plus resistance training promotes a protective role in bone mineral content associated with an improvement in adiponectin and leptin concentrations, favoring the control of the inflammatory state related to obesity in adolescents. Aerobic plus resistance training combined with interdisciplinary interventions provides important strategies to approach obesity, and these strategies may contribute to clinical practice. Topics: Adiponectin; Adolescent; Blood Glucose; Body Fat Distribution; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Diet; Exercise; Female; Ghrelin; Homeostasis; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Male; Obesity; Patient Education as Topic; Resistance Training; Weight Reduction Programs | 2014 |
Peri-conceptional obesogenic exposure induces sex-specific programming of disease susceptibilities in adult mouse offspring.
Vulnerability of the fetus upon maternal obesity can potentially occur during all developmental phases. We aimed at elaborating longer-term health outcomes of fetal overnutrition during the earliest stages of development. We utilized Naval Medical Research Institute (NMRI) mice to induce pre-conceptional and gestational obesity and followed offspring outcomes in the absence of any postnatal obesogenic influences. Male adult offspring developed overweight, insulin resistance, hyperleptinemia, hyperuricemia and hepatic steatosis; all these features were not observed in females. Instead, they showed impaired fasting glucose and a reduced fat mass and adipocyte size. Influences of the interaction of maternal diet∗sex concerned offspring genes involved in fatty liver disease, lipid droplet size regulation and fat mass expansion. These data suggest that a peri-conceptional obesogenic exposure is sufficient to shape offspring gene expression patterns and health outcomes in a sex- and organ-specific manner, indicating varying developmental vulnerabilities between sexes towards metabolic disease in response to maternal overnutrition. Topics: Adipocytes; Animals; Body Weight; Cell Size; Diet, High-Fat; Disease Susceptibility; Fatty Liver; Female; Gene Expression Regulation, Developmental; Glucose Tolerance Test; Hyperuricemia; Insulin Resistance; Leptin; Male; Mice, Inbred Strains; Obesity; Overweight; Pregnancy; Prenatal Exposure Delayed Effects; Reverse Transcriptase Polymerase Chain Reaction; Sex Factors; Subcutaneous Fat; Time Factors | 2014 |
Testosterone replacement ameliorates nonalcoholic fatty liver disease in castrated male rats.
Nonalcoholic fatty liver disease is common in developed countries and is associated with obesity, metabolic syndrome, and type 2 diabetes. T deficiency is a risk factor for developing these metabolic deficiencies, but its role in hepatic steatosis has not been well studied. We investigated the effects of T on the pathogenesis of hepatic steatosis in rats fed a high-fat diet (HFD). Adult male rats were randomly placed into four groups and treated for 15 weeks: intact rats on regular chow diet (RCD), intact rats on liquid HFD (I+HFD), castrated rats on HFD (C+HFD), and castrated rats with T replacement on HFD (C+HFD+T). Fat contributed 71% energy to the HFD but only 16% of energy to the RCD. Serum T level was undetectable in castrated rats, and T replacement led to 2-fold higher mean serum T levels than in intact rats. C+HFD rats gained less weight but had higher percentage body fat than C+HFD+T. Severe micro- and macrovesicular fat accumulated in hepatocytes with multiple inflammatory foci in the livers of C+HFD. I+HFD and C+HFD+T hepatocytes demonstrated only mild to moderate microvesicular steatosis. T replacement attenuated HFD-induced hepatocyte apoptosis in castrated rats. Serum glucose and insulin levels were not increased with HFD in any group. Immunoblots showed that insulin-regulated proteins were not changed in any group. This study demonstrates that T deficiency may contribute to the severity of hepatic steatosis and T may play a protective role in hepatic steatosis and nonalcoholic fatty liver disease development without insulin resistance. Topics: Adiponectin; Animals; Apoptosis; Body Composition; Body Weight; Castration; Eating; Fatty Acids, Nonesterified; Fatty Liver; Hormone Replacement Therapy; Insulin; Leptin; Liver; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Testosterone | 2014 |
Do ethnic differences in cord blood leptin levels differ by birthweight category? Findings from the Born in Bradford cohort study.
There is evidence that South Asian individuals have higher fat mass for a given weight than Europeans. One study reported that the greater fatness for a given birthweight may increase with increasing birth weight, suggesting that any attempt to increase mean birth weight in South Asians would markedly increase their fatness.. Our objective was to examine whether differences in cord leptin values between White British and Pakistani infants vary by birth weight category.. We examined the difference in cord leptin levels between 659 White British and 823 Pakistani infants recruited to the Born in Bradford cohort study, by clinical categories and thirds of the birth weight distribution.. Pakistani infants had a lower mean birthweight but higher cord leptin levels than White British infants [ratio of geometric mean(RGM) of cord leptin adjusted for birth weight = 1.36 (95% CI 1.26,1.46)]. Birthweight was positively associated with cord leptin levels in both groups, with no evidence that the regression lines in the two groups diverged from each other with increasing birthweight.The relative ethnic difference in cord leptin was similar in low (<2500 g), normal and high (≥4000 g) birthweight infants(P-value for interaction = 0.91). It was also similar across thirds of the birthweight distribution [RGM (95% CI) in lowest, mid and highest thirds were 1.37 (1.20, 1.57), 1.36 (1.20, 1.54) and 1.31 (1.16, 1.52), respectively, P-interaction = 0.51].. We found marked differences in cord leptin levels between Pakistani and White British infants but no evidence that this difference increases with increasing birthweight. Topics: Asian People; Birth Weight; Body Weight; Female; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Leptin; Male; Pakistan; United Kingdom; White People | 2014 |
Changes in mRNA expression of arcuate nucleus appetite-regulating peptides during lactation in rats.
The contribution of hypothalamic appetite-regulating peptides to further hyperphagia accompanying the course of lactation in rats was investigated by using PCR array and real-time PCR. Furthermore, changes in the mRNA expression for appetite-regulating peptides in the hypothalamic arcuate nucleus (ARC) were analyzed at all stages of pregnancy and lactation, and also after weaning. Food intake was significantly higher during pregnancy, lactation, and after weaning than during non-lactation periods. During lactation, ARC expression of mRNAs for agouti-related protein (AgRP) and peptide YY was increased, whereas that of mRNAs for proopiomelanocortin (POMC) and cholecystokinin (CCK) was decreased, in comparison with non-lactation periods. The increase in AgRP mRNA expression during lactation was especially marked. The plasma level of leptin was significantly decreased during the course of lactation, whereas that of acyl-ghrelin was unchanged. In addition, food intake was negatively correlated with the plasma leptin level during lactation. This study has clarified synchronous changes in the expression of many appetite-regulating peptides in ARC of rats during lactation. Our results suggest that hyperphagia during lactation in rats is caused by decreases in POMC and CCK expression and increases in AgRP expression in ARC, the latter being most notable. Together with the decrease in the blood leptin level, such changes in mRNA expression may explain the further hyperphagia accompanying the course of lactation. Topics: Adipose Tissue, White; Agouti-Related Protein; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Cholecystokinin; Eating; Female; Lactation; Leptin; Male; Neuropeptide Y; Neuropeptides; Organ Size; Pregnancy; Pro-Opiomelanocortin; Rats; Rats, Wistar; RNA, Messenger | 2014 |
The effect of supplementing zilpaterol hydrochloride on feeding performance and carcass characteristics of steers sorted by leptin genotype.
The focus of this investigation was to identify interactions that may exist among alleles of the leptin gene and supplementation of zilpaterol hydrochloride (ZH). Steers (n = 4,246; initial BW = 389.8 ± 8.8 kg) were genotyped and sorted into 1 of 3 leptin genotype (LG) groups (homozygous normal [CC], heterozygous [CT], or homozygous mutant ) from a candidate pool of 7,506 steers. Steers were allocated into 48 pens of which one-half were fed the β-adrenergic agonist ZH and the balance, a control diet. During the pretreatment period (d 1 to 102), cattle of the TT genotype exhibited increased (P = 0.02) DMI compared to other genotypes and lower G:F than the CC genotype (P = 0.03). Cattle of the CT genotype had lower (P = 0.02) ADG compared to other genotypes for the treatment period. Cattle fed ZH had improved (P < 0.01) ADG and G:F compared to cattle on the control diet for both the treatment and entire study periods (d 1 to 125). For the entire study period, cattle of the TT genotype had greater (P = 0.03) DMI than the CT allele, with CT cattle having the lowest (P < 0.01) ADG and CC cattle having greatest (P < 0.01) G:F of all alleles. Cattle of the TT genotype had greater (P = 0.03) final shrunk weight than the CT allele. Cattle of the TT genotype had lower (P = 0.04) dressed yield compared to CT cattle and greater (P = 0.01) marbling score compared to CC cattle, with a concurrent increase (P < 0.01) in calculated empty body fat (EBF) over all alleles. Cattle fed ZH had greater (P < 0.01) final shrunk weight, HCW, dressed yield, and LM area coupled with reduced (P < 0.01) marbling score, s.c. fat depth, EBF, and calculated USDA yield grade compared to control steers. Carcasses of the TT allele had a greater (P = 0.01) proportion of Choice carcasses than CT or CC alleles and lesser (P = 0.03) proportion of Select carcasses than CC alleles. Additionally, ZH supplemented cattle had fewer (P < 0.01) carcasses grading Premium Choice or better, Choice, and yield grade 3, 4, and 5 with subsequently more (P < 0.01) carcasses grading Select, Standard, and yield grade 1. Differences in live and carcass performance exist among leptin alleles, which may allow for sorting and improved timeliness of fed beef marketing. Topics: Adrenergic beta-Agonists; Animal Feed; Animals; Body Composition; Body Weight; Cattle; Diet; Dietary Supplements; Energy Intake; Genotype; Leptin; Male; Random Allocation; Trimethylsilyl Compounds | 2014 |
Effects of exposure to a cafeteria diet during gestation and after weaning on the metabolism and body weight of adult male offspring in rats.
In the present study, we investigated whether maternal exposure to a cafeteria diet affects the metabolism and body composition of offspring and whether such an exposure has a cumulative effect during the lifetime of the offspring. Female rats were fed a control (CON) or a cafeteria (CAF) diet from their own weaning to the weaning of their offspring. At 21 d of age, male offspring were divided into four groups by diet during gestation and after weaning (CON-CON, CON-CAF, CAF-CON and CAF-CAF). Blood was collected from dams (after weaning) and pups (at 30 and 120 d of age) by decapitation. CAF dams had significantly greater body weight and adipose tissue weight and higher concentrations of total cholesterol, insulin and leptin than CON dams (Student's t test). The energy intake of CAF rats was higher than that of CON rats regardless of the maternal diet (two-way ANOVA). Litters had similar body weights at weaning and at 30 d of age, but at 120 d, CON-CAF rats were heavier. At both ages, CAF rats had greater adipose tissue weight than CON rats regardless of the maternal diet, and the concentrations of TAG and cholesterol were similar between the two groups, as were blood glucose concentrations at 30 d of age. However, at 120 d of age, CAF rats were hyperglycaemic, hyperinsulinaemic and hyperleptinaemic regardless of the maternal diet. These findings suggest that maternal obesity does not modulate the metabolism of male offspring independently, modifying body weight only when associated with the intake of a cafeteria diet by the offspring. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Diet; Female; Hyperglycemia; Hyperinsulinism; Insulin; Leptin; Male; Metabolic Diseases; Obesity; Pregnancy; Pregnancy Complications; Prenatal Nutritional Physiological Phenomena; Rats; Rats, Wistar; Triglycerides; Weaning | 2014 |
The obesity paradox in men with coronary heart disease and heart failure: the role of muscle mass and leptin.
We have investigated the role of muscle mass, natriuretic peptides and adipokines in explaining the obesity paradox.. The obesity paradox relates to the association between obesity and increased survival in patients with coronary heart disease (CHD) or heart failure (HF).. Prospective study of 4046 men aged 60-79 years followed up for a mean period of 11 years, during which 1340 deaths occurred. The men were divided according to the presence of doctor diagnosed CHD and HF: (i) no CHD or HF ii), with CHD (no HF) and (iii) with HF.. Overweight (BMI 25-9.9 kg/m(2)) and obesity (BMI ≥ 30 kg/m(2)) were associated with lower mortality risk compared to men with normal weight (BMI 18.5-24.9 kg/m(2)) in those with CHD [hazards ratio (HR) 0.71 (0.56,0.91) and 0.77 (0.57,1.04); p=0.04 for trend] and in those with HF [HR 0.57 (0.28,1.16) and 0.41 (0.16,1.09; p=0.04 for trend). Adjustment for muscle mass and NT-proBNP attenuated the inverse association in those with CHD (no HF) [HR 0.78 (0.61,1.01) and 0.96 (0.68,1.36) p=0.60 for trend) but made minor differences to those with HF [p=0.05]. Leptin related positively to mortality in men without HF but inversely to mortality in those with HF; adjustment for leptin abolished the BMI mortality association in men with HF [HR 0.82 (0.31,2.20) and 0.99 (0.27,3.71); p=0.98 for trend].. The lower mortality risk associated with excess weight in men with CHD without HF may be due to higher muscle mass. In men with HF, leptin (possibly reflecting cachexia) explain the inverse association. Topics: Aged; Biomarkers; Body Mass Index; Body Weight; Coronary Disease; Follow-Up Studies; Heart Failure; Humans; Leptin; Male; Middle Aged; Muscle Strength; Muscle, Skeletal; Obesity; Prospective Studies; Survival Rate | 2014 |
Central visfatin potentiates glucose-stimulated insulin secretion and β-cell mass without increasing serum visfatin levels in diabetic rats.
Our previous study revealed that plasma visfatin levels were lower in pregnant women with gestational diabetes (GDM) than non-GDM independent of prepreganacy BMI. We examined whether central visfatin modulates energy and glucose homeostasis via altering insulin resistance, insulin secretion or islet morphometry in diabetic rats.. Partial pancreatectomized, type 2 diabetic, rats were interacerbroventricularly infused with visfatin (100ng/rat/day, Px-VIS), visfatin+visfatin antagonist, CHS-828 (100μg/rat/day, Px-VIS-ANT), or saline (control, Px-Saline) via osmotic pump, respectively, for 4weeks.. Central visfatin improved insulin signaling (pAkt→pFOXO-1) but not pSTAT3 in the hypothalamus. Central visfatin did not alter serum visfatin levels in diabetic rats whereas the levels were higher in non-diabetic rats than diabetic rats. Body weight at the 2nd week was lowered in the Px-VIS group due to decreased food intake in the first two weeks compared to the Px-Saline group and energy expenditure was not significantly different among the treatment groups of diabetic rats. Visfatin antagonist treatment nullified the central visfatin effect. Px-VIS increased whole body glucose disposal rates in euglycemic hyperinsulinemic clamp compared to Px-Saline and lowered hepatic glucose output, whereas Px-VIS-ANT blocked the visfatin effect on insulin resistance (P<0.05). In hyperglycemic clamp study, the area under the curve of insulin in first and second phase were significantly higher in the Px-VIS group than the Px-Saline group without modifying insulin sensitivity at the hyperglycemic state, whereas the increase in serum insulin levels was blocked in the Px-VIS-ANT group. Central visfatin also increased β-cell mass by increasing β-cell proliferation.. Central visfatin improved glucose homeostasis by increasing insulin secretion and insulin sensitivity at euglycemia through the hypothalamus in diabetic rats. Therefore, visfatin is a positive modulator of glucose homeostasis by delivering the hypothalamic signals into the peripheries. Topics: Adiposity; Animals; Apoptosis; Blood Glucose; Body Weight; Cell Proliferation; Diabetes Mellitus, Experimental; Energy Metabolism; Female; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Hypothalamus; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Liver; Male; Nicotinamide Phosphoribosyltransferase; Pregnancy; Rats; Rats, Sprague-Dawley; Signal Transduction | 2014 |
Chlorella modulates insulin signaling pathway and prevents high-fat diet-induced insulin resistance in mice.
The search for natural agents that minimize obesity-associated disorders is receiving special attention. In this regard, the present study aimed to evaluate the prophylactic effect of Chlorella vulgaris (CV) on body weight, lipid profile, blood glucose and insulin signaling in liver, skeletal muscle and adipose tissue of diet-induced obese mice.. Balb/C mice were fed either with standard rodent chow diet or high-fat diet (HFD) and received concomitant treatment with CV for 12 consecutive weeks. Triglyceride, free fatty acid, total cholesterol and fractions of cholesterol were measured using commercial assay. Insulin and leptin levels were determined by enzyme-linked immunosorbent assay (ELISA). Insulin and glucose tolerance tests were performed. The expression and phosphorylation of IRβ, IRS-1 and Akt were determined by Western blot analyses.. Herein we demonstrate for the first time in the literature that prevention by CV of high-fat diet-induced insulin resistance in obese mice, as shown by increased glucose and insulin tolerance, is in part due to the improvement in the insulin signaling pathway at its main target tissues, by increasing the phosphorylation levels of proteins such as IR, IRS-1 and Akt. In parallel, the lower phosphorylation levels of IRS-1(ser307) were observed in obese mice. We also found that CV administration prevents high-fat diet-induced dyslipidemia by reducing triglyceride, cholesterol and free fatty acid levels.. We propose that the modulatory effect of CV treatment preventing the deleterious effects induced by high-fat diet is a good indicator for its use as a prophylactic-therapeutic agent against obesity-related complications. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Chlorella vulgaris; Diet, High-Fat; Dyslipidemias; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred BALB C; Muscle, Skeletal; Obesity; Phosphorylation; Plant Extracts; Signal Transduction | 2014 |
Blockade of the cerebral aqueduct in rats provides evidence of antagonistic leptin responses in the forebrain and hindbrain.
Previously, we reported that low-dose leptin infusions into the fourth ventricle produced a small but significant increase in body fat. These data contrast with reports that injections of higher doses of leptin into the fourth ventricle inhibit food intake and weight gain. In this study, we tested whether exogenous leptin in the fourth ventricle opposed or contributed to weight loss caused by third ventricle leptin infusion by blocking diffusion of CSF from the third to the fourth ventricle. Male Sprague-Dawley rats received third ventricle infusions of PBS or 0.3 μg leptin/24 h from miniosmotic pumps. After 4 days, rats received a 3-μl cerebral aqueduct injection of saline or of thermogelling nanoparticles (hydrogel) that solidified at body temperature. Third ventricle leptin infusion inhibited food intake and caused weight loss. Blocking the aqueduct exaggerated the effect of leptin on food intake and weight loss but had no effect on the weight of PBS-infused rats. Leptin reduced both body fat and lean body mass but did not change energy expenditure. Blocking the aqueduct decreased expenditure of rats infused with PBS or leptin. Infusion of leptin into the third ventricle increased phosphorylated STAT3 in the VMHDM of the hypothalamus and the medial NTS in the hindbrain. Blocking the aqueduct did not change hypothalamic p-STAT3 but decreased p-STAT3 in the medial NTS. These results support previous observations that low-level activation of hindbrain leptin receptors has the potential to blunt the catabolic effects of leptin in the third ventricle. Topics: Animals; Body Composition; Body Weight; Cerebral Aqueduct; Eating; Energy Metabolism; Fourth Ventricle; Hydrogel, Polyethylene Glycol Dimethacrylate; Hypothalamus; Leptin; Male; Phosphorylation; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Third Ventricle | 2014 |
Short sleep duration is associated with decreased serum leptin, increased energy intake and decreased diet quality in postmenopausal women.
Short sleep duration induces hormonal perturbations contributing to hyperphagia, insulin resistance, and obesity. The majority of these studies are conducted in young adults. This analysis in a large (n = 769) sample of postmenopausal women (median age 63 years) sought to (a) confirm that sleep duration and sleep quality are negatively correlated with circulating leptin concentrations and (b) to examine the relationship between self-reported sleep, dietary energy intake, and diet quality, as well as, investigate the role of leptin in these associations.. Sleep duration/quality, insomnia, and dietary intake were determined via self-report. Blood samples were collected following an overnight fast to assess serum leptin concentration. All analyses were adjusted for total body fat mass.. Women reporting ≤6 hr sleep/night had lower serum leptin concentrations than those reporting ≥8 hr sleep (P = 0.04). Furthermore, those with ≤6 hr sleep/night reported higher dietary energy intake (P = 0.01) and lower diet quality (P = 0.04) than the reference group (7 hr sleep/night). Women sleeping ≥8 hr also reported lower diet quality than the reference group (P = 0.02). Importantly, serum leptin did not confound these associations.. These results provide evidence that sleep duration is inversely associated with serum leptin and dietary energy intake in postmenopausal women. Topics: Aged; Body Composition; Body Mass Index; Body Weight; Cross-Sectional Studies; Diet; Energy Intake; Female; Humans; Leptin; Life Style; Linear Models; Middle Aged; Motor Activity; Postmenopause; Sleep; Surveys and Questionnaires | 2014 |
Role of adiponectin in the metabolic effects of cannabinoid type 1 receptor blockade in mice with diet-induced obesity.
The adipocyte-derived hormone adiponectin promotes fatty acid oxidation and improves insulin sensitivity and thus plays a key role in the regulation of lipid and glucose metabolism and energy homeostasis. Chronic cannabinoid type 1 (CB1) receptor blockade also increases lipid oxidation and improves insulin sensitivity in obese individuals or animals, resulting in reduced cardiometabolic risk. Chronic CB1 blockade reverses the obesity-related decline in serum adiponectin levels, which has been proposed to account for the metabolic effects of CB1 antagonists. Here, we investigated the metabolic actions of the CB1 inverse agonist rimonabant in high-fat diet (HFD)-induced obese adiponectin knockout (Adipo(-/-)) mice and their wild-type littermate controls (Adipo(+/+)). HFD-induced obesity and its hormonal/metabolic consequences were indistinguishable in the two strains. Daily treatment of obese mice with rimonabant for 7 days resulted in significant and comparable reductions in body weight, serum leptin, free fatty acid, cholesterol, and triglyceride levels in the two strains. Rimonabant treatment improved glucose homeostasis and insulin sensitivity to the same extent in Adipo(+/+) and Adipo(-/-) mice, whereas it reversed the HFD-induced hepatic steatosis, fibrosis, and hepatocellular damage only in the former. The adiponectin-dependent, antisteatotic effect of rimonabant was mediated by reduced uptake and increased β-oxidation of fatty acids in the liver. We conclude that reversal of the HFD-induced hepatic steatosis and fibrosis by chronic CB1 blockade, but not the parallel reduction in adiposity and improved glycemic control, is mediated by adiponectin. Topics: Adiponectin; Adiposity; Animals; Body Weight; Cannabinoid Receptor Antagonists; Diet, High-Fat; Energy Intake; Fatty Liver; Leptin; Lipid Metabolism; Lipids; Liver; Mice; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant | 2014 |
N-acetylcysteine supplementation decreases osteoclast differentiation and increases bone mass in mice fed a high-fat diet.
Obesity induced by high-fat (HF) diets increases bone resorption, decreases trabecular bone mass, and reduces bone strength in various animal models. This study investigated whether N-acetylcysteine (NAC), an antioxidant and a glutathione precursor, alters glutathione status and mitigates bone microstructure deterioration in mice fed an HF diet. Forty-eight 6-wk-old male C57BL/6 mice were randomly assigned to 4 treatment groups (n = 12 per group) and fed either a normal-fat [NF (10% energy as fat)] or an HF (45% energy as fat) diet ad libitum with or without NAC supplementation at 1 g/kg diet for 17 wk. Compared with the NF groups, mice in the HF groups had higher body weight, greater serum leptin concentrations and osteoclast differentiation, and lower trabecular bone volume, trabecular number, and connectivity density (P < 0.05). NAC supplementation increased the serum-reduced glutathione concentration and bone volume and decreased osteoclast differentiation in HF-fed mice (P < 0.05). We further demonstrated that osteoclast differentiation was directly regulated by glutathione status. NAC treatment of murine macrophage RAW 264.7 cells in vitro increased glutathione status and decreased osteoclast formation. These results show that NAC supplementation increases the bone mass of obese mice induced by an HF diet through elevating glutathione status and decreasing bone resorption. Topics: Acetylcysteine; Animals; Antioxidants; Body Weight; Bone Density; Bone Resorption; Cell Differentiation; Cell Line, Tumor; Diet, High-Fat; Dietary Fats; Dietary Supplements; Disease Models, Animal; Glutathione; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Osteoclasts | 2014 |
Voglibose administration regulates body weight and energy intake in high fat-induced obese mice.
We tested whether long-term administration of voglibose (VO) prevents diet induced obesity in addition to hypoglycemic effects in high fat fed mice and further investigated the underlying mechanisms by which voglibose exerts its weight lowering effect. Male C57BL/6 mice were fed ad libitum for 12 weeks with the control diet (CTL), high-fat diet (HFD) or the HFD with VO supplementations. Blood lipid profile, plasma leptin levels and hepatic triglyceride content, as well as expressions of genes involved in appetite and mitochondrial function were examined. The results showed that VO significantly reduced body weight, fat mass and energy intakes in high fat fed mice. VO showed improved metabolic profiles including blood glucose, triglyceride and free fatty acid. Elevated levels of plasma leptin in HFD were significantly reduced with the VO, furthermore, VO modulated the hypothalamic expressions of leptin receptors and appetite related genes. VO showed the upregulated expressions of PGC-1 in the liver and epididymal adipose tissue. In conclusion, VO may exert antiobesity properties through reductions in energy intake and improvement in mitochondrial function, indicating that VO has potential therapeutic use in patients with obesity, type 2 diabetes, and related complications. Topics: Adiposity; Agouti-Related Protein; Animals; Appetite; Body Weight; Diet, High-Fat; Energy Intake; Gene Expression Regulation; Glucose Transporter Type 4; Hypothalamus; Inositol; Insulin; Insulin Resistance; Insulin-Secreting Cells; Leptin; Liver; Male; Mice; Mice, Obese; Nerve Tissue Proteins; Neuropeptide Y; Organ Specificity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pro-Opiomelanocortin; Receptors, Leptin; Transcription Factors; Triglycerides | 2014 |
Perinatal exposure to 4-nonylphenol affects adipogenesis in first and second generation rats offspring.
Maternal exposure to 4-nonylphenol (4-NP) during pregnancy was shown to alter adipogenesis in rodents, yet whether the effects are restricted to 4-NP-exposed offspring only or can be transmitted to the next generation are not known. Pregnant Wistar rats received either vehicle or 4-NP (5, 25 and 125μg/kg/day) from gestation to postnatal day 21. F1 pups were subjected to blood biochemistry tests, or killed to obtain their gonadal fat to determine gene expression. Some F1 adult female rats were mated with F1 males from control group to obtain F2 pups, but without any exposure to 4-NP in the perinatal stage. F2 pups underwent studies similar to those performed on F1 pups. Serum total cholesterol, leptin levels were significantly elevated, the quantity and size of fat cells were increased, gene expression of key regulators of adipogenesis and lipogenic pathway of fat tissue were perturbed by 4-NP (p<0.05 or p<0.01). In addition, the expression of mRNA levels and protein of ERα were downregulated in adipose tissue in the two generation offspring. Perinatal exposure to 4-NP affects the adipogenesis in both male and female F1 offspring, and this effect can be progressed to the F2 offspring through the maternal line. Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Body Weight; Cholesterol; Estrogen Receptor alpha; Female; Leptin; Male; Maternal Exposure; Phenols; Pregnancy; Prenatal Exposure Delayed Effects; Rats; RNA, Messenger; Signal Transduction | 2014 |
Hypothalamic expression of anorexigenic and orexigenic hormone receptors in obese females Neotomodon alstoni: effect of fasting.
Obesity is a world problem that requires a better understanding of its physiological and genetic basis, as well as the mechanisms by which the hypothalamus controls feeding behavior. The volcano mouse Neotomodon alstoni develops obesity in captivity when fed with regular chow diet, providing a novel model for the study of obesity. Females develop obesity more often than males; therefore, in this study, we analysed in females, in proestrous lean and obese, the differences in hypothalamus expression of receptors for leptin, ghrelin (growth hormone secretagogue receptor GHS-R), and VPAC, and correlates for plasma levels of total ghrelin. The main comparisons are between mice fed ad libitum and mice after 24 hours of fasting. Mice above 65 g body weight were considered obese, based on behavioral and physiological parameters such as food intake, plasma free fatty acids, and glucose tolerance. Hypothalamic tissue from obese and lean mice was analysed by western blot. Our results indicate that after ad libitum food access, obese mice show no significant differences in hypothalamic leptin receptors, but a significant increase of 60% in the GHS-R, and a nearly 62% decrease in VPAC2 was noted. After a 24-hour fast, plasma ghrelin increased nearly two fold in both lean and obese mice; increases of hypothalamic leptin receptors and GHS-R were also noted, while VPAC2 did not change significantly; levels of plasma free fatty acids were 50% less after fasting in obese than in lean animals. Our results indicate that in obese N. alstoni mice, the levels of orexigenic receptors in the hypothalamus correlate with overfeeding, and the fact that lean and obese females respond in different ways to a metabolic demand such as a 24-hour fast. Topics: Animals; Body Weight; Diet; Fasting; Female; Ghrelin; Hypothalamus; Leptin; Mice; Mice, Obese; Obesity; Receptors, Ghrelin; Receptors, Leptin; Receptors, Vasoactive Intestinal Peptide, Type II | 2014 |
Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation.
Obesity-induced endoplasmic reticulum (ER) stress causes chronic inflammation in adipose tissue and steatosis in the liver, and eventually leads to insulin resistance and type 2 diabetes (T2D). The goal of this study was to understand the mechanisms by which administration of bilirubin, a powerful antioxidant, reduces hyperglycemia and ameliorates obesity in leptin-receptor-deficient (db/db) and diet-induced obese (DIO) mouse models. db/db or DIO mice were injected with bilirubin or vehicle ip. Blood glucose and body weight were measured. Activation of insulin-signaling pathways, expression of inflammatory cytokines, and ER stress markers were measured in skeletal muscle, adipose tissue, and liver of mice. Bilirubin administration significantly reduced hyperglycemia and increased insulin sensitivity in db/db mice. Bilirubin treatment increased protein kinase B (PKB/Akt) phosphorylation in skeletal muscle and suppressed expression of ER stress markers, including the 78-kDa glucose-regulated protein (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein, X box binding protein (XBP-1), and activating transcription factor 4 in db/db mice. In DIO mice, bilirubin treatment significantly reduced body weight and increased insulin sensitivity. Moreover, bilirubin suppressed macrophage infiltration and proinflammatory cytokine expression, including TNF-α, IL-1β, and monocyte chemoattractant protein-1, in adipose tissue. In liver and adipose tissue of DIO mice, bilirubin ameliorated hepatic steatosis and reduced expression of GRP78 and C/EBP homologous protein. These results demonstrate that bilirubin administration improves hyperglycemia and obesity by increasing insulin sensitivity in both genetically engineered and DIO mice models. Bilirubin or bilirubin-increasing drugs might be useful as an insulin sensitizer for the treatment of obesity-induced insulin resistance and type 2 diabetes based on its profound anti-ER stress and antiinflammatory properties. Topics: Animals; Bilirubin; Body Weight; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Glucose Tolerance Test; Heme Oxygenase-1; Inflammation; Insulin; Insulin Resistance; Leptin; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle, Skeletal; Obesity; Protein Denaturation; Receptors, Leptin | 2014 |
The temporal pattern of cfos activation in hypothalamic, cortical, and brainstem nuclei in response to fasting and refeeding in male mice.
In this study we examined fasted and refed cfos activation in cortical, brainstem, and hypothalamic brain regions associated with appetite regulation. We examined a number of time points during refeeding to gain insight into the temporal pattern of neuronal activation and changes in endocrine parameters associated with fasting and refeeding. In response to refeeding, blood glucose and plasma insulin returned to basal levels within 30 minutes, whereas plasma nonesterified fatty acids and leptin returned to basal levels after 1 and 2 hours, respectively. Within the hypothalamic arcuate nucleus (ARC), fasting increased cfos activation in ∼25% of neuropeptide Y neurons, which was terminated 1 hour after refeeding. Fasting had no effect on cfos activation in pro-opiomelanocortin neurons; however, 1 and 2 hours of refeeding significantly activated ∼20% of ARC pro-opiomelanocortin neurons. Acute refeeding (30, 60, and 120 minutes), but not fasting, increased cfos activation in the nucleus accumbens, the cingulate cortex (but not the insular cortex), the medial and lateral parabrachial nucleus, the nucleus of the solitary tract, the area postrema, the dorsal raphe, and the ventromedial nucleus of the hypothalamus. After 6 hours of refeeding, cfos activity was reduced in the majority of these regions compared with that at earlier time points. Our data indicate that acute refeeding, rather than long-term fasting, activates cortical, brainstem, and hypothalamic neural circuits associated with appetite regulation and reward processing. Although the hypothalamic ARC remains a critical sensory node detecting changes in the metabolic state and feedback during fasting and acute refeeding, our results also reveal the temporal pattern in cfos activation in cortical and brainstem areas implicated in the control of appetite and body weight regulation. Topics: Amygdala; Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Brain Stem; Cerebral Cortex; Eating; Fatty Acids; Food Deprivation; Gene Expression Regulation; Gyrus Cinguli; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Neurons; Nucleus Accumbens; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-fos; Raphe Nuclei; Solitary Nucleus; Time Factors; Ventromedial Hypothalamic Nucleus | 2014 |
Palmitoylethanolamide prevents metabolic alterations and restores leptin sensitivity in ovariectomized rats.
It has been suggested a role of fatty acid ethanolamides in control of feeding behavior. Among these, palmitoylethanolamide (PEA) has not been directly implicated in appetite regulation and weight gain. The aim of this study was to investigate the effect of PEA on food intake and body weight and the interaction between PEA and hypothalamic leptin signaling in ovariectomized rats. Ovariectomy produced hyperphagia and increased weight gain, making it an useful model of mild obesity. Ovariectomized rats were treated with PEA (30 mg/kg sc) for 5 weeks. Then, blood was collected, and hypothalamus and adipose tissue were removed for histological, cellular, and molecular measurements. We showed that PEA caused a reduction of food intake, body weight, and fat mass. The mechanisms underlying PEA effects involved an improvement in hypothalamic leptin signaling, through a raise in signal transducer and activator of transcription 3 phosphorylation. We also reported that PEA reduced AMP-activated protein kinase-α phosphorylation and modulated transcription of anorectic and orexigenic neuropeptides in the hypothalamus. Moreover, PEA increased AMP-activated protein kinase-α phosphorylation and carnitine palmitoyltransferase 1 transcription in adipose tissue, suggesting an increase in ATP-producing catabolic pathway. PEA also polarized adipose tissue macrophages to M2 lean phenotype, associated to a reduction of inflammatory cytokines/adipokines. To demonstrate the direct effect of PEA on leptin sensitivity without interference of adiposity loss, we obtained consistent data in PEA-treated sham-operated animals and in vitro in SH-SY5Y neuroblastoma cell line. Therefore, our data provide a rationale for the therapeutic use of PEA in obese postmenopausal woman. Topics: Adenosine Triphosphate; Adipokines; Amides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cell Line, Tumor; Cytokines; Eating; Endocannabinoids; Ethanol; Ethanolamines; Fatty Acids; Feeding Behavior; Female; Glucose Tolerance Test; Humans; Leptin; Obesity; Ovariectomy; Palmitic Acids; Phosphorylation; Rats; Rats, Wistar; Signal Transduction; Weight Gain | 2014 |
Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance.
Induction of heat shock protein (HSP)72 protects against obesity-induced insulin resistance, but the underlying mechanisms are unknown. Here, we show that HSP72 plays a pivotal role in increasing skeletal muscle mitochondrial number and oxidative metabolism. Mice overexpressing HSP72 in skeletal muscle (HSP72Tg) and control wild-type (WT) mice were fed either a chow or high-fat diet (HFD). Despite a similar energy intake when HSP72Tg mice were compared with WT mice, the HFD increased body weight, intramuscular lipid accumulation (triacylglycerol and diacylglycerol but not ceramide), and severe glucose intolerance in WT mice alone. Whole-body VO2, fatty acid oxidation, and endurance running capacity were markedly increased in HSP72Tg mice. Moreover, HSP72Tg mice exhibited an increase in mitochondrial number. In addition, the HSP72 coinducer BGP-15, currently in human clinical trials for type 2 diabetes, also increased mitochondrial number and insulin sensitivity in a rat model of type 2 diabetes. Together, these data identify a novel role for activation of HSP72 in skeletal muscle. Thus, the increased oxidative metabolism associated with activation of HSP72 has potential clinical implications not only for type 2 diabetes but also for other disorders where mitochondrial function is compromised. Topics: AMP-Activated Protein Kinases; Animals; Blood Glucose; Blotting, Western; Body Weight; Cell Respiration; Diabetes Mellitus, Type 2; Diet, High-Fat; Energy Metabolism; Fatty Acids; HSP72 Heat-Shock Proteins; Insulin Resistance; Leptin; Male; Mice; Mitochondria, Muscle; Muscle, Skeletal; Obesity; Oxidation-Reduction; Oxidative Phosphorylation; Peroxisome Proliferator-Activated Receptors; Rats; Real-Time Polymerase Chain Reaction; Sirtuin 1 | 2014 |
ABCA1 in adipocytes regulates adipose tissue lipid content, glucose tolerance, and insulin sensitivity.
Adipose tissue contains one of the largest reservoirs of cholesterol in the body. Adipocyte dysfunction in obesity is associated with intracellular cholesterol accumulation, and alterations in cholesterol homeostasis have been shown to alter glucose metabolism in cultured adipocytes. ABCA1 plays a major role in cholesterol efflux, suggesting a role for ABCA1 in maintaining cholesterol homeostasis in the adipocyte. However, the impact of adipocyte ABCA1 on adipose tissue function and glucose metabolism is unknown. Our aim was to determine the impact of adipocyte ABCA1 on adipocyte lipid metabolism, body weight, and glucose metabolism in vivo. To address this, we used mice lacking ABCA1 specifically in adipocytes (ABCA1(-ad/-ad)). When fed a high-fat, high-cholesterol diet, ABCA1(-ad/-ad) mice showed increased cholesterol and triglyceride stores in adipose tissue, developed enlarged fat pads, and had increased body weight. Associated with these phenotypic changes, we observed significant changes in the expression of genes involved in cholesterol and glucose homeostasis, including ldlr, abcg1, glut-4, adiponectin, and leptin. ABCA1(-ad/-ad) mice also demonstrated impaired glucose tolerance, lower insulin sensitivity, and decreased insulin secretion. We conclude that ABCA1 in adipocytes influences adipocyte lipid metabolism, body weight, and whole-body glucose homeostasis. Topics: Adipocytes; Adipose Tissue; Animals; ATP Binding Cassette Transporter 1; Blood Glucose; Blotting, Western; Body Weight; Cholesterol; Diet, High-Fat; Gene Expression; Glucose; Glucose Transporter Type 4; Homeostasis; Insulin Resistance; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nicotinamide Phosphoribosyltransferase; Receptors, LDL; Reverse Transcriptase Polymerase Chain Reaction; Triglycerides | 2014 |
A serum component mediates food restriction-induced growth attenuation.
Proper nutrition in terms of calories and essential food components is required to maximize longitudinal growth in children. Our previous study showed that prepubertal male rats subjected to 10 days of 40% food restriction (RES) exhibited a dramatic reduction in weight and epiphyseal growth plate height, as well as changes in gene expression and microRNAs (miRNAs) in the epiphyseal growth plate. These findings reversed rapidly after renewal of the regular food supply (catch-up [CU]). To further elucidate the mechanisms underlying the nutrition-growth association, serum collected from the RES and CU rats and control rats fed ad libitum (AL) was added to the culture medium of the chondrocyte cell line ATDC5 (instead of fetal calf serum). Serum from the RES group induced a reduction in cell viability (25%, P < .05) concomitant with an increase in cell differentiation compared with that for the AL group serum. The most interesting observation, in our opinion, was the significant reduction in the expression of specific miRNAs, including the chondro-specific miR-140. These effects were not observed for serum from refed (CU) rats. Serum levels of IGF-I, leptin, and fibroblast growth factor 21 were reduced by food restriction. The addition of IGF-I and leptin to the culture increased cell viability, whereas fibroblast growth factor 21 reduced it, suggesting the involvement of IGF-I, leptin, and possibly other still unidentified serum factors in chondrocyte cell growth. In conclusion, specific miRNAs respond to nutritional cues, and these effects are mediated by serum-borne factors. These results may promote the development of superior interventions for children with malnutrition and growth abnormalities. Topics: Animals; Body Weight; Cell Differentiation; Cell Line; Cell Survival; Chondrocytes; Collagen Type X; Fibroblast Growth Factors; Food Deprivation; Gene Expression Regulation; Growth Plate; Insulin-Like Growth Factor I; Leptin; Male; Mice; MicroRNAs; Rats; Rats, Sprague-Dawley | 2014 |
Hyperleptinemia is associated with CRP, but not apolipoprotein E, and is reduced by exercise training.
The purpose of this study was to examine whether leptin levels affect the response of leptin to exercise training (ET) and whether this is also affected by C-reactive protein (CRP) or the three common Apolipoprotein E genotypes (APOE). Ninety-seven (male = 45, female = 52) sedentary individuals underwent 6 months of supervised ET. Blood was sampled before the initiation of ET, and again 24 and 72 hr after completion of the final training session. ET resulted in a small reduction in body mass (80.47 ± 18.03 vs 79.42 ± 17.34 kg, p < .01). Leptin was reduced 24 hr after the final exercise session (p < .01), but returned to normal after 72 hr (p > .05)--Pre: 13.51 ± 12.27, 24hr: 12.14 ± 12.34, 72 hr: 12.98 ± 11.40 ng/ml. The most hyperleptinemic individuals had a greater initial response, which was sustained through to 72 hr after the final session in the pooled study population (p < .01), and in both males (p < .05) and females (p < .05) separately. CRP was related to leptin independently of body weight and positively related to the reductions in leptin. APOE genotype was not related to leptin levels and did not affect the response to ET. Leptin levels may only be reduced by ET in those with hyperleptinemia. In addition, both the initial extent of hyperleptinemia and the subsequent reduction in leptin may be related to low grade chronic systemic inflammation. Topics: Adult; Apolipoproteins E; Body Weight; C-Reactive Protein; Exercise; Female; Genotype; Humans; Inflammation; Leptin; Male; Middle Aged; Physical Conditioning, Human; Sedentary Behavior | 2014 |
Leptin deficiency in rats results in hyperinsulinemia and impaired glucose homeostasis.
Leptin, an adipocyte-derived hormone, has well-established anorexigenic effects but is also able to regulate glucose homeostasis independent of body weight. Until recently, the ob/ob mouse was the only animal model of global leptin deficiency. Here we report the effects of leptin deficiency on glucose homeostasis in male and female leptin knockout (KO) rats. Leptin KO rats developed obesity by 6 to 7 weeks of age, and lipid mass was increased by more than 2-fold compared with that of wild-type (WT) littermates at 18 weeks of age. Hyperinsulinemia and insulin resistance were evident in both males and females and were sustained with aging. Male KO rats experienced transient mild fasting hyperglycemia between 14 and 25 weeks of age, but thereafter fasting glucose levels were comparable to those of WT littermates up to 36 weeks of age. Fasting glucose levels of female KO rats were similar to those of WT littermates. Male KO rats exhibited a 3-fold increase in the proportion of β-cell area relative to total pancreas at 36 weeks of age. Islets from 12-week-old KO rats secreted more insulin when stimulated than islets from WT littermates. Leptin replacement via miniosmotic pump (100 μg/d) reduced food intake, attenuated weight gain, normalized glucose tolerance, and improved glucose-stimulated insulin secretion and insulin sensitivity. Together, these data demonstrate that the absence of leptin in rats recapitulates some of the phenotype previously observed in ob/ob mice including development of hyperinsulinemia, obesity, and insulin resistance. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Disease Models, Animal; Female; Glucose Tolerance Test; Homeostasis; Hyperinsulinism; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Liver; Male; Muscles; Obesity; Phenotype; Rats; Rats, Sprague-Dawley; Rats, Transgenic | 2014 |
Beneficial effects of hydro-alcoholic extract of Caralluma fimbriata against high-fat diet-induced insulin resistance and oxidative stress in Wistar male rats.
The main aim of this study was to investigate the beneficial effects of hydro-alcoholic extract of Caralluma fimbriata (CFE) on the effects of high-fat diet feeding on insulin resistance and oxidative stress in Wistar rats. High-fat diet (60% of fat) and CFE (200 mg/kg body weight/day) were given concurrently to the rats for a period of 90 days. Feeding with high-fat diet resulted in the development of hyperglycemia, hyperinsulinemia, hyperleptinemia, and hypertriglyceridemia and impaired insulin sensitivity (P < 0.05). Administration of CFE to high-fat diet-fed rats for 90 days resulted in a significant improvement in plasma glucose, insulin, leptin, and triglycerides. Regarding liver antioxidant status, high-fat fed rats showed higher levels of lipid peroxidation, protein oxidation and lower GSH levels and lower activities of enzymatic antioxidants, while CFE treatment prevented all these observed abnormalities. In conclusion, intake of CFE may be beneficial for the suppression of high-fat diet-induced insulin resistance and oxidative stress. Topics: Alcohols; Animals; Apocynaceae; Blood Glucose; Body Weight; Diet, High-Fat; Insulin; Insulin Resistance; Leptin; Male; Oxidative Stress; Plant Extracts; Rats; Rats, Wistar; Triglycerides | 2014 |
Leptin receptor-deficient (knockout) medaka, Oryzias latipes, show chronical up-regulated levels of orexigenic neuropeptides, elevated food intake and stage specific effects on growth and fat allocation.
The first studies that identified leptin and its receptor (LepR) in mammals were based on mutant animals that displayed dramatic changes in body-weight and regulation of energy homeostasis. Subsequent studies have shown that a deficiency of leptin or LepR in homoeothermic mammals results in hyperphagia, obesity, infertility and a number of other abnormalities. The physiological roles of leptin-mediated signaling in ectothermic teleosts are still being explored. Here, we produced medaka with homozygous LepR gene mutation using the targeting induced local lesions in a genome method. This knockout mutant had a point mutation of cysteine for stop codon at the 357th amino acid just before the leptin-binding domain. The evidence for loss of function of leptin-mediated signaling in the mutant is based on a lack of response to feeding in the expression of key appetite-related neuropeptides in the diencephalon. The mutant lepr−/− medaka expressed constant up-regulated levels of mRNA for the orexigenic neuropeptide Ya and agouti-related protein and a suppressed level of anorexigenic proopiomelanocortin 1 in the diencephalon independent of feeding, which suggests that the mutant did not possess functional LepR. Phenotypes of the LepR-mutant medaka were analyzed in order to understand the effects on food intake, growth, and fat accumulation in the tissues. The food intake of the mutant medaka was higher in post-juveniles and adult stages than that of wild-type (WT) fish. The hyperphagia led to a high growth rate at the post-juvenile stage, but did not to significant alterations in final adult body size. There was no additional deposition of fat in the liver and muscle in the post-juvenile and adult mutants, or in the blood plasma in the adult mutant. However, adult LepR mutants possessed large deposits of visceral fat, unlike in the WT fish, in which there were none. Our analysis confirms that LepR in medaka exert a powerful influence on the control on food intake. Further analyses using the mutant will contribute to a better understanding of the role of leptin in fish. This is the first study to produce fish with leptin receptor deficiency. Topics: Agouti-Related Protein; Animals; Animals, Genetically Modified; Appetite; Body Weight; Diencephalon; Eating; Gene Knockout Techniques; Hyperphagia; Intra-Abdominal Fat; Leptin; Mutation; Neuropeptides; Obesity; Oryzias; Receptors, Leptin; Up-Regulation | 2014 |
Oxytocin reverses ovariectomy-induced osteopenia and body fat gain.
Osteoporosis and overweight/obesity constitute major worldwide public health burdens that are associated with aging. A high proportion of women develop osteoporosis and increased intraabdominal adiposity after menopause. which leads to bone fractures and metabolic disorders. There is no efficient treatment without major side effects for these 2 diseases. We previously showed that the administration of oxytocin (OT) normalizes ovariectomy-induced osteopenia and bone marrow adiposity in mice. Ovariectomized mice, used as an animal model mimicking menopause, were treated with OT or vehicle. Trabecular bone parameters and fat mass were analyzed using micro-computed tomography. Herein, we show that this effect on trabecular bone parameters was mediated through the restoration of osteoblast/osteoclast cross talk via the receptor activator of nuclear factor-κB ligand /osteoprotegerin axis. Moreover, the daily administration of OT normalized body weight and intraabdominal fat depots in ovariectomized mice. Intraabdominal fat mass is more sensitive to OT that sc fat depots, and this inhibitory effect is mediated through inhibition of adipocyte precursor's differentiation with a tendency to lower adipocyte size. OT treatment did not affect food intake, locomotors activity, or energy expenditure, but it did promote a shift in fuel utilization favoring lipid oxidation. In addition, the decrease in fat mass resulted from the inhibition of the adipose precursor's differentiation. Thus, OT constitutes an effective strategy for targeting osteopenia, overweight, and fat mass redistribution without any detrimental effects in a mouse model mimicking the menopause. Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Bone Diseases, Metabolic; Cell Culture Techniques; Coculture Techniques; Disease Models, Animal; Female; Leptin; Lipids; Menopause; Mice; Mice, Inbred C57BL; Osteoblasts; Osteoclasts; Osteoporosis; Ovariectomy; Oxygen; Oxytocin; Weight Gain; X-Ray Microtomography | 2014 |
Temporal changes in nutritional state affect hypothalamic POMC peptide levels independently of leptin in adult male mice.
Hypothalamic proopiomelanocortin (POMC) neurons constitute a critical anorexigenic node in the central nervous system (CNS) for maintaining energy balance. These neurons directly affect energy expenditure and feeding behavior by releasing bioactive neuropeptides but are also subject to signals directly related to nutritional state such as the adipokine leptin. To further investigate the interaction of diet and leptin on hypothalamic POMC peptide levels, we exposed 8- to 10-wk-old male POMC-Discosoma red fluorescent protein (DsRed) transgenic reporter mice to either 24-48 h (acute) or 2 wk (chronic) food restriction, high-fat diet (HFD), or leptin treatment. Using semiquantitative immunofluorescence and radioimmunoassays, we discovered that acute fasting and chronic food restriction decreased the levels of adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone (α-MSH), and β-endorphin in the hypothalamus, together with decreased DsRed fluorescence, compared with control ad libitum-fed mice. Furthermore, acute but not chronic HFD or leptin administration selectively increased α-MSH levels in POMC fibers and increased DsRed fluorescence in POMC cell bodies. HFD and leptin treatments comparably increased circulating leptin levels at both time points, suggesting that transcription of Pomc and synthesis of POMC peptide products are not modified in direct relation to the concentration of plasma leptin. Our findings indicate that negative energy balance persistently downregulated POMC peptide levels, and this phenomenon may be partially explained by decreased leptin levels, since these changes were blocked in fasted mice treated with leptin. In contrast, sustained elevation of plasma leptin by HFD or hormone supplementation did not significantly alter POMC peptide levels, indicating that enhanced leptin signaling does not chronically increase Pomc transcription and peptide synthesis. Topics: Animals; Body Weight; Diet; Eating; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nutritional Status; Pro-Opiomelanocortin; Time Factors | 2014 |
Hepatic glucose intolerance precedes hepatic steatosis in the male aromatase knockout (ArKO) mouse.
Estrogens are known to play a role in modulating metabolic processes within the body. The Aromatase knockout (ArKO) mice have been shown to harbor factors of Metabolic syndrome with central adiposity, hyperinsulinemia and male-specific hepatic steatosis. To determine the effects of estrogen ablation and subsequent replacement in males on whole body glucose metabolism, three- and six-month-old male ArKO mice were subjected to whole body glucose, insulin and pyruvate tolerance tests and analyzed for ensuing metabolic changes in liver, adipose tissue, and skeletal muscle. Estrogen-deficient male ArKO mice showed increased gonadal adiposity which was significantly reduced upon 17β-estradiol (E2) treatment. Concurrently, elevated ArKO serum leptin levels were significantly reduced upon E2 treatment and lowered serum adiponectin levels were restored to wild type levels. Three-month-old male ArKO mice were hyperglycemic, and both glucose and pyruvate intolerant. These phenotypes continued through to 6 months of age, highlighting a loss of glycemic control. ArKO livers displayed changes in gluconeogenic enzyme expression, and in insulin signaling pathways upon E2 treatment. Liver triglycerides were increased in the ArKO males only after 6 months of age, which could be reversed by E2 treatment. No differences were observed in insulin-stimulated ex vivo muscle glucose uptake nor changes in ArKO adipose tissue and muscle insulin signaling pathways. Therefore, we conclude that male ArKO mice develop hepatic glucose intolerance by the age of 3 months which precedes the sex-specific development of hepatic steatosis. This can be reversed upon the administration of exogenous E2. Topics: Adiponectin; Adipose Tissue; Animals; Aromatase; Blood Glucose; Body Weight; Estrogens; Gluconeogenesis; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscles; Organ Size; Phosphorylation; Pyruvic Acid; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Triglycerides | 2014 |
A twin study of differences in the response of plasma ghrelin to a milkshake preload in restrained eaters.
Genetic, physiological, and psychological factors can affect food intake, but twin studies can distinguish inherited from environmental contributors. We examined the influence of attempted cognitive control of eating ("restrained eating") on levels of appetite-regulating hormones.. Sixteen female, monozygotic twin pairs, discordant for Restraint Scale score (i.e., one twin a restrained eater with score>15 whereas the co-twin was unrestrained), were selected from the University of Washington Twin Registry. Serial plasma ghrelin concentrations were monitored during meals and a preload study paradigm involving intake of a milkshake followed by an ad libitum ice cream "taste test.". Body weight, body mass index, resting energy expenditure, and fasting leptin levels were very similar between restrained and unrestrained twins. In a preload study, twins ate similar amounts of ice cream shortly after drinking identical milkshakes (mean±SD; restrained 239±158 vs. unrestrained 228±132kcal; P=0.83). However, ghrelin concentrations during the preload study were significantly higher (P=0.03) in restrained twins than in their unrestrained co-twins. Regardless of restraint status, ghrelin levels prior to the preload study were prospectively and positively associated with ice cream intake (P=0.001).. Compared to their unrestrained co-twins, restrained twins had higher endogenous ghrelin levels during a preload study, but ate similar amounts. This finding is consistent with exertion of cognitive control relative to the state of physiologic appetite stimulation. Moreover, these findings in twins suggest that higher ghrelin levels result from restrained eating behavior and not from genetic predisposition. Topics: Adolescent; Adult; Body Mass Index; Body Weight; Eating; Energy Intake; Executive Function; Fasting; Feeding Behavior; Female; Ghrelin; Humans; Ice Cream; Leptin; Twins, Monozygotic; Young Adult | 2014 |
Spexin is a novel human peptide that reduces adipocyte uptake of long chain fatty acids and causes weight loss in rodents with diet-induced obesity.
Microarray studies identified Ch12:orf39 (Spexin) as the most down-regulated gene in obese human fat. Therefore, we examined its role in obesity pathogenesis.. Spexin effects on food intake, meal patterns, body weight, respiratory exchange ratio (RER), and locomotor activity were monitored electronically in C57BL/6J mice or Wistar rats with diet-induced obesity (DIO). Its effects on adipocyte [(3)H]-oleate uptake were determined.. In humans, Spexin gene expression was down-regulated 14.9-fold in obese omental and subcutaneous fat. Circulating Spexin changed in parallel, correlating (r = -0.797) with Leptin. In rats, Spexin (35 µg/kg/day SC) reduced caloric intake ∼32% with corresponding weight loss. Meal patterns were unaffected. In mice, Spexin (25 µg/kg/day IP) significantly reduced the RER at night, and increased locomotion. Spexin incubation in vitro significantly inhibited facilitated fatty acid (FA) uptake into DIO mouse adipocytes. Conditioned taste aversion testing (70 µg/kg/day IP) demonstrated no aversive Spexin effects.. Spexin gene expression is markedly down-regulated in obese human fat. The peptide produces weight loss in DIO rodents. Its effects on appetite and energy regulation are presumably central; those on adipocyte FA uptake appear direct and peripheral. Spexin is a novel hormone involved in weight regulation, with potential for obesity therapy. Topics: Adipocytes; Animals; Body Weight; Down-Regulation; Eating; Energy Intake; Fatty Acids; Feeding Behavior; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oleic Acid; Peptide Hormones; Protein Array Analysis; Rats; Rats, Wistar; Weight Loss | 2014 |
Long-term commercial cow's milk consumption and its effects on metabolic parameters associated with obesity in young mice.
Research has demonstrated that consumption of milk promotes weight loss and satiety, however conflicting evidence also exists. Therefore, we tested the effect of long-term milk consumption on body weight and metabolic parameters.. Newly weaned mice received whole milk, low-fat milk, or water as control for 17 weeks and serum, liver, and white adipose tissue (WAT) were tested for parameters associated with obesity and diabetes. Our results show that low-fat milk leads to the same overall caloric intake and body weight as the control group. However, the whole-milk group consumed more calories and reached a higher body weight. In addition, in the low-fat milk group, cholesterol, HDL-cholesterol, triglycerides, leptin, ghrelin, insulin, corticosterone, and glucagon were not significantly different than the control group. In contrast, in the whole-milk group, cholesterol, HDL-cholesterol, triglycerides, and glucagon were high compared with the control group. Metabolism in both liver and WAT showed only slight differences between the milk groups. Whereas the whole-milk group showed reduced insulin signaling in WAT, the low-fat milk group exhibited increased insulin signaling.. Whole-milk consumption leads to increased body weight and caloric intake and reduced insulin signaling in WAT, as opposed to low-fat milk consumption. Topics: Adipose Tissue, White; Amino Acids, Branched-Chain; Animals; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Corticosterone; Ghrelin; Glucagon; Hormones; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Milk; Obesity; Time Factors; Triglycerides | 2014 |
Extended exposure to a palatable cafeteria diet alters gene expression in brain regions implicated in reward, and withdrawal from this diet alters gene expression in brain regions associated with stress.
Like people, rodents exposed to energy-rich foods over-eat and become overweight. Removal of this diet activates stress systems, which may explain why people have difficulty dieting. We exposed rats to energy-rich foods in order to identify changes in the brain induced by that diet and by its removal. Sprague Dawley rats were fed lab-chow or an energy-rich cafeteria diet (plus chow). Following 6 or 15 weeks, half of each group was switched to the opposing diet. Rats were culled 48-h later. We measured fat mass, plasma hormones, and assessed brains for mRNA expression of several genes. Cafeteria-fed rats consumed more kilojoules, weighed more and had elevated leptin (plus reduced CORT at 15 weeks) relative to chow-fed rats. Fifteen weeks of cafeteria diet suppressed μ-opioid and CB1 receptor mRNA in the VTA, but elevated amygdala GR, and 6 weeks of cafeteria diet reduced BDNF, compared to chow-fed rats. Rats switched to the cafeteria diet ate similar amounts as rats maintained on the diet, and switching to cafeteria diet after 15 weeks reduced amygdala GR expression. Rats switched to chow ate less than rats maintained on chow, and switching to chow following 15 weeks of cafeteria diet increased hypothalamic CRH mRNA. Therefore, 15 weeks of cafeteria diet produced changes in brain regions implicated in reward processes. Switching these rats to chow activated the HPA axis, while switching chow-fed rats to the cafeteria diet decreased GR expression in the amygdala, a region associated with stress. These findings have implications for dieting in humans. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Brain; Corticosterone; Energy Intake; Feeding Behavior; Food, Formulated; Gene Expression Regulation; Insulin; Leptin; Male; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Opioid, mu; Stress, Physiological; Time Factors | 2014 |
The anti-tumor activity of a neutralizing nanobody targeting leptin receptor in a mouse model of melanoma.
Environmental and genetic activation of a brain-adipocyte axis inhibits cancer progression. Leptin is the primary peripheral mediator of this anticancer effect in a mouse model of melanoma. In this study we assessed the effect of a leptin receptor antagonist on melanoma progression. Local administration of a neutralizing nanobody targeting the leptin receptor at low dose adjacent to tumor decreased tumor mass with no effects on body weight or food intake. In contrast, systemic administration of the nanobody failed to suppress tumor growth. Daily intraperitoneal injection of high-dose nanobody led to weight gain, hyperphagia, increased adiposity, hyperleptinemia, and hyperinsulinemia, and central effects mimicking leptin deficiency. The blockade of central actions of leptin by systemic delivery of nanobody may compromise its anticancer effect, underscoring the need to develop peripherally acting leptin antagonists coupled with efficient cancer-targeting delivery. Topics: Adiposity; Animals; Body Weight; Cell Line, Tumor; Hyperinsulinism; Hyperphagia; Leptin; Male; Melanoma; Mice; Mice, Inbred C57BL; Receptors, Leptin; Single-Domain Antibodies | 2014 |
Effects of the traditional Mediterranean diet on adiponectin and leptin concentrations in men and premenopausal women: do sex differences exist?
Most of the interventional studies have investigated the impact of the diet on adiponectin and leptin concentrations only in men or in women. Consequently, it is still unknown whether the consumption of a healthy diet influences in a sex-specific manner these adipocytokines. We examined sex differences in the effects of the Mediterranean diet (MedDiet) on adiponectin and leptin concentrations, and determined whether changes in these adipocytokines are associated with changes in cardiovascular risk factors in both sexes.. Participants were 38 men and 32 premenopausal women (24-53 years) with slightly elevated low-density lipoprotein cholesterol concentrations (3.4-4.9 mmol/l) or total cholesterol/high-density lipoprotein cholesterol (HDL-C)⩾5.0. Adiponectin, leptin and cardiovascular risk factors were measured before and after a 4-week fully controlled isoenergetic MedDiet.. Adiponectin concentration decreased in response to the MedDiet, but this decrease reached statistical significance only in men (P<0.001 for men and P=0.260 for women; sex-by-time interaction, P=0.072). Adjustments for body weight or waist circumference did not change results obtained. Changes in adiponectin were positively associated with concomitant variations in HDL-C in men (r=0.52, P=0.003) and with variations in apolipoprotein A-1 and insulin sensitivity as calculated by both the homeostasis model assessment index for insulin sensitivity and Cederholm indices in women (respectively, r=0.44, P=0.021; r=0.79, P<0.001 and r=0.47, P=0.020). The MedDiet had no impact on leptin and the leptin-to-adiponectin ratio in both sexes.. Results suggest a sex difference in adiponectin response to the short-term consumption of the MedDiet, with only men experiencing a decrease. Also sex-specific patterns of associations between changes in adiponectin concentration and changes in cardiovascular risk factors were observed. Topics: Adiponectin; Adult; Apolipoprotein A-I; Blood Pressure; Body Weight; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diet, Mediterranean; Female; Homeostasis; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Premenopause; Risk Factors; Sex Factors; Triglycerides; Waist Circumference; Young Adult | 2014 |
Lipid-lowering effects of Pediococcus acidilactici M76 isolated from Korean traditional makgeolli in high fat diet-induced obese mice.
The effect of Pediococcus acidilactici M76 (lactic acid bacteria) isolated from makgeolli on mice fed a high fat diet was investigated to clarify the lipid lowering function. C57BL/6J male mice were randomly divided into a normal diet (ND) group, high fat diet (HD) group, HD plus Pediococcus acidilactici DSM 20284 reference strain (PR) group, and HD plus Pediococcus acidilactici M76 strain (PA) groups. The lyophilized PA and PR strain were dissolved in distilled water at a final concentration of 1.25 × 10⁹ cfu/mL and was given orally to animals at a dose of 4 mL/kg body weight for 12 weeks. The PA group had a lower final body weight, adipose tissue weight, and lipid profile than those in the HD group. Additionally, level of ACC, FAS and PPAR-γ, a key lipid synthesis enzyme, was markedly suppressed in the PA compared to those in the HD group. These data suggest that P. acidilactici M76 may exert a lipid-lowering effect in high fat diet-induced obese mice. Topics: Adipose Tissue; Alanine Transaminase; Alcoholic Beverages; Animals; Aspartate Aminotransferases; Body Weight; Cholesterol; Diet, High-Fat; Energy Intake; Hypolipidemic Agents; Insulin; Leptin; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pediococcus; PPAR gamma; RNA, Messenger; Triglycerides | 2014 |
Effect of restricted feeding on nocturnality and daily leptin rhythms in OVLT in aged male Wistar rats.
Circadian system has direct relevance to the problems of modern lifestyle, shift workers, jet lag etc. To understand non-photic regulation of biological clock, the effects of restricted feeding (RF) on locomotor activity and daily leptin immunoreactivity (ir) rhythms in three age groups [3, 12 and 24 months (m)] of male Wistar rats maintained in light:dark (LD) 12:12 h conditions were studied. Leptin-ir was examined in the suprachiasmatic nucleus (SCN), the medial preoptic area (MPOA) and organum vasculosum of the lamina terminalis (OVLT). Reversal of feeding time due to restricted food availability during daytime resulted in switching of the animals from nocturnality to diurnality with significant increase in day time activity and decrease in night time activity. The RF resulted in % diurnality of approximately 32, 29 and 73 from % nocturnality of 82, 92 and 89 in control rats of 3, 12 and 24 m age, respectively. The increase in such switching from nocturnality to diurnality with restricted feeding was found to be robust in 24 m rats. The OVLT region showed daily leptin-ir rhythms with leptin-ir maximum at ZT-0 in all the three age groups. However leptin-ir levels were minimum at ZT-12 in 3 and 12 m though at ZT-18 in 24 m. In addition the mean leptin-ir levels decreased with increase in food intake and body weight significantly in RF aged rats. Thus we report here differential effects of food entrained regulation in switching nocturnality to diurnality and daily leptin-ir rhythms in OVLT in aged rats. Topics: Animals; Body Weight; Caloric Restriction; Circadian Rhythm; Eating; Hypothalamus, Anterior; Leptin; Male; Motor Activity; Organum Vasculosum; Photoperiod; Preoptic Area; Rats, Wistar; Suprachiasmatic Nucleus | 2014 |
The impact of maternal consumption of cafeteria diet on reproductive function in the offspring.
Maternal obesity is a risk factor for the development of metabolic syndrome and childhood obesity, and early overnutrition seems to induce the development of pathologies in adulthood, including insulin resistance, cardiovascular diseases, type 2 diabetes mellitus, and a higher BMI. In addition, it is known that obesity can negatively affect fertility and reproductive function in men. The objective of this work was to investigate the impact of maternal obesity induced by the consumption of cafeteria diet on metabolic, endocrine and reproductive outcomes in the male offspring. Body weight, abdominal fat content and concentrations of insulin, leptin, glucose and total cholesterol were analyzed in dams. The same parameters were evaluated in pups when in adulthood, in addition to the analysis of sexual behavior, followed by measurement of plasma luteinizing hormone, follicle-stimulating hormone, testosterone, and prolactin. Maternal consumption of cafeteria diet affected reproductive hormone regulation in the offspring and such modifications were reflected on sexual performance. Also, these modifications were independent of time and of the reproductive period during which dams consumed the diet. Our results indicate, for the first time, that maternal nutrition may have a deep impact on the reproductive function of the adult male offspring. Topics: Abdominal Fat; Animals; Blood Glucose; Body Weight; Cholesterol; Diet; Female; Follicle Stimulating Hormone; Insulin; Leptin; Luteinizing Hormone; Male; Maternal Nutritional Physiological Phenomena; Obesity; Prolactin; Rats, Wistar; Reproduction; Sexual Behavior, Animal; Testosterone | 2014 |
Muscle-specific interleukin-6 deletion influences body weight and body fat in a sex-dependent manner.
Interleukin-6 (IL-6) is a major cytokine controlling not only the immune system but also basic physiological variables such as body weight and metabolism. While central IL-6 is clearly implicated in the latter, the putative role of peripheral IL-6 controlling body weight remains unclear. We herewith report results obtained in muscle-specific IL-6 KO (mIL-6 KO) mice. mIL-6 KO male mice fed a high-fat diet (HFD, 58.4% kcal from fat) or a control diet (18%) gained less weight and body fat than littermate floxed male mice, while the opposite pattern was observed in female mice. Food intake was not affected by muscle IL-6 deficiency, but male and female mIL-6 KO mice were more and less active, respectively, in the hole-board test. Moreover, female mIL-6 KO mice did not control adequately their body temperature upon exposure to 4°C, suggesting a role of muscle IL-6 in energy expenditure. At least part of this regulatory role of muscle IL-6 may be mediated by the hypothalamus, as IL-6 deficiency regulated the expression of critical hypothalamic neuropeptides (NPY, AgRP, POMC, CRH and preproOX). Leptin and insulin changes cannot explain the phenotype of these mice. In summary, the present results demonstrate that muscle IL-6 controls body weight and body fat in a sex-specific fashion, influencing the expression of the main neuropeptides involved in energy homeostasis. Topics: Adipose Tissue; Animals; Blood Glucose; Body Temperature Regulation; Body Weight; Energy Metabolism; Female; Hypothalamus; Insulin; Interleukin-6; Leptin; Male; Mice; Mice, Knockout; Muscle, Skeletal; Neuropeptides; Obesity; Sex Factors | 2014 |
Central mechanisms of adiposity in adult female mice with androgen excess.
Androgen excess in women is associated with visceral adiposity. However, little is known on the mechanism through which androgen promotes visceral fat accumulation.. To address this issue, female mice to chronic androgen excess using 5α-dihydrotestosterone (DHT) and studied the regulation of energy homeostasis was exposed.. DHT induced a leptin failure to decrease body weight associated with visceral adiposity but without alterations in leptin anorectic action. This paralleled leptin's failure to upregulate brown adipose tissue expression of uncoupling protein-1, associated with decreased energy expenditure (EE). DHT decreased hypothalamic proopiomelanocortin (pomc) mRNA expression and increased POMC intensity in neuronal bodies of the arcuate nucleus while simultaneously decreasing the intensity of POMC projections to the dorsomedial hypothalamus (DMH). This was associated with a failure of the melanocortin 4 receptor agonist melanotan-II to suppress body weight.. Taken together, these data indicate that androgen excess promotes visceral adiposity with reduced POMC neuronal innervation in the DMH, reduced EE but without hyperphagia. Topics: Adipose Tissue, Brown; Adiposity; alpha-MSH; Androgens; Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Body Weight; Dihydrotestosterone; Energy Metabolism; Female; Hyperphagia; Hypothalamus; Intra-Abdominal Fat; Ion Channels; Leptin; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Obesity; Peptides, Cyclic; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; RNA, Messenger; Uncoupling Protein 1; Up-Regulation | 2014 |
Central inflammation and leptin resistance are attenuated by ginsenoside Rb1 treatment in obese mice fed a high-fat diet.
A low-grade pro-inflammatory state is at the pathogenic core of obesity and type 2 diabetes. We tested the hypothesis that the plant terpenoid compound ginsenoside Rb1 (Rb1), known to exert anti-inflammatory effects, would ameliorate obesity, obesity-associated inflammation and glucose intolerance in the high-fat diet-induced obese mouse model. Furthermore, we examined the effect of Rb1 treatment on central leptin sensitivity and the leptin signaling pathway in the hypothalamus. We found that intraperitoneal injections of Rb1 (14 mg/kg, daily) for 21 days significantly reduced body weight gain, fat mass accumulation, and improved glucose tolerance in obese mice on a HF diet compared to vehicle treatment. Importantly, Rb1 treatment also reduced levels of pro-inflammatory cytokines (TNF-α, IL-6 and/or IL-1β) and NF-κB pathway molecules (p-IKK and p-IκBα) in adipose tissue and liver. In the hypothalamus, Rb1 treatment decreased the expression of inflammatory markers (IL-6, IL-1β and p-IKK) and negative regulators of leptin signaling (SOCS3 and PTP1B). Furthermore, Rb1 treatment also restored the anorexic effect of leptin in high-fat fed mice as well as leptin pSTAT3 signaling in the hypothalamus. Ginsenoside Rb1 has potential for use as an anti-obesity therapeutic agent that modulates obesity-induced inflammation and improves central leptin sensitivity in HF diet-induced obesity. Topics: Adiposity; Animals; Body Weight; Diet, High-Fat; Energy Metabolism; Ginsenosides; Glucose; Glucose Tolerance Test; Hormones; Hypothalamus; Inflammation; Leptin; Male; Mice; Mice, Obese; Neuropeptides; Obesity; Signal Transduction; Time Factors | 2014 |
Age versus nutritional state in the development of central leptin resistance.
Leptin, a catabolic adiposity signal acts in the hypothalamus via suppressing food intake and inducing hypermetabolism. Age and obesity are accompanied by leptin resistance. The present study aimed to clarify which components of the catabolic leptin effects are influenced most strongly by aging and which ones by nutritional state-induced alterations in body composition. In our biotelemetric study the effects of a 7-day intracerebroventricular leptin infusion on various parameters of energy balance (food intake, body weight, oxygen consumption, heart rate and body temperature) were analyzed in male Wistar rats of different age-groups (from 3 to 24 months) and nutritional states (normally fed, diet-induced obese and calorie-restricted). Leptin resistance of older animals affected hypermetabolic actions, whereas leptin induced anorexia in all age-groups. Weight reducing effect of leptin diminished in middle-aged and aging animals to become significant again in the oldest group. In diet-induced obese rats leptin-induced hypermetabolism of the young rats and hypermetabolism plus anorexia of the aging ones were suppressed. Calorie-restriction reduced body weight and fat mass to a similar extent in all age-groups. It strongly enhanced leptin-induced hypermetabolism at all ages and prevented the manifestation of anorexigenic actions of leptin with the exception of the oldest group. This latter finding suggests an unexpected increase of responsiveness to anorexigenic leptin actions in old rats. Accordingly, anorexia and hypermetabolism change in disparate ways with aging. Nutritional state predominantly influences hypermetabolic leptin actions. Resistance to both hypermetabolic and anorexigenic actions were promoted by obesity, while calorie-restriction enhanced responsiveness to leptin, especially in old rats. Topics: Aging; Animals; Body Composition; Body Weight; Caloric Restriction; Energy Metabolism; Leptin; Male; Obesity; Rats; Rats, Wistar | 2014 |
Identification of genetic loci associated with different responses to high-fat diet-induced obesity in C57BL/6N and C57BL/6J substrains.
We have recently demonstrated that C57BL/6NTac and C57BL/6JRj substrains are significantly different in their response to high-fat diet-induced obesity (DIO). The C57BL/6JRj substrain seems to be protected from DIO and genetic differences between C57BL/6J and C57BL/6N substrains at 11 single nucleotide polymorphism (SNP) loci have been identified. To define genetic variants as well as differences in parameters of glucose homeostasis and insulin sensitivity between C57BL/6NTac and C57BL/6JRj substrains that may explain the different response to DIO, we analyzed 208 first backcross (BC1) hybrids of C57BL/6NTac and C57BL/6JRj [(C57BL/6NTac × C57BL/6JRj)F1 × C57BL/6NTac] mice. Body weight, epigonadal and subcutaneous fat mass, circulating leptin, as well as parameters of glucose metabolism were measured after 10 wk of high-fat diet (HFD). Genetic profiling of BC1 hybrids were performed using TaqMan SNP genotyping assays. Furthermore, to assess whether SNP polymorphisms could affect mRNA level, we carried out gene expression analysis in murine liver samples. Human subcutaneous adipose tissue was used to verify murine data of SNAP29. We identified four sex-specific variants that are associated with the extent of HFD-induced weight gain and fat depot mass. BC1 hybrids carrying the combination of risk or beneficial alleles exhibit the phenotypical extremes of the parental strains. Murine and human SC expression analysis revealed Snap29 as strongest candidate. Our data indicate an important role of these loci in responsiveness to HFD-induced obesity and suggest genes of the synaptic vesicle release system such as Snap29 being involved in the regulation of high-fat DIO. Topics: Adipose Tissue; Alleles; Animals; Body Weight; Diet, High-Fat; Female; Genetic Loci; Genotype; Glucose; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Vesicular Transport Proteins; Weight Gain | 2014 |
Prenatal exposure to glucocorticoids affects body weight, serum leptin levels, and hypothalamic neuropeptide-Y expression in pre-pubertal female rat offspring.
Glucocorticoid secretion is a key endocrine response to stress. It has been reported that prenatal stress induces long-lasting alterations in body weight regulation systems, which persist after the stress has ceased. In this study, the long-term effects of prenatal glucocorticoid exposure on body weight changes and the expression of appetite-regulating factors were examined in female rats. Pregnant rats were given normal drinking water (control) or dexamethasone (1 μg/mL) dissolved in drinking water (DEX) from day 13 of pregnancy until delivery. Then, the body weight change, serum leptin levels, and hypothalamic NPY mRNA levels of their offspring were examined. The DEX dams gained significantly less body weight during pregnancy than the control dams. The DEX dams' offspring exhibited a significantly lower birth weight than the offspring of the control dams, and the same was true for body weight at postnatal days 20 and 28. The offspring of the DEX dams displayed significantly higher serum leptin levels and significantly lower hypothalamic NPY mRNA levels compared with the offspring of the control dams. Significant inverse correlations were detected between body weight and the serum leptin level, and between the serum leptin level and the hypothalamic NPY mRNA level. On the other hand, a significant positive correlation was detected between body weight and the hypothalamic NPY mRNA level. These results indicate that leptin production is increased in a long-lasting manner in offspring exposed to glucocorticoids during the prenatal period and that this results in attenuated body weight gain and hypothalamic NPY expression during the pre-pubertal period. Topics: Animals; Animals, Newborn; Body Weight; Dexamethasone; Female; Glucocorticoids; Hypothalamus; Leptin; Male; Neuropeptide Y; Pregnancy; Prenatal Exposure Delayed Effects; Radioimmunoassay; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors | 2014 |
Microbiome: A complicated relationship status.
Topics: Animals; Bacteroidetes; Body Mass Index; Body Weight; Case-Control Studies; Diet; Enterobacter; Feces; Gastrointestinal Transit; Germ-Free Life; Gram-Positive Bacteria; Humans; Intestines; Leptin; Male; Metagenome; Mice; Microbiota; Obesity; Prebiotics; Species Specificity; Verrucomicrobia | 2014 |
[Major hypoglycemic ingredients of Panax notoginseng saponins for treating diabetes].
To explore the mechanism of Panax notoginseng saponins (PNS) on diabetes treatment and mass loss in KK-Ay mice with genetic type 2 diabetes mellitus (DM), and to identify the main hypoglycemic ingredients.. C57 and KK-Ay DM mice were divided into eight groups each comprising six mice: healthy normal, DM model, and DM model treated with PNS (200 mg/kg body mass), ginsenoside Re (Re, 14 mg/kg body mass), ginsenoside Rd (Rd, 15 mg/kg body mass), ginsenoside Rgl (Rg1, 40 mg/kg body mass), ginsenoside Rb1 (Rb1, 60 mg/kg body mass) and notoginsenoside R1 (R1, 6 mg/kg body mass). The PNS were intraperitoneal injection administered for 30 d, while the Re, RB1, Rg1, Rd and Re were intraperitoneal injection administered for 12 d. The fasting blood sugar (FBG), glucose tolerance (GT), serum insulin, leptin, body weight, food consumption, and levels of adipose tissue and blood lipid were determined.. On 12 d, lower FBG levels were found in the PNS and Rb1 treated mice compared with the model mice (P < 0.05). No statistical differences in FBG levels were found between the rest of the treatment groups and the model group (P > 0.05). After 30 d continuous administration of PNS, the FBG level of the mice further declined (P < 0.01). Meanwhile, the serum insulin (P < 0.05) and insulin resistance index (P < 0.01) of the PNS treated mice also declined significantly. Compared with model group, the PNS group had lower levels of body weight growth, food consumption, adipose tissue, and leptin (P < 0.05). Lower FBG level was also found in Rb1 treated mice (12 d of administration), P < 0.05.. PNS has anti-hyperglycemic and anti-obesity activities by improving insulin and leptin sensitivities in KK-Ay mice. Rb1 may be the hypoglycemic ingredient in the PNS extract. Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Ginsenosides; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Lipids; Mice; Mice, Inbred C57BL; Obesity; Panax notoginseng; Saponins | 2014 |
Genetic variations in the leptin gene associated with growth and carcass traits in Nellore cattle.
The aim of the study was to detect polymorphisms in the leptin gene and to determine the association of these polymorphisms with growth and carcass traits in Nellore cattle. The single nucleotide polymorphisms (SNPs) -1457 (AJ571671:g.-1457A>G) and A59V (AF536174.1:g. 321C>T), as well as the microsatellite BM1500 (3.9 kb downstream), were genotyped. The measures of body weight and ultrasound examinations (rib eye area, back, and rump fat thickness) were performed in 3 different periods of animal management. During the first period, the animals were fed with grass and mineralized salt ad libitum. In the second period, they received grass and concentrate, and in the third, only concentrate. After the slaughter of animals, data were collected for classification and typification of carcasses. No significant association was found between the variables assessed and SNP -1457. Conversely, SNP A59V was associated with rump fat thickness and muscle color post-slaughter. BM1500 was associated with rump fat thickness in the first period (pre-slaughter), subcutaneous fat thickness in the second, weight of the animals in the third, and length of the carcass after slaughter. These results suggest that SNP A59V and the microsatellite BM1500 might be useful for marker-assisted selection in Nellore cattle. Topics: Animals; Body Weight; Cattle; Genetic Association Studies; Leptin; Meat; Phenotype; Polymorphism, Single Nucleotide | 2014 |
Role of orexin in respiratory and sleep homeostasis during upper airway obstruction in rats.
Chronic upper airway obstruction (UAO) elicits a cascade of complex endocrine derangements that affect growth, sleep, and energy metabolism. We hypothesized that elevated hypothalamic orexin has a role in maintaining ventilation during UAO, while at the same time altering sleep-wake activity and energy metabolism. Here, we sought to explore the UAO-induced changes in hypothalamic orexin and their role in sleep-wake balance, respiratory activity, and energy metabolism.. The tracheae of 22-day-old Sprague-Dawley rats were surgically narrowed; UAO and sham-operated control animals were monitored for 7 weeks. We measured food intake, body weight, temperature, locomotion, and sleep-wake activity. Magnetic resonance imaging was used to quantify subcutaneous and visceral fat tissue volumes. In week 7, the rats were sacrificed and levels of hypothalamic orexin, serum leptin, and corticosterone were determined. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and respiration was also explored.. UAO increased hypothalamic orexin mRNA and protein content by 64% and 65%, respectively. UAO led to 30% chronic sleep loss, excessive active phase sleepiness, decreased body temperature, increased food intake, reduction of abdominal and subcutaneous fat tissue volume, and growth retardation. Administration of almorexant normalized sleep but induced severe breathing difficulties in UAO rats, while it had no effect on sleep or on breathing of control animals.. In upper airway obstruction animals, enhanced orexin secretion, while crucially important for respiratory homeostasis maintenance, is also responsible for chronic partial sleep loss, as well as considerable impairment of energy metabolism and growth. Topics: Acetamides; Airway Obstruction; Animals; Body Temperature; Body Weight; Corticosterone; Eating; Energy Metabolism; Homeostasis; Hypothalamus; Intracellular Signaling Peptides and Proteins; Isoquinolines; Leptin; Locomotion; Male; Neuropeptides; Orexins; Rats; Rats, Sprague-Dawley; Respiration; Sleep; Sleep Stages; Subcutaneous Fat, Abdominal; Wakefulness | 2014 |
Intermittent fasting induces hypothalamic modifications resulting in low feeding efficiency, low body mass and overeating.
Intermittent fasting (IF) is an often-used intervention to decrease body mass. In male Sprague-Dawley rats, 24 hour cycles of IF result in light caloric restriction, reduced body mass gain, and significant decreases in the efficiency of energy conversion. Here, we study the metabolic effects of IF in order to uncover mechanisms involved in this lower energy conversion efficiency. After 3 weeks, IF animals displayed overeating during fed periods and lower body mass, accompanied by alterations in energy-related tissue mass. The lower efficiency of energy use was not due to uncoupling of muscle mitochondria. Enhanced lipid oxidation was observed during fasting days, whereas fed days were accompanied by higher metabolic rates. Furthermore, an increased expression of orexigenic neurotransmitters AGRP and NPY in the hypothalamus of IF animals was found, even on feeding days, which could explain the overeating pattern. Together, these effects provide a mechanistic explanation for the lower efficiency of energy conversion observed. Overall, we find that IF promotes changes in hypothalamic function that explain differences in body mass and caloric intake. Topics: Agouti-Related Protein; Animals; Body Weight; Eating; Energy Metabolism; Fasting; Feeding Behavior; Gene Expression; Hyperphagia; Hypothalamus; Immunoblotting; Leptin; Lipid Metabolism; Male; Mitochondria, Muscle; Neuropeptide Y; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Thyrotropin-Releasing Hormone; Time Factors | 2014 |
Beverage from Coleus aromaticus reduces leptin levels and improves appetite rating in human volunteers.
Coleus aromaticus, commonly called country borage or Indian borage, is a perennial herb grown throughout the Indian subcontinent. Traditionally, the leaves of the plant are used as a cure for cold, cough, and fever as well as to relieve pain from skin irritations. However, the appetite-enhancing potential of the herb was unexplored. Based on the encouraging results of animal studies, this study was taken up to establish the appetite-enhancing potential of Coleus aromaticus in humans by evaluating its ready-to-drink beverage.. A homogenous and healthy group of volunteers was selected. Ready-to-drink beverages based on the herb karpurvalli (Coleus aromaticus) containing three different concentrations (12% [sensorily optimized level], 18%, and 24%) of the herb juice and a placebo beverage were evaluated with the volunteers. The fasting and postprandial levels of plasma leptin were measured, and the appetite rating on a structured visual analog scale was obtained.. The study revealed a significant reduction in leptin levels with 12% juice, whereas a significant increase was seen after consumption of the beverage containing 24%. A similar pattern was obtained with the structured ratings.. The appetite-enhancing effect of the beverage was best when it contained the sensorily optimized level of karpurvalli juice and confirms the results obtained in animal study. To our knowledge, this is the first study validating the appetite-enhancing potential of the herb. Topics: Adipose Tissue; Adult; Appetite; Beverages; Body Height; Body Mass Index; Body Weight; Coleus; Fasting; Female; Humans; Leptin; Male; Muscle, Skeletal; Plant Extracts; Plant Leaves; Postprandial Period; Young Adult | 2014 |
IKKε is key to induction of insulin resistance in the hypothalamus, and its inhibition reverses obesity.
IKK epsilon (IKKε) is induced by the activation of nuclear factor-κB (NF-κB). Whole-body IKKε knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKKε is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKKε in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-κB activation in this tissue, relieving the inflammatory environment. Inhibition of IKKε activity, but not TBK1, reduced IRS-1(Ser307) phosphorylation and insulin and leptin resistance by an improvement of the IR/IRS-1/Akt and JAK2/STAT3 pathways in the hypothalamus. These improvements were independent of body weight and food intake. Increased insulin and leptin action/signaling in the hypothalamus may contribute to a decrease in adiposity and hypophagia and an enhancement of energy expenditure accompanied by lower NPY and increased POMC mRNA levels. Improvement of hypothalamic insulin action decreases fasting glycemia, glycemia after pyruvate injection, and PEPCK protein expression in the liver of HFD-fed and db/db mice, suggesting a reduction in hepatic glucose production. We suggest that IKKε may be a key inflammatory mediator in the hypothalamus of obese mice, and its hypothalamic inhibition improves energy and glucose metabolism. Topics: Animals; Body Weight; Diet, High-Fat; Hypothalamus; I-kappa B Kinase; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Obese; Neurons; Obesity; Phosphorylation; Signal Transduction; Up-Regulation | 2014 |
Regulatory effects of resveratrol on glucose metabolism and T-lymphocyte subsets in the development of high-fat diet-induced obesity in C57BL/6 mice.
High-fat diet (HFD)-induced obesity is often associated with immune dysfunction. Resveratrol (trans-3,5,4'-trihydroxystilbene), which has well-founded immunity-related beneficial properties, was used to elucidate the regulatory effect on glucose metabolism and T-lymphocyte subsets in the development of HFD-induced obesity. Resveratrol, being associated with decreases of plasma leptin and plasma lipids and the release of oxidative stress, significantly decreased the body weight and fat masses in HF mice after 26 weeks of feeding. Furthermore, resveratrol decreased the fasting blood glucose and fasting plasma insulin and increased the CD3(+)CD4(+)/CD3(+)CD8(+) subsets percentages and the regulatory T cells (Tregs) production after 13 and 26 weeks of feeding. The results indicate that resveratrol, as an effective supplement for HFD, maintained glucose homeostasis by activating the PI3K and SIRT1 signaling pathways. Moreover, resveratrol activated the Nrf2 signaling pathway-mediated antioxidant enzyme expression to alleviate inflammation by protecting against oxidative damage and T-lymphocyte subset-related chronic inflammatory response in the development of HFD-induced obesity. Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Blood Glucose; Body Weight; Diet, High-Fat; Fasting; Female; Inflammation; Insulin; Leptin; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Obesity; Oxidative Stress; Phosphatidylinositol 3-Kinases; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; T-Lymphocyte Subsets | 2014 |
Leptin level and oxidative stress contribute to obesity-induced low testosterone in murine testicular tissue.
This study evaluated the effects of obesity on the function of reproductive organs in male mice and the possible mechanism of male secondary hypogonadism (SH) in obesity.. Ninety-six mice were randomly assigned to three groups: the control group, diet-induced obesity group, and diet-induced obesity resistant group for 8 weeks and 19 weeks. The effects of short- and long-term high-fat diet on the reproductive organs were determined by measuring sperm count and motility, relative testis weight, testosterone level, pathological changes and apoptosis of Leydig cells. Oxidative stress was evaluated by determining malondialdehyde, H2O2, NO levels, and GSH in testis tissues. CAT, SOD, GSH-Px and Nrf2 mRNA were measured by real-time PCR.. Short- and long-term high-fat diet decreased sperm count and motility, relative testis weight, testosterone level; decreased CAT, SOD, GSH-Px and Nrf2 mRNA expression; increased MDA, H2O2, NO and leptin levels; inhibited the activity of CAT and GSH-Px enzymes. Pathological injury and apoptosis of Leydig cells were found in testis tissue.. Pathological damage of Leydig cells, oxidative stress in testis tissue, and high level of leptin may provide some evidence to clarify the mechanisms of male SH in obesity. Topics: Animals; Apoptosis; Body Weight; Diet, High-Fat; Hypogonadism; Leptin; Leydig Cells; Male; Mice; Mice, Inbred C57BL; Obesity; Oxidative Stress; Oxidoreductases; Reactive Oxygen Species; RNA, Messenger; Spermatozoa; Testis; Testosterone | 2014 |
The role of leptin, melanocortin, and neurotrophin system genes on body weight in anorexia nervosa and bulimia nervosa.
Although low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings, in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN; and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN.. Our sample consisted of 745 individuals with AN without a history of BN, 245 individuals with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems.. There were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p = 0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p = 0.0018).. To our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetic research and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders. Topics: Adult; Agouti-Related Protein; Anorexia Nervosa; Body Mass Index; Body Weight; Bulimia Nervosa; Case-Control Studies; Female; Genotyping Techniques; Humans; Leptin; Melanocortins; Membrane Glycoproteins; Middle Aged; Nerve Growth Factors; Polymorphism, Single Nucleotide; Protein Kinases; Protein-Tyrosine Kinases; Receptor, trkB | 2014 |
Genetically altering organismal metabolism by leptin-deficiency benefits a mouse model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease that causes death of motor neurons. ALS patients and mouse models of familial ALS display organismal level metabolic dysfunction, which includes increased energy expenditure despite decreased lean mass. The pathophysiological relevance of abnormal energy homeostasis to motor neuron disease remains unclear. Leptin is an adipocyte-derived hormone that regulates whole-animal energy expenditure. Here, we report that placing mutant superoxide dismutase 1 (SOD1) mice in a leptin-deficient background improves energy homeostasis and slows disease progression. Leptin-deficient mutant SOD1 mice possess increased bodyweight and fat mass, as well as decreased energy expenditure. These observations coincide with enhanced survival, improved strength and decreased motor neuron loss. These results suggest that altering whole-body energy metabolism in mutant SOD1 mice can mitigate disease progression. We propose that manipulations that increase fat mass and reduce energy expenditure will be beneficial in the setting of motor neuron disease. Topics: Amyotrophic Lateral Sclerosis; Animals; Body Weight; Disease Models, Animal; Energy Metabolism; Humans; Leptin; Male; Mice; Motor Neurons; Muscle, Skeletal; Superoxide Dismutase; Superoxide Dismutase-1 | 2014 |
Effects of Ang II receptor blocker irbesartan on adipose tissue function in mice with metabolic disorders.
Recent studies indicate that the functional renin-angiotensin system (RAS) exists in the adipose tissue. The adipose tissue RAS is proposed in the pathophysiology of metabolic disorders. In the present study, we examined therapeutic effects of irbesartan, an angiotensin II (Ang II) type 1 receptor (AT1R)-specific blocker, in genetically obese diabetic KKAy mice, a model of human metabolic disorders without any dietary loading, with our focus on the analysis on possible effect of irbesartan on the adipose tissue. The treatment with irbesartan significantly lowered systolic blood pressure with a concomitant decrease in body weight in KKAy mice. In addition, irbesartan significantly decreased the adipose leptin mRNA expression and tended to decrease IL-6 mRNA expression in the adipose tissue of KKAy mice. Furthermore irbesartan preserved the adipose gene expression of AT1R-associated protein (ATRAP), an endogenous inhibitory molecule of tissue AT1R signaling, with a concomitant tendency of up-regulation of adipose tissue ATRAP/AT1R ratio. Collectively, these results suggest that the irbesartan-induced beneficial suppressive effect on the leptin-IL-6 axis in the adipose tissue in KKAy mice is partly mediated by a trend of up-regulation of the adipose ATRAP/AT1R ratio as one of pleiotropic effects of irbesartan. Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue; Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Blood Pressure; Body Weight; Humans; Irbesartan; Leptin; Mice; Obesity; Receptor, Angiotensin, Type 1; Signal Transduction; Tetrazoles | 2014 |
Rat strains with different metabolic statuses differ in food olfactory-driven behavior.
In most species, food intake is influenced by olfactory cues and metabolic status can affect the olfactory function of animals and regulate feeding-related behaviors. We investigated whether modulation of the endocrine system that regulates or modifies energy balance affected the olfactory system by examining four rat strains, obese Zucker and obesity-resistant Lou/C rats and their counterparts. Such models were chosen because they differ largely in their energy status and in their insulin and leptin blood levels, two hormones known to impact olfactory behaviors. After evaluation of the main metabolic parameters, we analyzed the food-driven olfactory behaviors of the four strains by measuring general activity time and sniffing time in response to food cues together with food reward localization performances in fed and fasted states. In fed conditions, obese Zucker and Wistar rats exhibited a great interest for food odor, which was not enhanced by fasting, in contrast to Lou/C and Zucker lean rats. All strains, except Lou/C, showed decreased latencies to find a hidden food reward with time, whereas a 24-h fasting was necessary to improve food search performances in Lou/C. These metabolic and behavioral changes were partly associated with variations in the transcription profiles of leptin, insulin and orexin and their receptors in the hypothalamus and olfactory system. The results show that variations in metabolic-related genes expression along the olfactory pathways comes with obesity in influencing food odors-driven behaviors. Our data indicate that food-olfactory driven behaviors are clearly affected by the long-term metabolic status. Topics: Animals; Body Weight; Eating; Energy Metabolism; Feeding Behavior; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptides; Obesity; Odorants; Orexins; Rats; Rats, Inbred Strains; Rats, Wistar; Rats, Zucker; Species Specificity | 2014 |
Pluronic modified leptin with increased systemic circulation, brain uptake and efficacy for treatment of obesity.
Modification of hydrophilic proteins with amphiphilic block copolymers capable of crossing cell membranes is a new strategy to improve protein delivery to the brain. Leptin, a candidate for the treatment of epidemic obesity, has failed in part because of impairment in its transport across the blood-brain barrier (BBB) that develops with obesity. We posit that modification of leptin with poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), Pluronic P85 (P85) might permit this protein to penetrate the BBB independently of its transporter, thereby overcoming peripheral leptin resistance. Here we report that peripherally administered leptin-P85 conjugates exhibit biological activity by reducing food intake in mouse models of obesity (ob/ob, and diet-induced obese mouse). We further generated two new leptin-P85 conjugates: one, Lep(ss)-P85(L), containing one P85 chain and another, Lep(ss)-P85(H), containing multiple P85 chains. We report data on their purification, analytical characterization, peripheral and brain pharmacokinetics (PK). Lep(ss)-P85(L) crosses the BBB using the leptin transporter, and exhibits improved peripheral PK along with increased accumulation in the brain compared to unmodified leptin. Lep(ss)-P85(H) also has improved peripheral PK but in a striking difference to the first conjugate penetrates the BBB independently of the leptin transporter via a non-saturable mechanism. The results demonstrate that leptin analogs can be developed through chemical modification of the native leptin with P85 to overcome leptin resistance at the level of the BBB, thus improving the potential for the treatment of obesity. Topics: Animals; Anti-Obesity Agents; Blood-Brain Barrier; Body Weight; Cells, Cultured; Chemistry, Pharmaceutical; Disease Models, Animal; Drug Carriers; Drug Stability; Eating; Feeding Behavior; Injections, Intravenous; Injections, Subcutaneous; Leptin; Male; Mice; Obesity; Permeability; Poloxalene; Technology, Pharmaceutical | 2014 |
Relationship between adiposity, adipokines, inflammatory markers and lipid profile in hemodialysis patients.
Our aim is to study the correlations of leptin and adiponectin with inflammation markers, body composition and lipid profile in end stage renal disease (ESRD) patients.. Phase angle values and fat mass as calculated using BIA, Malnutrition-Inflammation Score (MIS), leptin, adiponectin, IL-6, IL-8 triglycerides, cholesterol and other common serum markers' concentrations were analyzed using simple and multiple linear regression models in 47 hemodialysis patients.. In contrast to leptin, adiponectin is inversely correlated to BMI and fat mass in hemodialysis patients. Triglycerides were the only parameter that retained its statistical correlation significance with adiponectin in the multiple regression model.. Fat mass is of important consideration when calculating adipokines levels and their possible correlations with other variables. The inverse correlation of adiponectin with triglycerides levels should be further delineated due to the important role of vascular diseases in total mortality and morbidity of ESRD patients. Topics: Adiponectin; Adiposity; Body Composition; Body Height; Body Weight; C-Reactive Protein; Cholesterol; Female; Humans; Interleukin-6; Interleukin-8; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Nutritional Status; Renal Dialysis; Triglycerides | 2014 |
Prenatal programming of obesity in a swine model of leptin resistance: modulatory effects of controlled postnatal nutrition and exercise.
The main role of early nutritional programming in the current rise of obesity and associated diseases is well known. However, translational studies are mostly based in postnatal food excess and, thus, there is a paucity of information on the phenotype of individuals with prenatal deficiencies but adequate postnatal conditions. Thus, we assessed the effects of prenatal programming (comparing descendants from females fed with a diet fulfilling 100 or only 50% of their nutritional requirements for pregnancy) on gene expression, patterns of growth and fattening, metabolic status and puberty attainment of a swine model of obesity/leptin resistance with controlled postnatal nutrition and opportunity of exercise. Maternal restriction was related to changes in the relationships among gene expression of positive (insulin-like growth factors 1 and 2) and negative (myostatin) regulators of muscle growth, with negative correlations in gilts from restricted pregnancies and positive relationships in the control group. In spite of these differences, the patterns of growth and fattening and the metabolic features during juvenile growth were similar in control gilts and gilts from restricted pregnancies. Concomitantly, there was a lack of differences in the timing of puberty attainment. However, after reaching puberty and adulthood, females from restricted pregnancies were heavier and more corpulent than control gilts, though such increases in weight and size were not accompanied by increases in adiposity. In conclusion, in spite of changes in gene expression induced by developmental programming, the propensity for higher weight and adiposity of individuals exposed to prenatal malnutrition may be modulated by controlled food intake and opportunity of physical exercise during infant and juvenile development. Topics: Adiposity; Animals; Animals, Newborn; Body Weight; Disease Models, Animal; Female; Leptin; Male; Obesity; Physical Conditioning, Animal; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Swine | 2014 |
Metabolic disease risk in children by salivary biomarker analysis.
The study of obesity-related metabolic syndrome or Type 2 diabetes (T2D) in children is particularly difficult because of fear of needles. We tested a non-invasive approach to study inflammatory parameters in an at-risk population of children to provide proof-of-principle for future investigations of vulnerable subjects.. We evaluated metabolic differences in 744, 11-year old children selected from underweight, normal healthy weight, overweight and obese categories by analyzing fasting saliva samples for 20 biomarkers. Saliva supernatants were obtained following centrifugation and used for analyses.. Salivary C-reactive protein (CRP) was 6 times higher, salivary insulin and leptin were 3 times higher, and adiponectin was 30% lower in obese children compared to healthy normal weight children (all P<0.0001). Categorical analysis suggested that there might be three types of obesity in children. Distinctly inflammatory characteristics appeared in 76% of obese children while in 13%, salivary insulin was high but not associated with inflammatory mediators. The remaining 11% of obese children had high insulin and reduced adiponectin. Forty percent of the non-obese children were found in groups which, based on biomarker characteristics, may be at risk for becoming obese.. Significantly altered levels of salivary biomarkers in obese children from a high-risk population, suggest the potential for developing non-invasive screening procedures to identify T2D-vulnerable individuals and a means to test preventative strategies. Topics: Adiponectin; Biomarkers; Body Mass Index; Body Weight; C-Reactive Protein; Child; Female; Humans; Inflammation Mediators; Insulin; Leptin; Male; Metabolic Diseases; Risk; Saliva | 2014 |
Intestinal deletion of leptin signaling alters activity of nutrient transporters and delayed the onset of obesity in mice.
The importance of B-isoform of leptin receptor (LEPR-B) signaling in the hypothalamus, pancreas, or liver has been well characterized, but in the intestine, a unique site of entry for dietary nutrition into the body, it has been relatively ignored. To address this question, we characterized a mouse model deficient for LEPR-B specifically in intestinal epithelial cells (IECs). (IEC)LEPR-B-knockout (KO) and wild-type (WT) mice were generated by Cre-Lox strategy and fed a normal or high-fat diet (HFD). The analyses of the animals involved histology and immunohistochemistry of intestinal mucosa, indirect calorimetric measurements, whole-body composition, and expression and activities of nutrient transporters. (IEC)LEPR-B-KO mice exhibited a 2-fold increase in length of jejunal villi and have normal growth on a normal diet but were less susceptible (P<0.01) to HFD-induced obesity. No differences occurred in energy intake and expenditure between (IEC)LEPR-B-WT and -KO mice, but (IEC)LEPR-B-KO mice fed an HFD showed increased excreted fats (P<0.05). Activities of the Na(+)/glucose cotransporter SGLT-1 and GLUT2 were unaffected in LEPR-B-KO jejunum, while GLUT5-mediated fructose transport and PepT1-mediated peptide transport were substantially reduced (P<0.01). These data demonstrate that intestinal LEPR-B signaling is important for the onset of diet-induced obesity. They suggest that intestinal LEPR-B could be a potential per os target for prevention against obesity. Topics: Animals; Blotting, Western; Body Composition; Body Weight; Cell Proliferation; Cells, Cultured; Diet, High-Fat; Energy Intake; Female; Glucose Transport Proteins, Facilitative; Glucose Transporter Type 2; Glucose Transporter Type 5; Immunoenzyme Techniques; Intestinal Mucosa; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Peptide Transporter 1; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Symporters | 2014 |
Overweight and CpG methylation of the Pomc promoter in offspring of high-fat-diet-fed dams are not "reprogrammed" by regular chow diet in rats.
This study aimed to determine whether epigenetic malprogramming induced by high-fat diet (HFD) has an obesogenic effect on nonmated and mated female rats and their offspring. Further, it aimed to reprogram offspring's epigenetic malprogramming and phenotype by providing normal diet after weaning. Body weight (BW) was measured, and plasma and hypothalamic arcuate nuclei were collected for analysis of hormones, mRNA, and DNA CpG methylation of the promoter of Pomc, a key factor in control of food intake. In nonmated females, HFD decreased Pomc/leptin ratio by ∼38%. This finding was associated with Pomc promoter hypermethylation. While heavier during pregnancy, during lactation HFD dams showed sharper BW decrease (2.5-fold) and loss of Pomc promoter hypermethylation. Moreover, their weight loss was correlated with demethylation (r=-0.707) and with gadd45b mRNA expression levels (r=0.905). Even though offspring of HFD dams ate standard chow from weaning, they displayed increased BW, Pomc promoter hypermethylation, and vulnerability to HFD challenge (3-fold kilocalorie intake increase). These findings demonstrate a long-term effect of maternal HFD on CpG methylation of the Pomc promoter in the offspring, which was not reprogrammed by standard chow from weaning. Further, the results suggest a possible mechanism of demethylation of the Pomc promoter following pregnancy and lactation. Topics: Adiposity; Animals; Antigens, Differentiation; Body Weight; CpG Islands; Diet, High-Fat; DNA Methylation; Eating; Female; Gene Expression Regulation, Developmental; Lactation; Leptin; Maternal Nutritional Physiological Phenomena; Obesity; Overweight; Pregnancy; Promoter Regions, Genetic; Proprotein Convertases; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Weaning | 2014 |
Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling.
Chronic inflammation constitutes an important link between obesity and its pathophysiological sequelae. In contrast to the belief that inflammatory signals exert a fundamentally negative impact on metabolism, we show that proinflammatory signaling in the adipocyte is in fact required for proper adipose tissue remodeling and expansion. Three mouse models with an adipose tissue-specific reduction in proinflammatory potential were generated that display a reduced capacity for adipogenesis in vivo, while the differentiation potential is unaltered in vitro. Upon high-fat-diet exposure, the expansion of visceral adipose tissue is prominently affected. This is associated with decreased intestinal barrier function, increased hepatic steatosis, and metabolic dysfunction. An impaired local proinflammatory response in the adipocyte leads to increased ectopic lipid accumulation, glucose intolerance, and systemic inflammation. Adipose tissue inflammation is therefore an adaptive response that enables safe storage of excess nutrients and contributes to a visceral depot barrier that effectively filters gut-derived endotoxin. Topics: Adipogenesis; Adiponectin; Adipose Tissue, White; Adrenergic Agonists; Animals; Body Weight; Diet, High-Fat; Fatty Acid-Binding Proteins; Fatty Liver; Female; Glucose Tolerance Test; Inflammation; Intra-Abdominal Fat; Leptin; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Animal; Recombinant Proteins; Serum Amyloid A Protein; Tumor Necrosis Factor-alpha | 2014 |
A predictive model of the dynamics of body weight and food intake in rats submitted to caloric restrictions.
Dynamics of body weight and food intake can be studied by temporally perturbing food availability. This perturbation can be obtained by modifying the amount of available food over time while keeping the overall food quantity constant. To describe food intake dynamics, we developed a mathematical model that describes body weight, fat mass, fat-free mass, energy expenditure and food intake dynamics in rats. In addition, the model considers regulation of food intake by leptin, ghrelin and glucose. We tested our model on rats experiencing temporally variable food availability. Our model is able to predict body weight and food intake variations by taking into account energy expenditure dynamics based on a memory of the previous food intake. This model allowed us to estimate this memory lag to approximately 8 days. It also explains how important variations in food availability during periods longer than these 8 days can induce body weight gains. Topics: Animals; Body Weight; Caloric Restriction; Eating; Energy Intake; Energy Metabolism; Leptin; Memory; Models, Theoretical; Rats; Rats, Wistar; Weight Gain | 2014 |
Association of leptin and adiponectin levels with three-year weight change among Japanese male workers.
The purpose of this study was to clarify, through a prospective study, the relationship between leptin and adiponectin levels, and subsequent weight change. The study subjects were 2,485 male office workers aged 35-64 employed by a company in Fukuoka Prefecture, Japan. Of these men, 1,936 (77.9%) received health check-ups both in 2005-2007 and 3 years later, in 2008-2010. Of the subjects who received both health check-ups, 352 were excluded duo to cancer, cardiac infarction, stroke or diabetes mellitus, leaving a total of 1,584. We divided them into tertiles according to baseline leptin and adiponectin levels, and compared the subsequent change in body mass index (BMI) over 3 years. The subjects with the lowest leptin levels showed a significantly greater increase in BMI (difference in change in BMI=0.178 kg/m2, 95% CI:0.025-0.331 kg/m2) over 3 years when those with the highest leptin levels were regarded as the reference even after adjusting for age, baseline BMI, smoking status, drinking status and exercise. The subjects with the highest adiponectin levels showed a greater increase in BMI (difference in change in BMI=0.099 kg/m2, 95% CI: -0.034-0.231 kg/m2) over 3 years when those with the lowest adiponectin levels were regarded as the reference, but this association was not statistically significant after adjusting for age, baseline BMI, smoking status, drinking status and exercise. Our findings suggest that higher leptin levels may suppress weight gain in Japanese male workers. Topics: Adiponectin; Adult; Asian People; Body Mass Index; Body Weight; Humans; Japan; Leptin; Male; Middle Aged; Obesity; Prospective Studies; Weight Gain | 2014 |
Effect of Sipjeondaebo-tang on cancer-induced anorexia and cachexia in CT-26 tumor-bearing mice.
Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor- α (TNF- α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia. Topics: Animals; Anorexia; Body Weight; Cachexia; Cell Line, Tumor; Chemokine CCL2; Drugs, Chinese Herbal; Ghrelin; Glucagon-Like Peptide 1; Inflammation; Interleukin-6; Intestinal Mucosa; Leptin; Male; Mice; Mice, Inbred BALB C; Muscles; Neoplasm Transplantation; Neoplasms; Peptide YY; Plant Preparations; Tumor Necrosis Factor-alpha | 2014 |
The effect of dietary α-lipoic acid, betaine, l-carnitine, and swimming on the obesity of mice induced by a high-fat diet.
We evaluate the effect of supplementation, at 300 mg kg(-1) body weight (BW), with the antioxidants α-lipoic acid (AL), betaine (BT), l-carnitine (LC), and the combination of these and exercise on obesity induced by a 9 week high-fat diet (HFD) in mice. Healthy 5 week-old male C57BL/6J mice were divided into 9 groups: (1) CON, control group fed with a commercial mice chow containing 10% crude fat; (2) HFD, high fat diet group fed with a commercial mice chow containing 60% crude fat; (3) HFD-AL, HFD group fed with AL; (4) HFD-BT, HFD group fed with BT; (5) HFD-LC, HFD group fed with LC; (6) HFD-SW, HFD with swimming as an exercise; (7) HFD-SWAL, HFD-AL with swimming; (8) HFD-SWBT, HFD-BT with swimming, and (9) HFD-SWLC, HFD-LC with swimming. The BW of mice with LC and swimming reduced the increase of BW after 9 weeks. Relative adipose tissue weights were reduced by the combinations of antioxidant supplementation and swimming. Levels of serum glucose and leptin were reduced in the HFD-SWLC group when compared with the HFD group. Serum triglyceride and total cholesterol and the size of adipose were also decreased in the HFD-LC and HFD-SWLC groups. These results show that LC at a dose of 300 mg kg(-1) BW was the most effective for reducing fat accumulation in mice with HFD for 9 weeks. In addition, exercise should be given in combination to enhance the BW reduction and serum lipid level. Topics: Adipocytes; Animals; Antioxidants; Betaine; Blood Glucose; Body Weight; Carnitine; Cholesterol; Diet, High-Fat; Dietary Supplements; Dose-Response Relationship, Drug; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Physical Conditioning, Animal; Swimming; Thioctic Acid; Triglycerides | 2014 |
Controlling access time to a high-fat diet during the inactive period protects against obesity in mice.
Free feeding (FF) with a high fat diet (HFD) causes excessive body weight gain, whereas restricted feeding (RF) with a HFD attenuates body weight gain. The effects of timing of feeding with a HFD (day vs. night) and feeding duration on energy homeostasis have not yet been investigated. In this study, we fed mice a HFD or a normal diet (ND) twice a day, during their active and inactive periods, on a schedule. The amount of food was regulated by feeding duration (2, 4 or 8 h). First, we investigated the effects of 4-h RF during active-inactive periods (ND-ND, HFD-HFD, ND-HFD or HFD-ND). Among all the 4-h RF groups, mice consumed almost the same amount of calories as those in the FF[ND] group, even those fed a HFD. Body weight and visceral fat in these three groups were lower than that in the FF[HFD] group. Second, we investigated the effects of RF duration. Body weight and visceral fat were higher in the 8-h groups than in the 4-h groups. Body weight and visceral fat were higher in the 2-h groups than in the 4-h groups even though the 2-h groups had less food. Third, we investigated the effects of eating a HFD during the inactive period, when RF duration was extended (2, 6 or 12 h). Mice were fed with a HFD during the inactive period for 2 h and fed with a ND during the active period for 2, 6 or 12 h. Body weight and visceral fat in these mice were comparable to those in the FF[ND] mice. The results of our first set of experiments suggest that 4-h RF was an adequate feeding duration to control the effect of a HFD on obesity. The results of our second set of experiments suggest 2-h RF (such as speed-eating) and 8-h RF, representative of eating disorders, are unhealthy feeding patterns related to obesity. The results of our third set of experiments suggest that eating a HFD for a short period during the night does not affect body weight and visceral fat. Taken together, these results indicate that consideration to feeding with a HFD during the inactive period and restricting eating habits relieve the risks of body weight gain and visceral fat accumulation. Topics: Animals; Blood Glucose; Body Weight; Circadian Rhythm; Diet, High-Fat; Dietary Fats; Energy Intake; Feeding Behavior; Insulin; Intra-Abdominal Fat; Leptin; Liver; Male; Mice; Mice, Inbred ICR; Obesity; Time Factors; Weight Gain | 2014 |
Pharmacological effects of JTT-551, a novel protein tyrosine phosphatase 1B inhibitor, in diet-induced obesity mice.
Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin signaling as well as insulin signaling. JTT-551 is a new PTP1B inhibitor, which is reported to improve glucose metabolism by enhancement of insulin signaling. We have evaluated an antiobesity effect of JTT-551 using diet-induced obesity (DIO) mice. A single administration of JTT-551 was provided to DIO mice with or without leptin, and DIO mice were given food containing JTT-551 for six weeks. A single administration of JTT-551 with leptin treatment enhanced the food inhibition and the signal transducer and activator of transcription 3 (STAT3) phosphorylation in hypothalamus. Moreover, chronic administration of JTT-551 showed an antiobesity effect and an improvement of glucose and lipid metabolism in DIO mice. JTT-551 shows an antiobesity effect possibly by enhancement of leptin signaling and could be useful in the treatment of type 2 diabetes and obesity. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose; Glycine; Hypothalamus; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Signal Transduction; STAT3 Transcription Factor; Thiazoles | 2014 |
Morbid obesity attenuates the skeletal abnormalities associated with leptin deficiency in mice.
Leptin-deficient ob/ob mice are morbidly obese and exhibit low total bone mass and mild osteopetrosis. In order to disassociate the skeletal effects of leptin deficiency from those associated with morbid obesity, we evaluated bone mass, architecture, gene expression, and indices of bone turnover in WT mice, ob/ob mice allowed to feed ad libitum (ob/ob), and ob/ob mice pair-fed equivalent to WT mice (pair-fed ob/ob). Mice were maintained at 32 °C (thermoneutral) from 6 to 18 weeks of age to minimize differences in resting energy expenditure. ob/ob mice were heavier, had more abdominal white adipose tissue (WAT), and were hyperglycemic compared with WT mice. Femur length, bone mineral content (BMC) and bone mineral density, and midshaft femur cortical thickness were lower in ob/ob mice than in WT mice. Cancellous bone volume (BV) fraction was higher but indices of bone formation and resorption were lower in ob/ob mice compared with WT mice; reduced bone resorption in ob/ob mice resulted in pathological retention of calcified cartilage. Pair-fed ob/ob mice were lighter and had lower WAT, uterine weight, and serum glucose than ob/ob mice. Similarly, femoral length, BMC, and cortical thickness were lower in pair-fed ob/ob mice compared with ob/ob mice, as were indices of cancellous bone formation and resorption. In contrast, bone marrow adiposity, calcified cartilage, and cancellous BV fraction were higher at one or more cancellous sites in pair-fed ob/ob mice compared with ob/ob mice. These findings indicate that the skeletal abnormalities caused by leptin deficiency are markedly attenuated in morbidly obese ob/ob mice. Topics: Adipose Tissue, White; Analysis of Variance; Animals; Blood Glucose; Body Weight; Bone and Bones; Bone Density; Collagen Type I; Eating; Female; Gene Expression Profiling; Leptin; Mice; Mice, Obese; Obesity, Morbid; Oligonucleotide Array Sequence Analysis; Osteocalcin; Osteogenesis; Peptides; Reverse Transcriptase Polymerase Chain Reaction; Tibia | 2014 |
Short-term periodic consumption of multiprobiotic from childhood improves insulin sensitivity, prevents development of non-alcoholic fatty liver disease and adiposity in adult rats with glutamate-induced obesity.
Today the impairment of metabolism and obesity are being extensively investigated due to the significant increase of the prevalence of these diseases. There is scientific evidence that probiotics are beneficial for human health. Thus, the aim of the study was to investigate the effect of multiprobiotic "Symbiter acidophilic concentrated" on obesity parameters in the rats under experimental obesity.. The study was carried out on 60 newborn Wistar rats, divided into 3 groups, 20 animals in each (females - n = 10, males - n = 10): intact rats, monosodium glutamate (MSG-) and MSG + probiotic group. Rats of intact group were administered with saline (8 μl/g, subcutaneously (s.c.)). Newborns rats of MSG-group and MSG + probiotic group were injected with a solution of MSG (4.0 mg/g) s.c. at 2nd - 10th postnatal days. The MSG + probiotic group was treated with 140 mg/kg (1.4 × 10(10) CFU/kg) of multiprobiotic "Symbiter". MSG-group was treated with 2.5 ml/kg of water (per os) respectively. Administration was started at the age of 4 weeks just after wean and continued for 3 month intermittently alternating two-week course of introduction with two-week course of break.. Neonatal treatment with MSG caused a stunted growth in both MSG-groups, which manifested with significantly smaller naso-anal length compared to adult intact rats. There was no significant difference in weight between intact and MSG-groups on 120th day. The adiponectin level in the serum of rats with MSG-induced obesity decreased by 2.43 times (p = 0.001) in males and 1.75 (p = 0.020) in females. Concentration of leptin in adipose tissue were significantly higher by 45.9% (p = 0.019) and 61.2% (p = 0.009) respectively in males and females compared to intact rats. Our study has indicated that daily oral administration of multiprobiotic to neonatal MSG-treated rats by 2-week courses led to significant reduce of total body and VAT weight with subsequent improvement in insulin sensitivity and prevention of non-alcoholic fatty liver (NAFLD) development.. These results have shown that periodic treatment with multiprobiotic prevents the MSG-induced obesity and NAFLD development. Topics: Adiponectin; Adiposity; Animals; Animals, Newborn; Body Weight; Drug Administration Schedule; Fatty Liver; Female; Insulin Resistance; Leptin; Male; Non-alcoholic Fatty Liver Disease; Obesity; Probiotics; Rats; Rats, Wistar; Sodium Glutamate | 2014 |
Inhibitory effects of Rubi Fructus extracts on hepatic steatosis development in high-fat diet-induced obese mice.
The present study was performed to investigate the potential effects of the unripened dried fruit of Rubus coreanus Miq., Rubi Fructus (RF), on hepatic steatosis and lipid metabolism in mice fed with a high-fat diet (HFD) known to induce obesity and hyperlipidaemia. Rubi Fructus extract (RFex) fed mice demonstrated a reduced body weight and adipose tissue weight. RFex fed mice also demonstrated decreased aminotransferase levels, lipid contents [triglyceride (TG), total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C)], leptin content and increased high‑density lipoprotein-cholesterol (HDL‑C) contents in the plasma. These effects were accompanied by a decreased expression of lipogenic genes, including sterol regulatory element binding protein-1c, liver X receptor, fatty acid synthase (FAS), acetyl‑CoA carboxylase, cluster of differentiation 36, lipoprotein lipase and decreased lipogenic enzyme FAS and 3-hydroxy-3 methylglutamyl coenzyme reductase enzyme activities, while elevating carnitine palmitoyltrasferase-1 activity. Based on these results, the present study hypothesized that the inhibitory effect on hepatic steatosis of RFex is the result of the suppression of lipid synthesis in mice fed with HFD, suggesting that RFex may be beneficial in preventing hepatic steatosis and liver lipotoxicity. Topics: Acetyl-CoA Carboxylase; Adipose Tissue; Animals; Body Weight; Cholesterol; Diet, High-Fat; Fatty Acid Synthases; Fatty Liver; Fruit; Gene Expression; Leptin; Lipid Metabolism; Lipoproteins, HDL; Lipoproteins, LDL; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Plant Extracts; Rubus; Sterol Regulatory Element Binding Protein 1; Triglycerides | 2014 |
Neonatal birth waist is positively predicted by second trimester maternal active ghrelin, a pro-appetite hormone, and negatively associated with third trimester maternal leptin, a pro-satiety hormone.
In pregnancy physiological mechanisms activated by maternal appetite contribute to adequate energy intake for the mother and for the fetus. The role of maternal appetite-related peptides and their possible association with neonatal energy stores and glucose metabolism have not been investigated as yet. The aim was to investigate, during pregnancy, the association of fasting maternal appetite-related hormones levels [ghrelin (active), GLP1 (active), total PYY and leptin] with neonatal waist, percent total body fat and insulin levels at birth.. Forty-two normal and thirty eight overweight women (mean±SD; age: 26.9±2.5years; pre-pregnancy BMI 26±2.2kg/m(2)) were seen during each of the three trimesters, had blood sampling and a 75g oral glucose tolerance test. At birth, neonates underwent anthropometry and cord blood sampling for c-peptide, glucose, insulin.. During all three trimesters maternal weight correlated positively with percent total neonatal body fat while during the second and third trimesters it correlated positively with birth weight. The second trimester maternal active ghrelin levels correlated positively with neonatal waist and were its best positive predictor. The third trimester maternal active ghrelin levels correlated positively with neonatal waist and negatively with percent total neonatal body fat, fetal cord blood insulin levels and were the best negative predictor of the latter. The third trimester maternal leptin levels correlated negatively with neonatal waist.. During pregnancy circulating maternal active ghrelin, a pro-appetite hormone, is associated with neonatal visceral energy storage (as expressed by neonatal waist). By inhibiting glucose-driven maternal insulin secretion, ghrelin might ensure adequate fasting glucose and nutrient supplies to the fetus while limiting overall fetal adipose tissue deposition. Topics: Adult; Body Weight; Female; Fetal Blood; Ghrelin; Humans; Infant, Newborn; Insulin; Leptin; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Satiation; Waist Circumference | 2014 |
Gender differences between hypocretin/orexin knockout and wild type mice: age, body weight, body composition, metabolic markers, leptin and insulin resistance.
Female hypocretin knockout (Hcrt KO) mice have increased body weight despite decreased food intake compared to wild type (WT) mice. In order to understand the nature of the increased body weight, we carried out a detailed study of Hcrt KO and WT, male, and female mice. Female KO mice showed consistently higher body weight than WT mice, from 4 to 20 months (20-60%). Fat, muscle, and free fluid levels were all significantly higher in adult (7-9 months) as well as old (18-20 months) female KO mice compared to age-matched WT mice. Old male KO mice showed significantly higher fat content (150%) compared to age-matched WT mice, but no significant change in body weight. Respiratory quotient (-19%) and metabolic rates (-14%) were significantly lower in KO mice compared to WT mice, regardless of gender or age. Female KO mice had significantly higher serum leptin levels (191%) than WT mice at 18-20 months, but no difference between male mice were observed. Conversely, insulin resistance was significantly higher in both male (73%) and female (93%) KO mice compared to age- and sex-matched WT mice. We conclude that absence of the Hcrt peptide has gender-specific effects. In contrast, Hcrt-ataxin mice and human narcoleptics, with loss of the whole Hcrt cell, show weight gain in both sexes. Topics: Aging; Animals; Body Composition; Body Weight; Female; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptides; Orexins; Sex Characteristics | 2014 |
The effect of topiramate on body weight and ghrelin, leptin, and neuropeptide-Y levels of prepubertal children with epilepsy.
Weight loss is one of the most frequent side effects of topiramate treatment. The aim of our study was to investigate the effect of topiramate on body mass index, serum glucose, insulin, cortisol, leptin, and neuropeptide-Y levels and the role of these variables on the pathogenesis of weight loss in prepubertal children with epilepsy.. Twenty prepubertal children with epilepsy who were treated with topiramate were enrolled in the study. Topiramate was used at a daily dose of 5 mg/kg. Body mass index and fasting insulin-to-glucose ratio were calculated. Serum glucose, insulin, leptin, neuropeptide-Y, ghrelin, and cortisol levels were measured for all patients before the treatment and at the third and sixth months of the treatment.. There were significant decreases in mean body mass index, fasting insulin-to-glucose ratio, and serum cortisol and leptin levels at the third and sixth months of the treatment compared with pretreatment levels. No significant changes were observed in serum glucose, ghrelin, neuropeptide-Y, or insulin levels.. The exact mechanism of topiramate on energy balance regulation is not clearly understood. Topiramate affects body mass index, fasting insulin-to-glucose ratio, and serum leptin and cortisol levels in prepubertal children. These changes may be key factors in weight loss due to topiramate. Topics: Anticonvulsants; Blood Glucose; Body Mass Index; Body Weight; Child; Child, Preschool; Epilepsy; Female; Fructose; Ghrelin; Humans; Hydrocortisone; Insulin; Leptin; Male; Neuropeptide Y; Topiramate | 2014 |
Dietary supplementation of omega-3 fatty acids rescues fragile X phenotypes in Fmr1-Ko mice.
Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are known to critically influence brain development and functions. Dietary supplementation with n-3 PUFAs has been suggested as a non-pharmacological therapy for a number of developmental disorders, e.g., autistic spectrum disorders (ASD), but human studies so far have led to conflicting results. Furthermore, it has been hypothesized that the therapeutic impact of n-3 PUFAs on these disorders might be explained by their anti-inflammatory properties and their promoting effects on synaptic function and plasticity, but no clear evidence has been produced in this direction. We evaluated the impact of n-3 PUFA dietary supplementation in a mouse model of fragile X syndrome (FXS), i.e., a major developmental disease and the most frequent monogenic cause of ASD. Fmr1-KO and wild-type mice were provided with a diet enriched or not with n-3 PUFAs from weaning until adulthood when they were tested for multiple FXS-like behaviors. The brain expression of several cytokines and of brain-derived neurotrophic factor (BDNF) was concomitantly assessed as inflammatory and synaptic markers. n-3 PUFA supplementation rescued most of the behavioral abnormalities displayed by Fmr1-KO mice, including alterations in emotionality, social interaction and non-spatial memory, although not their deficits in social recognition and spatial memory. n-3 PUFAs also rescued most of the neuroinflammatory imbalances of KOs, but had a limited impact on their BDNF deficits. These results demonstrate that n-3 PUFAs dietary supplementation, although not a panacea, has a considerable therapeutic value for FXS and potentially for ASD, suggesting a major mediating role of neuroinflammatory mechanisms. Topics: Animals; Biomarkers; Body Composition; Body Weight; Brain; Brain-Derived Neurotrophic Factor; Cytokines; Dietary Supplements; Disease Models, Animal; Eating; Fatty Acids, Omega-3; Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Leptin; Male; Mice; Mice, Knockout; Phenotype | 2014 |
Oestradiol modulates the effects of leptin on energy homeostasis by corticotrophin-releasing factor type 2 receptor.
In addition to its action in the control of the hypothalamic-pituitary-adrenal axis, corticotrophin-releasing factor (CRF) has been described as an anorexigenic neuropeptide, modulating food intake and energy expenditure. CRF synthesis is influenced by leptin, which would act to increase CRF neurone activation in the paraventricular nucleus (PVN). Gonadal hormones also participate in the regulation of energy homeostasis. The reduction of food intake and body weight gain in ovariectomised (OVX) rats treated with oestradiol is associated with an increase in CRF mRNA expression in the PVN. The present study aimed to investigate the role of CRF as a mediator of leptin responsiveness in the presence of oestradiol. Wistar female rats were bilaterally OVX and divided into three groups: OVX, OVX+E (i.e. treated with oestradiol) and OVX+PF (i.e. OVX pairfed with OVX+E). The rats received daily s.c. injections of either oestradiol cypionate or vehicle for 8 days. To evaluate the role of CRF on the effects of leptin, we performed an i.c.v. leptin injection (10 μg/5 μl) with or without previous i.c.v. treatment with an CRF-R2 antagonist. We observed that oestradiol replacement in OVX rats reduced body weight gain and food intake. The effects of exogenous leptin administration with respect to decreasing food intake and body weight, and increasing uncoupling protein-1 expression in the brown adipose tissue and neuronal activation in the arcuate nucleus, were reversed by previous administration of a CRF-R2 antagonist only in oestradiol-treated OVX rats. These effects appear to be mediated by CRF-2 receptor because the antagonist of this receptor reversed the action of oestradiol on the effects of leptin. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Energy Metabolism; Estradiol; Female; Homeostasis; Hypothalamo-Hypophyseal System; Leptin; Neurons; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Pituitary-Adrenal System; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone | 2014 |
Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on hormones of energy balance in a TCDD-sensitive and a TCDD-resistant rat strain.
One of the hallmarks of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a drastically reduced feed intake by an unknown mechanism. To further elucidate this wasting syndrome, we followed the effects of a single large dose (100 μg/kg) of TCDD on the serum levels of several energy balance-influencing hormones, clinical chemistry variables, and hepatic aryl hydrocarbon receptor (AHR) expression in two rat strains that differ widely in their TCDD sensitivities, for up to 10 days. TCDD affected most of the analytes in sensitive Long-Evans rats, while there were few alterations in the resistant Han/Wistar strain. However, analyses of feed-restricted unexposed Long-Evans rats indicated several of the perturbations to be secondary to energy deficiency. Notable increases in ghrelin and glucagon occurred in TCDD-treated Long-Evans rats alone, which links these hormones to the wasting syndrome. The newly found energy balance regulators, insulin-like growth factor 1 and fibroblast growth factor 21 (FGF-21), appeared to function in concert in body weight loss-induced metabolic state, and FGF-21 was putatively linked to increased lipolysis induced by TCDD. Finally, we demonstrate a reverse set of changes in the AHR protein and mRNA response to TCDD and feed restriction, suggesting that AHR might function also as a physiological regulator, possibly involved in the maintenance of energy balance. Topics: Adiponectin; Animals; Body Weight; Energy Metabolism; Fibroblast Growth Factors; Glucagon; Insulin; Insulin-Like Growth Factor I; Leptin; Liver; Polychlorinated Dibenzodioxins; Rats; Rats, Long-Evans; Rats, Wistar; Receptors, Aryl Hydrocarbon; RNA, Messenger; Species Specificity | 2014 |
Metabolic stressors and signals differentially affect energy allocation between reproduction and immune function.
Most free-living animals have finite energy stores that they must allocate to different physiological and behavioral processes. In times of energetic stress, trade-offs in energy allocation among these processes may occur. The manifestation of trade-offs may depend on the source (e.g., glucose, lipids) and severity of energy limitation. In this study, we investigated energetic trade-offs between the reproductive and immune systems by experimentally limiting energy availability to female Siberian hamsters (Phodopus sungorus) with 2-deoxy-d-glucose, a compound that disrupts cellular utilization of glucose. We observed how glucoprivation at two levels of severity affected allocation to reproduction and immunity. Additionally, we treated a subset of these hamsters with leptin, an adipose hormone that provides a direct signal of available fat stores, in order to determine how increasing this signal of fat stores influences glucoprivation-induced trade-offs. We observed trade-offs between the reproductive and immune systems and that these trade-offs depended on the severity of energy limitation and exogenous leptin signaling. The majority of the animals experiencing mild glucoprivation entered anestrus, whereas leptin treatment restored estrous cycling in these animals. Surprisingly, virtually all animals experiencing more severe glucoprivation maintained normal estrous cycling throughout the experiment; however, exogenous leptin resulted in lower antibody production in this group. These data suggest that variation in these trade-offs may be mediated by shifts between glucose and fatty acid utilization. Collectively, the results of the present study highlight the context-dependent nature of these trade-offs, as trade-offs induced by the same metabolic stressor can manifest differently depending on its intensity. Topics: Adipose Tissue; Animals; Antibody Formation; Blood Bactericidal Activity; Blood Glucose; Body Weight; Cricetinae; Deoxyglucose; Energy Metabolism; Estrous Cycle; Feeding Behavior; Female; Hydrocortisone; Leptin; Mice; Organ Size; Phodopus; Reproduction; Signal Transduction; Stress, Physiological; Triglycerides | 2014 |
Persistent inflammation and its relationship to leptin and insulin in phases of bipolar disorder from acute depression to full remission.
A proinflammatory phase with various immunomodulatory mechanisms has been noted in bipolar mania and major depression. Weight gain and increased production of leptin may be associated with immunomodulation and insulin resistance in bipolar disorder. However, immunomodulation and its linkage with leptin and insulin in the depressive episode of bipolar disorder remain unclear. We investigated alterations in inflammatory markers and their relationship with leptin and insulin levels in patients with phases of bipolar disorder from acute depression to full remission.. Thirty-two physically healthy bipolar I depressed patients aged <45 years and age- and sex-matched healthy controls participated in this study. We measured their circulating levels of leptin, insulin, high-sensitivity C-reactive protein (hs-CRP), soluble interleukin-2 receptor (sIL-2R), soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor receptor 1 (sTNF-R1), and interleukin-1 receptor antagonist (IL-1Ra) in three phases, i.e., acute depression, subsequent partial remission, and full remission.. In acute depression, subsequent partial remission, and full remission, patients with bipolar disorder had significantly higher mean levels of hs-CRP, IL-1Ra, sTNF-R1, and sIL-2R compared with control subjects. The IL-1Ra and sTNF-R1 levels in various affective phases were significantly correlated to body mass index, leptin level, circulating lipids, and medication status. The sIL-2R levels in the three affective phases were all independent of other inflammatory markers and clinical and laboratory variables. Patients showed no alteration of sIL-6R levels through the depressive episode.. Patients with bipolar disorder in depressive episodes may exhibit persistent inflammation with elevated levels of hs-CRP, IL-1Ra, sTNF-R1, and sIL-2R but not sIL-6R from the acute phases to full remission. Only sIL-2R production seems to be tightly linked with the pathophysiology of bipolar depression and is independent of insulin and leptin levels. Topics: Adult; Bipolar Disorder; Body Weight; C-Reactive Protein; Case-Control Studies; Cytokines; Disease Progression; Female; Humans; Inflammation; Insulin; Leptin; Male; Psychiatric Status Rating Scales; Recurrence; Smoking; Statistics as Topic; Young Adult | 2014 |
Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression.
The number of patients with Alzheimer's disease (AD) is increasing worldwide, and available drugs have shown limited efficacy. Hence, preventive interventions and treatments for presymptomatic AD are currently considered very important. Obesity rates have also been increasing dramatically and it is an independent risk factor of AD. Therefore, for the prevention of AD, it is important to elucidate the pathomechanism between obesity and AD. We generated high calorie diet (HCD)-induced obese tauopathy model mice (PS19), which showed hyperleptinemia but limited insulin resistance. HCD enhanced tau pathology and glial activation. Conversely, voluntary exercise with a running wheel normalized the serum leptin concentration without reducing body weight, and restored the pathological changes induced by HCD. Thus, we speculated that persistent hyperleptinemia played an important role in accelerating pathological changes in PS19 mice. Leptin primarily regulates food intake and body weight via leptin receptor b (LepRb). Interestingly, the nuclear staining for p-STAT3, which was activated by LepRb, was decreased in hippocampal neurons in HCD PS19 mice, indicating leptin resistance. Meanwhile, astroglial activation and the astrocytic expression of a short LepR isoform, LepRa, were enhanced in the hippocampus of HCD PS19 mice. Real-time PCR analysis demonstrated that leptin increased mRNA levels for pro-inflammatory cytokines including IL-1β and TNF-α in primary cultured astrocytes from wild type and LepRb-deficient mice. These observations suggest that persistent hyperleptinemia caused by obesity induces astrocytic activation, astrocytic leptin hypersensitivity with enhanced LepRa expression, and enhanced inflammation, consequently accelerating tau pathology in PS19 mice. Topics: Age Factors; Animals; Astrocytes; Body Weight; Cells, Cultured; Cerebral Cortex; Diet, High-Fat; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Exercise Therapy; Humans; Hyperlactatemia; Leptin; Membrane Proteins; Mice; Mice, Transgenic; Mutation; Nerve Tissue Proteins; Obesity; Phosphorylation; Receptors, Leptin; RNA, Messenger; STAT3 Transcription Factor; tau Proteins; Tauopathies | 2014 |
FTO is a relevant factor for the development of the metabolic syndrome in mice.
The metabolic syndrome is a worldwide problem mainly caused by obesity. FTO was found to be a obesity-risk gene in humans and FTO deficiency in mice led to reduction in adipose tissue. Thus, FTO is an important factor for the development of obesity. Leptin-deficient mice are a well characterized model for analysing the metabolic syndrome. To determine the relevance of FTO for the development of the metabolic syndrome we analysed different parameters in combined homozygous deficient mice (Lep(ob/ob);Fto(-/-)). Lep(ob/ob);Fto(-/-) mice showed an improvement in analysed hallmarks of the metabolic syndrome in comparison to leptin-deficient mice wild type or heterozygous for Fto. Lep(ob/ob);Fto(-/-) mice did not develop hyperglycaemia and showed an improved glucose tolerance. Furthermore, extension of beta-cell mass was prevented in Lep(ob/ob);Fto(-/-)mice and accumulation of ectopic fat in the liver was reduced. In conclusion this study demonstrates that FTO deficiency has a protective effect not only on the development of obesity but also on the metabolic syndrome. Thus, FTO plays an important role in the development of metabolic disorders and is an interesting target for therapeutic agents. Topics: Adipose Tissue; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Body Weight; Disease Models, Animal; Fatty Liver; Female; Genetic Predisposition to Disease; Hepatocytes; Hyperglycemia; Islets of Langerhans; Leptin; Lipid Metabolism; Male; Metabolic Syndrome; Mice; Mice, Knockout; Mixed Function Oxygenases; Oxo-Acid-Lyases | 2014 |
The effects of leptin in combination with a cannabinoid receptor 1 antagonist, AM 251, or cannabidiol on food intake and body weight in rats fed a high-fat or a free-choice high sugar diet.
High intake of fats and sugars has prompted a rapid growth in the number of obese individuals worldwide. To further investigate whether simultaneous pharmacological intervention in the leptin and cannabinoid system might change food and water intake, preferences for palatable foods, and body weight, we have examined the effects of concomitant intraperitoneal administration of leptin and AM 251, a cannabinoid 1 (CB1) receptor antagonist, or cannabidiol (CBD), a plant cannabinoid, in rats maintained on either a high-fat (HF) diet (45% energy from fat) or free-choice (FC) diet consisting of high-sucrose and normal rat chow (83% and 61% energy from carbohydrates, respectively). Leptin at a dose of 100 μg/kg injected individually for 3 subsequent days to rats fed a HF diet reduced significantly the daily caloric intake and inhibited body weight gain. The hormone had no significant effects, however, on either caloric intake, body weight or food preferences in rats fed an FC diet. Co-injection of leptin and 1 mg/kg AM 251 resulted in a further significant decrease in HF diet intake and a profound reduction in body weight gain both in HF diet- and FC diet-fed rats. This drug combination, however, had no effect on the consumption of high-sucrose chow. In contrast, 3mg/kg of CBD co-injected with leptin did not modify leptin effects on food intake in rats maintained on an FC or HF diet. None of the drug combinations affected water consumption. It is concluded that the concomitant treatment with leptin and AM 251 attenuated markedly body weight gain in rats maintained on high-calorie diets rich in fat and carbohydrates but did not affect preferences for sweet food. Topics: Animals; Body Weight; Cannabidiol; Cannabinoid Receptor Antagonists; Diet, High-Fat; Dietary Sucrose; Drug Combinations; Eating; Leptin; Male; Piperidines; Pyrazoles; Rats, Wistar; Receptor, Cannabinoid, CB1 | 2014 |
Oestradiol and diet modulate energy homeostasis and hypothalamic neurogenesis in the adult female mouse.
Leptin and oestradiol have overlapping functions in energy homeostasis and fertility, and receptors for these hormones are localised in the same hypothalamic regions. Although, historically, it was assumed that mammalian adult neurogenesis was confined to the olfactory bulbs and the hippocampus, recent research has found new neurones in the male rodent hypothalamus. Furthermore, some of these new neurones are leptin-sensitive and affected by diet. In the present study, we tested the hypothesis that diet and hormonal status modulate hypothalamic neurogenesis in the adult female mouse. Adult mice were ovariectomised and implanted with capsules containing oestradiol (E2 ) or oil. Within each group, mice were fed a high-fat diet (HFD) or maintained on standard chow (STND). All animals were administered i.c.v. 5-bromo-2'-deoxyuridine (BrdU) for 9 days and sacrificed 34 days later after an injection of leptin to induce phosphorylation of signal transducer of activation and transcription 3 (pSTAT3). Brain tissue was immunohistochemically labelled for BrdU (newly born cells), Hu (neuronal marker) and pSTAT3 (leptin sensitive). Although mice on a HFD became obese, oestradiol protected against obesity. There was a strong interaction between diet and hormone on new cells (BrdU+) in the arcuate, ventromedial hypothalamus and dorsomedial hypothalamus. HFD increased the number of new cells, whereas E2 inhibited this effect. Conversely, E2 increased the number of new cells in mice on a STND diet in all hypothalamic regions studied. Although the total number of new leptin-sensitive neurones (BrdU-Hu-pSTAT3) found in the hypothalamus was low, HFD increased these new cells in the arcuate, whereas E2 attenuated this induction. These results suggest that adult neurogenesis in the hypothalamic neurogenic niche is modulated by diet and hormonal status and is related to energy homeostasis in female mice. Topics: Animals; Body Weight; Diet, High-Fat; Energy Metabolism; Estradiol; Female; Homeostasis; Hypothalamus; Leptin; Mice; Neurogenesis; Neurons; Obesity; Phosphorylation | 2014 |
Second generation anti-epileptic drugs adversely affect reproductive functions in young non-epileptic female rats.
Reproductive endocrine disturbances are a major health concern in women with epilepsy due to their long term use of antiepileptic drugs (AEDs). Second generation AEDs such as topiramate (TPM) and gabapentin are frequently used for the treatment of epilepsy as well as migraine, bipolar disorder etc. Despite the widespread clinical complications, however the definitive mechanism(s) mediating the side effects of TPM and gabapentin remain obscure. The present study was aimed to evaluate the long term effects of TPM and gabapentin on reproductive functions in young female Wistar rats. Estrous cyclicity, ovarian histology as well as estradiol, LH, leptin and insulin hormones level were studied to elucidate the long-term effect of these AEDs monotherapy on reproductive functions in non-epileptic animals. Further to explore the effects on gonadotropin releasing hormone (GnRH) neuroendocrine plasticity, the expression of GnRH, gamma-amino butyric acid (GABA), glutamic acid decarboxylase (GAD), glial fibrilliary acidic protein (GFAP) and polysialylated form of neural cell adhesion molecule (PSA-NCAM) was studied in median eminence (ME) region of these animals by immunohistochemistry, Western blot hybridization and RT-PCR. Our results demonstrate that TPM and gabapentin treatment for 8 weeks cause reproductive dysfunction as ascertained by disturbed hormonal levels and estrous cyclicity as well as alterations in GABAergic system and GnRH neuronal-glial plasticity. Our findings suggest that treatment with TPM and gabapentin disrupts the complete hypothalamo-hypophyseal-gonadal axis (HPG) through GnRH pulse generator in hypothalamus. Topics: Amines; Animals; Anticonvulsants; Astrocytes; Blotting, Western; Body Weight; Cyclohexanecarboxylic Acids; Enzyme-Linked Immunosorbent Assay; Estradiol; Estrous Cycle; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Gonadotropin-Releasing Hormone; Hypothalamus; Insulin; Leptin; Luteinizing Hormone; Ovary; Rats, Wistar; Reproduction; Reverse Transcriptase Polymerase Chain Reaction; Topiramate | 2014 |
Metabolic adaptation following massive weight loss is related to the degree of energy imbalance and changes in circulating leptin.
To measure changes in resting metabolic rate (RMR) and body composition in obese subjects following massive weight loss achieved via bariatric surgery or calorie restriction plus vigorous exercise.. Body composition and RMR were measured in 13 pairs of obese subjects retrospectively matched for sex, body mass index, weight, and age who underwent either Roux-en-Y gastric bypass surgery (RYGB) or participated in "The Biggest Loser" weight loss competition (BLC).. Both groups had similar final weight loss (RYGB: 40.2 ± 12.7 kg, BLC: 48.8 ± 14.9 kg; P = 0.14); however, RYGB lost a larger proportion of their weight as fat-free mass (FFM) (RYGB: 30 ± 12%, BLC: 16 ± 8% [P < 0.01]). In both groups, RMR decreased significantly more than expected based on measured body composition changes. The magnitude of this metabolic adaptation was correlated with the degree of energy imbalance (r = 0.55, P = 0.004) and the decrease in circulating leptin (r = 0.47, P = 0.02).. Calorie restriction along with vigorous exercise in BLC participants resulted in preservation of FFM and greater metabolic adaption compared to RYGB subjects despite comparable weight loss. Metabolic adaptation was related to the degree of energy imbalance and the changes in circulating leptin. Topics: Adult; Basal Metabolism; Body Composition; Body Mass Index; Body Weight; Energy Metabolism; Female; Gastric Bypass; Humans; Leptin; Male; Middle Aged; Obesity, Morbid; Weight Loss | 2014 |
Effects of Ilex paraguariensis (yerba mate) treatment on leptin resistance and inflammatory parameters in obese rats primed by early weaning.
We evaluated the effects of yerba mate treatment over 30 days on body weight, food intake, hypothalamic leptin action and inflammatory profile in adult rats that were weaned early.. To induce early weaning, the teats of lactating rats were blocked with a bandage to interrupt milk access for the last 3 days of lactation (EW group). Control offspring had free access to milk throughout lactation. On postnatal day (PN) 150, EW offspring were subdivided into: EW and M groups were treated with water and mate aqueous solution (1g/kg BW/day, gavage), respectively, for 30 days. Control offspring received water by gavage. On PN180, offspring were killed.. EW group presented hyperphagia; higher adiposity; higher NPY and TNF-α expression in the ARC nucleus; higher TNF-α and IL-1β levels in the adipose tissue; and lower IL-10 levels in the adipose tissue. These characteristics were normal in M group. As expected, the leptin injection in control offspring caused lower food intake. However, EW group exhibited no change in food intake after the leptin injection, indicating leptin resistance. In contrast, M group had a normal response to the leptin injection.. Thirty days of mate treatment prevented the development of hyperphagia, overweight, visceral obesity and central leptin resistance. This beneficial effect on the satiety of M offspring most likely occurred after the improvement of inflammatory markers in the hypothalamus and adipocytes, which suggests that Ilex paraguariensis plays an important role in the management of obesity by acting on the inflammatory profile. Topics: Adiposity; Animals; Body Weight; Drug Resistance; Eating; Female; Hypothalamus; Ilex paraguariensis; Inflammation; Injections; Leptin; Male; Obesity; Phytotherapy; Plant Preparations; Rats; Rats, Wistar; Weaning | 2014 |
Effects of resistin on ovarian folliculogenesis and steroidogenesis in the vespertilionid bat, Scotophilus heathi.
The bat Scotophilus heathi exhibit prolonged anovulatory condition known as delayed ovulation coinciding with the period of extensive fat accumulation. The present study was undertaken to find out whether extensive accumulation of fat in S. heathi is responsible for suppression of ovarian activity by increasing production of adipokine resistin in the bat. This was achieved by (a) investigating variation in serum resistin level in relation to the changes in the body fat mass and (b) evaluating the effect of resistin treatment on ovarian activity with reference to steroid synthesis. An attempt was also made to determine whether resistin mediate its effects on ovary through signal transducer and activator of transcription 3 (STAT3) signaling mechanism. The results showed significant seasonal variation in serum resistin level with the peak level coinciding with the period of maximum fat accumulation, high circulating androgen level and period of anovulation. The treatment with resistin to the bat caused increase in androstenedione due to stimulatory effects on 3β-hydroxysteroid dehydrogenase, but decrease in estradiol level due to inhibitory effect on aromatase. Resistin treatment increased androgen receptor protein together with increased insulin receptor but not through conventional luteinizing hormone receptor and steroidogenic acute regulatory protein mediated pathways. This study further showed that resistin treatment increases androstenedione synthesis and up-regulates insulin receptor in the ovary through STAT3 mediated pathways. These findings suggest that obese women through increased resistin synthesis may causes development of non-ovulatory antral follicles through insulin receptor signaling cascade. Topics: Adiponectin; Adiposity; Androstenedione; Animals; Apoptosis; Blotting, Western; Body Weight; Cell Proliferation; Chiroptera; Estradiol; Female; Humans; Insulin; Leptin; Luteinizing Hormone; Organ Size; Ovarian Follicle; Progesterone; Receptors, Cell Surface; Reproducibility of Results; Resistin; Steroids | 2014 |
A prospective study of maternal prenatal weight and offspring cardiometabolic health in midchildhood.
To examine the relations of maternal prepregnancy body mass index (ppBMI) and gestational weight gain (GWG) with offspring cardiometabolic health.. We studied 1090 mother-child pairs in Project Viva, a Boston-area prebirth cohort. We measured overall (dual x-ray absorptiometry total fat; body mass index z-score) and central adiposity (dual x-ray absorptiometry trunk fat), and systolic blood pressure in offspring at 6 to 10 years. Fasting bloods (n = 687) were assayed for insulin and glucose (for calculation of homeostatic model assessment of insulin resistance), triglycerides, leptin, adiponectin, high sensitivity C-reactive protein, and interleukin 6. Using multivariable linear regression, we examined differences in offspring outcomes per 1 SD maternal ppBMI and GWG.. After adjustment for confounders, each 5 kg/m² higher ppBMI corresponded with 0.92 kg (95% confidence interval, 0.70-1.14) higher total fat, 0.27 BMI z-score (0.21-0.32), and 0.39 kg (0.29-0.49) trunk fat. ppBMI was also positively associated with homeostatic model assessment of insulin resistance, leptin, high sensitivity C-reactive protein, interleukin 6, and systolic blood pressure; and lower adiponectin. Each 5 kg of GWG predicted greater adiposity (0.33 kg [0.11-0.54] total fat; 0.14 kg [0.04-0.23] trunk fat) and higher leptin (6% [0%-13%]) in offspring after accounting for confounders and ppBMI.. Children born to heavier mothers have more overall and central fat and greater cardiometabolic risk. Offspring of women with higher GWG had greater adiposity and higher leptin. Topics: Adiponectin; Adolescent; Adult; Birth Weight; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Body Weights and Measures; Boston; C-Reactive Protein; Cardiovascular Diseases; Child; Female; Health Behavior; Humans; Insulin Resistance; Leptin; Male; Mothers; Prospective Studies; Socioeconomic Factors; Triglycerides; Young Adult | 2014 |
Clostridium ramosum promotes high-fat diet-induced obesity in gnotobiotic mouse models.
The intestines of obese humans and mice are enriched with Erysipelotrichi, a class within the Firmicutes. Clostridium ramosum, a member of the Erysipelotrichi, is associated with symptoms of the metabolic syndrome in humans. To clarify the possible obesogenic potential of this bacterial species and to unravel the underlying mechanism, we investigated the role of C. ramosum in obesity development in gnotobiotic mice. Mice were associated with a simplified human intestinal (SIHUMI) microbiota of eight bacterial species, including C. ramosum, with the SIHUMI microbiota except C. ramosum (SIHUMIw/oCra), or with C. ramosum only (Cra) and fed a high-fat diet (HFD) or a low-fat diet (LFD). Parameters related to the development of obesity and metabolic diseases were compared. After 4 weeks of HFD feeding, the mouse groups did not differ in energy intake, diet digestibility, gut permeability, and parameters of low-grade inflammation. However, SIHUMI and Cra mice fed the HFD gained significantly more body weight and body fat and displayed higher food efficiency than SIHUMIw/oCra mice fed the HFD. Gene expression of glucose transporter 2 (Glut2) in jejunal mucosa and of fatty acid translocase (CD36) in ileal mucosa was significantly increased in the obese SIHUMI and Cra mice compared with the less obese SIHUMIw/oCra mice. The data demonstrate that the presence of C. ramosum in SIHUMI and Cra mice enhanced diet-induced obesity. Upregulation of small intestinal glucose and fat transporters in these animals may contribute to their increased body fat deposition.. Obesity is a growing health problem worldwide. Changes in the proportions of Bacteroidetes and Firmicutes, the two dominant phyla in the human and the murine intestinal tract, link the intestinal microbiota to obesity. Erysipelotrichi, a class within the Firmicutes, increase in response to high-fat feeding in mice. Clostridium ramosum, a member of the Erysipelotrichi, has been linked to symptoms of the metabolic syndrome. We hypothesized that C. ramosum promotes obesity development and related pathologies. Our experiments in gnotobiotic mice show that C. ramosum promoted diet-induced obesity, probably by enhancing nutrient absorption. Identification of obesogenic bacteria and understanding their mode of action enable the development of novel strategies for the treatment of this epidemic disease. Pharmaceuticals that target obesogenic bacteria or their metabolism could help to prevent and treat obesity and related disorders in the future. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Clostridium; Diet, High-Fat; Disease Models, Animal; Energy Intake; Germ-Free Life; Glucose Transporter Type 2; Humans; Intestinal Mucosa; Intestines; Leptin; Male; Mice; Mice, Inbred C3H; Microbiota; Obesity; Transcription, Genetic; Up-Regulation | 2014 |
Leptin receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake.
Pontine parabrachial nucleus (PBN) neurons integrate visceral, oral, and other sensory information, playing an integral role in the neural control of feeding. Current experiments probed whether lateral PBN (lPBN) leptin receptor (LepRb) signaling contributes to this function. Intra-lPBN leptin microinjection significantly reduced cumulative chow intake, average meal size, and body weight in rats, independent of effects on locomotor activity or gastric emptying. In contrast to the effects observed following LepRb activation in other nuclei, lPBN LepRb stimulation did not affect progressive ratio responding for sucrose reward or conditioned place preference for a palatable food. Collectively, results suggest that lPBN LepRb activation reduces food intake by modulating the neural processing of meal size/satiation signaling, and highlight the lPBN as a novel site of action for leptin-mediated food intake control. Topics: Animals; Body Weight; Cerebral Aqueduct; Diet, High-Fat; Eating; Food Preferences; Gastric Emptying; Leptin; Male; Parabrachial Nucleus; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Satiation; Signal Transduction | 2014 |
Sleep deprivation alters energy homeostasis through non-compensatory alterations in hypothalamic insulin receptors in Wistar rats.
Studies have shown a gradual reduction of sleep time in the general population, accompanied by increased food intake, representing a risk for developing obesity, type II diabetes and cardiovascular disease. Rats subjected to paradoxical sleep deprivation (PSD) exhibit feeding and metabolic alterations, both of which are regulated by the communication between peripheral signals and the hypothalamus. This study aimed to investigate the daily change of 96 h of PSD-induced food intake, body weight, blood glucose, plasma insulin and leptin concentrations and the expression of their receptors in the hypothalamus of Wistar rats. Food intake was assessed during the light and dark phases and was progressively increased in sleep-deprived animals, during the light phase. PSD produced body weight loss, particularly on the first day, and decreased plasma insulin and leptin levels, without change in blood glucose levels. Reduced leptin levels were compensated by increased expression of leptin receptors in the hypothalamus, whereas no compensations occurred in insulin receptors. The present results on body weight loss and increased food intake replicate previous studies from our group. The fact that reduced insulin levels did not lead to compensatory changes in hypothalamic insulin receptors, suggests that this hormone may be, at least in part, responsible for PSD-induced dysregulation in energy metabolism. Topics: Animals; Blood Glucose; Body Weight; Eating; Energy Metabolism; Homeostasis; Hypothalamus; Insulin; Leptin; Male; Obesity; Rats; Rats, Wistar; Receptor, Insulin; Sleep Deprivation | 2014 |
Reciprocal changes in leptin and NPY during nutritional acceleration of puberty in heifers.
Feeding a high-concentrate diet to heifers during the juvenile period, resulting in increased body weight (BW) gain and adiposity, leads to early-onset puberty. In this study, we tested the hypothesis that the increase in GnRH/LH release during nutritional acceleration of puberty is accompanied by reciprocal changes in circulating leptin and central release of neuropeptide Y (NPY). The heifers were weaned at 3.5 months of age and fed to gain either 0.5 (Low-gain; LG) or 1.0 kg/day (High-gain; HG) for 30 weeks. A subgroup of heifers was fitted surgically with third ventricle guide cannulas and was subjected to intensive cerebrospinal fluid (CSF) and blood sampling at 8 and 9 months of age. Mean BW was greater in HG than in LG heifers at week 6 of the experiment and remained greater thereafter. Starting at 9 months of age, the percentage of pubertal HG heifers was greater than that of LG heifers, although a replicate effect was observed. During the 6-h period in which CSF and blood were collected simultaneously, all LH pulses coincided with or shortly followed a GnRH pulse. At 8 months of age, the frequency of LH pulses was greater in the HG than in the LG group. Beginning at 6 months of age, concentrations of leptin were greater in HG than in LG heifers. At 9 months of age, concentrations of NPY in the CSF were lesser in HG heifers. These observations indicate that increased BW gain during juvenile development accelerates puberty in heifers, coincident with reciprocal changes in circulating concentrations of leptin and hypothalamic NPY release. Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Cattle; Diet; Female; Gonadotropin-Releasing Hormone; Hypothalamus; Leptin; Luteinizing Hormone; Neuropeptide Y; Radioimmunoassay; Sexual Maturation; Time Factors; Weaning | 2014 |
[The blood leptin and the activity of the system inflammatory response in patients with diabetes mellitus type 2 with different body weight and disease duration].
Recent studies focused on the adipose tissue hormones role, especially leptin as one of the basic and generalized nonspecific inflammation markers among them. Some of the major markers are IL-2, IL -6 and TNF-alpha in the pathogenesis of diabetes (DM) and its complications. It is established that patients with type 2 diabetes lasting from 5 to 10 years represent the highest leptin and cytokines levels, and during this period cardiovascular complications of type 2 diabetes are formed. Also it is found that the leptin level was significantly lower in patients with normal body weight, while the levels of IL-6 and TNF-a are the highest in these patients. Obviously, the increased level of these cytokines helps to maintain a normal body weight in these patients. Despite the fact that type 2 diabetes is considered a non-autoimmune disease, it is known that for a long glucose toxicity and lipotoxicity metabolic immunosuppression occurs, which causes changes in T-cell immunity, and consequently to autoimmunity. Topics: Adipose Tissue; Body Weight; Cytokines; Diabetes Mellitus, Type 2; Female; Humans; Interleukin-2; Interleukin-6; Leptin; Male; Obesity; Time Factors; Tumor Necrosis Factor-alpha | 2014 |
Shp2 signaling in POMC neurons is important for leptin's actions on blood pressure, energy balance, and glucose regulation.
Previous studies showed that Src homology-2 tyrosine phosphatase (Shp2) is an important regulator of body weight. In this study, we examined the impact of Shp2 deficiency specifically in proopiomelanocortin (POMC) neurons on metabolic and cardiovascular function and on chronic blood pressure (BP) and metabolic responses to leptin. Mice with Shp2 deleted in POMC neurons (Shp2/Pomc-cre) and control mice (Shp2(flox/flox)) were implanted with telemetry probes and venous catheters for measurement of mean arterial pressure (MAP) and leptin infusion. After at least 5 days of stable control measurements, mice received leptin infusion (2 μg·kg(-1)·day(-1) iv) for 7 days. Compared with Shp2(flox/flox) controls, Shp2/Pomc-cre mice at 22 wk of age were slightly heavier (34 ± 1 vs. 31 ± 1 g) but consumed a similar amount of food (3.9 ± 0.3 vs. 3.8 ± 0.2 g/day). Leptin infusion reduced food intake in Shp2(flox/flox) mice (2.6 ± 0.5 g) and Shp2/Pomc-cre mice (3.2 ± 0.3 g). Despite decreasing food intake, leptin infusion increased MAP in control mice, whereas no significant change in MAP was observed in Shp2/Pomc-cre mice. Leptin infusion also decreased plasma glucose and insulin levels in controls (12 ± 1 to 6 ± 1 μU/ml and 142 ± 12 to 81 ± 8 mg/100 ml) but not in Shp2/Pomc-cre mice. Leptin increased V̇o2 by 16 ± 2% in controls and 7 ± 1% in Shp2/Pomc-cre mice. These results indicate that Shp2 signaling in POMC neurons contributes to the long-term BP and antidiabetic actions of leptin and may play a modest role in normal regulation of body weight. Topics: Animals; Arterial Pressure; Blood Glucose; Body Weight; Brain; Eating; Energy Metabolism; Homeostasis; Infusions, Intravenous; Insulin; Leptin; Male; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Neurons; Oxygen Consumption; Pro-Opiomelanocortin; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Signal Transduction; Time Factors | 2014 |
Chronic glucocorticoid exposure-induced epididymal adiposity is associated with mitochondrial dysfunction in white adipose tissue of male C57BL/6J mice.
Prolonged and excessive glucocorticoids (GC) exposure resulted from Cushing's syndrome or GC therapy develops central obesity. Moreover, mitochondria are crucial in adipose energy homeostasis. Thus, we tested the hypothesis that mitochondrial dysfunction may contribute to chronic GC exposure-induced epididymal adiposity in the present study. A total of thirty-six 5-week-old male C57BL/6J mice (∼20 g) were administrated with 100 µg/ml corticosterone (CORT) or vehicle through drinking water for 4 weeks. Chronic CORT exposure mildly decreased body weight without altering food and water intake in mice. The epididymal fat accumulation was increased, but adipocyte size was decreased by CORT. CORT also increased plasma CORT, insulin, leptin, and fibroblast growth factor 21 concentrations as measured by RIA or ELISA. Interestingly, CORT increased plasma levels of triacylglycerols and nonesterified fatty acids, and up-regulated the expression of both lipolytic and lipogenic genes as determined by real-time RT-PCR. Furthermore, CORT impaired mitochondrial biogenesis and oxidative function in epididymal WAT. The reactive oxygen species production was increased and the activities of anti-oxidative enzymes were reduced by CORT treatment as well. Taken together, these findings reveal that chronic CORT administration-induced epididymal adiposity is, at least in part, associated with mitochondrial dysfunction in mouse epididymal white adipose tissue. Topics: Adipose Tissue, White; Adiposity; Animals; Body Weight; Corticosterone; Eating; Epididymis; Fatty Acids, Nonesterified; Fibroblast Growth Factors; Glucocorticoids; Insulin; Leptin; Male; Mice; Mitochondria; Reactive Oxygen Species; Triglycerides | 2014 |
Anti-atherogenic effect of hydrogen sulfide by over-expression of cystathionine gamma-lyase (CSE) gene.
Hydrogen sulfide (H2S) is an important gaseous signaling molecule that functions in physiological and pathological conditions, such as atherosclerosis. H2S dilates vessels and therefore has been suggested as an anti-atherogenic molecule. Since cystathionine gamma-lyase (CSE) enzyme is responsible for producing H2S in the cardiovascular system, we hypothesized that up-regulation of CSE expression in vivo with preservation of H2S bioactivity can slow down plaque formation and, can serve as a therapeutic strategy against atherosclerosis. In this study, C57BL/6 wild type mice (WT), ApoE knockout mice (KO) and transgenic ApoE knockout mice overexpressing CSE (Tg/KO) at four weeks of age were weaned. They were then fed with either normal or atherogenic diet for 12 weeks. At week 16, serial plasma lipid levels, body weight, and blood pressure were measured prior to euthanization of the mice and the size of atherosclerotic plaques at their aortic roots was measured. Tg/KO mice showed an increase in endogenous H2S production in aortic tissue, reduced atherosclerotic plaque sizes and attenuation in plasma lipid profiles. We also showed an up-regulation in plasma glutathionine peroxidase that could indicate reduced oxidative stress. Furthermore, there was an increase in expression of p-p53 and down regulation of inflammatory nuclear factor-kappa B (NF-κB) in aorta. To conclude, alteration of endogenous H2S by CSE gene activation was associated with reduced atherosclerosis in ApoE-deficient mice. Up-regulation of CSE/H2S pathway attenuates atherosclerosis and this would be a potential target for therapeutic intervention against its formation. Topics: Adiponectin; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Blood Pressure; Body Weight; Cystathionine gamma-Lyase; Down-Regulation; Glutathione Peroxidase; Hydrogen Sulfide; Leptin; Lipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myocardium; NF-kappa B; Oxidative Stress; Plaque, Atherosclerotic; Tumor Suppressor Protein p53; Up-Regulation | 2014 |
Distinct Roles for JNK and IKK Activation in Agouti-Related Peptide Neurons in the Development of Obesity and Insulin Resistance.
Activation of c-Jun N-terminal kinase 1 (JNK1)- and inhibitor of nuclear factor kappa-B kinase 2 (IKK2)-dependent signaling plays a crucial role in the development of obesity-associated insulin and leptin resistance not only in peripheral tissues but also in the CNS. Here, we demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons of the hypothalamus is sufficient to induce weight gain and adiposity in mice as a consequence of hyperphagia. JNK activation increases spontaneous action potential firing of AgRP cells and causes both neuronal and systemic leptin resistance. Similarly, activation of IKK2 signaling in AgRP neurons also increases firing of these cells but fails to cause obesity and leptin resistance. In contrast to JNK activation, IKK2 activation blunts insulin signaling in AgRP neurons and impairs systemic glucose homeostasis. Collectively, these experiments reveal both overlapping and nonredundant effects of JNK- and IKK-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome. Topics: Action Potentials; Adiposity; Agouti-Related Protein; Animals; Body Weight; Enzyme Activation; Glucose; Homeostasis; I-kappa B Kinase; Insulin; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Leptin; Male; MAP Kinase Signaling System; Mice, Inbred C57BL; Mutant Proteins; Neurons; Obesity | 2014 |
Relationships among body composition, circulating concentrations of leptin and follistatin, and the onset of puberty and fertility in young female sheep.
The onset of puberty depends on the attainment of critical body mass, so should also be affected by increases in the rate of accumulation of muscle and adipose tissue. Adipose tissue and reproduction are linked by leptin. For muscle, a link has not yet been identified, although one possibility is follistatin. We assessed the relationships among circulating concentrations of follistatin and leptin and the rates of growth and accumulation of muscle and fat during pubertal development in female sheep. We used 326 animals with known phenotypic values for live weight (LW), depths of eye muscle (EMD) and fat (FAT), and known breeding values at post-weaning age for body mass (PWT) and depths of eye muscle (PEMD) and fat (PFAT). Leptin concentration was positively correlated with values for EMD, PEMD, FAT, PFAT, LW and PWT (P<0.001), whereas follistatin concentration was negatively correlated with values for EMD and PWT (P<0.001), and PEMD (P<0.01) and FAT (P<0.05). Leptin concentration was negatively related to age and positively related to live weight at first oestrus and the proportion of females that attained puberty (P≤0.05), and to fertility and reproductive rate (P<0.01). Follistatin concentration was negatively related to live weight at first oestrus and to fertility (P<0.01) and reproductive rate (P<0.05). There were positive correlations (P<0.001) between muscle accumulation and leptin concentration, and between muscle accumulation and reproductive performance. We conclude that leptin and follistatin are probably both involved in effects of accelerated accumulation of muscle and adipose tissues on the onset of puberty. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Female; Fertility; Follistatin; Leptin; Muscle, Skeletal; Sexual Maturation; Sheep, Domestic | 2014 |
Relationship between fat mass measured by dual-energy X-ray absorptiometry and leptin in preterm infants between term age and 6 months' corrected age.
In term subjects, fat mass (FM) is positively associated with leptin, whereas studies in preterm infants show conflicting results. However, none of these studies measured FM by dual-energy X-ray absorptiometry (DEXA). This study aims to relate FM measured by DEXA in relation to leptin and growth in preterm infants.. In 139 preterm infants, weight (kg) and length (cm) were measured at birth, term age, and 6 months' corrected age (CA). FM (kg), measured by whole-body DEXA, and leptin (µg/l) were measured at term age and 6 months' CA.. At term age and 6 months' CA, FM was associated with leptin (β = 1.94, 95% CI: 1.51-2.36, and β = 0.37, 95% CI: 0.26-0.48, respectively; p < 0.001). Gain in weight standard deviation score (SDS) between term age and 6 months' CA was associated with FM and leptin at 6 months' CA (β = 0.24, 95% CI: 0.18-0.30, and β = 0.25, 95% CI: 0.16-0.33, respectively; p < 0.001).. In preterm infants, FM measured by DEXA is associated with leptin, which indicates that leptin is a marker of body FM during the first 6 months after term age. Gain in weight SDS between term age and 6 months' CA results in higher FM and higher leptin at 6 months' CA. Topics: Absorptiometry, Photon; Adipose Tissue; Age Factors; Birth Weight; Body Composition; Body Weight; Female; Gestational Age; Humans; Infant; Infant, Newborn; Infant, Premature; Leptin; Male; Organ Size | 2014 |
Effect of high-fat or high-glucose diet on obesity and visceral adipose tissue in mice.
To investigate the effect of high-fat or high-glucose diet on obesity and visceral adipose tissue in C57BL/6 mice.. Four-week-old C57BL/6 mice were allocated into normal diet group,high-fat diet group,and high-glucose diet group according to the random number table until 20 weeks old. Body weight,epididymal adipose tissue weight,blood leptin,fat infiltration in liver,M1/M2 macrophage subtypes,and monocyte chemoattractant protein-1 mRNA in epididymal adipose tissues were measured.. Compared with normal diet group,body weight,epididymal adipose tissue weight,and leptin concentration in high fat diet group at 20 weeks were significantly increased (P < 0.05),and oil red O staining showed more prominent adipocyte infiltration in liver in high-fat diet group than those in normal diet and high-glucose diet group. However,no apparent differences were seen in high-glucose diet group at 20 weeks in terms of body weight,epididymal adipose tissue weight and leptin concentration. In high-fat diet group,the macrophages infiltration in epididymal adipose tissue increased with time and the percentage of M2 macrophage decreased in high-fat diet group than that in high-glucose diet group(P<0.05). Compared with normal diet group,monocyte chemoattractant protein-1 mRNA expression increased significantly in high-fat diet group(P<0.05). In high-glucose group,however,no significant differences were discerned (P > 0.05).. High-fat diet,rather than 60% high glucose diet,will lead to obesity and macrophage infiltration in adipose tissues. Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Chemokine CCL2; Diet, High-Fat; Glucose; Intra-Abdominal Fat; Leptin; Macrophages; Mice; Mice, Inbred C57BL; Obesity; RNA, Messenger | 2014 |
Ilex paraguariensis (yerba mate) improves endocrine and metabolic disorders in obese rats primed by early weaning.
We showed that early weaned rats developed obesity, hyperleptinemia, leptin and insulin resistance at adulthood. Here, we studied the potential beneficial effects of Ilex paraguariensis aqueous solution upon body composition, glycemia, lipid and hormonal profiles, leptin signaling and NPY content.. To induce early weaning, lactating rats' teats were blocked with a bandage to interrupt lactation during the last 3 days (EW group), while control offspring had free access to milk throughout lactation (C group). In postnatal day (PN) 150, EW offspring were subdivided into: EW and EW+ mate groups treated, respectively, with water or yerba mate aqueous solution (1 g/kg BW/day, gavage) during 30 days. C offspring received water for gavage. In PN180, offspring were killed.. EW+ mate group presented lower body weight (-10 %), adipose mass (retroperitoneal:-40 % and epididymal:-44 %), total body fat (-43 %), subcutaneous fat (-46 %), visceral adipocyte area (-21 %), triglyceridemia (-31 %) and hypothalamic NPY content (-37 %) compared to EW group. However, hyperglycemia and lower HDL-c levels observed in EW group were not reverted with mate treatment. Although the hyperleptinemia, lower hypothalamic JAK2 and pSTAT3 content of EW group were not corrected by mate treatment, the hyperphagia and higher hypothalamic SOCS-3 content were normalized in EW+ mate group, indicating that the central leptin resistance could be restored.. Thus, the therapy with yerba mate solution was capable to reverse abdominal obesity, leptin resistance and hypertriglyceridemia, suggesting an important role of this bioactive component in the management of obesity in this programming model. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Disease Models, Animal; Dyslipidemias; Female; Hyperglycemia; Hypothalamus; Ilex paraguariensis; Insulin Resistance; Janus Kinase 2; Lactation; Leptin; Neuropeptide Y; Obesity; Plant Extracts; Rats; STAT3 Transcription Factor; Subcutaneous Fat; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Weaning | 2014 |
Progression of cardiovascular and endocrine dysfunction in a rabbit model of obesity.
In rabbits, mean arterial pressure (MAP) increases in response to fat feeding, but does not increase further with progressive weight gain. We documented the progression of adiposity and the alterations in endocrine/cardiovascular function in response to fat feeding in rabbits, to determine whether stabilization of MAP after 3 weeks could be explained by stabilization of neurohormonal factors. Rabbits were fed a control diet or high-fat diet for 9 weeks (n=23). Fat feeding progressively increased body mass and adiposity. Heart rate (HR) was elevated by week 3 (15±3%) but changed little thereafter. The effects of fat feeding on MAP were dependent on baseline MAP and peaked at 3 weeks. From baseline, MAP 80 mm Hg, MAP had increased by 8.1±1.3, 4.7±1.7 and 5.6±1.2 mm Hg, respectively, 3, 6 and 9 weeks after commencing the high-fat diet, but by only 2.6±1.5, 3.0±1.7 and 3.9±1.4 mm Hg, respectively, in control rabbits. Fat feeding did not increase MAP from a baseline >80 mm Hg. Plasma concentrations of leptin and insulin increased during the first 3-6 weeks of fat feeding and then stabilized (increasing by 111±17% and 731±302% by week 9, respectively), coinciding with the pattern of changes in MAP and HR. Plasma total cholesterol, triglycerides, renin activity, aldosterone and atrial natriuretic peptide were not significantly altered by fat feeding. Given that the changes in plasma leptin and insulin mirrored the changes in MAP and HR, leptin and insulin may be important factors in the development of hypertension and tachycardia in the rabbit model of obesity. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Cardiovascular Diseases; Disease Models, Animal; Endocrine System Diseases; Hemodynamics; Insulin; Leptin; Male; Obesity; Rabbits; Renin-Angiotensin System | 2013 |
Adipocytokines levels at delivery, functional variation of TFAP2β, and maternal and neonatal anthropometric parameters.
Adipocytokines participate in the regulation of glucose metabolism and fetal development. The transcription factor activating protein 2B (TFAP2β) has been associated with adipocytokine regulation, and gene variations with type 2 diabetes and obesity. This study investigated associations between maternal TFAP2B variation, adipocytokine levels, and maternal and neonatal anthropometric characteristics.. A population-based sample of women was followed from delivery to 6 months postpartum. Adiponectin, leptin, and interleukin-6 levels at delivery, and maternal as well as neonatal anthropometric variables were assessed. The TFAP2β intron 1 variable number tandem repeat (VNTR) was genotyped.. Maternal interleukin-6 correlated positively with leptin at delivery, with peripartum weight changes and weight of newborn males, adjusted for potential confounders. Leptin at delivery was associated with TFAP2β intron 1 VNTR genotype, adjusted for confounders, maternal weight and negatively with birth weight among female neonates. A path model suggested a link between TFAP2β genotype, leptin levels, and newborn females' weight.. The present results stress a role for the TFAP2 β in adiposity-related conditions and intrauterine growth. The association between neonatal birth weight and maternal adipocytokine levels, together with the observed sex effect, call for further studies on the mechanisms behind neuroendocrine fetal programming. Topics: Adipokines; Adiposity; Adult; Birth Weight; Blood Pressure; Body Mass Index; Body Weight; Diabetes, Gestational; Female; Genetic Variation; Humans; Infant, Newborn; Interleukin-6; Leptin; Longitudinal Studies; Male; Minisatellite Repeats; Pregnancy; Risk Factors; Transcription Factor AP-2 | 2013 |
Leptin and adiponectin in cord blood from children of normal weight, overweight and obese mothers.
To study cord blood concentrations of adiponectin and leptin in children born by normal weight, overweight and obese mothers and to study these parameters in relation to a weight gain intervention programme for obese mothers.. Ten millilitre cord blood was collected and analysed for leptin and adiponectin concentrations in children with gestational age >37 weeks born by 60 normal weight, 45 overweight and 145 obese mothers. 82 obese mothers took part in a weight gain intervention programme.. Concentrations of leptin and adiponectin were higher in cord blood from children of overweight and obese mothers compared with children of normal weight mothers (leptin: Md 13.2, 30, 3 and 90.2 ng/mL respectively, p < 0.001; adiponectin 35.9, 205.4, 213.8 ng/L p < 0.001). No differences were found between overweight and obese mothers. The weight gain intervention programme for obese pregnant women had significant effects on the weight gain during pregnancy but had no effects on cord blood serum concentrations of leptin and adiponectin.. Cord blood leptin and adiponectin concentrations were higher in children born by overweight or obese women compared with children of normal weight mothers. A weight gain intervention programme for obese pregnant women did not affect these results. Intrauterine exposition to high concentrations of leptin and adiponectin may play a role in weight development later in life. Topics: Adiponectin; Adult; Body Weight; Female; Fetal Blood; Fetus; Humans; Infant, Newborn; Leptin; Mothers; Overweight; Prospective Studies | 2013 |
Ablation of Rnf213 retards progression of diabetes in the Akita mouse.
Moyamoya disease (MMD) and moyamoya syndrome are vasculopathies characterized by progressive stenosis in the circle of Willis and its branches. The RNF213 gene, which encodes a novel class of proteins, characterized by both E3 ligase and AAA+ATPase activities, has been identified as the susceptibility gene for MMD. However, its physiological functions remain unknown. MMD and moyamoya syndrome are often accompanied by diabetes mellitus. In this study, we generated Rnf213 knockout (KO) C57BL/6 mice (Rnf213(-/-); Ins2(+/+)), which were mated with Akita (C57BL/6 Rnf213(+/+); Ins2(+/C96Y)) mice, a strain that develops diabetes spontaneously by 5 weeks of age, to obtain mice lacking Rnf213 and carrying the Akita mutation (KO/Akita, Rnf213(-/-); Ins2(+/C96Y)). Body weight and blood glucose concentration were measured from 6 to 20 weeks. Glucose tolerance, insulin resistance, plasma insulin and leptin concentrations, food consumption, pancreatic insulin content and histopathology were evaluated at 18 weeks of age. We found that glucose tolerance, as indicated by AUC, was 20% lower (p<0.05) and insulin contents in pancreas were 150% higher (p<0.05), in KO/Akita than in Akita mice. The number of CHOP positive β-cells assayed by histopathological examination was 30% lower and food consumption was 34% lower in KO/Akita than in Akita mice (p<0.05 each). These findings indicated that the disruption of Rnf213 improved glucose tolerance by protecting islet β cells. Topics: Adenosine Triphosphatases; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Disease Progression; Glucose Tolerance Test; Insulin; Insulin-Secreting Cells; Leptin; Mice; Mice, Knockout; Moyamoya Disease; Transcription Factor CHOP; Ubiquitin-Protein Ligases | 2013 |
Ameliorating effects of casein glycomacropeptide on obesity induced by high-fat diet in male Sprague-Dawley rats.
The effect of casein glycomacropeptide (GMP) as a specific regulating mediator in obese rats induced by high-fat (HF) diet was investigated. Male obese Sprague-Dawley (SD) rats induced by high-fat diet for 8 weeks period were fed high-fat, high-fat with GMP of 100 mg/kg BW (HFLG), 200 mg/kg BW (HFMG) and 400mg/kg BW (HFHG) for 6 weeks. Compared with the high-fat control (HFC) group GMP supplementation significantly decreased adipose tissue weight, activity of fatty acid synthase (FAS) and glycerol-3-phosphate dehydrogenase (GPDH). Hepatic lipid droplet size, plasma and hepatic lipid levels markedly reduced. Moreover, GMP reduces plasma total cholesterol and low-density lipoprotein (LDL) cholesterol as well as hepatic-cholesterol and triglycerides. The liver steatosis observed in obese rats was also prevented by GMP supplement. In addition, GMP significantly diminished mitochondrial and liver malondialdehyde (MDA) production, and obviously elevated the activities of mitochondrial and hepatic superoxidase dismutase (SOD) and glutathione peroxidase (GSH-Px). Leptin production and proinflammatory cytokines such as TNF-α and IL-6 secretion decreased. Taken together, GMP can reduce lipid accumulation and enhance antioxidant capability of obese rats. It suggests that GMP can counteract high-fat diet-induced obesity, which might make it a potential ingredient with anti-obesity activity. Topics: Adipose Tissue; Animals; Body Weight; Caseins; Cholesterol; Diet, High-Fat; Fatty Acid Synthases; Fatty Liver; Glycerolphosphate Dehydrogenase; Interleukin-6; Leptin; Liver; Male; Obesity; Peptide Fragments; Rats; Rats, Sprague-Dawley; Triglycerides; Tumor Necrosis Factor-alpha | 2013 |
Involvement of hypothalamic AMP-activated protein kinase in leptin-induced sympathetic nerve activation.
In mammals, leptin released from the white adipose tissue acts on the central nervous system to control feeding behavior, cardiovascular function, and energy metabolism. Central leptin activates sympathetic nerves that innervate the kidney, adipose tissue, and some abdominal organs in rats. AMP-activated protein kinase (AMPK) is essential in the intracellular signaling pathway involving the activation of leptin receptors (ObRb). We investigated the potential of AMPKα2 in the sympathetic effects of leptin using in vivo siRNA injection to knockdown AMPKα2 in rats, to produce reduced hypothalamic AMPKα2 expression. Leptin effects on body weight, food intake, and blood FFA levels were eliminated in AMPKα2 siRNA-treated rats. Leptin-evoked enhancements of the sympathetic nerve outflows to the kidney, brown and white adipose tissues were attenuated in AMPKα2 siRNA-treated rats. To check whether AMPKα2 was specific to sympathetic changes induced by leptin, we examined the effects of injecting MT-II, a melanocortin-3 and -4 receptor agonist, on the sympathetic nerve outflows to the kidney and adipose tissue. MT-II-induced sympatho-excitation in the kidney was unchanged in AMPKα2 siRNA-treated rats. However, responses of neural activities involving adipose tissue to MT-II were attenuated in AMPKα2 siRNA-treated rats. These results suggest that hypothalamic AMPKα2 is involved not only in appetite and body weight regulation but also in the regulation of sympathetic nerve discharges to the kidney and adipose tissue. Thus, AMPK might function not only as an energy sensor, but as a key molecule in the cardiovascular, thermogenic, and lipolytic effects of leptin through the sympathetic nervous system. Topics: alpha-MSH; AMP-Activated Protein Kinases; Animals; Blood Glucose; Blotting, Western; Body Weight; Catecholamines; Eating; Fatty Acids, Nonesterified; Hemodynamics; Hypothalamus; Injections, Intraventricular; Leptin; Male; Peptides, Cyclic; Protein Subunits; Rats; Rats, Wistar; RNA Interference; Sympathetic Nervous System | 2013 |
Weight status and dietary intake determine serum leptin concentrations in pregnant and lactating women and their infants.
Leptin regulates energy homeostasis and immune and metabolic functions. Highly elevated leptin concentrations during pregnancy may be associated with aberrations in maternal metabolism and long-term health consequences both in women and children. The objective of the present study was to evaluate whether dietary counselling, probiotic supplementation, maternal characteristics or dietary intake during pregnancy has an impact on serum leptin concentrations in women, cord blood or in children. A total of 256 pregnant women were randomised to a control group (n 85) or to receive dietary counselling with probiotics (n 85) or placebo (n 86). Dietary counselling aimed at affecting the type of fat used and to increase the amount of fibre in the women's diet. Women's dietary intake and serum leptin concentrations were analysed at the first and third trimesters of pregnancy and at 1 month postpartum. Furthermore, leptin concentrations were measured from the cord blood and from children's serum at 1 and 6 months of age. Weight status and dietary composition were the key determinants of leptin concentrations. Specifically, high dietary fibre and low SFA intakes were related to low serum leptin concentrations in women. Female sex and birth weight were associated with higher infant leptin, whereas cord blood leptin was additionally affected by maternal leptin concentration and protein intake. Probiotics or dietary counselling did not affect leptin concentrations. Weight control to recommended levels and modification of diet towards higher fibre and lower SFA intakes during pregnancy may through leptin concentrations provide health benefits to both women and children. Topics: Adult; Body Mass Index; Body Weight; Breast Feeding; Diet; Female; Fetal Blood; Humans; Infant; Lactation; Leptin; Milk, Human; Pregnancy | 2013 |
The protective effect of intermittent calorie restriction on mammary tumorigenesis is not compromised by consumption of a high fat diet during refeeding.
Previously we reported that intermittent calorie restriction (ICR) provided greater prevention of mammary tumors (MTs) than chronic calorie restriction (CCR). Here the impact of increased fat intake during refeeding in an ICR protocol was evaluated. MMTV-TGF-α female mice were assigned to one of three groups: ad libitum (AL) fed (n = 45) with free access to a moderately high fat diet (22 % fat calories); ICR (n = 45) 50 % calorie restricted for 3-week intervals followed by 3 weeks of 100 % of AL intake; and CCR (n = 45) fed 75 % of AL mice, matching each 6-week cycle of ICR mice. ICR mice were further designated as ICR-Restricted or ICR-Refed for data obtained during these intervals. All mice consumed the same absolute amount of dietary fat. Mice were followed to assess MT incidence, body weight and serum IGF-1, IGFBP3, leptin and adiponectin levels until 79 (end of final 3-week restriction) or 82 (end of final 3-weeks refeeding) weeks of age. Age of MT detection was significantly extended for CCR (74 weeks) and ICR (82 weeks) mice, compared to 57.5 weeks for AL mice. MT incidence for AL, ICR and CCR mice was 66.7, 4.4, and 52.3 %, respectively. Mammary and fat pad weights were reduced significantly following 50 % calorie restriction in ICR-Restricted mice compared to AL, CCR and ICR-Refed mice. IGF-1 and leptin levels also tended to be reduced in ICR-Restricted mice over the course of the study while adiponectin was not compared to AL, CCR, and ICR-Refed mice. The adiponectin:leptin ratio was consistently higher following 50 % restriction in ICR-Restricted mice. There was no relationship of IGF-1, leptin, or adiponectin with the presence of MTs in any groups. Thus the manner in which calories are restricted impacts the protective effect of calorie restriction independently of high fat intake. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Caloric Restriction; Cell Transformation, Neoplastic; Diet, High-Fat; Eating; Female; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Transforming Growth Factor alpha | 2013 |
Central PACAP mediates the sympathetic effects of leptin in a tissue-specific manner.
We previously demonstrated that the peptidergic neurotransmitter pituitary adenylate cyclase-activating polypeptide (PACAP) affects the autonomic system and contributes to the control of metabolic and cardiovascular functions. Previous studies have demonstrated the importance of centrally-mediated sympathetic effects of leptin for obesity-related hypertension. Here we tested whether PACAP signaling in the brain is implicated in leptin-induced sympathetic excitation and appetite suppression. In anesthetized mice, intracerebroventricular (ICV) pre-treatment with PACAP6-38, an antagonist of the PACAP receptors (PAC1-R and VPAC2), inhibited the increase in white adipose tissue sympathetic nerve activity (WAT-SNA) produced by ICV leptin (2μg). In contrast, leptin-induced stimulation of renal sympathetic nerve activity (RSNA) was not affected by ICV pre-treatment with PACAP6-38. Moreover, in PACAP-deficient (Adcyap1-/-) mice, ICV leptin-induced WAT-SNA increase was impaired, whereas RSNA response was preserved. The reductions in food intake and body weight evoked by ICV leptin were attenuated in Adcyap1-/- mice. Our data suggest that hypothalamic PACAP signaling plays a key role in the control by leptin of feeding behavior and lipocatabolic sympathetic outflow, but spares the renal sympathetic traffic. Topics: Adipose Tissue, White; Animals; Body Weight; Eating; Hypothalamus; Injections, Intraventricular; Kidney; Leptin; Male; Mice; Mice, Knockout; Organ Specificity; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Sympathetic Nervous System | 2013 |
Cell suspension culture of Eriobotrya japonica regulates the diabetic and hyperlipidemic signs of high-fat-fed mice.
The present study investigates the anti-hyperlipidemic and antihyperglycemic effects and mechanism in high-fat (HF)-fed mice of cell suspension culture of Eriobotrya japonica (TA), which contains a great number of pentacyclic terpenoids. Firstly, C57BL/6J mice were randomly divided into two groups: the control (CON) group was fed with a low-fat diet (n = 9), whereas the experimental group was fed a 45% HF diet for 8 weeks. Afterwards, the CON group was treated with vehicle, whereas the HF group was subdivided into five groups and was orally given TA or rosiglitazone or not for 4 weeks. Blood and visceral adipose tissue, liver tissue and skeletal muscle were examined. Treatment with TA reduced body weight gain, weights of white adipose tissue (WAT) (including epididymal, perirenal, mesenteric WAT and visceral fat), and hepatic triacylglycerol content significantly without affecting food intake in diet-induced diabetic mice. TA effectively prevented HF diet-induced increases in the levels of blood glucose, insulin, leptin and HOMA-IR index (p < 0.001, p < 0.05, p < 0.05, p < 0.01, respectively) and attenuated insulin resistance. Treatment with TA, adipocytes in the visceral depots showed a reduction in size. TA effectively significantly increased the protein contents of phosphorylation of AMPK-α (Thr172) both in liver and adipose tissue. It is shown that TA exhibits hypolipidemic effect in HF-fed mice by decreasing gene expressions of fatty acid synthesis, including acyl-coenzyme A: diacylglycerol acyltransferase (DGAT) 2, which catalyzes the final step in the synthesis of triglycerides, and antidiabetic properties occurred as a result of decreased hepatic glucose production via phosphenolpyruvate carboxykinase (PEPCK) down- regulation, improved insulin sensitization and TA (at 1.0 g/kg dose) decreased expression of hepatic and adipose 11-β-hydroxysteroid dehydroxygenase (11β-HSD1) gene, which contributed in attenuating diabetic state. Futhermore, TA at doses of 0.5 and 1.0 g/kg had serum lipid-lowering action characterized by the inhibition of DGAT 1 expression. Thus, amelioration of diabetic and dyslipidemic state by TA in HF-fed mice occurred by regulation of PEPCK, DGAT2 and AMPK phosphorylation. Topics: Adipocytes; Adiponectin; Adipose Tissue, White; AMP-Activated Protein Kinases; Animals; Blood Glucose; Body Weight; Cell Culture Techniques; Culture Media, Conditioned; Diet, High-Fat; Eriobotrya; Gene Expression Regulation; Glucose Tolerance Test; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Mice; Muscle, Skeletal; Organ Size; Phosphorylation; Triterpenes | 2013 |
Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice.
Cholecystokinin (CCK) and leptin are important hormones with effects on energy balance. The present study assessed the biological effects of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, smaller isoforms of CCK and leptin, respectively.. The actions and overall therapeutic use of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, alone and in combination, were evaluated in normal and high-fat-fed mice.. (pGlu-Gln)-CCK-8 had prominent (p < 0.01 to p < 0.001), acute feeding-suppressive effects, which were significantly augmented (p < 0.05 to p < 0.01) by [D-Leu-4]-OB3. In agreement, the acute dose-dependent glucose-lowering and insulinotropic actions of (pGlu-Gln)-CCK-8 were significantly enhanced by concurrent administration of [D-Leu-4]-OB3. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in high-fat-fed mice for 18 days decreased body weight (p < 0.05 to p < 0.001), energy intake (p < 0.01), circulating triacylglycerol (p < 0.01), non-fasting glucose (p < 0.05 to p < 0.001) and triacylglycerol deposition in liver and adipose tissue (p < 0.001). All treatment regimens improved glucose tolerance (p < 0.05 to p < 0.001) and insulin sensitivity (p < 0.001). Combined treatment with (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3 resulted in significantly lowered plasma insulin levels, normalisation of circulating LDL-cholesterol and decreased triacylglycerol deposition in muscle. These effects were superior to either treatment regimen alone. There were no changes in overall locomotor activity or respiratory exchange ratio, but treatment with (pGlu-Gln)-CCK-8 significantly reduced (p < 0.001) energy expenditure.. These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes. Topics: Animals; Area Under Curve; Blood Glucose; Body Weight; Calorimetry, Indirect; Chemokines, CC; Diet, High-Fat; Insulin; Insulin Resistance; Leptin; Mice; Obesity; Peptides; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; Signal Transduction; Time Factors; Up-Regulation | 2013 |
High susceptibility of heterozygous (+/fa) lean Zucker rats to 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis.
Susceptibility to 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis was investigated in lean Zucker (+/fa) rats carrying one mutated leptin receptor gene and wild-type controls (+/+). Rats with both genotypes were given a single DMBA administration and divided into two groups, one group was fed on basal diet mixed with 10% corn oil and the other was fed on basal diet alone. The minimum latency period of palpable carcinomas in +/fa rats of both groups was 8 weeks following DMBA treatment, in contrast to the 11-12 weeks in +/+. The incidence and multiplicity of carcinomas increased or showed a tendency for increase in the early stages in +/fa rats of both groups as compared to the +/+ counterparts. The volumes of carcinomas showed a tendency to increase in the corn oil diet groups of both genotypes. The major histopathological phenotype of carcinomas in all groups was well-differentiated without distinct atypia (multiplicity, 0.69-1.09/rat), but moderately/poorly differentiated carcinomas with atypia were also found, predominantly in +/fa rats (0.09-0.21). These latter tumors were characterized by elevated ERK activity but not estrogen receptor expression. Serum leptin concentrations in +/fa rats at 7 weeks of age were higher than those in +/+ and were elevated by the corn oil diet; however, no obvious change was detected in other serum parameters examined. In conclusion, +/fa rats proved more susceptible to DMBA-induced mammary carcinogenesis than +/+ controls, and hyperleptinemia was suggested to contribute to tumor growth as well as to susceptibility to tumorigenesis and more aggressive phenotypes in Zucker lean rats. Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Weight; Carcinogenesis; Cell Differentiation; Corn Oil; Diet; Eating; Female; Heterozygote; Leptin; Mammary Neoplasms, Experimental; MAP Kinase Signaling System; Rats; Rats, Zucker; Receptors, Estrogen; Receptors, Leptin; Survival Rate | 2013 |
A comparative genotoxicity study of a supraphysiological dose of triiodothyronine (T₃) in obese rats subjected to either calorie-restricted diet or hyperthyroidism.
This study was designed to determine the genotoxicity of a supraphysiological dose of triiodothyronine (T3) in both obese and calorie-restricted obese animals. Fifty male Wistar rats were randomly assigned to one of the two following groups: control (C; n = 10) and obese (OB; n = 40). The C group received standard food, whereas the OB group was fed a hypercaloric diet for 20 weeks. After this period, half of the OB animals (n = 20) were subjected to a 25%-calorie restriction of standard diet for 8 weeks forming thus a new group (OR), whereas the remaining OB animals were kept on the initial hypercaloric diet. During the following two weeks, 10 OR animals continued on the calorie restriction diet, whereas the remaining 10 rats of this group formed a new group (ORS) given a supraphysiological dose of T3 (25 µg/100 g body weight) along with the calorie restriction diet. Similarly, the remaining OB animals were divided into two groups, one that continued on the hypercaloric diet (OB, n = 10), and one that received the supraphysiological dose of T3 (25 µg/100 g body weight) along with the hypercaloric diet (OS, n = 10) for two weeks. The OB group showed weight gain, increased adiposity, insulin resistance, increased leptin levels and genotoxicity; T3 administration in OS animals led to an increase in genotoxicity and oxidative stress when compared with the OB group. The OR group showed weight loss and normalized levels of adiposity, insulin resistance, serum leptin and genotoxicity, thus having features similar to those of the C group. On the other hand, the ORS group, compared to OR animals, showed higher genotoxicity. Our results indicate that regardless of diet, a supraphysiological dose of T3 causes genotoxicity and potentiates oxidative stress. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Caloric Restriction; Comet Assay; Energy Intake; Hyperthyroidism; Insulin Resistance; Leptin; Male; Malondialdehyde; Obesity; Rats; Triiodothyronine | 2013 |
Sleeve gastrectomy and gastric plication in the rat result in weight loss with different endocrine profiles.
Restrictive bariatric surgery procedures currently used include adjustable gastric banding, sleeve gastrectomy (SG), and gastric plication (GP), of which the last two techniques still lack sufficient data and long-term studies on weight loss, surgical complications, resolution of comorbidities, and mechanisms of weight loss. Therefore, gastric plication and sleeve gastrectomy as a standalone procedure are still considered experimental. Our aim was to analyze the effects of SG and GP on body weight, food intake, and endocrine profile.. Forty-four male Wistar rats were randomized into six weight-matched groups and submitted either to SG, GP, or sham-operated. Sham-operated rats were divided into pair-fed and fed ad libitum controls, one for each procedure. Animals were followed up for 21 days after surgery, while body weight and food intake were recorded daily, when fasting ghrelin, leptin, insulin and glucose plasma levels, and ghrelin expression in the stomach were measured.. Rats submitted to SG and GP showed a significant decrease in body weight gain to the same extent as rats pair-fed to the surgical groups when compared to sham-operated fed ad libitum controls. After surgery, SG rats showed no difference in body composition, ghrelin, leptin, insulin, or glucose levels, while GP rats displayed lower body fat content and leptin levels compared to controls. Ghrelin was also lower in GP rats compared to sham-operated pair-fed rats. Ghrelin expression displayed a pattern similar to circulating ghrelin.. SG and GP result in weight loss, although with differences in body composition and metabolic and endocrine profiles. Topics: Animals; Body Weight; Eating; Feeding Behavior; Gastric Mucosa; Gastroplasty; Ghrelin; Insulin; Leptin; Male; Obesity; Rats; Rats, Wistar; Stomach; Weight Loss | 2013 |
A superactive leptin antagonist alters metabolism and locomotion in high-leptin mice.
Transgenic alpha murine urokinase-type plasminogen activator (αMUPA) mice are resistant to obesity and their locomotor activity is altered. As these mice have high leptin levels, our objective was to test whether leptin is responsible for these characteristics. αMUPA, their genetic background control (FVB/N), and C57BL mice were injected s.c. every other day with 20 mg/kg pegylated superactive mouse leptin antagonist (PEG-SMLA) for 6 weeks. We tested the effect of PEG-SMLA on body weight, locomotion, and bone health. The antagonist led to a rapid increase in body weight and subsequent insulin resistance in all treated mice. Food intake of PEG-SMLA-injected animals increased during the initial period of the experiment but then declined to a similar level to that of the control animals. Interestingly, αMUPA mice were found to have reduced bone volume (BV) than FVB/N mice, although PEG-SMLA increased bone mass in both strains. In addition, PEG-SMLA led to disrupted locomotor activity and increased corticosterone levels in C57BL but decreased levels in αMUPA or FVB/N mice. These results suggest that leptin is responsible for the lean phenotype and reduced BV in αMUPA mice; leptin affects corticosterone levels in mice in a strain-specific manner; and leptin alters locomotor activity, a behavior determined by the central circadian clock. Topics: Animals; Body Weight; Bone and Bones; Bone Density; Eating; Energy Metabolism; Insulin; Leptin; Mice; Mice, Transgenic; Motor Activity; Polyethylene Glycols; Urokinase-Type Plasminogen Activator | 2013 |
Fatty liver accompanies an increase in lactobacillus species in the hind gut of C57BL/6 mice fed a high-fat diet.
High-fat (HF) diets can produce obesity and have been linked to the development of nonalcoholic fatty liver disease and changes in the gut microbiome. To test the hypothesis that HF feeding increases certain predominant hind gut bacteria and development of steatohepatitis, C57BL/6 mice were fed an HF (45% energy) or low-fat (LF) (10% energy) diet for 10 wk. At the end of the feeding period, body weights in the HF group were 34% greater than those in the LF group (P < 0.05). These changes were associated with dramatic increases in lipid droplet number and size, inflammatory cell infiltration, and inducible nitric oxide (NO) synthase protein concentration in the livers of mice fed the HF diet. Consistent with the fatty liver phenotype, plasma leptin and tumor necrosis factor-α concentrations were also elevated in mice fed the HF diet, indicative of chronic inflammation. Eight of 12 pairs of polymerase chain reaction (PCR) primers for bacterial species that typically predominate hind gut microbial ecology generated specific PCR products from the fecal DNA samples. The amount of DNA from Lactobacillus gasseri and/or Lactobacillus taiwanensis in the HF group was 6900-fold greater than that in the LF group. Many of these bacteria are bile acid resistant and are capable of bile acid deconjugation. Because bile acids are regulators of hepatic lipid metabolism, the marked increase of gut L. gasseri and/or L. taiwanensis species bacteria with HF feeding may play a role in development of steatohepatitis in this model. Topics: Animals; Bile Acids and Salts; Body Weight; Diet, High-Fat; Dietary Fats; DNA, Bacterial; Energy Intake; Fatty Liver; Feces; Inflammation; Intestine, Large; Lactobacillus; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Polymerase Chain Reaction; Tumor Necrosis Factor-alpha | 2013 |
Effects of sugar-sweetened beverages on plasma acylation stimulating protein, leptin and adiponectin: relationships with metabolic outcomes.
The effects of fructose and glucose consumption on plasma acylation stimulating protein (ASP), adiponectin, and leptin concentrations relative to energy intake, body weight, adiposity, circulating triglycerides, and insulin sensitivity were determined.. Thirty two overweight/obese adults consumed glucose- or fructose-sweetened beverages (25% energy requirement) with their ad libitum diets for 8 weeks, followed by sweetened beverage consumption for 2 weeks with a standardized, energy-balanced diet. Plasma variables were measured at baseline, 2, 8, and 10 weeks, and body adiposity and insulin sensitivity at baseline and 10 weeks.. Fasting and postprandial ASP concentrations increased at 2 and/or 8 weeks. ASP increases correlated with changes in late-evening triglyceride concentrations. At 10 weeks, fasting adiponectin levels decreased in both groups, and decreases were inversely associated with baseline intra-abdominal fat volume. Sugar consumption increased fasting leptin concentrations; increases were associated with body weight changes. The 24-h leptin profiles increased during glucose consumption and decreased during fructose consumption. These changes correlated with changes of 24-h insulin levels.. The consumption of fructose and glucose beverages induced changes in plasma concentrations of ASP, adiponectin, and leptin. Further study is required to determine if these changes contribute to the metabolic dysfunction observed during fructose consumption. Topics: Adiponectin; Adiposity; Adult; Aged; Beverages; Blood Glucose; Body Weight; Complement C3; Diet; Energy Intake; Female; Fructose; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Intra-Abdominal Fat; Leptin; Male; Middle Aged; Nutritive Sweeteners; Obesity; Postmenopause; Postprandial Period; Triglycerides | 2013 |
Hypothyroidism compromises hypothalamic leptin signaling in mice.
The impact of thyroid hormone (TH) on metabolism and energy expenditure is well established, but the role of TH in regulating nutritional sensing, particularly in the central nervous system, is only poorly defined. Here, we studied the consequences of hypothyroidism on leptin production as well as leptin sensing in congenital hypothyroid TRH receptor 1 knockout (Trhr1 ko) mice and euthyroid control animals. Hypothyroid mice exhibited decreased circulating leptin levels due to a decrease in fat mass and reduced leptin expression in white adipose tissue. In neurons of the hypothalamic arcuate nucleus, hypothyroid mice showed increased leptin receptor Ob-R expression and decreased suppressor of cytokine signaling 3 transcript levels. In order to monitor putative changes in central leptin sensing, we generated hypothyroid and leptin-deficient animals by crossing hypothyroid Trhr1 ko mice with the leptin-deficient ob/ob mice. Hypothyroid Trhr1/ob double knockout mice showed a blunted response to leptin treatment with respect to body weight and food intake and exhibited a decreased activation of phospho-signal transducer and activator of transcription 3 as well as a up-regulation of suppressor of cytokine signaling 3 upon leptin treatment, particularly in the arcuate nucleus. These data indicate alterations in the intracellular processing of the leptin signal under hypothyroid conditions and thereby unravel a novel mode of action by which TH affects energy metabolism. Topics: Adipose Tissue, Brown; Agouti-Related Protein; Animals; Body Weight; Eating; Gene Expression Regulation; Hypothalamus; Hypothyroidism; Leptin; Male; Mice; Mice, Inbred C57BL; Oxygen Consumption; Pro-Opiomelanocortin; Receptors, Leptin; Receptors, Thyroid Hormone; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Thyroid Hormones | 2013 |
Levels of leptin and IL-6 in lungs and blood are associated with the severity of chronic obstructive pulmonary disease in patients and rat models.
The aim of the present study was to compare leptin and interleukin (IL)-6 expression in patients and rat models with chronic obstructive pulmonary disease (COPD). Leptin and IL-6 levels were determined in patients with an acute exacerbation of COPD (AECOPD), stable COPD and in healthy controls. Rat models of COPD were developed, histological and immunohistochemical analyses were performed and leptin and IL-6 levels were determined. Leptin and IL-6 levels in the serum and sputum were higher in patients with AECOPD compared with stable COPD and control patients. In rats, leptin and IL-6 were expressed in bronchial epithelial and inflammatory cells, while leptin expression was observed in alveolar cells and IL-6 expression in blood vessel cells only. Serum levels of leptin and IL-6 were significantly higher in COPD1 and COPD2 rats compared with the control rats, and were even higher in COPD1 rats than COPD2 rats. In conclusion, leptin and IL-6 levels were demonstrated to be associated with the severity of COPD. Topics: Adult; Animals; Body Weight; Disease Models, Animal; Humans; Immunohistochemistry; Interleukin-6; Leptin; Lung; Male; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Sputum | 2013 |
Overexpression of neuropeptide Y in the dorsomedial hypothalamus causes hyperphagia and obesity in rats.
We sought to determine a role for NPY overexpression in the dorsomedial hypothalamus (DMH) in obesity etiology using the rat model of adeno-associated virus (AAV)-mediated expression of NPY (AAVNPY) in the DMH. Rats received bilateral DMH injections of AAVNPY or control vector and were fed on regular chow. Five-week postviral injection, half the rats from each group were switched to access to a high-fat diet for another 11 weeks. We examined variables including body weight, food intake, energy efficiency, meal patterns, glucose tolerance, fat mass, plasma insulin, plasma leptin, and hypothalamic gene expression. Rats with DMH NPY overexpression had increased food intake and body weight and lowered metabolic efficiency. The hyperphagia was mediated through increased meal size during the dark. Although these rats had normal blood glucose, their plasma insulin levels were increased in both basal and glucose challenge conditions. While high-fat diet induced hyperphagia, obesity, and hyperinsulinemia, these effects were amplified in rats with DMH NPY overexpression. Arcuate Npy, agouti-related protein and proopiomelanocortin expression was appropriately regulated in response to positive energy balance. These results indicate that DMH NPY overexpression can cause hyperphagia and obesity and DMH NPY may have actions in glucose homeostasis. Topics: Agouti-Related Protein; Animals; Body Weight; Dependovirus; Diet, High-Fat; Disease Models, Animal; Energy Metabolism; Gene Expression Regulation; Glucose; Glucose Tolerance Test; Homeostasis; Hyperphagia; Hypothalamus; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley | 2013 |
Leptin activates oxytocin neurons of the hypothalamic paraventricular nucleus in both control and diet-induced obese rodents.
The adipocyte-derived hormone leptin acts in the brain to reduce body weight and fat mass. Recent studies suggest that parvocellular oxytocin (OXT) neurons of the hypothalamic paraventricular nucleus (PVN) can mediate body weight reduction through inhibition of food intake and increased energy expenditure. However, the role of OXT neurons of the PVN as a primary target of leptin has not been investigated. Here, we studied the potential role of OXT neurons of the PVN in leptin-mediated effects on body weight regulation in fasted rats. We demonstrated that intracerebroventricular (ICV) leptin activates STAT3 phosphorylation in OXT neurons of the PVN, showed that this occurs in a subpopulation of OXT neurons that innervate the nucleus of the solitary tract (NTS), and provided further evidence suggesting a role of OXT to mediate leptin's actions on body weight. In addition, our results indicated that OXT neurons are responsive to ICV leptin and mediate leptin effects on body weight in diet induced obese (DIO) rats, which are resistant to the anorectic effects of the hormone. Thus, we conclude that leptin targets a specific subpopulation of parvocellular OXT neurons of the PVN, and that this action may be important for leptin's ability to reduce body weight in both control and obese rats. Topics: Analysis of Variance; Animals; Body Weight; DNA Primers; Gene Expression Profiling; Immunohistochemistry; Infusions, Intraventricular; Leptin; Male; Neurons; Obesity; Oxytocin; Paraventricular Hypothalamic Nucleus; Phosphorylation; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Stilbamidines | 2013 |
Role of proopiomelanocortin neuron Stat3 in regulating arterial pressure and mediating the chronic effects of leptin.
Although signal transducer and activator of transcription 3 (Stat3) is a key second messenger by which leptin regulates appetite and body weight, its role in specific neuronal populations in metabolic regulation and in mediating the chronic effects of leptin on blood pressure is unknown. The current study tested the hypothesis that Stat3 signaling in proopiomelanocortin (POMC) neurons mediates the chronic effects of leptin on mean arterial pressure (MAP), as well as on glucose regulation, energy expenditure, and food intake. Stat3(flox/flox) mice were crossed with POMC-Cre mice to generate mice with Stat3 deletion specifically in POMC neurons (Stat3(flox/flox)/POMC-Cre). Oxygen consumption (Vo2), carbon dioxide respiration (Vco2), motor activity, heat production, food intake, and MAP were measured 24 hours/d. After baseline measurements, leptin was infused (4 μg/kg per min, IP) for 7 days. Stat3(flox/flox)/POMC-Cre mice were hyperphagic, heavier, and had increased respiratory quotients compared with control Stat3(flox/flox) mice. Baseline MAP was not different between the groups, and chronic leptin infusion reduced food intake similarly in both groups (27 versus 29%). Vo2, Vco2, and heat production responses to leptin were not significantly different in control and Stat3(flox/flox)/POMC-Cre mice. However, leptin-mediated increases in MAP were completely abolished, and blood pressure responses to acute air-jet stress were attenuated in male Stat3(flox/flox)/POMC-Cre mice. These results indicate that Stat3 signaling in POMC neurons is essential for leptin-mediated increases in MAP, but not for anorexic or thermogenic effects of leptin. Topics: Animals; Appetite; Blood Pressure; Body Weight; Energy Metabolism; Female; Glucose; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Models, Animal; Neurons; Oxygen Consumption; Pro-Opiomelanocortin; Sex Factors; Signal Transduction; STAT3 Transcription Factor | 2013 |
Evaluation of body weight, insulin resistance, leptin and adiponectin levels in premenopausal women with hyperprolactinemia.
The effects of hyperprolactinemia on metabolic parameters are not clear and a few data evaluating adiponectin levels in prolactinoma and idiopathic hyperprolactinemia exist. The aim of this study was to evaluate the effects of hyperprolactinemia on body weight, insulin resistance, beta cell function, and leptin and adiponectin levels in premenopausal women with hyperprolactinemia. Forty premenopausal women with prolactinoma or idiopathic hyperprolactinemia were compared to 41 age-matched healthy premenopausal women with regard to body weight, body mass index, waist and hip circumferences, waist to hip ratio, fasting plasma glucose, insulin levels, insulin resistance measured by homeostasis model assessment (HOMA)-insulin resistance index, beta cell function measured by HOMA-β index, leptin and adiponectin levels. Plasma insulin levels and HOMA indexes (both insulin resistance and beta indexes) were significantly higher in hyperprolactinemic women. The other parameters were similar between both groups. There was a positive correlation between prolactin levels and fasting plasma glucose in hyperprolactinemic women. The results of this study showed that high prolactin levels may be associated with hyperinsulinemia and insulin resistance in premenopausal women. This effect seems to be independent of body weight, leptin and adiponectin levels. High prolactin levels may directly stimulate insulin secretion from pancreas and directly cause hepatic and whole-body insulin resistance. Topics: Adiponectin; Adolescent; Adult; Blood Glucose; Body Composition; Body Weight; Female; Humans; Hyperprolactinemia; Insulin; Insulin Resistance; Leptin; Middle Aged; Premenopause; Waist-Hip Ratio | 2013 |
Extracellular signal-regulated kinase in the ventromedial hypothalamus mediates leptin-induced glucose uptake in red-type skeletal muscle.
Leptin is a key regulator of glucose metabolism in mammals, but the mechanisms of its action have remained elusive. We now show that signaling by extracellular signal-regulated kinase (ERK) and its upstream kinase MEK in the ventromedial hypothalamus (VMH) mediates the leptin-induced increase in glucose utilization as well as its insulin sensitivity in the whole body and in red-type skeletal muscle of mice through activation of the melanocortin receptor (MCR) in the VMH. In contrast, activation of signal transducer and activator of transcription 3 (STAT3), but not the MEK-ERK pathway, in the VMH by leptin enhances the insulin-induced suppression of endogenous glucose production in an MCR-independent manner, with this effect of leptin occurring only in the presence of an increased plasma concentration of insulin. Given that leptin requires 6 h to increase muscle glucose uptake, the transient activation of the MEK-ERK pathway in the VMH by leptin may play a role in the induction of synaptic plasticity in the VMH, resulting in the enhancement of MCR signaling in the nucleus and leading to an increase in insulin sensitivity in red-type muscle. Topics: Animals; Body Weight; Butadienes; Chromones; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Glucose; Insulin; Leptin; Male; Melanocyte-Stimulating Hormones; Mice; Morpholines; Muscle, Skeletal; Nitriles; Phosphorylation; Receptors, Corticotropin; Signal Transduction; Ventromedial Hypothalamic Nucleus | 2013 |
Selective leptin insensitivity and alterations in female-reproductive patterns linked to hyperleptinemia during infancy.
The dramatic increase in the prevalence of childhood obesity worldwide makes the investigation of its early developmental stages and effective prevention strategies an urgent issue. CCK1 deficient OLETF rats are a model of obesity previously used to study the early phases of this disorder. Here, we exposed wild type (LETO) females to an early obesogenic environment and genetically obese OLETF females to a lean postnatal environment, to assess long term alterations in leptin sensitivity, predisposition to diet induced obesity and adult female health. We found that genetically lean females reared by obese mothers presented early postnatal hyperleptemia, selectively reduced response to leptin and sensitivity to diet induced obesity when exposed to a high palatable diet as adults. The estrous cycle structure and intake profile were permanently disrupted, despite presenting normal adiposity/body weight/food intake. Genetically obese females reared by lean dams showed normalized early levels of leptin and reduced body weight, food intake and body fat at adulthood; normalized estrous cycle structure and food intake across the cycle, improved hormonal profile and peripheral leptin sensitivity and a remarkable progress in self-control when exposed to a high fat/palatable diet. Altogether, it appears that the early postnatal environment plays a critical role in determining later life coping with metabolic challenges and has an additive effect on the genetic predisposition that makes OLETF females morbidly obese as adults. This work also links, for the first time, alterations in the leptin system during early development to later life abnormalities related to female reproduction and health. Topics: Absorptiometry, Photon; Aging; Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Body Composition; Body Weight; Eating; Estradiol; Estrous Cycle; Female; Genotype; Hyperphagia; Leptin; Mice; Protein Isoforms; Rats; Rats, Inbred Strains; Receptors, Leptin; Reproduction; Time Factors; Weaning | 2013 |
Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis.
Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase). As a major mechanism of central nervous system (CNS) metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR) in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos) in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene (Ugcg) display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV)-mediated Ugcg delivery to the arcuate nucleus (Arc) significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis. Topics: Animals; Arcuate Nucleus of Hypothalamus; Blotting, Western; Body Weight; Cells, Cultured; Central Nervous System; Dependovirus; Energy Metabolism; Fatty Acids, Nonesterified; Female; Fluorescent Antibody Technique; Glucosyltransferases; Homeostasis; Hypothalamus; Immunoprecipitation; Leptin; Male; Mice; Mice, Mutant Strains; Motor Activity; Neurons | 2013 |
FAT/CD36: a major regulator of neuronal fatty acid sensing and energy homeostasis in rats and mice.
Hypothalamic "metabolic-sensing" neurons sense glucose and fatty acids (FAs) and play an integral role in the regulation of glucose, energy homeostasis, and the development of obesity and diabetes. Using pharmacologic agents, we previously found that ~50% of these neurons responded to oleic acid (OA) by using the FA translocator/receptor FAT/CD36 (CD36). For further elucidation of the role of CD36 in neuronal FA sensing, ventromedial hypothalamus (VMH) CD36 was depleted using adeno-associated viral (AAV) vector expressing CD36 short hairpin RNA (shRNA) in rats. Whereas their neuronal glucosensing was unaffected by CD36 depletion, the percent of neurons that responded to OA was decreased specifically in glucosensing neurons. A similar effect was seen in total-body CD36-knockout mice. Next, weanling rats were injected in the VMH with CD36 AAV shRNA. Despite significant VMH CD36 depletion, there was no effect on food intake, body weight gain, or total carcass adiposity on chow or 45% fat diets. However, VMH CD36-depleted rats did have increased plasma leptin and subcutaneous fat deposition and markedly abnormal glucose tolerance. These results demonstrate that CD36 is a critical factor in both VMH neuronal FA sensing and the regulation of energy and glucose homeostasis. Topics: Animals; Blood Glucose; Body Weight; CD36 Antigens; Eating; Energy Metabolism; Fatty Acids; Homeostasis; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Oleic Acid; Rats; Rats, Sprague-Dawley; Ventromedial Hypothalamic Nucleus | 2013 |
Sexual dimorphism in adipose tissue function as evidenced by circulating adipokine concentrations in the fasting state and after an oral glucose challenge.
Do the circulating levels of a panel of adipokines involved in glucose metabolism exhibit sexual dimorphism in the fasting state and after an oral glucose load?. Our results indicate sexual dimorphism in the circulating concentrations of adipokines involved in intermediate metabolism in the fasting state and during an oral glucose load. This finding suggests an influence of sex steroids on adipose tissue function.. Sexual dimorphism in adipose tissue distribution fully develops after puberty and modulates the risk for cardiometabolic disorders. However, the possibility that adipose tissue function exhibits sexual dimorphism as well as its distribution is unproved.. Cross-sectional case-control study including 32 subjects.. Sixteen subjects with weight excess (8 men and 8 women, including 4 overweight and 4 obese subjects in each group) and 16 normal weight healthy volunteers (8 men and 8 women) presenting with similar age were submitted to a 75-g oral glucose tolerance test (oGTT). We measured circulating concentrations of insulin, glucose, chemerin, lipocalin-2, omentin-1, leptin and adiponectin and calculated their areas under the oGTT curve (AUC).. Leptin and adiponectin concentrations were higher throughout the oGTT in women compared with men. Lipocalin-2 concentrations decreased during the oGTT in the whole group of study subjects. However, these levels remained higher in men with weight excess compared with normal weight men, whereas in women with weight excess lipocalin-2 levels at the end of the oGTT were lower compared with normal weight women. Sex was among the main determinants of the AUC of omentin-1 and leptin in linear regression models, and lower estradiol and testosterone concentrations were related to higher AUC of chemerin and omentin-1, respectively. Subjects with weight excess had higher AUC of chemerin and leptin and lower AUC of omentin-1 and adiponectin levels, independently of sex.. We included a relatively small sample size and, because this was a cross-sectional study, we cannot infer causality to the associations between the changes in circulating adipokine concentrations and the variables studied here.. Sexual dimorphism in adipose tissue function should be considered when studying adiposity and obesity, and also when designing strategies for their diagnosis and management. Topics: Adipokines; Adiponectin; Adipose Tissue; Adult; Body Weight; Fasting; Female; Glucose Tolerance Test; Humans; Leptin; Male; Overweight; Risk Factors; Sex Characteristics | 2013 |
Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations.
Targeted disruption of RIIβ-protein kinase A (PKA) in mice leads to a lean phenotype, increased nocturnal locomotor activity, and activation of brown adipose tissue. Because RIIβ is abundantly expressed in both white and brown adipose tissue as well as the brain, the contribution of neuronal vs. peripheral PKA to these phenotypes was investigated. We used a Cre-Lox strategy to reexpress RIIβ in a tissue-specific manner in either adipocytes or neurons. Mice with adipocyte-specific RIIβ reexpression remained hyperactive and lean, but pan-neuronal RIIβ reexpression reversed both phenotypes. Selective RIIβ reexpression in all striatal medium spiny neurons with Darpp32-Cre corrected the hyperlocomotor phenotype, but the mice remained lean. Further analysis revealed that RIIβ reexpression in D2 dopamine receptor-expressing medium spiny neurons corrected the hyperlocomotor phenotype, which demonstrated that the lean phenotype in RIIβ-PKA-deficient mice does not develop because of increased locomotor activity. To identify the neurons responsible for the lean phenotype, we used specific Cre-driver mice to reexpress RIIβ in agouti-related peptide (AgRP)-, proopiomelanocortin (POMC)-, single-minded 1 (Sim1)-, or steroidogenic factor 1 (SF1)-expressing neurons in the hypothalamus, but observed no rescue of the lean phenotype. However, when RIIβ was reexpressed in multiple regions of the hypothalamus and striatum driven by Rip2-Cre, or specifically in GABAergic neurons driven by Vgat-ires-Cre, both the hyperactive and lean phenotypes were completely corrected. Bilateral injection of adeno-associated virus1 (AAV1)-Cre directly into the hypothalamus caused reexpression of RIIβ and partially reversed the lean phenotype. These data demonstrate that RIIβ-PKA deficiency in a subset of hypothalamic GABAergic neurons leads to the lean phenotype. Topics: Adiposity; Analysis of Variance; Animals; Blotting, Western; Body Weight; Brain; Calorimetry, Indirect; Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; DNA Primers; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Genotype; Homeostasis; Immunohistochemistry; Integrases; Leptin; Locomotion; Mice; Mice, Knockout; Neurons; Polymerase Chain Reaction; Receptor-Interacting Protein Serine-Threonine Kinase 2; Receptor-Interacting Protein Serine-Threonine Kinases | 2013 |
Extensive impact of saturated fatty acids on metabolic and cardiovascular profile in rats with diet-induced obesity: a canonical analysis.
Although hypercaloric interventions are associated with nutritional, endocrine, metabolic, and cardiovascular disorders in obesity experiments, a rational distinction between the effects of excess adiposity and the individual roles of dietary macronutrients in relation to these disturbances has not previously been studied. This investigation analyzed the correlation between ingested macronutrients (including sucrose and saturated and unsaturated fatty acids) plus body adiposity and metabolic, hormonal, and cardiovascular effects in rats with diet-induced obesity.. Normotensive Wistar-Kyoto rats were submitted to Control (CD; 3.2 Kcal/g) and Hypercaloric (HD; 4.6 Kcal/g) diets for 20 weeks followed by nutritional evaluation involving body weight and adiposity measurement. Metabolic and hormonal parameters included glycemia, insulin, insulin resistance, and leptin. Cardiovascular analysis included systolic blood pressure profile, echocardiography, morphometric study of myocardial morphology, and myosin heavy chain (MHC) protein expression. Canonical correlation analysis was used to evaluate the relationships between dietary macronutrients plus adiposity and metabolic, hormonal, and cardiovascular parameters.. Although final group body weights did not differ, HD presented higher adiposity than CD. Diet induced hyperglycemia while insulin and leptin levels remained unchanged. In a cardiovascular context, systolic blood pressure increased with time only in HD. Additionally, in vivo echocardiography revealed cardiac hypertrophy and improved systolic performance in HD compared to CD; and while cardiomyocyte size was unchanged by diet, nuclear volume and collagen interstitial fraction both increased in HD. Also HD exhibited higher relative β-MHC content and β/α-MHC ratio than their Control counterparts. Importantly, body adiposity was weakly associated with cardiovascular effects, as saturated fatty acid intake was directly associated with most cardiac remodeling measurements while unsaturated lipid consumption was inversely correlated with these effects.. Hypercaloric diet was associated with glycemic metabolism and systolic blood pressure disorders and cardiac remodeling. These effects directly and inversely correlated with saturated and unsaturated lipid consumption, respectively. Topics: Adiposity; Animals; Blood Glucose; Blood Pressure; Body Weight; Cardiovascular System; Dietary Fats; Echocardiography; Energy Intake; Fatty Acids; Heart; Insulin; Insulin Resistance; Leptin; Male; Myosin Heavy Chains; Obesity; Rats; Rats, Inbred WKY; Ventricular Remodeling | 2013 |
Microstructural brain and multivoxel spectroscopy in very low birth weight infants related to insulin-like growth factor concentration and early growth.
Very low birth weight (VLBW) children have higher risk of neurologic disabilities and growth factors are essential for brain maturation.. To assess whether there are differences in neurologic findings, psychometric parameters and microstructural brain morphology in 1-year-old VLBW infants versus term healthy controls and whether these differences are related to hormonal/growth changes.. Prospective anthropometry, prefeed venous blood sample [insulin, insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), leptin, glucose], neurologic and imaging assessment, at age 1 year in 34 VLBW infants (12 SGA; 10 M) and 10 healthy term controls (5 M).. IGF-I concentrations at 1 month of corrected age were 20% lower in SGA versus appropriate for gestational age VLBW (p < 0.02). Gray and white matter volume and fractional anisotropy in 15/27 regions were decreased (p < 0.001). Abnormal spectroscopy was observed in 4 zones in VLBW versus term controls (p < 0.001). Some of these changes were associated with different periods of first-year growth and IGF-I/IGF-II, leptin and HOMA-IR.. VLBW infants show differences in brain volumes and microstructural brain morphology as compared to term controls, changes related to circulating growth factor and anthropometry changes in the first year. This apparent reorganization of the developing brain offers a unique opportunity to investigate the relationship between changes in cortical anatomy, cognitive and social impairments and periods of early growth. Topics: Body Height; Body Weight; Brain; Female; Humans; Infant; Infant, Small for Gestational Age; Infant, Very Low Birth Weight; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Magnetic Resonance Imaging; Male; Prospective Studies | 2013 |
Age-dependent modulation of central ghrelin effects on food intake and lipid metabolism in rats.
Ghrelin is an endogenous peptide potentially useful in therapy of anorexia and other age-related metabolic disturbances. We evaluated the influence of age on the orexigenic and lipid metabolism-altering effects of ghrelin. Peripubertal, young, adult and middle-aged rats (1, 2, 7 and 12 months old, respectively) were treated with 5 daily intracerebroventricular injections of ghrelin (0.15 nmol) or saline (control). The food intake was measured daily before treatment, while white adipose tissue and serum/plasma samples for detection of lipid metabolites/hormones were collected at the end of the experiment. The values of cumulative food intake and body weight gain declined, while the white adipose tissue deposits and blood concentrations of triglycerides, cholesterol and free fatty acids all increased with age. Ghrelin significantly increased all parameters, but the stimulatory effects on body weight gain and food intake were more pronounced in peripubertal/young rats, while the increase in white adipose mass, triglyceride and low-density lipoprotein cholesterol levels was more noticeable in adult/middle-aged animals. The decrease in sensitivity to ghrelin-mediated stimulation of food intake in older animals could not be explained by alterations in ghrelin's ability to reduce anorexigenic hormones insulin and leptin. However, the higher responsiveness of aged rats to ghrelin-mediated increase in lipid metabolites was accompanied by an increase in adrenocorticotropic hormone and corticosterone levels. These results indicate that aging, while reducing sensitivity to ghrelin-mediated increase in body weight gain and food intake, might enhance the responsiveness to the stimulatory effects of ghrelin on lipid metabolites and hypothalamic-pituitary-adrenal axis activity. Topics: Adipose Tissue, White; Adrenocorticotropic Hormone; Aging; Animals; Body Weight; Corticosterone; Eating; Ghrelin; Insulin; Leptin; Lipid Metabolism; Male; Rats; Rats, Wistar | 2013 |
Single nucleotide polymorphisms in the leptin-a gene and associations with growth traits in the orange-spotted grouper (Epinephelus coioides).
Leptin is a multifunctional protein involved in processes such as body weight regulation, energy expenditure, fat metabolism, food intake, and appetite regulation. Duplicate leptin genes, leptin-a and leptin-b, were previously detected in the orange-spotted grouper. In this study, we cloned the full-length open reading frame (ORF) of the leptin-a gene in the orange-spotted grouper, searched for polymorphisms, and performed association analyses between these polymorphisms and seven growth traits. Six polymorphisms, consisting of 2 SNPs in intron 1 (c.182T > G, c.183G > T) and 4 SNPs in exon 2 (c.339C > G, c.345C > T, c.447G > A, c.531C > T), were identified and genotyped in 200 individuals. The c.182T > G and c.183G > T polymorphisms showed complete linkage and were analyzed together. Association analyses revealed that the c.182 + 183TG > GT polymorphism was significantly associated with body weight (BWT) and body width (BWH), with the AB (TG/GT) genotype showing positive effects on growth traits. Additionally, the SNP c.447G > A was significantly associated with BWT, BWH, overall length (OL), trunk width (TW), and head length (HL), with the GA genotype displaying positive effects on growth traits. The c.531C > T SNP showed a close association between the TT genotype and decreased growth. Our results demonstrate that several polymorphisms in the leptin-a gene are associated with growth traits and can be used for marker-assisted selection (MAS) in orange-spotted grouper populations. Topics: Animals; Bass; Body Weight; Female; Fish Proteins; Genetic Association Studies; Genetic Markers; Leptin; Male; Polymorphism, Single Nucleotide | 2013 |
Changes in growth pattern, leptin ghrelin and neuropeptide Y levels after adenotonsillectomy in prepubertal children.
The purpose of this prospective study was to evaluate whether surgical treatment of adenotonsillar hypertrophy has an effect on growth patterns and circulating concentrations of leptin, ghrelin and neuropeptide Y, which are all significant in energy balance.. The study group consisted of 20 children who underwent tonsillectomy with or without adenoidectomy due to chronic adenotonsillar hypertrophy. The ages ranged from 4.3 to 9.2 years with normal weight. The healthy control subjects consisted of 30 age- and sex-matched children (control group) with ages between 3.2 and 8.1 years. Serum levels of leptin ghrelin and neuropeptide Y were measured in the preoperative period and at the end of the postoperative period, which was 6 months in the study group, serum levels were only measured during the first examination in the control group.. When the study group (preoperative) is compared with the control group, it is observed that the leptin and ghrelin levels were higher in the study group and that the neuropeptide Y levels were similar (p=0.01, p=0.005, p=0.19, respectively). When the preoperative and postoperative anthropometric data were compared, it was observed that weight, height, body mass index (BMI) and BMI-standard deviation score (SDS) values increased in the 6th month postoperatively (p<0.001, p<0.001, p=0.01, p=0.03, respectively). However, the leptin, ghrelin and neuropeptide Y levels were similar (p=0.70, p=0.12, p=0.60, respectively).. Following adenotonsillectomy, an increase in weight and height occurred in the children. In the postoperative period, dietary and lifestyle suggestions as well as growth monitoring might be useful. Topics: Adenoidectomy; Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Female; Ghrelin; Humans; Leptin; Male; Neuropeptide Y; Tonsillectomy | 2013 |
Ablation of ghrelin O-acyltransferase does not improve glucose intolerance or body adiposity in mice on a leptin-deficient ob/ob background.
Type 2 Diabetes is a global health burden and based on current estimates will become an even larger problem in the future. Developing new strategies to prevent and treat diabetes is a scientific challenge of high priority. The stomach hormone ghrelin has been associated with playing a role in the regulation of glucose homeostasis. However, its precise mechanism and impact on whole glucose metabolism remains to be elucidated. This study aims to clarify the role of the two ghrelin isoforms acyl- and desacyl ghrelin in regulating glucose homeostasis. Therefore ghrelin activating enzyme Ghrelin-O-acyltransferase (GOAT) was ablated in leptin-deficient ob/ob mice to study whether specific acyl ghrelin deficiency or desacyl ghrelin abundance modifies glucose tolerance on a massively obese background. As targeted deletion of acyl ghrelin does not improve glucose homeostasis in our GOAT-ob/ob mouse model we conclude that neither acyl ghrelin nor the increased ratio of desacyl/acyl ghrelin is crucial for controlling glucose homeostasis in the here presented model of massive obesity induced by leptin deficiency. Topics: Acylation; Acyltransferases; Adiposity; Animals; Body Weight; Female; Gene Knockout Techniques; Ghrelin; Glucose; Glucose Intolerance; Homeostasis; Leptin; Male; Membrane Proteins; Mice; Mice, Knockout; Mice, Obese; Obesity; Phenotype; Protein Processing, Post-Translational | 2013 |
[Relationships between serum ghrelin and lipid profile and serum leptin, adiponectin, and insulin among children in Beijing, China].
To study the relationship between serum ghrelin and lipid profile and serum leptin, adiponectin, and insulin among children in Beijing.. A total of 879 pupils aged 8 - 10 years were randomly selected. Height, body weight, waist circumference, body mass index (BMI), body fat percentage (%BF), blood lipid, serum leptin, insulin, adiponectin and ghrelin were measured in all samples.. Ghrelin associated negatively with body weight, waist circumference, BMI, %BF, serum leptin level and positively with HDL-C. Factor analysis has shown five factors which were sufficient to explain correlations between variables-body composition and leptin, dyslipidemia, glucose metabolism and adiponectin.. Serum ghrelin level correlated strongly with body weight, waist circumference, BMI, %BF and leptin, Our finding suggested significantly increased leptin levels following decreased ghrelin levels could mostly disordered adipose metabolism at early obesity in children. Topics: Adiponectin; Body Mass Index; Body Weight; Child; China; Cross-Sectional Studies; Female; Ghrelin; Humans; Insulin; Leptin; Lipids; Male; Sampling Studies | 2013 |
Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway.
Hypothalamic feeding circuits are essential for the maintenance of energy balance. There have been intensive efforts to discover new biological molecules involved in these pathways. Here we report that central administration of clusterin, also called apolipoprotein J, causes anorexia, weight loss and activation of hypothalamic signal transduction-activated transcript-3 in mice. In contrast, inhibition of hypothalamic clusterin action results in increased food intake and body weight, leading to adiposity. These effects are likely mediated through the mutual actions of the low-density lipoprotein receptor-related protein-2, a potential receptor for clusterin, and the long-form leptin receptor. In response to clusterin, the low-density lipoprotein receptor-related protein-2 binding to long-form leptin receptor is greatly enhanced in cultured neuronal cells. Furthermore, long-form leptin receptor deficiency or hypothalamic low-density lipoprotein receptor-related protein-2 suppression in mice leads to impaired hypothalamic clusterin signalling and actions. Our study identifies the hypothalamic clusterin-low-density lipoprotein receptor-related protein-2 axis as a novel anorexigenic signalling pathway that is tightly coupled with long-form leptin receptor-mediated signalling. Topics: Animals; Anorexia; Body Weight; Cell Line; Clusterin; Epididymis; Feeding Behavior; Humans; Hypothalamus; Immunohistochemistry; Injections, Intraventricular; Leptin; Low Density Lipoprotein Receptor-Related Protein-2; Male; Mice; Obesity; Phosphorylation; Protein Binding; Rats; Receptors, Leptin; Signal Transduction; Starvation; STAT3 Transcription Factor | 2013 |
Increased leptin response and inhibition of apoptosis in thymocytes of young rats offspring from protein deprived dams during lactation.
We investigated the consequences of mild maternal malnutrition in rat dams, in terms of thymocyte responses and the putative role of leptin. The young progeny of dams submitted to protein deprivation (PD) during lactation showed at 30 days of age lower body and thymus weights, significant alterations in CD4/CD8-defined T cell subsets without modifications in total thymocyte number as well as in proliferative response. Despite, the rats from PD group did not present alterations in leptin circulating levels, the expression of leptin receptor ObRb was enhanced in their thymocytes. This change was accompanied by an increase in leptin signaling response of thymocytes from PD rats, with an increase in JAK2 and STAT3 phosphorylation after leptin stimulation. Thymocytes from PD rats also presented a decreased rate of spontaneous apoptosis when compared to controls. Accordingly, higher expression of anti-apoptotic protein Bcl-2, and lower of pro-apoptotic protein Bax, with no change of pro-apoptotic Bad, and higher pro-caspase 3 content were detected in PD thymocytes. Moreover, thymocytes from PD group exhibited a constitutive higher nuclear content of p65 NF-kB associated to a lower IkB content in the cytoplasm. Finally, although there was no change in ob gene expression in PD thymocytes, a higher mRNA expression for the Ob gene was observed in the thymic microenvironment from PD animals. Taken together, the results show that mild maternal protein deprivation during lactation affects thymic homeostasis, enhancing leptin activity, which in turn protects thymocytes from apoptosis in the young progeny, with possible consequences upon the immune response of these animals in adult life. Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Body Weight; Cellular Microenvironment; Diet, Protein-Restricted; Female; Gene Expression Regulation; Immunophenotyping; Janus Kinase 2; Lactation; Leptin; Male; NF-kappa B; Protein-Energy Malnutrition; Rats; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; T-Lymphocyte Subsets; Thymocytes; Thymus Gland | 2013 |
Neither signal transducer and activator of transcription 3 (STAT3) or STAT5 signaling pathways are required for leptin's effects on fertility in mice.
The hormone leptin is critical for the regulation of energy balance and fertility. The long-form leptin receptor (LepR) regulates multiple intracellular signaling cascades, including the classic Janus kinase-signal transducer and activator of transcription (STAT) pathways. Previous studies have shown that deletion of STAT3 or the closely related STAT5 from the brain results in an obese phenotype, but their roles in fertility regulation are not clear. This study tested whether STAT3 and STAT5 pathways of leptin signaling are required for fertility, and whether absence of one pathway might be compensated for by the other in a redundant manner. A Cre-loxP approach was used to generate 3 models of male and female transgenic mice with LepR-specific deletion of STAT3, STAT5, or both STAT3 and STAT5. Body weight, puberty onset, estrous cyclicity, and fertility were measured in all knockout (KO) mice and their control littermates. Knocking out STAT3 or both STAT3 and 5 from LepR expressing cells, but not STAT5 alone, led to significant increase in body weight. All STAT3 and STAT5 single KO mice exhibited normal puberty onset and subsequent fertility compared to their control littermates. Surprisingly, all STAT3 and STAT5 double KO mice also exhibited normal puberty onset, estrous cyclicity, and fertility, although they had severely disrupted body weight regulation. These results suggest that, although STAT3 signaling is crucial for body weight regulation, neither STAT3 nor STAT5 is required for the regulation of fertility by leptin. It remains to be determined what other signaling molecules mediate this effect of leptin, and whether they interact in a redundant manner. Topics: Animals; Body Weight; Estrous Cycle; Female; Fertility; Genotype; Hypothalamus; Immunohistochemistry; Leptin; Male; Mice; Mice, Knockout; Puberty; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; STAT5 Transcription Factor | 2013 |
[Assessment of neuropeptide Y, leptin and leptin-receptor concentrations in teenagers suffering from anorexia nervosa].
Anorexia nervosa (AN) is the third most common chronic disorder affecting adolescents and is associated with high mortality risk. The predominant symptom of anorexia nervosa is persistent and intentional striving to achieve weight loss initiated and/or sustained by the patient, leading to cachexia. Until now the cause of the condition remains unknown, but seems to be multifactoral. Patients with AN develop multi-organ complications and endocrine disorders affecting multiple disturbances of energy metabolism. Neuropeptide Y and leptin can be found between chemical substances regulating feelings of hunger and satiety. Neuropeptide Y plays the main role in the regulation of energetic homeostasis of the organism, feeding customs, sexual and reproductive functions. Concentration of neuropeptide Y increases during starvation and decreases after feeding. In anorexia nervosa the concentration of neuropeptide Y increases and, by doing that, decreases the excrection of gonadoliberines and gonadotropines. Leptin influences the feeling of hunger and its synthesis takes part, among others, in adiposal tissue. It also influences the menstruation disturbances. Rising leptin concentrations, with accompanying increasing adiposity is known to be the main factor influencing the puberty and the reverse of the malfunction of hypothalamic-pituitary-gonadal axis in malnourished persons. During hunger and low calorie intake, leptin concentration decreases, independently of adiposity.. The main aim of the study was to assess concentrations of neuropeptide Y, leptin and leptin receptor in teenagers treated for anorexia nervosa.. The study was conducted between 2007- 2011 in a group of 45 female teenagers with anorexia nervosa and a control group consisting of 59 healthy regularly menstruating female age peers. Concentrations of leptin, leptin receptor and neuropeptide Y (NPY) have been determined by using immunoenzymatic tests. Blood samples were obtained in fasting state. The Ethics Committee of the Medical University of Lodz approved of the study.. There were statistically significant differences between mean values of BMI (14.6 vs. 19.83), median value of leptin concentration (3.79 vs. 12.09), proportions of LEP/BMI (0.1986 vs. 0.5701) in the study group when compared to controls. Higher values were found in the study group if compared to the percentage of body mass insufficiency--(23.09 vs. 3.97), neuropeptide Y concentration--(0.33 vs. 0.19), proportions of NPY/BMI--(0.023 vs. 0.0095), concentration of leptin receptor--(30.25 vs. 19.45), proportions of LR/BMI--(2.1048 vs. 0.9744).. Low concentrations of leptine correlate to high concentrations of leptin receptor. A positive correlation between low body mass index and leptin receptor concentration and proportions of LR to BMI was found. A negative correlation was found between body mass loss and leptin concentration. The increasing concentration of neuropeptide Y, correlated to body mass deficency with existing high concentrations of leptin, could suggest disturbances of their regulatory axis. Topics: Adolescent; Anorexia Nervosa; Biomarkers; Body Constitution; Body Mass Index; Body Weight; Case-Control Studies; Energy Metabolism; Female; Humans; Leptin; Neuropeptide Y; Poland; Receptors, Leptin; Reference Values; Risk Factors | 2013 |
Body adiposity index and other indexes of body composition in the SAPHIR study: association with cardiovascular risk factors.
The accuracy of anthropometric surrogate markers such as the body adiposity index (BAI) and other common indexes like the body mass index (BMI), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) to predict metabolic sequelae is essential for its use in clinical practice.. Thus, we evaluated the strength of BAI and other indexes to relate with anthropometric parameters, adipocytokines, blood lipids, parameters of glucose-homeostasis and blood pressure in 1,770 patients from the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study in a crosssectional design. Measurements were BAI, BMI, WHR, WHtR, abdominal subcutaneous and visceral adipose tissue (aSAT and VAT), total body adipose tissue mass, body weight, waist- and hip circumference (WC and HC), leptin, adiponectin, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides (TG), fasting plasma glucose, fasting plasma insulin, the homeostasis model assessment of insulin resistance (HOMAIR), systolic and diastolic blood pressure.. BAI was significantly associated with leptin and HC. We conclude that BAI was the best calculator for leptin. BAI was inferior to BMI to predict anthropometric parameters other than HC, adiponectin, blood lipids, parameters of glucose homeostasis, and blood pressure in this cross-sectional study. Topics: Adiponectin; Adipose Tissue; Adiposity; Adult; Aged; Austria; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Cross-Sectional Studies; Fasting; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Prospective Studies; Risk Factors; Triglycerides; Waist Circumference; Waist-Hip Ratio | 2013 |
Gut microbiota composition in male rat models under different nutritional status and physical activity and its association with serum leptin and ghrelin levels.
Several evidences indicate that gut microbiota is involved in the control of host energy metabolism.. To evaluate the differences in the composition of gut microbiota in rat models under different nutritional status and physical activity and to identify their associations with serum leptin and ghrelin levels.. In a case control study, forty male rats were randomly assigned to one of these four experimental groups: ABA group with food restriction and free access to exercise; control ABA group with food restriction and no access to exercise; exercise group with free access to exercise and feed ad libitum and ad libitum group without access to exercise and feed ad libitum. The fecal bacteria composition was investigated by PCR-denaturing gradient gel electrophoresis and real-time qPCR.. In restricted eaters, we have found a significant increase in the number of Proteobacteria, Bacteroides, Clostridium, Enterococcus, Prevotella and M. smithii and a significant decrease in the quantities of Actinobacteria, Firmicutes, Bacteroidetes, B. coccoides-E. rectale group, Lactobacillus and Bifidobacterium with respect to unrestricted eaters. Moreover, a significant increase in the number of Lactobacillus, Bifidobacterium and B. coccoides-E. rectale group was observed in exercise group with respect to the rest of groups. We also found a significant positive correlation between the quantity of Bifidobacterium and Lactobacillus and serum leptin levels, and a significant and negative correlation among the number of Clostridium, Bacteroides and Prevotella and serum leptin levels in all experimental groups. Furthermore, serum ghrelin levels were negatively correlated with the quantity of Bifidobacterium, Lactobacillus and B. coccoides-Eubacterium rectale group and positively correlated with the number of Bacteroides and Prevotella.. Nutritional status and physical activity alter gut microbiota composition affecting the diversity and similarity. This study highlights the associations between gut microbiota and appetite-regulating hormones that may be important in terms of satiety and host metabolism. Topics: Animals; Anorexia; Appetite; Bacteria; Body Weight; Denaturing Gradient Gel Electrophoresis; Diet; Feces; Feeding Behavior; Gastrointestinal Tract; Ghrelin; Leptin; Male; Microbiota; Models, Animal; Nutritional Status; Phylogeny; Physical Conditioning, Animal; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction | 2013 |
Leptin antagonist ameliorates chronic colitis in IL-10⁻/⁻ mice.
Although the etiology of two major forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are unknown and evidence suggests that chronic intestinal inflammation is caused by an excessive immune response to mucosal antigens. Previous studies support the role for TGF-β1 through 3 in the initiation and maintenance of tolerance via the induction of regulatory T cells (Tregs) to control intestinal inflammation. Leptin, a satiety hormone produced primarily by adipose tissue, has been shown to increase during colitis progression and is believed to contribute to disease genesis and/or progression.. We investigated the ability of a pegylated leptin antagonist (PG-MLA) to ameliorate the development of chronic experimental colitis.. Compared to vehicle control animals, PG-MLA treatment of mice resulted in an (1) attenuated clinical score; (2) reversed colitis-associated pathogenesis including a decrease in body weight; (3) reduced systemic and mucosal inflammatory cytokine expression; (4) increased insulin levels and (5) enhanced systemic and mucosal Tregs and CD39⁺ Tregs in mice with chronic colitis. The percentage of systemic and mucosal TGF-β1, -β2 and -β3 expressing CD4⁺ T cells were augmented after PG-MLA treatment. The activation of STAT1 and STAT3 and the expression of Smad7 were also reduced after PG-MLA treatment in the colitic mice. These findings clearly suggest that PG-MLA treatment reduces intestinal Smad7 expression, restores TGF-β1-3 signaling and reduces STAT1/STAT3 activation that may increase the number of Tregs to ameliorate chronic colitis.. This study clearly links inflammation with the metabolic hormone leptin suggesting that nutritional status influences immune tolerance through the induction of functional Tregs. Inhibiting leptin activity through PG-MLA might provide a new and novel therapeutic strategy for the treatment of IBD. Topics: Animals; Antigens, CD; Apyrase; Body Weight; Chronic Disease; Colitis; Down-Regulation; Female; Insulin; Interleukin-10; Intestinal Mucosa; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Polyethylene Glycols; Recombinant Proteins; Signal Transduction; Smad7 Protein; STAT1 Transcription Factor; STAT3 Transcription Factor; T-Lymphocytes, Regulatory; Transforming Growth Factor beta | 2013 |
Long-term ingestion of monosodium L-glutamate did not induce obesity, dyslipidemia or insulin resistance: a two-generation study in mice.
The use of monosodium glutamate (MSG) as a flavor enhancer spans more than 100 y and there are many studies indicating the safety of general use of MSG. Recently, however, Collison et al. (2010) reported a two-generation study with a low dose of MSG that caused abdominal obesity, insulin resistance and dyslipidemia in mice. Due to public health concerns over metabolic syndrome, their report merits careful analysis. The present study attempted to repeat the Collison et al. findings. Groups of male or female C57BL/6J mice were fed a control diet or one supplemented with high-fructose corn syrup (HFCS) at a level of 20%. Drinking water control was provided or treatment groups were given 0.064% MSG solution (w/v). Diets and MSG administration continued throughout mating and during gestation and lactation periods. To further investigate the effects of ingestion of MSG, the offspring were continued on the same dosing conditions until they reached 32 wk of age. MSG administration in mice fed a normal or a HFCS diet throughout gestation and for 32 wk after birth, did not affect growth, girth size, abdominal fat weight or body composition. This study reports that MSG did not trigger insulin resistance, dyslipidemia or hepatic steatosis, regardless of the diet, not reproducing the results of the above-mentioned study (Collison et al., 2010). Topics: Abdominal Fat; Adiponectin; Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Body Composition; Body Weight; Cholesterol; Diet; Dose-Response Relationship, Drug; Dyslipidemias; Fatty Liver; Female; Flavoring Agents; Fructose; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; Sodium Glutamate | 2013 |
Dietary supplementation of calcium may counteract obesity in mice mediated by changes in plasma fatty acids.
The scope of this study was to assess the impact of calcium and conjugated linoleic acid (CLA) supplementation on plasma fatty acid profiles and to evaluate potential synergistic effects of both compounds against dietary obesity. Mice separated into five experimental groups were followed: control (C), high-fat diet (HF), HF with calcium (Ca), HF plus CLA and HF with both Ca and CLA. Plasma metabolites and fatty acids were determined by commercial kits and gas chromatography, respectively. Both dietary calcium and CLA supplementation contributed to lower body fat gain under a HF diet. Maximum efficacy was seen with calcium; no additional effect was associated with the combined treatment with CLA. Plasma leptin, adiponectin and HOMA index were in accordance with an altered glucose/insulin homeostasis in the HF and HF + CLA groups, whereas control levels were attained under Ca-enriched diets. Plasma fatty acids showed minor changes associated to CLA treatment, but a high impact on PUFA was observed under Ca-enriched diets. Our results show that the mechanism underlying the anti-obesity effects of calcium supplementation is mediated mainly by changes in PUFA plasma profile. In addition, the lack of synergy on body weight reduction in combination with associated lipid profiles of calcium and CLA suggests that calcium may interfere with absorption and/or bioactivity of CLA, which can be of relevance when using CLA-fortified dairy products against human obesity. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Calcium; Diet, High-Fat; Dietary Supplements; Fatty Acids; Isomerism; Leptin; Linoleic Acids, Conjugated; Male; Mice; Mice, Inbred C57BL; Obesity | 2013 |
Characterization of a novel genetically obese mouse model demonstrating early onset hyperphagia and hyperleptinemia.
Obesity is a critical risk factor for the development of metabolic syndrome, and many obese animal models are used to investigate the mechanisms responsible for the appearance of symptoms. To establish a new obese mouse model, we screened ∼13,000 ICR mice and discovered a mouse demonstrating spontaneous obesity. We named this mouse "Daruma" after a traditional Japanese ornament. Following the fixation of the genotype, these animals exhibited obese phenotypes according to Mendel's law of inheritance. In the Daruma mouse, the leptin receptor gene sequence carried two base mutations that are good candidates for the variation(s) responsible for the obese phenotype. The Daruma mice developed characteristic visceral fat accumulation at 4 wk of age, and the white adipose and liver tissues exhibited increases in cell size and lipid droplets, respectively. No histological abnormalities were observed in other tissues of the Daruma mice, even after the mice reached 25 wk of age. Moreover, the onset of impaired leptin signaling was early and manifested as hyperleptinemia and hyperinsulinemia. Pair feeding completely inhibited obesity, although these mice rapidly developed hyperphagia and obesity followed by hyperleptinemia when pair feeding ceased and free-access feeding was permitted. Therefore, the Daruma mice exhibited unique characteristics and may be a good model for studying human metabolic syndrome. Topics: Adipose Tissue; Animals; Body Weight; Cholesterol; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Ghrelin; Glucose Tolerance Test; Hemodynamics; Hyperphagia; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mutation; Obesity; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Tomography, X-Ray Computed; Triglycerides | 2013 |
Long-day photoperiod interacts with vasopressin and food restriction to modulate reproductive status and vasopressin receptor expression of male golden spiny mice.
We tested the effects of photoperiod, water and food availability on body mass, reproductive status and arginine vasopressin receptor 1A (Avpr1a) mRNA expression in males of desert-adapted golden spiny mice, Acomys russatus. In Experiment 1, males were acclimated to short-day (SD; 8 h:16 h light:dark) or long-day (LD; 16 h:8 h light:dark) photoperiods with either saline (control) or vasopressin treatment for 3 weeks. The results of this experiment revealed that under control conditions, SD mice increased body mass by ~5% while LD mice decreased it by ~4%. SD photoperiod had no effect on reproductive status and leptin levels, whereas LD males increased testes mass and serum testosterone, but the photoperiod had no effect on leptin levels. Vasopressin administration decreased LD-induced reproductive enhancement. Because no consistent effect of SD treatment was found on reproductive status, Experiment 2 was carried out only on LD-acclimated males kept under 75% food restriction (decrease from ad libitum) with saline or leptin treatment. Body mass, testes mass, serum testosterone, leptin concentrations and Avpr1a mRNA expression were measured. Food restriction remarkably decreased body mass, with a more potent effect in leptin-treated males, showing enhanced reproductive status and a significant increase in serum leptin compared with controls. Avpr1a expression was significantly upregulated in LD, vasopressin-treated and food-restricted males, with higher levels in the hypothalamus compared with the testes. We conclude that in A. russatus, LD photoperiod interacts with water and food availability to advance reproductive responses. Avpr1a is suggested to integrate nutritional and osmotic signals to optimize reproduction by modulating reproductive and energetic neuroendocrine axes at the central level. The interaction between photoperiod and other environmental cues is of an adaptive value to desert-adapted small rodents for timing reproduction in unpredictable ecosystems such as extreme deserts. Topics: Animals; Body Weight; Food Deprivation; Gene Expression Regulation; Leptin; Male; Models, Biological; Murinae; Organ Size; Photoperiod; Receptors, Vasopressin; Reproduction; RNA, Messenger; Testosterone; Vasopressins | 2013 |
Plasma leptin, glucose and non-esterified fatty acid variations in dromedary camels exposed to prolonged periods of underfeeding or dehydration.
The involvement of plasma leptin in the adaptation of dromedary camels to harsh conditions such as food or water shortages was studied through 2 experiments. In experiment 1, fourteen female camels were either fed at 68% of maintenance energy requirements (MER) during 112d (n=4) or overfed at 134% of MER during the first 56d and then underfed at 17% of MER the next 56d (OV-UN, n=5), or underfed and then overfed for the same durations and energy intake levels (UN-OV, n=5). Weekly plasma samples showed that leptin, glucose and non-esterified fatty acid (NEFA) concentrations were significantly modulated by energy intake level. NEFA increased sharply but transiently in underfed camels of the UN-OV or OV-UN groups, whereas glucose and leptin concentrations decreased with underfeeding and increased with overfeeding with more significant effects in camels that were previously overfed or underfed, respectively. In experiment 2 twelve female camels were either normally watered (n=6) or dehydrated (n=6) during 23d and then rehydrated during 4d. Dehydration specifically increased blood hematocrit, plasma NEFA and glucose whereas leptin decreased slightly. For both experiments, leptinemia was positively related to hump adipocyte volume. Taken together these results provide new data for a better understanding of lipid and energy metabolism in camels. Topics: Adipocytes; Animals; Blood Glucose; Blood Proteins; Body Weight; Camelus; Cell Size; Dehydration; Fatty Acids, Nonesterified; Female; Food Deprivation; Hematocrit; Leptin | 2013 |
The role of viscosity and fermentability of dietary fibers on satiety- and adiposity-related hormones in rats.
Dietary fiber may contribute to satiety. This study examined the effect of two dietary fiber characteristics, small intestinal contents viscosity and large intestinal fermentability, on satiety-and adiposity-related hormones in rats. Diets contained fiber sources that were non-viscous, somewhat viscous, or highly viscous, and either highly fermentable or non-fermentable, in a 2 × 3 factorial design. In the fed state (2 h postprandial), rats fed non-fermentable fibers had significantly greater plasma GLP-1 concentration than fermentable fibers. In the fasted state, among non-fermentable fibers, viscosity had no effect on GLP-1 concentration. However, among fermentable fibers, greater viscosity reduced GLP-1 concentration. Plasma peptide tyrosine tyrosine (PYY) concentrations in the fasted state were not influenced by the fermentability of the fiber overall, however animals consuming a fructooligosaccharide greater PYY concentration. In both the fed and fasted states, rats fed non-fermentable fibers had a significantly lower plasma ghrelin concentration than rats fed fermentable fibers. In the fasted state, rats fed non-fermentable fibers had a significantly lower plasma leptin concentration than rats fed fermentable fibers. Thus, fermentability and viscosity of dietary fiber interacted in complex ways to influence satiety- and adiposity-related plasma hormone concentrations. However, the results suggest that highly viscous, non-fermentable fibers may limit weight gain and reduce adiposity and non-fermentable fibers, regardless of viscosity, may promote meal termination. Topics: Adiposity; Animals; Body Weight; Diet; Dietary Fiber; Fermentation; Ghrelin; Glucagon-Like Peptide 1; Insulin; Leptin; Male; Organ Size; Peptide YY; Rats; Rats, Wistar; Satiation; Viscosity | 2013 |
Ewe lambs with higher breeding values for growth achieve higher reproductive performance when mated at age 8 months.
We studied the relationships among growth, body composition and reproductive performance in ewe lambs with known phenotypic values for depth of eye muscle (EMD) and fat (FAT) and Australian Sheep Breeding Values for post-weaning live weight (PWT) and depth of eye muscle (PEMD) and fat (PFAT). To detect estrus, vasectomized rams were placed with 190 Merino ewe lambs when on average they were 157 days old. The vasectomized rams were replaced with entire rams when the ewe lambs were, on average, 226 days old. Lambs were weighed every week and blood was sampled on four occasions for assay of ghrelin, leptin and ß-hydroxybutyrate. Almost 90% of the lambs attained puberty during the experiment, at an average live weight of 41.4 kg and average age of 197 days. Ewe lambs with higher values for EMD (P < 0.001), FAT (P < 0.01), PWT (P < 0.001), PEMD (P < 0.05) and PFAT (P < 0.05) were more likely to achieve puberty by 251 days of age. Thirty-six percent of the lambs conceived and, at the estimated date of conception, the average live weight was 46.9 ± 0.6 kg and average age was 273 days. Fertility, fecundity and reproductive rate were positively related to PWT (P < 0.05) and thus live weight at the start of mating (P < 0.001). Reproductive performance was not correlated with blood concentrations of ghrelin, leptin or ß-hydroxybutyrate. Many ewe lambs attained puberty, as detected by vasectomized rams, but then failed to become pregnant after mating with entire rams. Nevertheless, we can conclude that in ewe lambs mated at 8 months of age, higher breeding values for growth, muscle and fat are positively correlated with reproductive performance, although the effects of breeding values and responses to live weight are highly variable. Topics: 3-Hydroxybutyric Acid; Age Factors; Animals; Body Composition; Body Fat Distribution; Body Weight; Breeding; Ghrelin; Leptin; Reproduction; Sexual Maturation; Sheep | 2013 |
Serum osteopontin concentration is decreased by exercise-induced fat loss but is not correlated with body fat percentage in obese humans.
To evaluate the extent to which fat mass contributes to serum osteopontin (OPN) concentration, we investigated whether serum OPN levels are decreased by exercise-induced fat mass loss and whether they are associated with body fat percentage in obese humans. Twenty‑three female college students were recruited to participate in an 8‑week body weight control program. Body composition [body weight, soft lean mass, body fat mass, body fat percentage, waist-hip ratio and body mass index (BMI)] were assessed prior to and following the program. Serum lipid profiles and serum adiponectin, leptin and osteopontin levels were measured from serum collected prior to and following the program. To understand the effect of fat mass loss on the serum levels of adipokine, which is mainly produced in adipose tissue, the leptin and adiponectin levels were also measured prior to and following the program. Serum leptin levels (mean ± standard error of the mean) decreased significantly following the program (from 9.82±0.98 to 7.23±0.67 ng/ml) and were closely correlated with body fat percentage. In addition, serum adiponectin levels were negatively correlated with body fat percentage, while serum adiponectin levels were not significantly altered. By contrast, serum OPN levels decreased significantly following the program (from 16.03±2.34 to 10.65±1.22 ng/ml). However, serum OPN levels were not correlated with body fat percentage, suggesting that serum OPN levels are controlled by several other factors in humans. In conclusion, a high expression of OPN in adipose tissues may not be correlated with serum OPN levels in obese humans. Thus, tissues or physiological factors other than fat mass may have a greater contribution to the serum OPN levels. Topics: Adipose Tissue; Adiposity; Adult; Body Composition; Body Mass Index; Body Weight; Exercise; Female; Humans; Leptin; Lipids; Muscle, Skeletal; Obesity; Organ Size; Osteopontin; Time Factors; Young Adult | 2013 |
Dietary supplementation with purified mulberry (Morus australis Poir) anthocyanins suppresses body weight gain in high-fat diet fed C57BL/6 mice.
We present our experiment about adding anthocyanins to the daily food of mice. Three kinds of anthocyanins (cyanidin-3-glucoside, cyanidin-3-rutinoside and pelargonidin-3-glucoside) purified from Chinese mulberry (Morus australis Poir) were evaluated for suppressing body weight gain of the male C57BL/6 mice fed with high-fat diet (HFD). The results from a 12-week experiment show that consumption of purified mulberry anthocyanins (MACN) of 40 or 200mg/kg can significantly inhibit body weight gain, reduce the resistance to insulin, lower the size of adipocytes, attenuate lipid accumulation and decrease the leptin secretion. Thus, dietary supplementation with MACN can protect against body weight gain of the diet-induced obese mice. Topics: Animals; Anthocyanins; Body Weight; Diet, High-Fat; Dietary Supplements; Humans; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Morus; Obesity; Plant Extracts; Weight Gain | 2013 |
Association of the leptin gene with carcass characteristics in Nellore cattle.
Advances in DNA technology have created biotechnological tools that can be used in animal selection and new strategies for increasing herd productivity and quality. The objective of the present work was to associate the genotypes of leptin gene exon 2 polymorphisms with productive traits in Nellore cattle. Blood was collected from Nellore males and PCR-RFLP reactions were performed with the restriction enzymes Cla I and Kpn 2I. The gene frequencies resulting from digestion by Cla I were 0.60 and 0.40 for allele A and T, respectively; the genotypic frequencies were AA = 0.20 and AT = 0.80. The gene frequencies from digestion by Kpn 2I were 0.81 for allele C and 0.194 for allele T; the genotypic frequencies were CC = 0.62 and CT = 0.38. The populations in both cases were not in Hardy-Weinberg equilibrium (p > 0.05), and the TT genotype was not found. Significant associations were noted between leptin gene exon 2 polymorphisms and five productive traits in Nellore cattle: carcass fat distribution, the intensity of red muscle coloration, pH, marbling, and post-slaughter fat thickness. Topics: Analysis of Variance; Animals; Body Composition; Body Weight; Brazil; Cattle; Chi-Square Distribution; Electrophoresis, Agar Gel; Leptin; Meat; Phenotype; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length | 2013 |
Oral salmon calcitonin protects against impaired fasting glycemia, glucose intolerance, and obesity induced by high-fat diet and ovariectomy in rats.
Oral salmon calcitonin (sCT) has demonstrated clinical efficacy in treating osteoporosis in postmenopausal women. The postmenopausal state is also associated with obesity-related insulin resistance (IR) and type 2 diabetes. The aim of this study was to investigate the preventive effects of oral sCT on energy and glucose homeostasis in high-fat diet (HFD)- and ovariectomy (OVX)-induced obese rats. Furthermore, the weight-regulatory and gluco-regulatory effects of short-term oral sCT intervention on HFD-induced obese rats were explored.. For prevention, female rats exposed to HFD with or without OVX were treated with oral sCT for 5 weeks. As intervention, HFD-induced obese male rats were treated with oral sCT for 4 days. Body weight, food intake, and plasma glucose, insulin, and leptin levels were measured, and the clinical homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated. In addition, oral glucose tolerance was evaluated in the systemic and portal circulations.. For prevention, oral sCT reduced body weight by ∼16% to 19% (P < 0.001), reduced plasma insulin and leptin by ∼50%, and improved impaired fasting glycemia (P < 0.05) concomitantly with amelioration of IR (HOMA-IR; P < 0.01) in HFD- and OVX-induced obesity. Furthermore, oral sCT significantly reduced the incremental area under the curve for plasma glucose and insulin by ∼40% and ∼70%, respectively, during glucose tolerance testing. As intervention in HFD-induced obese rats, oral sCT reduced body weight, fasting glycemia, and insulinemia in conjunction with HOMA-IR (P < 0.001). Finally, oral sCT alleviated glucose intolerance predominantly in the portal circulation.. Oral sCT treatment displays weight-regulatory and glucoregulatory efficacy in HFD- and OVX-induced obese rats, indicating the clinical usefulness of oral sCT in postmenopausal obesity-related IR and type 2 diabetes. Topics: Animals; Blood Glucose; Body Weight; Calcitonin; Diabetes Mellitus, Type 2; Diet, High-Fat; Fasting; Female; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Male; Obesity; Ovariectomy; Rats; Rats, Sprague-Dawley | 2013 |
Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies.
Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10(-6)), CNR1 (P=9.6 × 10(-5)) and the leptin (LEP) promoter (P=1.4 × 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event. Topics: Adolescent; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Amidohydrolases; Antipsychotic Agents; Body Weight; Child; Child Development Disorders, Pervasive; Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Leptin; Male; Proteins; Receptor, Cannabinoid, CB1; Receptor, Melanocortin, Type 4; Risperidone; Weight Gain | 2013 |
Perinatal undernutrition programmes thyroid function in the adult rat offspring.
Increasing evidence suggests that alterations in early nutrition programme physiological changes in adulthood. In the present study, we determined the effects of undernutrition during gestation and lactation on the programming of thyroid function in adult rat offspring. Perinatal undernutrition was achieved by a 40% food restriction in female Wistar rats from the mating day to weaning. On postpartum day 21, the offspring of the control and food-restricted dams were weaned and given free access to a commercial diet until adulthood. The results showed that undernourished rats exhibited decreased 3,5,3'-triiodothyronine (T3) levels but had normal thyroxine (T4) and thyrotropin (TSH) levels at weaning; on day 90, these rats displayed a significant flip, exhibiting normalised T3 (total and free) and total T4 levels, but low free T4 and persistently higher TSH levels, which were maintained even on postnatal day 140. This profile was accompanied by a scarce fat depot, a lower RMR and an exacerbated sympathetic brown adipose tissue (BAT) tone (deiodinase type 2 expression) in basal conditions. Moreover, when a functional challenge (cold exposure) was applied, the restricted group exhibited partial changes in TSH (29 v. 100%) and T4 (non-response v. 17%) levels, a significant decrease in leptin levels (75 v. 32%) and the maintenance of a sympathetic BAT over-response (higher noradrenaline levels) in comparison with the control group. The findings of the present study suggest that undernutrition during the perinatal period produces permanent changes in the hypothalamus-pituitary-thyroid axis with consequent low body weight and decreased RMR and facultative thermogenesis. We hypothesise that these changes predispose individuals to exhibiting adult subclinical hypothyroidism. Topics: Adipose Tissue, Brown; Animals; Basal Metabolism; Body Weight; Cold Temperature; Female; Humans; Hypothyroidism; Infant Nutritional Physiological Phenomena; Infant, Newborn; Lactation; Leptin; Malnutrition; Norepinephrine; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Rats; Rats, Wistar; Thermogenesis; Thyroid Gland; Thyroid Hormones | 2013 |
Anthocyanin-Rich Juice Lowers Serum Cholesterol, Leptin, and Resistin and Improves Plasma Fatty Acid Composition in Fischer Rats.
Obesity and obesity-associated diseases e.g. cardiovascular diseases and type 2 diabetes are spread worldwide. Anthocyanins are supposed to have health-promoting properties, although convincing evidence is lacking. The aim of the present study was to investigate the effect of anthocyanins on several risk factors for obesity-associated diseases. Therefore, Fischer rats were fed anthocyanin-rich grape-bilberry juice or an anthocyanin-depleted control juice for 10 weeks. Intervention with anthocyanin-rich grape-bilberry juice reduced serum cholesterol and tended to decrease serum triglycerides. No effects were seen for serum non-esterified fatty acids, glucose, and insulin. Anthocyanin-rich grape-bilberry juice intervention reduced serum leptin and resistin, but showed no influence on serum adiponectin and secretion of adipokines from mesenteric adipose tissue. Furthermore, anthocyanin-rich grape-bilberry juice increased the proportion of polyunsaturated fatty acids and decreased the amount of saturated fatty acids in plasma. These results indicate that anthocyanins possess a preventive potential for obesity-associated diseases. Topics: Adipokines; Animals; Anthocyanins; Beverages; Blood Glucose; Body Weight; Cholesterol; Fatty Acids, Nonesterified; Feeding Behavior; Insulin; Leptin; Male; Rats; Rats, Inbred F344; Resistin; Triglycerides | 2013 |
Calorie restriction delays the progression of lesions to pancreatic cancer in the LSL-KrasG12D; Pdx-1/Cre mouse model of pancreatic cancer.
Since pancreatic cancer is a lethal disease, developing prevention strategies is an important goal. We determined whether calorie restriction would prevent the development and delay progression of pancreatic intraepithelial neoplasms to pancreatic ductal adenocarcinoma (PDA) in LSL-KrasG12D/+; Pdx-1/Cre mice that develop all the precursor lesions that progress to PDA. Eight-week-old LSL-KrasG12D; Pdx-1/Cre mice were assigned to three groups: (1) ad libitum (AL) fed the AIN93M diet or (2) intermittently calorie restricted (ICR) a modified AIN93M at 50% of AL intake followed by one week intervals at 100% of AL intake, or (3) chronically calorie restricted (CCR) an AIN93M diet at 75% of AL intake. AL fed mice had a greater percentage of pancreatic ducts with PanIN-2 (13.6%) than did the ICR (1.0%) and CCR groups (1.6%), P < 0.0001. Calorie restriction (ICR [0%] and CCR [0.7%]) reduced the percentage of ducts with PanIN-3 lesions compared to the AL group (7.0%), P < 0.0001. The incidence of PanIN-2 or more lesions was significantly reduced in both ICR (27%; n = 16) and CCR (40%) mice (n = 15; P < 0.001) compared to AL (70%) fed mice (n = 11). The delayed progression of lesions in ICR and CCR mice was associated with reduced proliferation measured by proliferating cell nuclear antigen staining, reduced protein expression of Glut1, increased protein expression of Sirt1, increased serum adiponectin, and decreased serum leptin. CCR resulted in decreased phosphorylated mammalian target of rapamycin and decreased serum insulin-like growth factor-1. In summary, this is the first study to show in LSL-KrasG12D; Pdx-1/Cre mice that ICR and CCR delay the progression of lesions to PDA. Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Caloric Restriction; Cell Proliferation; Cell Survival; Disease Models, Animal; Disease Progression; Feeding Behavior; Homeodomain Proteins; Humans; Insulin-Like Growth Factor I; Integrases; Leptin; Mice; Mice, Transgenic; Organ Size; Pancreas; Pancreatic Ducts; Pancreatic Neoplasms; Phosphorylation; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins p21(ras); Signal Transduction; Sirtuin 1; Trans-Activators | 2013 |
Experimental hyperleptinemia in neonatal rats leads to selective leptin responsiveness, hypertension, and altered myocardial function.
The prevalence of obesity among pregnant women is increasing. Evidence from human cohort studies and experimental animals suggests that offspring cardiovascular and metabolic function is compromised through early life exposure to maternal obesity. Previously, we reported that juvenile offspring of obese rats develop sympathetically mediated hypertension associated with neonatal hyperleptinemia. We have now addressed the hypothesis that neonatal exposure to raised leptin in the immediate postnatal period plays a causal role. Pups from lean Sprague-Dawley rats were treated either with leptin (3 mg/kg IP) or with saline twice daily from postnatal day 9 to 15 to mimic the exaggerated postnatal leptin surge observed in offspring of obese dams. Cardiovascular function was assessed by radiotelemetry at 30 days, and 2 and 12 months. In juvenile (30 days) leptin-treated rats, hearts were heavier and night-time (active period) systolic blood pressure was raised (mm Hg; mean ± SEM: male leptin-treated, 132 ± 1 versus saline-treated, 119 ± 1, n=6, P<0.05; female leptin-treated, 132 ± 2 versus saline-treated, 119 ± 1, n=6, P<0.01), and the pressor response to restraint stress and leptin challenge increased compared with saline-treated rats. Heart rate variability demonstrated an increased low:high frequency ratio in 30-day leptin-treated animals, indicative of heightened sympathetic efferent tone. Echocardiography showed altered left ventricular structure and systolic function in 30-day female leptin versus saline-treated rats. These disorders persisted to adulthood. In isolated hearts, contractile function was impaired at 5 months in male leptin-treated rats. Exogenously imposed hyperleptinemia in neonatal rats permanently influences blood pressure and cardiac structure and function. Topics: Adipose Tissue; Animals; Animals, Newborn; Blood Pressure; Body Weight; Cardiovascular System; Female; Heart; Heart Rate; Hypertension; Leptin; Male; Myocardial Contraction; Myocardium; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley | 2013 |
Excess of methyl donor in the perinatal period reduces postnatal leptin secretion in rat and interacts with the effect of protein content in diet.
Methionine, folic acid, betaine and choline interact in the one-carbon metabolism which provides methyl groups for methylation reactions. An optimal intake of these nutrients during pregnancy is required for successful completion of fetal development and evidence is growing that they could be involved in metabolic long-term programming. However, the biological pathways involved in the action of these nutrients are still poorly known. This study investigated the interaction between methyl donors and protein content in maternal diet during the preconceptual, pregnancy and lactation periods and the consequences on the rat offspring in the short and long term. Methyl donor supplementation reduced leptin secretion in offspring, whereas insulin levels were mostly affected by protein restriction. The joint effect of protein restriction and methyl donor excess strongly impaired postnatal growth in both gender and long term weight gain in male offspring only, without affecting food intake. In addition, rats born from protein restricted and methyl donor supplemented dams gained less weight when fed a hypercaloric diet. Methylation of the leptin gene promoter in adipose tissue was increased in methyl donor supplemented groups but not affected by protein restriction only. These results suggest that maternal methyl donor supplementation may influence energy homeostasis in a gender-dependent manner, without affecting food intake. Moreover, we showed that macronutrients and micronutrients in maternal diet interact to influence the programming of the offspring. Topics: Animals; Base Sequence; Body Weight; Diet; Dietary Proteins; Dietary Supplements; DNA Methylation; Eating; Female; Gene Expression Regulation, Developmental; Lactation; Leptin; Litter Size; Male; Molecular Sequence Data; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley | 2013 |
Apelin administration ameliorates high fat diet-induced cardiac hypertrophy and contractile dysfunction.
Apelin has been recognized as an adipokine that plays an important role in regulating energy metabolism and is credited with antiobesity and antidiabetic properties. This study was designed to examine the effect of exogenous apelin on obesity-associated cardiac dysfunction. Oral glucose tolerance test, echocardiography, cardiomyocyte contractile and intracellular Ca(2+) properties were assessed in adult C57BL/6J mice fed - low or a - high-fat diet for 24weeks followed by apelin treatment (100nmol/kg, i.p. for 2weeks). High-fat diet resulted in increased left ventricular diastolic and systolic diameters, and wall thickness, compromised fractional shortening, impaired cardiomyocyte mechanics (peak-shortening, maximal velocity of shortening/relengthening, and duration of shortening and relengthening) and compromised intracellular Ca(2+) handling, all of which were reconciled by apelin. Apelin treatment also reversed high fat diet-induced changes in intracellular Ca(2+) regulatory proteins, ER stress, and autophagy. In addition, microRNAs (miR) -133a, miR-208 and miR-1 which were elevated following high-fat feeding were attenuated by apelin treatment. In cultured cardiomyocytes apelin reconciled palmitic acid-induced cardiomyocyte contractile anomalies. Collectively, these data depict a pivotal role of apelin in obesity-associated cardiac contractile dysfunction, suggesting a therapeutic potential of apelin in the management of cardiac dysfunction associated with obesity. Topics: Adipokines; Animals; Apelin; Autophagy; Body Weight; Cardiomegaly; Cells, Cultured; Diet, High-Fat; Endoplasmic Reticulum Stress; Female; Gene Expression Regulation; Glucose; Intercellular Signaling Peptides and Proteins; Leptin; Mice; MicroRNAs; Mitochondria, Heart; Myocardial Contraction; Myocytes, Cardiac; Palmitic Acid; Triglycerides | 2013 |
Upregulation of gene expression in reward-modulatory striatal opioid systems by sleep loss.
Epidemiological studies have shown a link between sleep loss and the obesity 'epidemic,' and several observations indicate that sleep curtailment engenders positive energy balance via increased palatable-food 'snacking.' These effects suggest alterations in reward-modulatory brain systems. We explored the effects of 10 days of sleep deprivation in rats on the expression of striatal opioid peptide (OP) genes that subserve food motivation and hedonic reward, and compared effects with those seen in hypothalamic energy balance-regulatory systems. Sleep-deprived (Sleep-Dep) rats were compared with yoked forced-locomotion apparatus controls (App-Controls), food-restricted rats (Food-Restrict), and unmanipulated controls (Home-Cage). Detection of mRNA levels with in situ hybridization revealed a subregion-specific upregulation of striatal preproenkephalin and prodynorhin gene expression in the Sleep-Dep group relative to all other groups. Neuropeptide Y (NPY) gene expression in the hippocampal dentate gyrus and throughout neocortex was also robustly upregulated selectively in the Sleep-Dep group. In contrast, parallel gene expression changes were observed in the Sleep-Dep and Food-Restrict groups in hypothalamic energy-sensing systems (arcuate nucleus NPY was upregulated, and cocaine- and amphetamine-regulated transcript was downregulated), in alignment with leptin suppression in both groups. Together, these results reveal a novel set of sleep deprivation-induced transcriptional changes in reward-modulatory peptide systems, which are dissociable from the energy-balance perturbations of sleep loss or the potentially stressful effects of the forced-locomotion procedure. The recruitment of telencephalic food-reward systems may provide a feeding drive highly resistant to feedback control, which could engender obesity through the enhancement of palatable feeding. Topics: Animals; Body Weight; Eating; Enkephalins; Fasting; Insulin; Leptin; Male; Neostriatum; Nerve Tissue Proteins; Neuroimaging; Neuropeptide Y; Opioid Peptides; Protein Precursors; Rats; Rats, Sprague-Dawley; Reward; Sleep Deprivation; Up-Regulation | 2013 |
Diminished leptin signaling can alter circadian rhythm of metabolic activity and feeding.
Leptin, a hormone mainly produced by fat cells, shows cell-specific effects to regulate feeding and metabolic activities. We propose that an important feature of metabolic dysregulation resulting in obesity is the loss of the circadian rhythm of biopotentials. This was tested in the pan-leptin receptor knockout (POKO) mice newly generated in our laboratory. In the POKO mice, leptin no longer induced pSTAT-3 signaling after intracerebroventricular injection. Three basic phenotypes were observed: the heterozygotes had similar weight and adiposity as the wild-type (WT) mice (>60% of the mice); the homozygotes were either fatter (∼30%), or rarely leaner (<5%) than the WT mice. By early adulthood, the POKO mice had higher average body weight and adiposity than their respective same-sex WT littermate controls, and this was consistent among different batches. The homozygote fat POKO showed significant reduction of midline estimating statistic of rhythm of circadian parameters, and shifts of ultradian rhythms. The blunted circadian rhythm of these extremely obese POKO mice was also seen in their physical inactivity, longer feeding bouts, and higher food intake. The extent of obesity correlated with the blunted circadian amplitude, accumulative metabolic and locomotor activities, and the severity of hyperphagia. This contrasts with the heterozygote POKO mice which showed little obesity and metabolic disturbance, and only subtle changes of the circadian rhythm of metabolic activity without alterations in feeding behavior. The results provide a novel aspect of leptin resistance, almost manifesting as an "all or none" phenomenon. Topics: Adiposity; Animals; Body Weight; Circadian Rhythm; Dietary Fats; Eating; Feeding Behavior; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Receptors, Leptin; Signal Transduction; Thinness | 2013 |
A comparative study between nanoparticle-targeted therapeutics and bioconjugates as obesity medication.
Antiangiogenesis has been the focus of a new strategy for the treatment of obesity. However, little is known regarding the issue of whether targeting angiogenesis by nanoparticle-targeted therapeutic is advantageous or not in debugging the co-morbidity associated with diet-induced obesity (DIO) and the metabolic syndrome. We report herein on the positive effect of prohibitin (an adipose vascular marker)-targeted nanoparticle (PTNP) encapsulated in a proapoptotic peptide [(D)(KLAKLAK)₂, KLA] on DIO and dysfunctional adipose tissue, a major mediator of the metabolic syndrome, as evidenced by ectopic fat deposition. The systemic injection of DIO mice with a low dose of KLA-PTNP, rather than a bioconjugate composed of the same targeting peptide and KLA (Adipotide) resulted in a reduction in body weight, as evidenced by a significant decrease in serum leptin levels, in parallel with an antiobesity effect on dysfunctional adipose cells, including adipocytes and macrophages. In addition, the KLA-PTNP treatment resulted in a reduction in ectopic fat deposits in liver and muscle with the lipolytic action of elevated serum adiponectin, with no detectable hepatoxicity. Notably, drug delivery via PTNP that had accumulated in obese fat via the enhanced permeability and retention effect was enhanced by multivalent active targeting and cytoplasmic delivery into adipose endothelial cells via escaping from endosomes/lysosomes. Thus, vascular-targeted nanotherapy has the potential to contribute to the control of adipose function and ectopic fat deposition associated with obesity and the metabolic syndrome. Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Intercellular Signaling Peptides and Proteins; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Nanoparticles; Obesity; Peptides; Peptidomimetics; Prohibitins; Repressor Proteins | 2013 |
Deletion of selenoprotein M leads to obesity without cognitive deficits.
Selenium is an essential trace element that is co-translationally incorporated into selenoproteins in the form of the 21st amino acid, selenocysteine. This class of proteins largely functions in oxidation-reduction reactions and is critically involved in maintaining proper redox balance essential to health. Selenoprotein M (SelM) is a thioredoxin-like endoplasmic reticulum-resident protein that is highly expressed in the brain and possesses neuroprotective properties. In this study, we first assessed the regional pattern of SelM expression in the mouse brain to provide insights into the potential functional implications of this protein in physiology and behavior. Next, we generated transgenic mice with a targeted deletion of the SelM gene and subjected them to a battery of neurobehavioral tests to evaluate motor coordination, locomotion, and cognitive function in comparison with wild-type controls. Finally, these mice were tested for several measures of metabolic function and body composition. Our results show that SelM knock-out (KO) mice display no deficits in measures of motor coordination and cognitive function but exhibit increased weight gain, elevated white adipose tissue deposition, and diminished hypothalamic leptin sensitivity. These findings suggest that SelM plays an important role in the regulation of body weight and energy metabolism. Topics: Animals; Behavior, Animal; Body Weight; Cognition; Energy Metabolism; Gene Deletion; Hypothalamus; Leptin; Locomotion; Mice; Mice, Knockout; Nerve Tissue Proteins; Obesity; Selenoproteins | 2013 |
Adipocytokine levels in women with anorexia nervosa. Relationship with weight restoration and disease duration.
Starvation-induced depletion of fat stores in anorexia nervosa (AN) is known to be accompanied by alterations in some circulating adipocytokines. We analyzed a panel of circulating adipocytokines in women with AN compared with normal-weight controls and their relation with the disease duration and weight restoration.. We analyzed circulating adipocytokine levels in 28 patients with AN and in 33 normal-weight controls who were eating healthily. We determined by enzyme-linked immunosorbent assay the circulating levels of total and high molecular weight (HMW) adiponectin, lipocalin-2 (LCN2), leptin, tumor necrosis factor receptor-II (TNFRII), interleukin-6 (IL6), adipocyte fatty acid binding protein-4 (FABP4), ghrelin, and resistin.. The two circulating forms of adiponectin are higher in AN women compared with controls. Both total and HMW adiponectin related negatively to the duration of the disease (r = -0.372, p = 0.033; r = -0.450, p = 0.038, respectively). Furthermore, the lipid binding-proteins LCN2 and FABP4 are lower in AN compared to the control group. Finally, leptin levels are lower in AN against controls and correlated positively with disease duration (r = 0.537, p = 0.007). Resistin, ghrelin, TNFRII, and IL6 have similar values in both groups, although TNFRII and ghrelin related negatively to body mass index variation at the end of treatment (r = -0.456, p = 0.039; r = -0.536, p = 0.015, respectively).. These results suggest there is a need to investigate if changes in adipocytokine levels could serve as weight restoration biomarkers. Further studies are warranted to elucidate the specific role of these molecules in the timing of weight restoration. Topics: Adipokines; Adiponectin; Adult; Anorexia Nervosa; Biomarkers; Body Mass Index; Body Weight; Case-Control Studies; Fatty Acid-Binding Proteins; Female; Ghrelin; Humans; Interview, Psychological; Leptin; Resistin; Risk Assessment; Spain | 2013 |
Alteration of sweet taste in high-fat diet induced obese rats after 4 weeks treatment with exenatide.
Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is effective in inducing weight loss. The exact mechanisms are not fully understood. Reduced appetite and food intake may play important roles. Sweet taste contributes to food palatability, which promotes appetite. Interestingly, GLP-1 and its receptor are expressed in the taste buds of rodents and their interaction has an effect on mediating sweet taste sensitivity. Our aim was to investigate whether sweet taste will be changed after long term treatment with exenatide. The results showed that high-fat diet induced obese rats (HF-C) presented metabolic disorders in food intake, body weight, blood glucose and lipid metabolism compared with long term exenatide treated obese rats (EX) and normal chow fed control rats (NC). Meanwhile, greater preference for sweet taste was observed in HF-C rats but not in EX rats. Compared with NC rats, brain activities induced by sweet taste stimulation were stronger in HF-C rats, however these stronger activities were not found in EX rats. We further found reduced sweet taste receptor T1R3 in circumvallte taste buds of HF-C rats, while GLP-1 was increased. Besides, serum leptin was evaluated in HF-C rats with decreased leptin receptor expressed in taste buds. These changes were not observed in EX rats, which suggest them to be the underlying hormone and molecular mechanisms responsible for alterations in sweet taste of HF-C rats and EX rats. In summary, our results suggest that long term treatment with exenatide could benefit dietary obese rats partially by reversing sweet taste changes. Topics: Animals; Blood Glucose; Body Weight; Choice Behavior; Diet, High-Fat; Drug Administration Schedule; Eating; Exenatide; Gene Expression; Glucagon-Like Peptide 1; Hypoglycemic Agents; Leptin; Lipid Metabolism; Male; Obesity; Peptides; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Taste; Taste Buds; Venoms | 2013 |
Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation.
Exposure to bisphenol A (BPA) is implicated in many aspects of metabolic disease in humans and experimental animals. We fed pregnant CD-1 mice BPA at doses ranging from 5 to 50,000μg/kg/day, spanning 10-fold below the reference dose to 10-fold above the currently predicted no adverse effect level (NOAEL). At BPA doses below the NOAEL that resulted in average unconjugated BPA between 2 and 200pg/ml in fetal serum (AUC0-24h), we observed significant effects in adult male offspring: an age-related change in food intake, an increase in body weight and liver weight, abdominal adipocyte mass, number and volume, and in serum leptin and insulin, but a decrease in serum adiponectin and in glucose tolerance. For most of these outcomes non-monotonic dose-response relationships were observed; the highest BPA dose did not produce a significant effect for any outcome. A 0.1-μg/kg/day dose of DES resulted in some but not all low-dose BPA outcomes. Topics: Abdominal Fat; Adipocytes; Adiponectin; Animals; Benzhydryl Compounds; Body Weight; Cell Count; Cell Size; Eating; Endocrine Disruptors; Female; Glucose; Glucose Tolerance Test; Insulin; Leptin; Male; Maternal-Fetal Exchange; Mice; Phenols; Pregnancy | 2013 |
Adult-onset obesity induced by early life overnutrition could be reversed by moderate caloric restriction.
Overnutrition during the suckling period (small litter, SL) results in the development of adult-onset obesity. Our aim was to investigate whether two levels of caloric restriction (CR) in the early postweaning period can reverse obese phenotype in SL rats. The normal litter (NL) had 12 pups/dam and SL had 3 male pups/dam from the postnatal day 3 until day 21. After weaning, rats consumed lab chow as indicated: 1) NL and SL groups were on ad libitum regimen up to day 140, 2) another SL group was pair-fed (SL/PF) to NL(∼14% reduction), 3) SL/PF/AL group was pair-fed up to day 94 and then switched to ad libitum feeding, 4) SL/CR group received 24% reduction (moderate CR) in food intake compared with SL, and 5) SL/CR/AL group was on 24% CR up to day 94 and then switched to ad libitum feeding. Pair-feeding reduced body weight gains and serum insulin and leptin levels compared with SL rats, but these parameters were restored to SL levels in the SL/PF/AL rats after switching to ad libitum feeding. Interestingly, the moderate CR normalized these parameters in SL/CR and SL/CR/AL rats compared with NL. The expression of neuropeptide Y, proopiomelanocortin, and leptin receptor returned to control levels in hypothalami from SL/CR and SL/CR/AL rats. These results indicate that appropriate manipulation of energy intake during the early postweaning period could lead to longer-lasting effects on the regulation of body weight homeostasis via reversal of the early preweaning programming effects on the hypothalamic appetite regulation mechanism. Topics: Animals; Animals, Suckling; Body Weight; Caloric Restriction; Female; Insulin; Lactation; Leptin; Male; Obesity; Overnutrition; Rats; Rats, Sprague-Dawley | 2013 |
The LIM domain only 4 protein is a metabolic responsive inhibitor of protein tyrosine phosphatase 1B that controls hypothalamic leptin signaling.
Protein tyrosine phosphatase 1B (PTP1B) counteracts leptin signaling and is a therapeutic target for obesity and diabetes. Here we found that LIM domain only 4 (LMO4) inhibits PTP1B activity by increasing the oxidized inactive form of PTP1B. Mice with neuronal ablation of LMO4 have elevated PTP1B activity and impaired hypothalamic leptin signaling, and a PTP1B inhibitor normalized PTP1B activity and restored leptin control of circulating insulin levels. LMO4 is palmitoylated at its C-terminal cysteine, and deletion of this residue prevented palmitoylation and retention of LMO4 at the endoplasmic reticulum and abolished its inhibitory effect on PTP1B. Importantly, LMO4 palmitoylation is sensitive to metabolic stress; mice challenged with a brief high-fat diet or acute intracerebroventricular infusion of saturated fatty acid had less palmitoylated LMO4, less oxidized PTP1B, and increased PTP1B activity in the hypothalamus. Thus, unleashed PTP1B activity attributable to loss of LMO4 palmitoylation may account for rapid loss of central leptin signaling after acute exposure to saturated fat. Topics: Adaptor Proteins, Signal Transducing; Adrenal Glands; Animals; Bacterial Proteins; Blood Pressure; Body Weight; Cell Line, Transformed; Cholestanes; Endoplasmic Reticulum; Glucose Tolerance Test; Homeostasis; Hypothalamus; In Vitro Techniques; Infusions, Intraventricular; Insulin Resistance; Leptin; LIM Domain Proteins; Luminescent Proteins; Mice; Mice, Knockout; Norepinephrine; Pancreas; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Signal Transduction; Spermine | 2013 |
Evidence that leptin-induced weight loss requires activation of both forebrain and hindbrain receptors.
Previous studies with chronic decerebrate rats and rats infused with leptin into the 4th ventricle suggest that hindbrain leptin receptors attenuate the catabolic effect of forebrain leptin receptor activation. To test this further, rats were fitted with both 3rd and 4th ventricle cannulae. They were infused for 12 days with different combinations of saline, low dose leptin or leptin receptor antagonist (leptin mutein protein). Infusion of 0.1 μg leptin/day into the 3rd ventricle or 0.6 μg leptin/day into the 4th ventricle had no significant effect on food intake, energy expenditure or body composition. Infusion of 2 μg mutein/day into either ventricle caused a small, but significant weight gain. When mutein was infused into one ventricle and leptin into the other, the rats lost weight irrespective of which combination was applied. Surprisingly, rats that received leptin infusions into both ventricles showed an initial hypophagia, no change in energy expenditure, but a 75% loss of carcass fat after 12 days. These data suggest that neuronal pathways activated by leptin receptors in either the forebrain or hindbrain modulate each other's effects. In normal conditions hindbrain leptin may attenuate the catabolic effect of forebrain leptin, but if activity in one area is blocked with mutein, then the catabolic response to leptin in the other ventricle is exaggerated. When receptors in both areas are activated there is an integration of response to produce negative energy balance. This may ensure that leptin causes a loss of fat only when leptin is elevated in both the CSF and periphery. Topics: Adiposity; Animals; Body Composition; Body Weight; Calorimetry; Eating; Fourth Ventricle; Injections, Intraventricular; Leptin; Male; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Rhombencephalon; Third Ventricle; Weight Loss | 2013 |
Relationship between obesity phenotypes and genetic determinants in a mouse model for juvenile obesity.
Obesity, a state of imbalance between lean mass and fat mass, is important for the etiology of diseases affected by the interplay of multiple genetic and environmental factors. Although genome-wide association studies have repeatedly associated genes with obesity and body weight, the mechanisms underlying the interaction between the muscle and adipose tissues remain unknown. Using 351 mice (at 10 wk of age) of an intercross population between Berlin Fat Mouse Inbred (BFMI) and C57BL/6NCrl (B6N) mice, we examined the causal relationships between genetic variations and multiple traits: body lean mass and fat mass, adipokines, and bone mineral density. Furthermore, evidence from structural equation modeling suggests causality among these traits. In the BFMI model, juvenile obesity affects lean mass and impairs bone mineral density via adipokines secreted from the white adipose tissues. While previous studies have indicated that lean mass has a causative effect on adiposity, in the Berlin Fat Mouse model that has been selected for juvenile obesity (at 9 wk of age) for >90 generations, however, the causality is switched from fat mass to lean mass. In addition, linkage studies and statistical modeling have indicated that quantitative trait loci on chromosomes 5 and 6 affect both lean mass and fat mass. These lines of evidence indicate that the muscle and adipose tissues interact with one another and the interaction is modulated by genetic variations that are shaped by selections. Experimental examinations are necessary to verify the biological role of the inferred causalities. Topics: Adiponectin; Adipose Tissue; Adiposity; Animals; Body Weight; Bone Density; Crosses, Genetic; Disease Models, Animal; Female; Genetic Association Studies; Genetic Linkage; Genetic Variation; Leptin; Male; Mice; Mice, Inbred C57BL; Muscles; Obesity; Phenotype; Quantitative Trait Loci | 2013 |
Maternal weight status, cord blood leptin and fetal growth: a prospective mother-child cohort study (Rhea study).
Leptin is an adipocyte-secreted hormone that regulates energy homeostasis, while its role in fetal programming remains poorly understood. We aimed to evaluate the effect of maternal weight status on cord blood leptin levels and their combined effect on fetal growth.. We included 638 mother-child pairs from the prospective mother-child cohort 'Rhea' study in Crete, Greece with singleton pregnancies, providing cord blood serum samples for leptin analysis and complete data on birth outcomes. Multivariable logistic and linear regression models were used adjusting for confounders. Generalised additive models were used to explore the form of the relationship between cord leptin and continuous birth outcomes.. Log cord leptin was positively associated with birthweight {β-coef: 176.5 [95% confidence interval (CI): 133.0, 220.0] }, ponderal index (β-coef: 1.0 [95% CI: 0.6, 1.4] ) and gestational age (β-coef: 0.7 [95% CI: 0.5, 0.8] ). Excessive weight gain during pregnancy was associated with a threefold increased risk for cord hyperleptinaemia {relative risk (RR): 3.0, [95% CI: 1.5, 6.3] }. Maternal pre-pregnancy overweight/obesity [body mass index (BMI) ≥25 kg/m(2) ] increased the risk of giving birth to a hyperleptinaemic neonate (RR: 2.1 [95% CI: 1.4, 3.2] and the effect of log leptin on birthweight (β-coef: 219.1 [95% CI: 152.3, 285.9] compared with women with a BMI <25 kg/m(2) (β-coef: 150.5 [95% CI: 93.1, 207.9].. Higher cord blood leptin levels are associated with increased size at birth and gestational age, while maternal pre-pregnancy BMI and weight gain during pregnancy represent significant indicators of cord blood leptin. Topics: Adult; Body Mass Index; Body Weight; Cohort Studies; Female; Fetal Blood; Fetal Development; Gestational Age; Greece; Humans; Leptin; Mothers; Pregnancy; Prospective Studies; Regression Analysis; Weight Gain | 2013 |
The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy.
Antiepileptic drugs may affect the endocrine system. We investigated the effects of valproic acid and topiramate on the levels of insulin, c-peptide and adipocytokines in pre-pubertal patients with idiopathic partial and generalized epilepsy.. Forty-one children with epilepsy were included. The patients were divided into two groups (valproic acid; n = 21, topiramate; n = 20). The weight, height, body mass index and homeostasis model assessment of insulin resistance (HOMA-IR) were recorded and insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin and resistin levels were determined at 0, 6 and 12 months of therapy.. In the valproate group, weight and height increased significantly. Seven of 21 patients were overweight at the end of one year. Leptin was higher in the overweight subgroup. Although insulin and HOMA-IR increased (p < 0.05), none of the patients showed hyperinsulinism or IR. Resistin had decreased at the 6th and 12th months (p < 0.05). In the topiramate group, some statistically nonsignificant changes were demonstrated.. The mechanisms behind valproate and topiramate-related weight control are still unclear, especially in children. Valproate and topiramate affect the weight, BMI, and insulin, leptin and adipocytokine levels in prepubertal children. We suggest that further studies including more patients with a long follow-up period are necessary to draw a firm conclusion regarding an association between the treatment with these drugs and the levels of leptin, insulin and adipocytokines. Topics: Adiponectin; Anticonvulsants; Body Mass Index; Body Weight; C-Peptide; Child; Epilepsy; Female; Fructose; Humans; Insulin; Leptin; Male; Neuropeptide Y; Nicotinamide Phosphoribosyltransferase; Resistin; Topiramate; Valproic Acid | 2013 |
Immature mice are more susceptible to the detrimental effects of high fat diet on cancellous bone in the distal femur.
With the increasing prevalence of obesity among children and adolescents, it is imperative to understand the implications of early diet-induced obesity on bone health. We hypothesized that cancellous bone of skeletally immature mice is more susceptible to the detrimental effects of a high fat diet (HFD) than mature mice, and that removing excess dietary fat will reverse these adverse effects. Skeletally immature (5weeks old) and mature (20weeks old) male C57BL/6J mice were fed either a HFD (60% kcal fat) or low fat diet (LFD; 10% kcal fat) for 12weeks, at which point, the trabecular bone structure in the distal femoral metaphysis and third lumbar vertebrae were evaluated by micro-computed tomography. The compressive strength of the vertebrae was also measured. In general, the HFD led to deteriorations in cancellous bone structure and compressive biomechanical properties in both age groups. The HFD-fed immature mice had a greater decrease in trabecular bone volume fraction (BVF) in the femoral metaphysis, compared to mature mice (p=0.017 by 2-way ANOVA). In the vertebrae, however, the HFD led to similar reductions in BVF and compressive strength in the two age groups. When mice on the HFD were switched to a LFD (HFD:LFD) for an additional 12weeks, the femoral metaphyseal BVF in immature mice showed no improvements, whereas the mature mice recovered their femoral metaphyseal BVF to that of age-matched lean controls. The vertebral BVF and compressive strength of HFD:LFD mouse bones, following diet correction, were equivalent to those of LFD:LFD mice in both age groups. These data suggest that femoral cancellous metaphyseal bone is more susceptible to the detrimental effects of HFD before skeletal maturity and is less able to recover after correcting the diet. Negative effects of HFD on vertebrae are less severe and can renormalize with LFD:LFD mice after diet correction, in both skeletally immature and mature animals. Topics: Animals; Blood Glucose; Body Weight; Diet, High-Fat; Fasting; Femur; Leptin; Male; Mice; Mice, Inbred C57BL; X-Ray Microtomography | 2013 |
High fat diet induces hypermethylation of the hypothalamic Pomc promoter and obesity in post-weaning rats.
Impaired response of the brain to the leptin signal leads to a persisting dysregulation of food intake and energy balance. High plasma leptin or insulin should activate proopiomelanocortin (POMC), the precursor of the anorexigenic neuropeptide α-melanocyte-stimulating hormone (α-MSH) in the hypothalamic arcuate nucleus (ARC). Nevertheless, in obesity, this signal transduction pathway might be impaired. In this study we investigated whether chronic high fat (HF) diet consumption from post-weaning to adulthood increases CpG methylation of the Pomc promoter. The hypothesis that this would disrupt the essential binding of the transcription factor Sp1 to the Pomc promoter was tested. Male rats were raised from postnatal day 21 till 90 on either HF or standard diet. As a result HF fed rats were significantly heavier, with high leptin and insulin levels in their plasma but almost no changes in ARC mRNA expression levels of Pomc. The Pomc promoter area in the HF-treated rats was found to be hypermethylated. Furthermore, there was a direct correlation in individual rats between CpG methylation at specific sites that affect Sp1 binding and plasma leptin levels and/or body weight. Although, as expected the HF diet resulted in up-regulation of Sp1, the binding of Sp1 to the hypermethylated Pomc promoter was significantly reduced. Therefore, we suggest that hypermethylation on the promoter region of the Pomc gene can emerge at post-lactation periods and interfere with transcription factor binding, thus blocking the effects of high leptin levels, leading to obesity. Topics: Animals; Blotting, Western; Body Weight; Chromatin Immunoprecipitation; CpG Islands; Diet, High-Fat; DNA Methylation; Eating; Insulin; Leptin; Male; Obesity; Pro-Opiomelanocortin; Promoter Regions, Genetic; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sp1 Transcription Factor | 2013 |
Loss of the anorexic response to systemic 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside administration despite reducing hypothalamic AMP-activated protein kinase phosphorylation in insulin-deficient rats.
This study tested whether chronic systemic administration of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) could attenuate hyperphagia, reduce lean and fat mass losses, and improve whole-body energy homeostasis in insulin-deficient rats. Male Wistar rats were first rendered diabetic through streptozotocin (STZ) administration and then intraperitoneally injected with AICAR for 7 consecutive days. Food and water intake, ambulatory activity, and energy expenditure were assessed at the end of the AICAR-treatment period. Blood was collected for circulating leptin measurement and the hypothalami were extracted for the determination of suppressor of cytokine signaling 3 (SOCS3) content, as well as the content and phosphorylation of AMP-kinase (AMPK), acetyl-CoA carboxylase (ACC), and the signal transducer and activator of transcription 3 (STAT3). Rats were thoroughly dissected for adiposity and lean body mass (LBM) determinations. In non-diabetic rats, despite reducing adiposity, AICAR increased (∼1.7-fold) circulating leptin and reduced hypothalamic SOCS3 content and food intake by 67% and 25%, respectively. The anorexic effect of AICAR was lost in diabetic rats, even though hypothalamic AMPK and ACC phosphorylation markedly decreased in these animals. Importantly, hypothalamic SOCS3 and STAT3 levels remained elevated and reduced, respectively, after treatment of insulin-deficient rats with AICAR. Diabetic rats were lethargic and displayed marked losses of fat and LBM. AICAR treatment increased ambulatory activity and whole-body energy expenditure while also attenuating diabetes-induced fat and LBM losses. In conclusion, AICAR did not reverse hyperphagia, but it promoted anti-catabolic effects on skeletal muscle and fat, enhanced spontaneous physical activity, and improved the ability of rats to cope with the diabetes-induced dysfunctional alterations in glucose metabolism and whole-body energy homeostasis. Topics: Acetyl-CoA Carboxylase; Adipose Tissue; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Appetite Depressants; Body Composition; Body Weight; Diabetes Mellitus; Drinking; Energy Metabolism; Hypothalamus; Insulin; Leptin; Male; Muscle, Skeletal; Phosphorylation; Rats; Rats, Wistar; Ribonucleosides; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins | 2013 |
The impact of weight loss on the 24-h profile of circulating peptide YY and its association with 24-h ghrelin in normal weight premenopausal women.
Peptide YY (PYY) and ghrelin exhibit a reciprocal association and antagonistic physiological effects in the peripheral circulation. Research has yet to clarify the effect of weight loss on the 24h profile of PYY or its association to 24h ghrelin. We sought to determine if diet- and exercise-induced weight loss affects the 24h profile of PYY and its association with 24h ghrelin in normal weight, premenopausal women. Participants (n = 13) were assessed at baseline (BL) and after a 3-month diet and exercise intervention (post). Blood samples obtained q10 min for 24h were assayed for total PYY and total ghrelin q60 min from 0800 to 1000 h and 2000 to 0800 h and q20 min from 1000 to 2000 h. The ghrelin/PYY ratio was used as an index of hormonal exposure. Statistical analyses included paired t-tests and linear mixed effects modeling. Body weight (-1.85 ± 0.67 kg; p = 0.02), and body fat (-2.53 ± 0.83%; p = 0.01) decreased from BL to post. Ghrelin AUC (5252 ± 2177 pg/ml/24h; p=0.03), 24h mean (216 ± 90 pg/ml; p = 0.03) and peak (300 ± 134 pg/ml; p = 0.047) increased from BL to post. No change occurred in PYY AUC (88.2 ± 163.7 pg/ml; p = 0.60), 24h mean (4.8 ± 6.9 pg/ml; p = 0.50) or peak (3.6 ± 6.4 pg/ml; p = 0.58). The 24h association between PYY and ghrelin at baseline (p = 0.04) was weakened at post (p = 0.14); however, the ghrelin/PYY lunch ratio increased (p = 0.01) indicating the potential for ghrelin predominance over PYY in the circulation. PYY and ghrelin are reciprocally associated during a period of weight stability, but not following weight loss. An "uncoupling" may have occurred, particularly at lunch, due to factors that modulate ghrelin in response to weight loss. Topics: Adult; Body Composition; Body Weight; Female; Ghrelin; Humans; Leptin; Peptide YY; Premenopause; Weight Loss; Young Adult | 2013 |
Day-to-day variation in food intake and energy expenditure in healthy women: the Dietitian II Study.
Because day-to-day food intake varies, we tested the hypothesis that ad libitum food intake and energy expenditure show corrective responses over periods of 1 to 10 days in healthy young women. Food intake and accelerometry measurements were collected daily for 17 days in 15 young women. Total daily energy expenditure (TDEE) using doubly labeled water was also measured. The daily deviations in macronutrient and energy intake and energy expenditure from the average values were compared with the deviations observed over succeeding intervals to estimate the corrective responses. The intraindividual coefficients of variation for energy intake averaged ±25%, ranging from 16% to 34%. TDEE had a coefficient of variation of 8.3%, and accelerometry had a coefficient of variation of 8.4% (range=4.6% to 16.4%). Energy expenditure by accelerometry (2,087±191 kcal/day) was not significantly different from TDEE (2,128±177 kcal/day), but reported daily energy intake was 20.4% lower (1,693±276 kcal/day). There were significant corrective responses in energy from fat and total energy intake. This occurred from Days 3 to 6, with a peak at Day 5 that disappeared when data were randomized within each subject. Human beings show corrective responses to deviations from average energy and macronutrient intakes with a lag time of 3 to 6 days, but not 1 to 2 days. These corrective responses are likely to play a role in bringing about weight stability. Topics: Adult; Body Composition; Body Mass Index; Body Weight; Diet; Dietetics; Eating; Energy Intake; Energy Metabolism; Female; Humans; Leptin; Nutritionists | 2013 |
Deficiency of p62/Sequestosome 1 causes hyperphagia due to leptin resistance in the brain.
The cytoplasmic regulatory protein p62 (Sequestosome 1/A170) is known to modulate various receptor-mediated intracellular signaling pathways. p62 deficiency was shown to result in mature-onset obesity in mice, but the mechanisms underlying this abnormality remained unclear. Here we report that hyperphagia due to central leptin resistance is the cause of obesity in p62(-/-) mice. We found that these mice show hyperphagia. Restriction of food to the amount eaten by wild-type mice prevented excess body weight gain and fat accumulation, suggesting that overfeeding is the primary cause of obesity in p62(-/-) mice. Brain-specific p62 deficiency caused mature-onset obesity to the same extent as in p62(-/-) mice, further supporting a neuronal mechanism as the major cause of obesity in these mice. Immunohistochemical analysis revealed that p62 is highly expressed in hypothalamic neurons, including POMC neurons in the arcuate nucleus. Central leptin resistance was observed even in young preobese p62(-/-) mice. We found a defect in intracellular distribution of the transcription factor Stat3, which is essential for the action of leptin, in p62(-/-) mice. These results indicate that brain p62 plays an important role in bodyweight control by modulating the central leptin-signaling pathway and that lack of p62 in the brain causes leptin resistance, leading to hyperphagia. Thus, p62 could be a clinical target for treating obesity and metabolic syndrome. Topics: Animals; Body Weight; Brain; Eating; Embryo, Mammalian; Food Deprivation; Gene Expression Regulation; Hyperphagia; In Vitro Techniques; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nestin; Neuropeptide Y; Oxygen Consumption; Pro-Opiomelanocortin; Receptors, Leptin; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factor TFIIH; Transcription Factors | 2013 |
Effects of acute intermittent hypoxia on energy balance and hypothalamic feeding pathways.
This study was done to investigate the effects of acute intermittent hypoxia (IH) on metabolic factors associated with energy balance and body weight, and on hypothalamic satiety-inducing pathways. Adult male Sprague-Dawley rats were exposed to either 8h IH or normoxic control conditions. Food intake, locomotion and body weights were examined after IH. Additionally, plasma levels of leptin, adiponectin corticosterone, insulin and blood glucose were measured following exposure to IH. Furthermore, adipose tissue was removed and analyzed for leptin and adiponectin content. Finally, the hypothalamic arcuate nucleus (ARC) was assessed for alterations in protein signaling associated with satiety. IH reduced body weight, food intake and active cycle locomotion without altering adipose tissue mass. Leptin protein content was reduced while adiponectin content was elevated in adipose tissue after IH. Plasma concentration of leptin was significantly increased while adiponectin decreased after IH. No changes were found in plasma corticosterone, insulin and blood glucose. In ARC, phosphorylation of signal transducer and activator of transcription-3 and pro-opiomelanocortin (POMC) expression were elevated. In addition, POMC-expressing neurons were activated as determined by immediate early gene FRA-1/2 expression. Finally, ERK1/2 and its phosphorylation were reduced in response to IH. These data suggest that IH induces significant alterations to body energy balance through changes in the secretion of leptin which exert effects on satiety-inducing pathways within the hypothalamus. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Disease Models, Animal; Drinking; Energy Metabolism; Feeding Behavior; Hypothalamus; Hypoxia; Leptin; Locomotion; Male; Nerve Tissue Proteins; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Signal Transduction; Transcription Factors | 2013 |
Individual genetic variations related to satiety and appetite control increase risk of obesity in preschool-age children in the STRONG kids program.
The burden of the childhood obesity epidemic is well recognized; nevertheless, the genetic markers and gene-environment interactions associated with the development of common obesity are still unknown. In this study, candidate genes associated to satiety and appetite control pathways with obesity-related traits were tested in Caucasian preschoolers from the STRONG Kids project.. Eight genetic variants in genes related to obesity (BDNF, LEPR, FTO, PCSK1, POMC, TUB, LEP, and MC4R) were genotyped in 128 children from the STRONG Kids project (mean age 39.7 months). Data were analyzed for individual associations and to test for genetic predisposition scores (GPSs) with body mass index (BMI) and anthropometric traits (Z-scores, e.g. height-for-age Z-score, HAZ). Covariates included age, sex, and breastfeeding (BF) duration.. Obesity and overweight prevalence was 6.3 and 19.5%, respectively, according to age- and sex-specific BMI percentiles. Individual genetic associations of MC4R and LEPR markers with HAZ were strengthened when BF duration was included as a covariate. Our GPSs show that, as the number of risk alleles increased, the risk of higher BMI and HAZ also increased. Overall, the GPSs assembled were able to explain 2-3% of the variability in BMI and HAZ phenotypes.. Genetic associations with common obesity-related phenotypes were found in the STRONG Kids project. GPSs assembled for specific candidate genes were associated with BMI and HAZ phenotypes. Topics: Alleles; Appetite; Body Height; Body Weight; Child, Preschool; Genetic Predisposition to Disease; Genetic Variation; Humans; Leptin; Melanocortins; Pediatric Obesity; Phenotype; Risk Factors; Satiety Response; Signal Transduction | 2013 |
Honeysuckle anthocyanin supplementation prevents diet-induced obesity in C57BL/6 mice.
This study investigated the anti-obesity effects of honeysuckle anthocyanins (HA) in a high fat diet-induced mouse model. The mice were initially fed with a low-fat diet (LFD) or high-fat diet (HFD) for 8 weeks. After that, the HFD-fed mice were divided into five groups, with 12 mice in each group, including a HFD group, a HFD plus Orlistat group, and three HFD plus HA (at a dose of 50, 100, or 200 mg kg(-1)) groups, for another 8-week experiment. HA at 100 or 200 mg kg(-1) can suppress body weight gain, reduce serum and liver lipid profiles, ameliorate impaired hepatic function, and significantly increase serum adiponectin concentration while decreasing serum insulin and leptin levels. These results suggest that the anti-obesity effect of HA might be through the blockage of lipid accumulation. Topics: Animals; Anthocyanins; Anti-Obesity Agents; Body Weight; Dietary Supplements; Fruit; Humans; Insulin; Leptin; Lipids; Liver; Lonicera; Male; Mice; Mice, Inbred C57BL; Obesity; Plant Extracts | 2013 |
Reconstruction of the drive underlying food intake and its control by leptin and dieting.
The intake of food and the expenditure of calories is modelled by a system of differential equations. The state variables are the amount of calories stored in adipose tissue and the level of plasma leptin. The model has as input a drive that controls the intake of food. This drive consists of a collective of physiological and psychological incentives to eat or to stop eating. An individual based approach is presented by which the parameters of the system can be set using data of a subject. The method of analysis is fully worked out using weight data of two persons. The model is prone to extensions by transferring incentives being part of the input to the collection of state variables. Topics: Adult; Body Weight; Diet; Eating; Female; Humans; Leptin | 2013 |
Influence of abnormally high leptin levels during pregnancy on metabolic phenotypes in progeny mice.
Maternal obesity increases the risk of obesity in offspring, and obesity is accompanied by an increase in blood leptin levels. The "yellow" mutation at the mouse agouti locus (A(y)) increases blood leptin levels in C57BL preobese pregnant mice without affecting other metabolic characteristics. We investigated the influence of the A(y) mutation or leptin injection at the end of pregnancy in C57BL mice on metabolic phenotypes and the susceptibility to diet-induced obesity (DIO) in offspring. In both C57BL-A(y) and leptin-treated mice, the maternal effect was more pronounced in male offspring. Compared with males born to control mothers, males born to A(y) mothers displayed equal food intake (FI) but decreased body weight (BW) gain after weaning, equal glucose tolerance, and enhanced FI-to-BW ratios on the standard diet but the same FI and BW on the high-fat diet. Males born to A(y) mothers were less responsive to the anorectic effect of exogenous leptin and less resistant to fasting (were not hyperphagic and gained less weight during refeeding after food deprivation) compared with males born to control mothers. However, all progeny displayed equal hypothalamic expression of Agouti gene-related protein (AgRP), neuropeptide Y (NPY), and proopiomelanocortin (POMC) and equal plasma leptin and glucose levels after food deprivation. Leptin injections in C57BL mice on day 17 of pregnancy decreased BW in both male and female offspring but inhibited FI and DIO only in male offspring. Our results show that hyperleptinemia during pregnancy has sex-specific long-term effects on energy balance regulation in progeny and does not predispose offspring to developing obesity. Topics: Agouti-Related Protein; Animals; Body Composition; Body Weight; Eating; Energy Metabolism; Female; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Phenotype; Pregnancy; Pregnancy Complications; Pro-Opiomelanocortin; Sex Factors; Weight Gain | 2013 |
Common variant of FTO gene, rs9939609, and obesity in Pakistani females.
Numerous studies confirmed the association of FTO (fat mass and obesity associated gene) common variant, rs9939609, with obesity in European populations. However, studies in Asian populations revealed conflicting results. We examined the association of rs9939609 variant of FTO gene with obesity and obesity-related anthropometric and metabolic parameters in Pakistani population. Body weight, height, waist circumference, hip circumference, and blood pressure (BP) were measured. BMI and waist-to-hip ratio (WHR) were calculated. Levels of fasting blood glucose (FBG), insulin, leptin, and leptin receptors were measured by enzyme linked immunosorbent assay (ELISA), and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The results showed association of FTO gene, rs9939609, with obesity in females (>18 years of age). FTO minor allele increased the risk of obesity by 2.8 times (95% CI = 1.3-6.0) in females. This allele showed association with body weight, BMI, waist circumference, hip circumference, WHR, BP, plasma FBG levels, HOMA-IR, plasma insulin levels, and plasma leptin levels. In conclusion, FTO gene, rs9939609, is associated with BMI and risk of obesity in adult Pakistani females. Association of rs9939609 variant with higher FBG, plasma insulin, and leptin levels indicates that this polymorphism may disturb the metabolism in adult females and predispose them to obesity and type 2 diabetes. However, the above-mentioned findings were not seen in children or males. Topics: Adolescent; Adult; Alleles; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Blood Glucose; Body Mass Index; Body Weight; Child; Child, Preschool; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Pakistan; Proteins | 2013 |
Inhibition of olanzapine-induced weight gain by the retinoid analog AM-80.
Weight gain and metabolic abnormalities are common side effects of antipsychotic treatment. Retinoids have been suggested as promising substances to suppress obesity. This study has investigated the effects of a retinoid agonist AM-80 on olanzapine-induced weight gain and metabolic changes in rats.. Female Sprague-Dawley rats (7 weeks) were treated with AM-80 (1 mg/kg/day, subcutaneously) and/or olanzapine (4 mg/kg/day, intraperitoneally) for 21 days. Body weight and food/water intake were measured daily. The open field (OFT) and prepulse inhibition (PPI) tests were done on days 18 and 21, respectively. Animals were sacrificed on day 22 to measure weight of adipose tissues and serum levels of adiponectin and leptin levels.. Olanzapine significantly increased body weight, food/water intake and the mass of inguinal adipose tissue (IAT) compared to vehicle-treated rats. AM-80 demonstrated significant inhibition of weight gain. No significant effect of olanzapine or AM-80 was found on behaviors or serum adiponectin/leptin levels.. These findings suggests that AM-80 is a potential therapeutic agent to attenuate weight gain and metabolic side effects associated with olanzapine. Topics: Adiponectin; Adiposity; Animals; Antipsychotic Agents; Benzoates; Benzodiazepines; Body Weight; Drinking; Eating; Female; Leptin; Motor Activity; Olanzapine; Rats; Retinoids; Sensory Gating; Tetrahydronaphthalenes; Weight Gain | 2013 |
Blueberry and mulberry juice prevent obesity development in C57BL/6 mice.
To establish whether blueberry (Vaccinium ashei) and mulberry (Morus australis Poir) juice, anthocyanin rich fruit juice, may help counteract obesity.. And Methods: Four-week-old C57BL/6 mice were fed a high-fat diet (HFD) with or without blueberry and mulberry juice for 12 weeks. Body weight, serum and hepatic lipids, liver and adipose tissues morphology, insulin and leptin were assessed.. Mice fed HFD exhibited increased body weight, insulin resistance, serum and hepatic lipids. In comparison, blueberry and mulberry juice inhibited body weight gain, decreased the serum cholesterol, reduced the resistance to insulin, attenuated lipid accumulation and decreased the leptin secretin.. These results indicate that blueberry and mulberry juice may help counteract obesity. Topics: Adiponectin; Adipose Tissue, White; Animals; Anthocyanins; Beverages; Blueberry Plants; Body Weight; Diet, High-Fat; Drinking; Insulin; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Morus; Obesity | 2013 |
Dietary zinc deficiency exaggerates ethanol-induced liver injury in mice: involvement of intrahepatic and extrahepatic factors.
Clinical studies have demonstrated that alcoholics have a lower dietary zinc intake compared to health controls. The present study was undertaken to determine the interaction between dietary zinc deficiency and ethanol consumption in the pathogenesis of alcoholic liver disease. C57BL/6N mice were subjected to 8-week feeding of 4 experimental liquid diets: (1) zinc adequate diet, (2) zinc adequate diet plus ethanol, (3) zinc deficient diet, and (4) zinc deficient diet plus ethanol. Ethanol exposure with adequate dietary zinc resulted in liver damage as indicated by elevated plasma alanine aminotransferase level and increased hepatic lipid accumulation and inflammatory cell infiltration. Dietary zinc deficiency alone increased hepatic lipid contents, but did not induce hepatic inflammation. Dietary zinc deficiency showed synergistic effects on ethanol-induced liver damage. Dietary zinc deficiency exaggerated ethanol effects on hepatic genes related to lipid metabolism and inflammatory response. Dietary zinc deficiency worsened ethanol-induced imbalance between hepatic pro-oxidant and antioxidant enzymes and hepatic expression of cell death receptors. Dietary zinc deficiency exaggerated ethanol-induced reduction of plasma leptin, although it did not affect ethanol-induced reduction of white adipose tissue mass. Dietary zinc deficiency also deteriorated ethanol-induced gut permeability increase and plasma endotoxin elevation. These results demonstrate, for the first time, that dietary zinc deficiency is a risk factor in alcoholic liver disease, and multiple intrahepatic and extrahepatic factors may mediate the detrimental effects of zinc deficiency. Topics: Adipose Tissue, White; Animals; Biomarkers; Body Weight; Cytokines; Diet; Endotoxemia; Ethanol; Fatty Liver; Gene Expression Regulation; Inflammation Mediators; Intestinal Mucosa; Intestines; Leptin; Lipid Metabolism; Lipid Peroxidation; Lipids; Liver; Liver Diseases, Alcoholic; Male; Mice; Neutrophil Infiltration; Organ Size; Oxidative Stress; Permeability; Receptors, Death Domain; Zinc | 2013 |
Leptin increases blood pressure and markers of endothelial activation during pregnancy in rats.
Raised leptin levels have been reported in the placentae and serum of women with elevated blood pressure and proteinuria during pregnancy. The role of leptin in this however remains unknown. This study investigates the effect of leptin administration on systolic blood pressure (SBP) and proteinuria and serum markers of endothelial activation during pregnancy in Sprague Dawley rats. From day 1 of pregnancy, 24 rats were randomised into those given either saline (group 1) or leptin at 60 or 120 μ g/kg/body weight/day (groups 2 and 3 resp.). SBP was measured every 5 days and 24-h urinary protein was measured at days 0 and 20 of pregnancy. Animals were euthanised on day 20 of pregnancy, and serum was collected for estimation of E-selectin and ICAM-1. Compared to group 1, SBP during the latter part of the pregnancy was significantly higher in the leptin-treated group (P < 0.01). Urinary protein excretion, serum E-selectin, and ICAM-1 were significantly higher in leptin-treated rats (P < 0.05). It seems that leptin administration to normotensive Sprague Dawley rats during pregnancy significantly increases SBP, urinary protein excretion, and markers of endothelial activation. However, further studies are required to examine the underlying mechanism responsible for this and its relevance to preeclampsia in humans. Topics: Animals; Biomarkers; Blood Pressure; Body Weight; Drinking Behavior; E-Selectin; Endothelial Cells; Female; Intercellular Adhesion Molecule-1; Leptin; Pregnancy; Proteinuria; Rats; Rats, Sprague-Dawley; Systole | 2013 |
Maternal malnutrition and offspring sex determine juvenile obesity and metabolic disorders in a swine model of leptin resistance.
The present study aimed to determine, in a swine model of leptin resistance, the effects of type and timing of maternal malnutrition on growth patterns, adiposity and metabolic features of the progeny when exposed to an obesogenic diet during their juvenile development and possible concomitant effects of the offspring sex. Thus, four groups were considered. A CONTROL group involved pigs born from sows fed with a diet fulfilling their daily maintenance requirements for pregnancy. The treated groups involved the progeny of females fed with the same diet but fulfilling either 160% or 50% of pregnancy requirements during the entire gestation (OVERFED and UNDERFED, respectively) or 100% of requirements until Day 35 of pregnancy and 50% of such amount from Day 36 onwards (LATE-UNDERFED). OVERFED and UNDERFED offspring were more prone to higher corpulence and fat deposition from early postnatal stages, during breast-feeding; adiposity increased significantly when exposed to obesogenic diets, especially in females. The effects of sex were even more remarkable in LATE-UNDERFED offspring, which had similar corpulence to CONTROL piglets; however, females showed a clear predisposition to obesity. Furthermore, the three groups of pigs with maternal malnutrition showed evidences of metabolic syndrome and, in the case of individuals born from OVERFED sows, even of insulin resistance and the prodrome of type-2 diabetes. These findings support the main role of early nutritional programming in the current rise of obesity and associated diseases in ethnics with leptin resistance. Topics: Adiposity; Animals; Animals, Newborn; Body Weight; Diet; Female; Insulin Resistance; Lactation; Leptin; Male; Malnutrition; Metabolic Diseases; Obesity; Overnutrition; Pregnancy; Prenatal Exposure Delayed Effects; Swine | 2013 |
Co-agonist of glucagon and GLP-1 reduces cholesterol and improves insulin sensitivity independent of its effect on appetite and body weight in diet-induced obese C57 mice.
Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors reduce body weight without inducing hyperglycemia in rodents. However, the effect of a co-agonist on insulin sensitivity and lipid metabolism has not been thoroughly assessed. Diet-induced obese (DIO) mice received 0.5 mg·kg(-1) of co-agonist or 2.5 mg·kg(-1) of glucagon or 8 μg·kg(-1) of exendin-4 by subcutaneous route, twice daily, for 28 days. A separate group of mice was pair-fed to the co-agonist-treated group for 28 days. Co-agonist treatment reduced food intake and reduced body weight up to 28 days. In addition, it reduced leptin levels and increased fibroblast growth factor 21 (FGF21) levels in plasma, when compared with control and pair-fed groups. Co-agonist treatment decreased triglyceride levels in serum and liver and reduced serum cholesterol, mainly due to reduction in low-density lipoprotein (LDL) cholesterol. These changes were not seen with pair-fed controls. Co-agonist treatment improved glucose tolerance and increased insulin sensitivity, as observed during glucose and insulin-tolerance test, hyperinsulinemic clamp, and reduced gluconeogenesis, as observed in pyruvate-tolerance test. The effects on insulin sensitivity and lipid levels are mostly independent of the food intake or body weight lowering effect of the co-agonist. Topics: Animals; Appetite; Body Weight; Cholesterol; Cholesterol, LDL; Diet; Eating; Fibroblast Growth Factors; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Gluconeogenesis; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Receptors, Glucagon; Triglycerides | 2013 |
A high-fat diet enriched with low omega-6 to omega-3 fatty acid ratio reduced fat cellularity and plasma leptin concentration in Sprague-Dawley rats.
This study was aimed to investigate the effects of dietary fatty acids on the accretion pattern of major fat pads, inguinal fat cellularity, and their relation with plasma leptin concentration. Forty Sprague-Dawley rats were randomly assigned into four groups and received the following diets for 22 weeks: (1) standard rat chow diet (CTRL), (2) CTRL + 10% (w/w) butter (HFAR), (3) CTRL + 3.33% (w/w) menhaden fish oil + 6.67% (w/w) soybean oil (MFAR), and (4) CTRL + 6.67% (w/w) menhaden fish oil + 3.33% (w/w) soybean oil (LFAR). Inguinal fat cellularity and plasma leptin concentration were measured in this study. Results for inguinal fat cellularity showed that the mean adipocyte number for the MFAR (9.2 ∗ 10⁵ ± 3.6) and LFAR (8.5 ∗ 10⁵ ± 5.1) groups was significantly higher (P < 0.05) than the rest, while the mean adipocyte diameter of HFAR group was larger (P < 0.05) (46.2 ± 2.8) than the rest. The plasma leptin concentration in the HFAR group was higher (P < 0.05) (3.22 ± 0.32 ng/mL), than the other groups. The higher inguinal fat cellularity clearly indicated the ability of the polyunsaturated fatty acids (PUFA) and butter supplemented diets to induce hyperplasia and hypertrophy of fat cells, respectively, which caused adipocyte remodeling due to hyperleptinemia. Topics: Adipocytes; Animal Feed; Animals; Body Composition; Body Weight; Butter; Cell Count; Dietary Fats; Dietary Supplements; Drug Evaluation, Preclinical; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fish Oils; Intra-Abdominal Fat; Leptin; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Soybean Oil | 2013 |
Oral leptin treatment in suckling rats ameliorates detrimental effects in hypothalamic structure and function caused by maternal caloric restriction during gestation.
A poor prenatal environment brings about perturbations in leptin surge and hypothalamic circuitry that program impaired ability to regulate energy homeostasis in adulthood. Here, using a rat model of moderate maternal caloric restriction during gestation, we aimed to investigate whether leptin supplementation with physiological doses throughout lactation is able to ameliorate the adverse developmental malprogramming effects exerted in offspring hypothalamus structure and function. Three groups of male and female rats were studied: the offspring of ad libitum fed dams (controls), the offspring of 20% calorie restricted dams during the first part of pregnancy (CR), and CR rats supplemented with physiological doses of leptin throughout lactation (CR-Leptin). Animals were sacrificed on postnatal day 25. Morphometric and immunohistochemical studies on arcuate (ARC) and paraventicular (PVN) nucleus were performed and hypothalamic expression levels of selected genes were determined. In CR males, leptin treatment restored, at least in part, the number of immunoreactive neuropeptide Y (NPY(+)) cells in ARC, the total number of cells in PVN, hypothalamic NPY, cocaine- and amphetamine-regulated transcript (CART) and suppressor of cytokine signalling-3 (SOCS-3) mRNA levels, and plasma leptin levels, which were decreased in CR animals. CR-Leptin males showed higher hypothalamic long-form leptin receptor (ObRb) mRNA levels, compared to control and CR animals. In CR females, leptin treatment reverted the increased number of cells in ARC and cell density in ARC and PVN, and reduced hypothalamic SOCS-3 mRNA expression to levels similar to controls. Leptin treatment also reverted the increased relative area of NPY(+) fibers in the PVN occurring in CR animals. In conclusion, leptin supplementation throughout lactation is able to revert, at least partly, most of the developmental effects on hypothalamic structure and function caused by moderate maternal caloric restriction during gestation, and hence making this metabolic malprogramming reversible to some extent. Topics: Administration, Oral; Animals; Animals, Suckling; Base Sequence; Body Weight; Caloric Restriction; DNA Primers; Female; Hypothalamus; Leptin; Male; Pregnancy; Rats; Rats, Wistar; RNA, Messenger | 2013 |
Adipokines and parameters of peritoneal membrane transport in newly started peritoneal dialysis patients.
Adiponectin and leptin are two adipokines playing important roles in the regulation of body weight, appetite, carbohydrate and lipid metabolism. In patients with chronic kidney disease (CKD) adipokines accumulate in serum due to reduced renal clearance. Since adipokines have pleiotropic actions, the adipokine balance may have an impact on peritoneal membrane transport. The aim of this study was to assess whether serum adiponectin and leptin levels were related to peritoneal transport and residual renal function (RRF) in newly started peritoneal dialysis patients.. 25 clinically stable patients, 4 to 6 weeks after the onset of PD, were included in the study. For each patient clinical and laboratory data were reviewed and standard PET test was performed. Serum adiponectin and leptin concentrations were determined and leptin/adiponectin (L/A) ratio was calculated.. Serum adiponectin correlated negatively with weight, BMI and glucose concentration. Serum leptin and L/A ratio correlated positively with BMI. Serum adiponectin correlated positively with dialysate to plasma (D/P) creatinine ratio and ultrafiltration in PET test. Serum leptin level and L/A ratio correlated strongly negatively with peritoneal creatinine clearance.. Serum adiponectin concentration is positively associated with baseline solute transport. Leptin concentration and L/A ratio are negatively associated with dialysis adequacy in newly started PD patients. Topics: Adiponectin; Adult; Blood Glucose; Body Mass Index; Body Weight; Female; Humans; Leptin; Male; Membrane Transport Modulators; Middle Aged; Peritoneal Dialysis; Positron-Emission Tomography; Renal Insufficiency, Chronic | 2013 |
Developmental changes in the responsiveness of hypothalamic ER alpha mRNA levels to food deprivation.
Estrogen plays an important role in feeding and energy balance, and the critical role of estrogen in the control of appetite and energy balance is mediated by hypothalamic estrogen receptor (ER) alpha. In undernourished rodents, hypothalamic ER alpha mRNA expression are decreased. Responses of some hypothalamic factors to negative energy balance develop during the early neonatal period.. In this study, we examined the developmental changes of fasting-induced alterations in hypothalamic ER alpha mRNA expression in female rats.. ER alpha mRNA expression was reduced after a 12-h or 24-h fast at postnatal days 15 and 25, but not at day 5. Serum estradiol levels in postnatal day 25 rats were not changed by fasting. Although serum leptin levels were suppressed by fasting at all ages, hypothalamic ER alpha mRNA expression at postnatal day 25 was not changed by leptin administration after a 24-h fast.. These data show that the sensitivity of hypothalamic ER alpha to negative energy balance may not be established in the early neonatal period, and that it develops by postnatal day 15. Decreased leptin levels might not be involved in the alterations of hypothalamic ER alpha mRNA expression in the undernourished condition. Topics: Age Factors; Animals; Animals, Newborn; Body Weight; Energy Metabolism; Estrogen Receptor alpha; Female; Food Deprivation; Hypothalamus; Leptin; Pregnancy; Rats; RNA, Messenger | 2013 |
[Body mass, energy budget and leptin of mice under stochastic food restriction and refeeding].
Periods of restricted food intake that lead to lower body weight are often followed by rapid regaining of the lost weight after ad libitum refeeding, an event generally known as the "compensatory growth". To explore the physiological mechanisms underlying "compensatory growth", we evaluated a series of energetic parameters (energy intake, energy expenditure, body composition and serum leptin levels) of adult KM mice subjected to three cycles of stochastic food restriction following by ad libitum refeeding (SFR-Re). The results indicated that animals lost their body mass after stochastic food restriction and then regained to the control level after refeeding. After the final cycle, SFR-Re mice showed higher basal metabolic rate, lower nonshivering thermogenesis, and their cytochrome c oxydase activities, as well as uncoupling protein 1(UCP1) contents of brown adipose tissue all decreased compared with controls. Meanwhile, higher energy intake and digestibility, as well as heavier fat pads also were found in SFR-Re mice. But, serum leptin levels showed no difference between SFR-Re and control mice. On the whole, these findings indicated that when food is resourceful, SFR-Re mice are under rapid "compensatory growth" by increasing their food intake and energy storage efficiency, meanwhile, decreasing energy consumption in thermogenesis. Moreover, leptin may be a possible player in the regulations of energy budget and thermogenesis during "compensatory growth".. 为阐明限食和重喂食(SFR-Re)诱导的体重“补偿性增长”生理机制,该文测定了SFR-Re驯化的KM小鼠能量摄入与支出、身体成分以及血清瘦素水平。结果显示,随机限食使体重显著降低,重喂食后体重增加至对照组水平。驯化结束后,SFR-Re驯化小鼠基础代谢率增加,产热降低,褐色脂肪组织(BAT)细胞色素c氧化酶(COX)活性和解偶联蛋白1(UCP1)水平显著降低,摄入能、消化率和脂肪重量均显著高于自由取食的对照组小鼠,但血清瘦素水平组间差异不显著。即在食物资源丰富的条件下,经历食物短缺的动物将增加能量摄入和消化吸收效率以及脂肪组织能量贮存,从而导致体重的“补偿性增长”,同时,血清瘦素可能在该过程中发挥重要作用。 Topics: Animals; Basal Metabolism; Body Weight; Eating; Energy Intake; Ion Channels; Leptin; Male; Mice; Mitochondrial Proteins; Thermogenesis; Uncoupling Protein 1 | 2013 |
Voluntary post weaning exercise restores metabolic homeostasis in offspring of obese rats.
Physical exercise reduces obesity, insulin resistance and dyslipidemia. We previously found that maternal obesity alters central appetite circuits and contributes to increased adiposity, glucose intolerance and metabolic disease in offspring. Here we hypothesized that voluntary exercise would ameliorate the adverse metabolic effects of maternal obesity on offspring.. Sprague-Dawley females fed chow (C) or high-fat diet HFD (H) were mated. Female offspring from C dams were weaned onto chow (CC); those from H dams recieved chow (HC) or HFD (HH). Half of each group was provided with running wheels (CC(EX), HC(EX), HH(EX); n=10-12). Maternal obesity increased body weight (12%), adiposity, plasma lipids and induced glucose intolerance (HC vs CC; P<0.05). These were exaggerated by postweaning HFD (HH vs HC; P<0.01), showed doubled energy intake, a 37% increase in body weight, insulin resistance and glucose intolerance (HH vs HC; P<0.01). Exercise reduced fat mass, plasma lipids, HOMA and fasting glucose in HC(EX) (vs HC; P<0.05) and HH(EX) (vs HH; P<0.01). Values in HC(EX) were indistinguishable from CC, however in HH(EX) these metabolic parameters remained higher than the sedentary HC and CC rats (P<0.01). mRNA expression of hypothalamic pro-opiomelanocortin, and adipose tumour necrosis factor α and 11β-hydroxysteroid dehydrogenase type 1 were reduced by exercise in HH(EX) (vs HH; P<0.05).. While voluntary exercise almost completely reversed the metabolic effects of maternal obesity in chow fed offspring, it did not fully attenuate the increased adiposity, glucose intolerance and insulin resistance in offspring weaned onto HFD. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adiposity; Animal Nutritional Physiological Phenomena; Animals; Appetite; Blood Glucose; Blood Pressure; Body Weight; Diet, High-Fat; Dyslipidemias; Energy Intake; Fatty Acids, Nonesterified; Female; Homeostasis; Hypothalamus; Insulin; Insulin Resistance; Leptin; Maternal Nutritional Physiological Phenomena; Obesity; Physical Conditioning, Animal; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Triglycerides; Tumor Necrosis Factor-alpha; Weaning | 2013 |
Effects of cigarette smoke exposure and its cessation on body weight, food intake and circulating leptin, and ghrelin levels in the rat.
Smoking is associated with loss of body weight (BW) and reduced appetite, while smoking abstinence with the opposite effect. The role of peripheral signaling by appetite-controlling hormones leptin and ghrelin is not clear. In the present study, the relationship of circulating leptin and ghrelin with BW and food intake rate (FIR) changes was studied during cigarette smoke exposure (CSE) and after its cessation in the rat.. Male Wistar rats were subjected to CSE for 8 weeks by confinement to plexiglass chambers (Group S). Control animals were confined to identical chambers without smoke (Group C). During CSE and an equivalent follow-up period, BW and FIR was recorded and serum leptin and ghrelin levels were measured.. A sharp decrease in BW was noted during the first 4 weeks of CSE, while FIR, after a substantial decrease noted at Week 1, returned to control levels. Thereafter, rats started to regain their BW until they reached control levels by the 1st week postCSE. BW regain was accompanied by a rebound increase of FIR, which plateaued during the first 4 weeks postCSE and then normalized. Serum leptin was decreased in Group S during both periods, normalizing at the 7th week postCSE. Ghrelin levels did not differ between groups.. Circulating leptin could not explain by its own BW and FIR changes during the first few week of CSE in rats, in contrast to the rest of the CSE period as well as after its cessation. Serum ghrelin levels did not justify BW and FIR changes. Topics: Animals; Appetite; Body Weight; Cotinine; Eating; Ghrelin; Leptin; Male; Rats; Rats, Wistar; Smoking | 2013 |
Association between epicardial fat thickness and weight homeostasis hormones in patients with noncachectic heart failure.
The relationship between echocardiographically measured epicardial fat thickness (EFT) and plasma concentrations of leptin, ghrelin, and adiponectin has not been evaluated in patients with noncachectic heart failure (HF). Patients with noncachectic HF and age- and sex-matched controls did not differ significantly in EFT, whereas EFT values showed significant positive correlation with body mass index (BMI) in both groups and were negatively related with brain natriuretic peptide and positively with log leptin values in the HF group. In the control group, a positive correlation with high-sensitivity C-reactive protein (hsCRP) and a negative correlation with log ghrelin were found. In multivariable analysis, log leptin was a significant predictor of EFT in patients with HF, but this effect was not retained after adjusting for BMI. In contrast, log ghrelin and hsCRP were significant predictors of EFT in controls even after adjusting for BMI. Topics: Adipose Tissue; Adiposity; Aged; Aged, 80 and over; Body Mass Index; Body Weight; C-Reactive Protein; Female; Ghrelin; Heart Failure; Homeostasis; Humans; Leptin; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Pericardium; Ultrasonography | 2013 |
Changes in cardiac energy metabolic pathways in overweighed rats fed a high-fat diet.
Heart produces ATP through long-chain fatty acids beta oxidation.. To analyze whether in ventricular myocardium, high-fat diet may modify the expression of proteins associated with energy metabolism before myocardial function was affected.. Wistar Kyoto rats were divided into two groups: (a) rats fed standard diet (control; n = 6) and (b) rats fed high-fat diet (HFD; n = 6). Proteins from left ventricles were analyzed by two-dimensional electrophoresis, mass spectrometry and Western blotting.. Rats fed with HFD showed higher body weight, insulin, glucose, leptin and total cholesterol plasma levels as compared with those fed with standard diet. However, myocardial functional parameters were not different between them. The protein expression of 3-ketoacyl-CoA thiolase, acyl-CoA hydrolase mitochondrial precursor and enoyl-CoA hydratase, three long-chain fatty acid β-oxidation-related enzymes, and carnitine-O-palmitoyltransferase I was significantly higher in left ventricles from HFD rats. Protein expression of triosephosphate isomerase was higher in left ventricles from HFD rats than in those from control. Two α/β-enolase isotypes and glyceraldehyde-3-phosphate isomerase were significantly increased in HFD rats as compared with control. Pyruvate and lactate contents were similar in HFD and control groups. Expression of proteins associated with Krebs cycle and mitochondrial oxidative phosphorylation was higher in HFD rats.. Expression of proteins involved in left ventricle metabolic energy was enhanced before myocardial functionality was affected in rats fed with HFD. These findings may probably indicate higher cardiac energy requirement due to weight increase by HFD. Topics: Acetyl-CoA C-Acyltransferase; Animals; Blotting, Western; Body Weight; Carnitine O-Palmitoyltransferase; Cholesterol; Diet, High-Fat; Energy Metabolism; Enoyl-CoA Hydratase; Fatty Acids; Glyceraldehyde 3-Phosphate; Image Processing, Computer-Assisted; Insulin; Lactic Acid; Leptin; Male; Metabolic Networks and Pathways; Mitochondrial Proteins; Myocardium; Overweight; Oxidative Phosphorylation; Palmitoyl-CoA Hydrolase; Phosphopyruvate Hydratase; Pyruvic Acid; Rats; Rats, Inbred WKY; Triglycerides; Triose-Phosphate Isomerase | 2013 |
Hypophagia and induction of serotonin transporter gene expression in raphe nuclei of male and female rats after short-term fluoxetine treatment.
Serotonin (5-HT) is one of the regulators of feeding in humans. Drugs acting on the serotoninergic system are used to treat bulimia nervosa and to enhance the effect of hypocaloric diets in overweight subjects. They act rapidly to normalise feeding when used to treat eating-related problems. To explore the role of the 5-HT transporter (serotonin transporter (SERT)) in the short-term action of serotonin selective reuptake inhibitor fluoxetine, rats were i.p. given the drug for five consecutive days. Acute administration of fluoxetine in male and female rats produced a strong reduction in food intake, an effect that held up when daily treatment was maintained for five consecutive days. This reduction translated into a diminution of body weight that was statistically significant in the case of the males. As a reflection of the body weight change in rats killed after the fifth daily drug injection, retroperitoneal fat pad also decreased; a diminution that was statistically significant in the case of male rats. In these conditions, plasma leptin levels of both male and female rats were lower than in untreated animals. While acute fluoxetine administration did not modify SERT gene expression, subchronic drug treatment increased the content of SERT mRNA in the midbrain raphe complex of both rat genders. These findings may contribute to explain the role of SERT in fluoxetine action on binging and as an adjunct to hypocaloric diets. Topics: Animals; Anorexia; Body Weight; Eating; Female; Fluoxetine; Gene Expression; Humans; Injections, Intraperitoneal; Intra-Abdominal Fat; Leptin; Male; Raphe Nuclei; Rats; Rats, Sprague-Dawley; RNA-Binding Proteins; Selective Serotonin Reuptake Inhibitors; Serotonin | 2013 |
Omeprazole improves the anti-obesity and antidiabetic effects of exendin-4 in db/db mice (-4 db/db)*.
In addition to its glucoregulatory actions, exendin-4, a stable glucagon-like peptide-1 receptor agonist, exhibits protective effects in the pancreas and anti-obesity effects. Suitable combination treatment with other anti-obesity or pancreas protective agents would be an effective approach to optimize these additional effects. In the present study, we investigated the effects of the addition of omeprazole, a proton pump inhibitor, to exendin-4 in db/db mice, an experimental model of obesity and type 2 diabetes.. The effects repeated dose treatment for 14 days with exendin-4 (8 μg/kg, s.c.) and omeprazole (30 mg/kg, s.c.) on glycemic control, food intake, and body weight were determined in obese and hyperglycemic db/db mice. The effects of these treatments on plasma gastrin, ghrelin, and leptin levels were determined, along with effects on nausea-like symptoms. The pancreatic effects of the repeated dose treatment were assessed by measuring %HbA1c in the circulation as well as pancreatic insulin and glucagon content and glucokinase activity.. Combination treatment resulted in significant decreases in plasma leptin and ghrelin levels after repeated dosing. Omeprazole improved the anorectic and body weight-lowering effects and reversed the inhibitory effect of exendin-4 on gastrin levels after repeated dose treatment. The 14-day combination treatment significantly reduced glucose excursion and improved insulin levels, with a concomitant decrease in %HbA1c levels. It also improved glucokinase activity and pancreatic insulin content, with a significant decrease in glucagon content.. Combined treatment with omeprazole with exendin-4 reduces food intake and body weight gain, most likely through changes in plasma ghrelin and leptin levels, and improves pancreatic insulin and glucagon content by improving glucokinase activity. Topics: Animals; Anti-Obesity Agents; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Gastrins; Glucagon; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Omeprazole; Peptides; Venoms | 2013 |
Yerba mate extract (Ilex paraguariensis) attenuates both central and peripheral inflammatory effects of diet-induced obesity in rats.
To clarify the effects of natural dietary components on the metabolic consequences of obesity, we examined the effects of yerba mate extract Ilex paraguariensis on both central and peripheral inflammatory effects of diet-induced obesity and correlated the hypothalamic tumor necrosis factor (TNF)-α level with adipose depot weight. Wistar rats were divided into four groups: a control group (CTL) fed with chow diet, a second group fed with chow diet plus yerba mate extract (CTL+E), a third group fed with a high-fat diet rich in saturated fatty acids (HFD) and a fourth group fed with HFD plus yerba mate extract (HFD+E). Enzyme-linked immunosorbent assay, Western blotting, colorimetric method and treatment by gavage were utilized as materials and methods. The HFD groups showed a significant increase in food intake (kcal), body weight, adipose tissue and leptin level in comparison to CTL and CTL+E. HFD leads to increase of both central and peripheral inflammatory effects, and deregulation of insulin pathway. In addition, yerba mate extract intake blunted the proinflammatory effects of diet-induced obesity in rats by reducing the phosphorylation of hypothalamic IKK and NFκBp65 expression and increasing the phosphorylation of IκBα, the expression of adiponectin receptor-1 and consequently the amount of IRS-2. Moreover, the increase in interleukin (IL)-6 levels in the liver and muscle and of the IL-10/TNF-α ratio in groups that received yerba mate extract showed the anti-inflammatory effects of this natural substance. Taken together, our data suggest that the use of yerba mate extract may be useful for reducing low-grade obesity-associated inflammation. Topics: Adipose Tissue; Animals; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Diet, High-Fat; Energy Intake; Enzyme-Linked Immunosorbent Assay; fas Receptor; Fasting; Fatty Acids; Hypothalamus; I-kappa B Proteins; Ilex paraguariensis; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Interleukin-10; Interleukin-6; Leptin; Liver; Male; Muscles; NF-kappa B; NF-KappaB Inhibitor alpha; Obesity; Phosphorylation; Plant Extracts; Rats; Rats, Wistar; Receptors, Adiponectin; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha | 2013 |
Increased expression of transthyretin in leptin-deficient ob/ob mice is not causative for their major phenotypic abnormalities.
The hormone leptin is a critical regulator of adipogenesis and energy metabolism. Similarly, leptin-deficient ob/ob mice display various metabolic abnormalities, including not only obesity and insulin resistance, but also hypogonadism and high bone mass. By genome-wide expression analysis using hypothalamus RNA from wild-type and ob/ob mice, we observed the increased expression of the gene for transthyretin (Ttr) in the latter, as confirmed by quantitative real-time-polymerase chain reaction. Because Ttr encodes a carrier protein for retinol transport, and because we further found increased retinol levels in the serum of ob/ob mice, we investigated whether the additional absence of Ttr would influence the ob/ob phenotype. It was found that Ttr-deficient ob/ob mice were indistinguishable from ob/ob littermates in terms of body weight, as well as serum glucose, insulin and cholesterol levels. Although all of these parameters were identical to wild-type controls in Ttr-deficient mice, we found that the sole deletion of Ttr caused a significant increase of trabecular bone mass, bone marrow adiposity and mean adipocyte area in white adipose tissue. Interestingly, all these latter parameters were highest in Ttr-deficient ob/ob mice, and only in these mice did we observe a full penetrance of liver steatosis at 24 weeks of age. Taken together, our data demonstrate that the increased expression of Ttr in ob/ob mice does not cause (but rather attenuates) their phenotypic abnormalities. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Bone and Bones; Fatty Liver; Female; Hypothalamus; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Knockout; Mice, Obese; Mutation; Obesity; Phenotype; Prealbumin; RNA, Messenger | 2013 |
Diet-induced obesity in ad libitum-fed mice: food texture overrides the effect of macronutrient composition.
Diet-induced obesity in mice can be achieved through the use of diets with different macronutrient compositions and textures. We aimed at determining the contribution of macronutrient composition to obesity development and associated pathophysiological changes in mice. C57BL/6N mice were offered a control, a high-fat or a Western-style diet, either as pellet (H for hard) or with identical composition in powder form (S for soft), resulting in C-S, C-H, HF-H, HF-S, W-H and W-S groups, respectively. Body fat distribution, expression levels of selected target genes in adipose tissues, clinical chemistry and hormone concentration in the blood, as well as liver TAG content were measured. The most striking finding was that all mice fed the different powder diets developed obesity with similar weight gain, whereas among the mice fed the pellet diets, only those given the HF and W diets became obese. This allowed us to separate diet-specific effects from obesity-mediated effects. Irrespective of the food texture, the W diet induced a more severe hepatosteatosis and higher activities of serum transaminases compared with the two other diets. Adipose tissue gene expression analysis revealed that leptin and adiponectin levels were not affected by the dietary composition per se, whereas uncoupling protein 1 and 11β-hydroxysteroid dehydrogenase type 1 levels were decreased by both dietary composition and changes in body weight. In conclusion, diets differing in macronutrient composition elicit specific pathophysiological changes, independently of changes in body weight. A diet high in both fat and sugars seems to be more deleterious for the liver than a HF diet. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adiponectin; Adipose Tissue; Analysis of Variance; Animals; Body Fat Distribution; Body Weight; Diet; Dietary Fats; Dietary Sucrose; Gene Expression; Insulin; Ion Channels; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Obesity; Organ Size; Resistin; Uncoupling Protein 1 | 2013 |
Peripheral leptin regulates bone formation.
Substantial evidence does not support the prevailing view that leptin, acting through a hypothalamic relay, decreases bone accrual by inhibiting bone formation. To clarify the mechanisms underlying regulation of bone architecture by leptin, we evaluated bone growth and turnover in wild-type (WT) mice, leptin receptor-deficient db/db mice, leptin-deficient ob/ob mice, and ob/ob mice treated with leptin. We also performed hypothalamic leptin gene therapy to determine the effect of elevated hypothalamic leptin levels on osteoblasts. Finally, to determine the effects of loss of peripheral leptin signaling on bone formation and energy metabolism, we used bone marrow (BM) from WT or db/db donor mice to reconstitute the hematopoietic and mesenchymal stem cell compartments in lethally irradiated WT recipient mice. Decreases in bone growth, osteoblast-lined bone perimeter and bone formation rate were observed in ob/ob mice and greatly increased in ob/ob mice following subcutaneous administration of leptin. Similarly, hypothalamic leptin gene therapy increased osteoblast-lined bone perimeter in ob/ob mice. In spite of normal osteoclast-lined bone perimeter, db/db mice exhibited a mild but generalized osteopetrotic-like (calcified cartilage encased by bone) skeletal phenotype and greatly reduced serum markers of bone turnover. Tracking studies and histology revealed quantitative replacement of BM cells following BM transplantation. WT mice engrafted with db/db BM did not differ in energy homeostasis from untreated WT mice or WT mice engrafted with WT BM. Bone formation in WT mice engrafted with WT BM did not differ from WT mice, whereas bone formation in WT mice engrafted with db/db cells did not differ from the low rates observed in untreated db/db mice. In summary, our results indicate that leptin, acting primarily through peripheral pathways, increases osteoblast number and activity. Topics: Adipose Tissue, White; Animals; Body Weight; Bone Marrow Transplantation; Bone Resorption; Feeding Behavior; Female; Genetic Therapy; Hypothalamus; Leptin; Mice; Models, Biological; Organ Size; Osteogenesis; Receptors, Leptin; Subcutaneous Tissue | 2013 |
Maternal protein deprivation: sexually dimorphic programming of hypertension in the mouse.
Epidemiological data in humans and experiments in laboratory animals have demonstrated that the developmental programming of hypertension may occur as a consequence of dietary manipulations during pregnancy. Surprisingly, there is a scarcity of data regarding the development of hypertension as a consequence of a maternal low-protein diet (MLPD), particularly in the mouse. Furthermore, the role of sex in developmental programming is not well understood. We used FVB/NJ mice, because of their value in genetic/mechanistic analysis, to test the hypothesis that a MLPD during gestation leads to the sexually dimorphic developmental programming of hypertension and related disorders, such as intra-uterine growth restriction (IUGR), type 2 diabetes mellitus and obesity. We administered iso-caloric, normal (control), moderate protein (moderate MLPD) and severe protein (severe MLPD) diets to the mice, beginning 1 week before mating and continuing until the delivery of the pups. From 4 weeks onward, using a non-invasive tail-cuff method, we measured blood pressure and other parameters in the offspring. Our results demonstrate the following: (1) MLPD caused IUGR (low birthweight) in a dose-dependent manner; (2) Female offspring developed severe hypertension, whereas males were affected only moderately; (3) The blood glucose level was elevated only in females from the moderate MLPD group, although their insulin levels remained normal; (4) Rapid catch-up growth was observed in both sexes, with moderate MLPD females and severe MLPD males becoming overweight. Notably, blood leptin levels in the control group were significantly higher in females than in male offspring and were reduced in females from the severe MLPD group. We conclude that an antenatal MLPD during gestation leads to sexually dimorphic programming in mice. Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Diet, Protein-Restricted; Dietary Proteins; Female; Fetal Growth Retardation; Heart Rate; Hypertension; Insulin; Leptin; Male; Mice; Mice, Inbred Strains; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Sex Characteristics | 2013 |
Leptin overexpression in VTA trans-activates the hypothalamus whereas prolonged leptin action in either region cross-desensitizes.
High-fat feeding or CNS leptin overexpression in chow-fed rats results in a region-specific cellular leptin resistance in medial basal hypothalamic regions and the ventral tegmental area (VTA). The present investigation examined the effects of targeted chronic leptin overexpression in the VTA as compared with the medial basal hypothalamus on long-term body weight homeostasis. The study also examined if this targeted intervention conserves regional leptin sensitivity or results in localized leptin resistance. Cellular leptin resistance was assessed by leptin-stimulated phosphorylation of signal transducers and activators of transcription 3 (STAT3). Tyrosine hydroxylase was measured in hypothalamus and VTA along with brown adipose tissue uncoupling protein 1. Leptin overexpression in VTA tempered HF-induced obesity, but to a slightly lesser extent than that with leptin overexpression in the hypothalamus. Moreover, the overexpression of leptin in the VTA stimulated cellular STAT3 phosphorylation in several regions of the medial basal hypothalamus, whereas verexpression in the hypothalamus did not activate STAT3 signaling in the VTA. This unidirectional trans-stimulation did not appear to involve migration of either the vector or the gene product. Long-term leptin overexpression in either the medial basal hypothalamus or VTA caused desensitization of leptin signaling in the treated region and cross-desensitization of leptin signaling in the untreated region. These results demonstrate a role of leptin receptors in the VTA in long-term body weight regulation, but the trans-activation of the hypothalamus following VTA leptin stimulation suggests that an integrative response involving both brain regions may account for the observed physiological outcomes. Topics: Animals; Body Weight; Diet, High-Fat; Eating; Gene Expression Regulation; Hypothalamus; Leptin; Male; Rats; Rats, Inbred BN; Rats, Inbred F344; Trans-Activators; Ventral Tegmental Area | 2013 |
Hervey, Harris, and the parabiotic search for lipostatic signals.
This paper is an introduction to the papers by Hervey and Harris that describe their experimental use of parabiosis in rats and mice to search for circulating lipostatic signals. Beginning in 1959 with Hervey's foundational paper, they detected three parabiotic signals: the Hervey signal decreases food intake and fat mass in rats; the antilipogenic factor (ALF) decreased fat mass, but not food intake in rats; and the leptin-dependent signal in lean partners of ob/ob mice decreased fat mass, but not food intake. The known lipostatic signals, leptin and insulin, have been candidates for the Hervey and ALF signals, but insulin has been excluded and the evidence for leptin is inconclusive. The site of production of the three parabiotic signals and their molecular structure are not known and specific mechanisms of their lipostatic control are incompletely understood. Given their potential importance for understanding the physiology of lipostatic controls and for developing new therapies for obesity, Hervey and Harris make a strong argument for further research on the three parabiotic signals. Topics: Animals; Body Weight; Eating; Energy Intake; Female; History, 20th Century; History, 21st Century; Insulin; Leptin; Lipid Metabolism; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Nutritional Sciences; Obesity; Parabiosis; Rats; Rats, Zucker; Ventromedial Hypothalamic Nucleus | 2013 |
Rapid onset and reversal of peripheral and central leptin resistance in rats offered chow, sucrose solution, and lard.
We previously reported that rats offered choice diet (chow, 30% sucrose solution, lard) increase body fat by 130% within 3 weeks. We tested the effects of choice diet on the development of leptin resistance in rats. Intraperitoneal injection of 2mg/kg leptin inhibited 14 h food intake and weight gain of all rats after 2 days and 4 days of diet. On day 8, choice rats were leptin insensitive and by day 16 they were resistant. Chow rats remained leptin responsive. A second study showed that on day 16 choice, but not chow rats, were centrally leptin resistant (1.5 μg leptin, 3rd ventricle). In both studies, rats were switched back to chow only after approximately 3 weeks on choice diet and were leptin responsive after 4 days. A third study showed that carcass fat was reduced by 30% 4 days after switching back to chow. A final experiment showed that leptin responsive chow rats, but not leptin resistant choice rats, increased energy expenditure by 12% during the 2.6h after a central leptin injection. Thus, choice diet rapidly induces leptin resistance, but leptin responsiveness is quickly restored when choice is replaced with chow. This rapid onset and reversal of leptin resistance may be associated with changes in either substrate metabolism or adiposity. Topics: Adipose Tissue; Adiposity; Animal Feed; Animals; Body Weight; Choice Behavior; Diet; Dietary Fats; Dietary Sucrose; Drug Tolerance; Energy Intake; Energy Metabolism; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley | 2013 |
Inhibition of immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion by injected leptin in rats.
Leptin, originally identified as an anti-obesity hormone, also has an important role in the regulation of mood and emotion. The present study was designed to monitor effects of injected leptin on immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion in rats. Exposure to 2 h immobilization stress decreased food intake and body weight in saline-injected animals. Animals exposed to open field, elevated plus maze, and light-dark transition tests the day following immobilization exhibited anxiety-like behavior. Leptin injected at doses of 0.1 and 0.5 mg/kg also decreased food intake and body weight in unstressed animals and elicited anxiolytic effects at dose of 0.5 mg/kg, monitored on the following day. Immobilization-induced decreases in food intake, body weight, as well as stress-induced behavioral deficits in the open field, elevated plus maze, and light-dark transition test were reversed by exogenous leptin in a dose-dependent (0.1-0.5 mg/kg) manner. Acute exposure to 2 h immobilization produced a fourfold rise in plasma levels of corticosterone. Animals injected with leptin at a dose of 0.1 mg/kg, but not at dose of 0.5 mg/kg, exhibited a marginal increase in plasma corticosterone. Immobilization-induced increases of plasma corticosterone were reversed by leptin injected at doses of 0.1 or 0.5 mg/kg. The data suggest that exogenous leptin can reduce stress perception, resulting in an inhibition of stress effects on the activity of hypothalamic-pituitary-adrenal axis and behavior. The reported pharmacological effects of leptin represent an innovative approach for the treatment of stress-related disorders. Topics: Animals; Anorexia; Behavior, Animal; Biomarkers; Body Weight; Corticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Hypothalamo-Hypophyseal System; Injections, Intraperitoneal; Leptin; Male; Motor Activity; Pituitary-Adrenal System; Rats; Rats, Wistar; Restraint, Physical; Stress, Psychological; Time Factors; Up-Regulation | 2013 |
Anthropometric measures of visceral and subcutaneous fat are important in the determination of metabolic dysregulation in boys and girls at risk for nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is increasing at alarming rates in obese children. The study aim was to describe body composition/somatotype and its interrelationships to biomarkers of liver disease, insulin resistance, and lipid and cytokine expression in youth with NAFLD.. Somatotype and body composition of children (7-18 years) diagnosed with NAFLD (n= 18) were compared with obese (n = 11) and lean children (n = 17). Anthropometric variables assessed included weight, height, body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHTR), and multiple skinfold thicknesses. Fat mass (FM) and somatotype analysis were measured using validated methodologies. Fasting liver biochemistries (aspartate aminotransferase [AST], alanine aminotransferase [ALT], γ-glutamyltransferase [GGT]), insulin, glucose, leptin, C-reactive protein (CRP), tumor necrosis factor-α, interleukin (IL) factors 6/10, apolipoproteins B-100/B-48 and C-III, triglycerides, and high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol were measured. Insulin resistance was assessed by the homeostasis model of insulin resistance (HOMA-IR).. BMI z score, WC, FM, and somatotype did not differ between NAFLD and obese groups; however, lean children were lighter/leaner across all anthropometric measures (P < .001). Children with NAFLD had a higher sum-of-trunk to sum-of-extremity ratio (1.6 ± 0.4) than did obese (1.3 ± 0.2) and lean (1.1 ± 0.5) children (P < .001). Markers of central visceral (WC/WHTR) and subcutaneous fat (subscapular, abdominal, suprailiac skinfolds) were associated with elevated plasma concentrations of insulin, HOMA-IR, ALT, GGT, and AST and lower HDL cholesterol and IL-10 (P < .001).. Comprehensive assessment of body composition, including measurement of surrogate markers of subcutaneous and visceral fat, provides information regarding metabolic dysregulation and liver disease risk in obese children with NAFLD. Topics: Adolescent; Alanine Transaminase; Anthropometry; Aspartate Aminotransferases; Blood Glucose; Body Composition; Body Mass Index; Body Weight; C-Reactive Protein; Child; Cholesterol, HDL; Cross-Sectional Studies; Fatty Liver; Female; gamma-Glutamyltransferase; Humans; Insulin; Insulin Resistance; Interleukin-10; Intra-Abdominal Fat; Leptin; Male; Non-alcoholic Fatty Liver Disease; Prospective Studies; Risk Factors; Subcutaneous Fat; Tumor Necrosis Factor-alpha; Ultrasonography; Waist Circumference | 2013 |
The impact of temperature on the metabolome and endocrine metabolic signals in Atlantic salmon (Salmo salar).
The aim was to elucidate the effects of elevated temperature on growth performance, growth- and appetite-regulating hormones and metabolism in Atlantic salmon, Salmo salar. Post-smolts in seawater (average mass 175g) that had been reared at 12°C were kept at three temperatures (8, 12 and 18°C) and sampled after one and three months. After three months, the fish kept in 18°C had decreased growth rate and condition factor, and elevated plasma levels of growth hormone (GH) and leptin, compared with fish kept at the lower temperatures. Food conversion efficiency was also decreased at 18°C, while at the same time protein uptake was improved and thus was not a limiting mechanism for growth. Redistribution of energy stores in fish at the highest temperature is evident as a preference of maintaining length growth during times of limited energy availability. NMR-based metabolomics analyses of plasma revealed that several metabolites involved in energy metabolism were negatively affected by temperature in the upper temperature range of Atlantic salmon. Specifically, the high temperature induced a decline of several amino acids (glutamine, tyrosine and phenylalanine) and a shift in lipid metabolism. It appears likely that the decreased food intake at the highest temperature is linked to an anorexigenic function of leptin, but also that the decreased food intake, feed conversion efficiency and condition factor can be linked to changes in GH endocrinology. Topics: Acclimatization; Amino Acids; Animals; Body Weight; Eating; Endocrine System; Energy Metabolism; Growth Hormone; Leptin; Lipid Metabolism; Liver; Magnetic Resonance Spectroscopy; Metabolome; Muscles; Salmo salar; Seawater; Signal Transduction; Temperature; Time Factors | 2013 |
Apolipoprotein E knockout as the basis for mouse models of dyslipidemia-induced neuropathy.
Dyslipidemia has been identified as an important pathogenic risk factor for diabetic neuropathy, but current animal models do not adequately reproduce the lipid profile observed in human diabetics (increased triglycerides with an elevated LDL-cholesterol and reduced HDL-cholesterol). High fat feeding of mice produces hyperlipidemia, but mice are resistant to increases in the LDL to HDL ratio, reducing the potential for peripheral lipid deposits to impact neuropathy, as is postulated to occur in human subjects. Genetic manipulations provide an alternative approach to reproducing a neuropathic plasma lipid profile. Based on findings from the atherosclerosis literature, we began with knockout of ApoE. Since knockout of ApoE alone only partially mimics the human diabetic lipid profile, we examined the impact of its combination with a well-characterized model of type 2 diabetes exhibiting neuropathy, the db/db mouse. We added further gene manipulations to increase hyperlipidemia by using mice with both ApoE and ApoB48 knockout on the ob/+ (leptin mutation) mice. In all of these models, we found that either the db/db or ob/ob genotypes had increased body weight, hyperlipidemia, hyperglycemia, and evidence of neuropathy compared with the control groups (db/+ or ob/+, respectively). We found that ApoE knockout combined with leptin receptor knockout produced a lipid profile most closely modeling human dyslipidemia that promotes neuropathy. ApoE knockout combined with additional ApoB48 and leptin knockout produced similar changes of smaller magnitude, but, notably, an increase in HDL-cholesterol. Our data suggest that the overall effects of ApoE knockout, either directly upon nerve structure and function or indirectly on lipid metabolism, are insufficient to significantly alter the course of diabetic neuropathy. Although these models ultimately do not deliver optimal lipid profiles for translational diabetic neuropathy research, they do present glycemic and lipid profile properties of value for future therapeutic investigations. Topics: Animals; Apolipoproteins E; Behavior, Animal; Blood Glucose; Body Weight; Cholesterol; Data Interpretation, Statistical; Disease Models, Animal; Dyslipidemias; Electrophysiological Phenomena; Leptin; Lipids; Lipoproteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pain Measurement; Peripheral Nervous System Diseases; Triglycerides | 2013 |
Influence of dietary saturated fat content on adiposity, macrophage behavior, inflammation, and metabolism: composition matters.
We examined the effects of three high-fat diets (HFD), differing in the percentage of total calories from saturated fat (SF) (6%, 12%, and 24%) but identical in total fat (40%), on body composition, macrophage behavior, inflammation, and metabolic dysfunction in mice. Diets were administered for 16 weeks. Body composition and metabolism [glucose, insulin, triglycerides, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), total cholesterol (TC)] were examined monthly. Adipose tissue (AT) expression of marker genes for M1 and M2 macrophages and inflammatory mediators [Toll-like receptor (TLR)-2, TLR-4, MCP-1, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, suppressor of cytokine signaling (SOCS)1, IFN-γ] was measured along with activation of nuclear factor kappa-B (NFκB), c-Jun N-terminal kinase (JNK), and p38- mitogen-activated protein kinase (MAPK). AT macrophage infiltration was examined using immunohistochemistry. Circulating MCP-1, IL-6, adiponectin, and leptin were also measured. SF content, independent of total fat, can profoundly affect adiposity, macrophage behavior, inflammation, and metabolic dysfunction. In general, the 12%-SF diet, most closely mimicking the standard American diet, led to the greatest adiposity, macrophage infiltration, and insulin resistance (IR), whereas the 6%-SF and 24%-SF diets produced lower levels of these variables, with the 24%-SF diet resulting in the least degree of IR and the highest TC/HDL-C ratio. Macrophage behavior, inflammation, and IR following HFD are heavily influenced by dietary SF content; however, these responses are not necessarily proportional to the SF percentage. Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Diet, High-Fat; Dietary Fats; Energy Intake; Fatty Acids; Inflammation; Insulin Resistance; Leptin; Macrophages; Male; Mice | 2013 |
Anorexic effects of intra-VTA leptin are similar in low-fat and high-fat-fed rats but attenuated in a subgroup of high-fat-fed obese rats.
Leptin is an adiposity hormone that plays an important role in regulating food intake and energy homeostasis. This study investigated the effects of a high-fat (HF) and a low-fat, high-carbohydrate/sugar (LF) diet on leptin sensitivity in the ventral tegmental area (VTA) in rats. The animals were exposed to a HF or LF diet for 16 weeks. Then the effects of intra-VTA leptin (150 and 500 ng/side, unilateral dose) on food intake and body weights were investigated while the animals were maintained on the HF or LF diet. Long-term exposure to the HF or LF diet led to similar body weight gain in these groups. The HF-fed animals consumed a smaller amount of food by weight than the LF-fed animals but both groups consumed the same amount of calories. The bilateral administration of leptin into the VTA decreased food intake (72 h) and body weights (48 h) to a similar degree in the HF and LF-fed animals. When the HF-fed animals were ranked by body weight gain it was shown that the diet-induced obese rats (HF-fed DIO, upper quartile for weight gain) were less sensitive to the effects of leptin on food intake and body weights than the diet-resistant rats (HF-fed DR, lower quartile for weight gain). A control experiment with fluorescent Cy3-labeled leptin showed that leptin did not spread beyond the borders of the VTA. This study indicates that leptin sensitivity in the VTA is the same in animals that are exposed to a HF or LF diet. However, HF-fed DIO rats are less sensitive to the effects of leptin in the VTA than HF-fed DR rats. Leptin resistance in the VTA might contribute to overeating and weight gain when exposed to a HF diet. Topics: Animals; Anorexia; Appetite Depressants; Body Weight; Diet, Fat-Restricted; Diet, High-Fat; Dietary Carbohydrates; Dietary Fats; Eating; Energy Intake; Leptin; Male; Microinjections; Obesity; Rats; Rats, Sprague-Dawley; Ventral Tegmental Area | 2013 |
Modulation of lipid metabolism by polyphenol-rich grape skin extract improves liver steatosis and adiposity in high fat fed mice.
This study investigated the influence of polyphenol-rich grape skin extract (GSE) on adiposity and hepatic steatosis in mice fed a high fat diet (HFD) and its underlying mechanisms based on adipose and hepatic lipid metabolism. C57BL/6J mice were fed a normal diet or a HFD (20% fat, w/w) with or without GSE (0.15%, w/w) for 10 weeks. The supplementation of GSE significantly lowered body weight, fat weight, plasma free fatty acid level, and hepatic lipid accumulation compared to the HFD group. Plasma leptin level was significantly lower, while the plasma adiponectin level was higher in the GSE group than in the HFD group. GSE supplementation significantly suppressed the activities of lipogenic enzymes in both adipose and liver tissues, which was concomitant with β-oxidation activation. Furthermore, GSE reversed the HFD-induced changes of the expression of genes involved in lipogenesis and β-oxidation in the liver. These findings suggest that GSE may protect against diet-induced adiposity and hepatic steatosis by regulating mRNA expression and/or activities of enzymes that regulate lipogenesis and fatty acid oxidation in the adipose tissue and liver. Topics: Adiponectin; Adiposity; Animals; Body Weight; Diet, High-Fat; Dietary Supplements; Fatty Liver; Leptin; Lipid Metabolism; Lipogenesis; Liver; Mice; Mice, Inbred C57BL; Plant Extracts; Polyphenols; RNA, Messenger; Vitis | 2013 |
Expression of ghrelin and leptin during the development of type 2 diabetes mellitus in a rat model.
The aim of this study was to investigate the syste-matic changes in ghrelin and leptin expression, as well as their correlation with insulin resistance (IR) during the development of type 2 diabetes mellitus (T2DM) in a rat model. T2DM was induced in rats fed a high-fat (HF)-diet followed by the intraperitoneal injection of low-dose streptozotocin (STZ, 35 mg/kg). Sixty male Sprague-Dawley rats were divided into 4 groups: the control, HF-4W (HF diet for 4 weeks), HF-8W (HF diet for 8 weeks) and the T2DM group. During the development of T2DM, the production of ghrelin in the stomach and leptin in adipose tissue, the blood levels of ghrelin and leptin, and the expression of leptin and ghrelin receptors (OB-Rb and GHS-R1a) in the hypothalamus were measured by enzyme-linked immunosorbent assay (ELISA), radioimmunology assay (RIA), immunohistochemistry (IHC) and real-time reverse transcription-polymerase chain reaction (real-time RT-PCR). IR was assessed using the hyperinsulinemic-euglycemic clamp technique. The production of ghrelin in the stomach, the plasma ghrelin levels and the expression of GHS-R1a in the hypothalamus were significantly reduced in the HF-4W and HF-8W rats compared with the control rats; however, no significant difference was found between the HF-8W and T2DM group rats. Comparing the control to the T2DM group, the production of leptin in the adipose tissue and the serum leptin levels increased, whereas the expression of OB-Rb in the hypothalamus decreased. At the same time, the glucose infusion rate (GIR), indicating the insulin sensitivity, decreased significantly; GIR positively correlated with plasma ghrelin and negatively correlated with serum leptin levels. In conclusion, increased leptin levels are associated with obesity and T2DM, while decreased ghrelin levels are associated with obesity/IR rather than T2DM. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Regulation; Ghrelin; Insulin; Leptin; Lipids; Male; Rats | 2013 |
Association of nutrition in early life with body fat and serum leptin at adult age.
There is overwhelming evidence that experiences during early life could have long-term health consequences. However, the role of early nutrition in programming obesity and leptin resistance is still poorly understood.. We aimed at determining whether nutritional intakes in early life are associated with body composition and hormonal status at 20 years.. Healthy infants participating in the two-decade-long prospective ELANCE (Etude Longitudinale Alimentation Nutrition Croissance des Enfants) study were examined at 10 months and 2 years. At 20 years, weight, height, subscapular and triceps skinfold thicknesses, fat mass (FM) and fat-free mass (FFM) assessed via bioelectrical impedance analysis, and serum leptin concentration were recorded in 73 subjects still participating in the follow-up.. In adjusted linear regression models, an increase by 100 kcal in energy intake at 2 years was associated with higher subscapular skinfold thickness (β=6.4% SF, 95% confidence interval 2.53-10.30, P=0.002) and higher FFM (0.50 kg, 0.06-0.95, P=0.03) at 20 years. An increase by 1% energy from fat at 2 years was associated with lower subscapular skinfold thickness (-2.3% SF, -4.41 to -0.18, P=0.03), lower FM (-0.31 kg, -0.60 to -0.01, P=0.04) and lower serum leptin concentration (-0.21 μg l(-1), -0.39 to -0.03, P=0.02) at 20 years.. Low-fat intake in early life was negatively associated with body fat (particularly at the trunk site) and serum leptin concentration at 20 years, suggesting that early low-fat intake could increase the susceptibility to develop overweight and leptin resistance at later ages. These findings substantiate current recommendations against restricting fat intake in early life and open new directions for investigating the origin of obesity. Topics: Adipose Tissue; Biomarkers; Body Height; Body Mass Index; Body Weight; Child, Preschool; Diet Records; Disease Susceptibility; Energy Intake; Female; Follow-Up Studies; France; Humans; Infant; Infant Nutritional Physiological Phenomena; Leptin; Male; Nutritional Status; Obesity; Prospective Studies; Skinfold Thickness; Weight Gain; Young Adult | 2013 |
Sweet tea leaves extract improves leptin resistance in diet-induced obese rats.
Dietary obesity is usually characterized by leptin resistance and abnormal lipid metabolism. Lithocarpus polystachyus Rehd.(Sweet Tea) leaf is a kind of Chinese folkloric medicine, and it has been widely used for obesity, diabetes, and hypertension in South China. The present study is aimed at investigating the pharmacological mechanism of the anti-hyperleptinaemia effects of Sweet Tea leaves extract in high fat diet-induced obese rats.. We induced high fat diet obesity for 14 weeks to test the corrective effects of three ST doses (75, 150 and 300 mg/kg per day) for 8 weeks. At the end of the experiment, body weight, fasting blood glucose and serum lipids, superoxide dismutase (SOD), malondialdehyde (MDA), fasting serum insulin and leptin, C-reactive protein, adiponectin and resistin levels were measured, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was also calculated. mRNA gene expression of PPARγ (peroxisome proliferator-activated receptor γ) and C/EBPα(CCAAT/enhancer-binding protein α) in epididymal adipose tissue of DIO control and experimental groups were evaluated.. Sweet Tea leaves extract could significantly decrease the levels of serum lipids, attenuate body weight gain and lower circulating leptin and insulin levels, ameliorate the state of oxidative stress, raise serum adiponectin, reduce circulating CRP and resistin levels, and depress the expression of PPARγ and C/EBPα in epididymal adipose tissue of obese rats.. The present findings suggest that ST can effectively attenuate the leptin resistance at least through anti-hyperlipidemic activity and thus has the therapeutic potential in treating hyperlipidemia and hyperleptinaemia related to dietary obesity. Topics: Adiponectin; Adipose Tissue; Animals; Beverages; Blood Glucose; Body Weight; C-Reactive Protein; CCAAT-Binding Factor; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Fagaceae; Gene Expression; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Male; Malondialdehyde; Obesity; Plant Leaves; PPAR gamma; Rats; Rats, Sprague-Dawley; Resistin; Superoxide Dismutase | 2013 |
Early onset of reproductive function in female rats treated with a high-fat diet.
Puberty onset in mammals is tightly coupled to the animal's nutritional and metabolic state. In the present study, we evaluated the effects of a high-fat diet on leptin and adiponectin levels, leptin mRNA expression and puberty onset in female rats. On day 21, female rats were divided into 2 groups, normal food (NF) and high-fat food (HF). The HF group showed a significantly earlier (P<0.001) date of vaginal opening and lower body weight (P<0.001) than the NF group. The rats fed the HF food had a significantly heavier uterus (P<0.05) than those fed the NF food, whereas the serum leptin and adiponectin levels and leptin mRNA expression were not significantly different between the NF and HF groups. We speculate that the fat-induced nutritional imbalance in young females may lead to neuroendocrine dysfunction during adolescence. Topics: Adiponectin; Animals; Body Weight; Dietary Fats; Eating; Female; Leptin; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sexual Maturation | 2013 |
Influence of the core circadian gene "Clock" on obesity and leptin resistance in mice.
Alterations in metabolism could be due to cell-autonomous effects associated with altered expression of Clock in central nervous system feeding centers and/or peripheral tissues involved in metabolism. Clock mutant mice are hyperphagic and obese, which indicates that Clock is related to obesity. In the present study, we used intracerebroventricular injection of recombinant adenoviral vector harboring Clock genes to explore the role of Clock on diet induced obesity and the mechanisms involved in leptin resistance and leptin signaling in mice. The results demonstrated that expression of Clock in the arcuate nucleus of diet induced obesity mice was down-regulated. The recombinant adenoviral vector harboring Clock genes could reduce obesity indexes of diet induced obesity mice including body weight, BMI and total fat mass, attenuate hyperleptinemia, increase leptin sensitivity and decrease accumulated suppressor of cytokine signaling-3 in the arcuate nucleus. These results indicate that Clock plays an important role on obesity, which may be involved in leptin resistance and regulation of suppressor of cytokine signaling-3 in arcuate nucleus. Topics: Animals; Blotting, Western; Body Composition; Body Mass Index; Body Weight; Cerebral Ventricles; Circadian Rhythm Signaling Peptides and Proteins; Dependovirus; Genetic Vectors; Injections, Intraventricular; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins | 2013 |
Obese rats with deficient leptin signaling exhibit heightened sensitivity to olfactory food cues.
The Zucker rat is used as a model of genetic obesity, and while Zucker rats have been well studied for their reduced sensitivity to leptin signaling and subsequent weight gain, little work has examined their responses to environmental signals that are associated with "hedonic" feeding. This study evaluated the effects of a high-fat food olfactory cue (bacon) in stimulating nose-poke food-seeking behavior on first exposure (novel) and after a period of access for consumption (familiar) in lean and obese Zucker rats at either 4 or 12 months of age, and under ad-lib fed (unrestricted; U) or chronically food-restricted (70% of ad-lib; R) conditions. Baseline nose-poke levels were comparable amongst all groups. At 4 months of age, only ObU rats displayed increased behavioral activation to familiar food cues. Twelve-month-old Ob rats, regardless of diet, exhibited substantially greater food-seeking behavior when exposed to both the novel and familiar olfactory cues. A strong positive correlation between body weight and nose-poke entries for the familiar food cue was observed at both ages, while this correlation for the novel food cue was significant in 12-month-old rats only. Similarly, there were strong positive correlations between food intake and poke entries for the familiar food cue was observed at both ages, while this correlation for the novel food cue was significant in 12-month-old rats only. Although it is possible that differences in olfactory sensitivity contribute to these behavioral effects, our findings support the interactions between food intake, obesity, and food-seeking behavior and are consistent with leptin inhibiting the brain's reactivity to food cues and suggest that the enhanced sensitivity to the food cues with leptin deficiency is likely to contribute to overeating and weight gain. Topics: Animals; Behavior, Animal; Body Weight; Case-Control Studies; Cues; Eating; Feeding Behavior; Leptin; Male; Obesity; Rats; Rats, Zucker; Signal Transduction; Smell | 2013 |
Resistance exercise modulates lipid plasma profile and cytokine content in the adipose tissue of tumour-bearing rats.
Cancer cachexia is a multifactorial syndrome characterised by progressive weight loss, frequently accompanied by anorexia, sarcopenia, and chronic systemic inflammation. The white adipose tissue is markedly affected by cachexia and contributes to this syndrome throught the secretion of pro-inflammatory factors which reach the adjacent tissues and the circulation. A nonpharmacologic intervention that may attenuate cancer cachexia is chronic physical activity, but the effect of resistance training upon adipose tissue inflammation in cachexia has never been examined. For that purpose we designed a protocol in which animals were randomly assigned to a control group (CT, n=7), a Tumour bearing group (TB, n=7), a Resistance Trained group (RT, n=7) and a Resistance Trained tumour bearing group (RTTB, n=7). Trained rats climbed a vertical ladder with an extra load attached to the tail, representing 75-90% of total body mass, 3 times per week, for 8 weeks. In the 6 th week of resistance training, tumour cells (3 × 10(7) Walker 256 carcinosarcoma) were inoculated in the tumour groups. Body, adipose tissue, muscle and tumour mass was determined, as well a blood biochemical parameters, and the hormone and cytokine profile assessed. The glycogen content of the liver and muscle was measured. IL-10, IL-6 and TNF-α protein expression was evaluated in the mesenteric adipose tissue (MEAT) examined. Resistance training increased by 9% body weight gain in RTTB (final weight 310.8 ± 9.8 g), when compared with TB (final weight 288.3 ± 4.9 g). LDL-c levels were decreased in RTTB (0.28 ± 0.9 mmol/L) by 43% when compared with TB (0.57 ± 0.1 mmol/L). HDL-c levels were increased in RTTB (1.31 ± 0.12 mmol/L) by 15% in regard to CT (1.13 ± 0.7 mmol/L) and 22% as compared with TB (1.07 ± 0.07 mmol/L). RTTB testosterone levels (577 ± 131 ng/mL) were 55% higher when compared with CT (254 ± 41.3 ng/mL) and 63% higher when compared with TB (221 ± 23.1 ng/mL). Adiponectin levels were augmented in RT (23 μg/mL) by 43% when compared with TB (11 μg/mL). Protein expression of IL-6 was increased 38% in TB MEAT (5.95 pg/μg), as compared with CT (3.64 pg/μg) and 50% compared with RTTB (2.91 pg/μg). Similar results with respect to TNF-α TB (7.18 pg/μg) were observed: 39% and 46%, higher protein expression in comparison with CT (4.63 pg/μg) and RTTB (3.8 pg/μg), respectively. IL-10 protein expression was found to be increased in TB (4.4 pg/μg) and RTTB (3.2 pg/μg) 50% and 47%, respectively, in comp Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Cytokines; Leptin; Lipids; Liver; Male; Muscle, Skeletal; Organ Size; Physical Conditioning, Animal; Rats; Rats, Wistar; Resistance Training; Sarcoma; Triglycerides | 2013 |
Effect of leptin administration on myelination in ob/ob mouse cerebrum after birth.
Brain weight and size are known to be reduced in adult leptin-deficient Lep/Lep (OB) mice when compared with the wild-type (+/+) mice (C57BL/6: B6). We here analyzed leptin's effects on myelination by examining morphometrically the myelin sheath (MS) in the cerebrum of postnatal day (P) 14 and P28 OB that had received leptin 1 nmol/capita/day from P7 to P14 or P28 (OB+lep), in comparison with OB and B6. We examined myelin basic protein (MBP) mRNA levels and the differentiation of oligodendrocytes by comparing the number of oligodendrocyte precursor cells (OPCs) and the mature oligodendrocytes in the cerebrum between OB, OB+lep, and B6 on P14 and P28. MBP-mRNA expression was lower in OB than in B6 on P14 and P28. On P14, it was higher in OB+lep than in OB but was still lower than in B6, whereas on P28 it was even higher in OB+lep than in B6. On P28, the radii of myelinated axons were larger in OB than in B6 and OB+lep. The MS on P28 was significantly thinner in OB than in B6, but there was no significant difference between OB and OB+lep. There were significantly fewer mature oligodendrocytes in OB and OB+lep than in B6 on P28, whereas on P14 there were significantly fewer OPCs in OB and OB+lep than in B6. Our results suggested that leptin regulates the myelination of oligodendrocytes and that the replenishment of leptin in OB recovered myelination but did not affect the differentiation of OPCs from P7 to P28. Topics: Age Factors; Animals; Animals, Newborn; Antigens; Body Weight; Cell Differentiation; Cerebrum; Gangliosides; Gene Expression Regulation, Developmental; Leptin; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Microscopy, Electron, Transmission; Myelin Basic Protein; Myelin Sheath; O Antigens; Oligodendroglia; Proteoglycans; Receptor, Platelet-Derived Growth Factor alpha; RNA, Messenger | 2013 |
Serum leptin and total dietary energy intake: the INTERLIPID Study.
It has been hypothesized that leptin-induced appetite suppression is impaired in obese individuals, but little human evidence is available documenting this. We investigated relations between serum leptin and total energy intake using INTERLIPID/INTERMAP data on Japanese-Americans in Hawaii and Japanese in Japan.. Serum leptin and nutrient intakes were examined by standardized methods in men and women aged 40-59 years from two population samples, one Japanese-American in Hawaii (88 men, 94 women), the other Japanese in central Japan (123 men, 111 women). Multiple linear regression analyses stratified by BMI category (<25 kg/m(2), 25-29.9 kg/m(2), and ≥ 30 kg/m(2)) with adjustment for possible confounders were used to examine the relation between log-leptin and total dietary energy intake.. In multivariate regression analyses, in those with BMI < 25 kg/m(2) and in those with BMI between 25 and 29.9 kg/m(2), log-leptin was not significantly related to total dietary energy intake; in those with BMI ≥ 30 kg/m(2), it was significantly inversely related to total dietary energy intake (P = 0.029), independent of body weight and physical activity. Physical activity score was significantly positively related to total dietary energy intake only in participants with BMI < 25 kg/m(2) (P < 0.001).. Leptin was significantly inversely associated with dietary energy intake in obese persons, but not in overweight and normal-weight persons. Topics: Adult; Appetite; Asian; Asian People; Body Mass Index; Body Weight; Cross-Sectional Studies; Energy Intake; Female; Hawaii; Humans; Japan; Leptin; Life Style; Linear Models; Male; Middle Aged; Motor Activity; Obesity; Overweight | 2013 |
Aspalathin improves hyperglycemia and glucose intolerance in obese diabetic ob/ob mice.
Although several researches have demonstrated that rooibos extract has hypoglycemic effect, the role of aspalathin, a main polyphenol in the extract, remains unclear. Our aims were to find specific mechanisms for anti-diabetic action of aspalathin employing a rat skeletal muscle-derived cell line (L6 myocytes) and a rat-derived pancreatic β-cell line (RIN-5F cells) and to investigate its effect in type 2 diabetic model ob/ob mice.. We investigated in vitro the effect of aspalathin on the glucose metabolism through the studies on molecular mechanisms of glucose uptake using cultured L6 myotubes. We also measured the antioxidative ability of aspalathin against reactive oxygen species (ROS) generated by artificial advanced glycation end product (AGE) in RIN-5F cells. In vivo, ob/ob mice were fed 0.1 % aspalathin-containing diet for 5 weeks, and the effect of aspalathin on fasting blood glucose level, glucose intolerance, and hepatic gene expression was studied.. Aspalathin dose dependently increased glucose uptake by L6 myotubes and promoted AMP-activated protein kinase (AMPK) phosphorylation. Aspalathin enhanced GLUT4 translocation to plasma membrane in L6 myoblasts and myotubes. In RIN-5F cells, aspalathin suppressed AGE-induced rises in ROS. In vivo, aspalathin significantly suppressed the increase in fasting blood glucose levels and improved glucose intolerance. Furthermore, aspalathin decreased expression of hepatic genes related to gluconeogenesis and lipogenesis.. Hypoglycemic effect of aspalathin is related to increased GLUT4 translocation to plasma membrane via AMPK activation. In addition, aspalathin reduces the gene expression of hepatic enzymes related to glucose production and lipogenesis. These results strongly suggest that aspalathin has anti-diabetic potential. Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Blood Glucose; Body Weight; Cell Line; Chalcones; Cholesterol; Diabetes Mellitus, Experimental; Gluconeogenesis; Glucose Intolerance; Glucose Transporter Type 4; Glycogenolysis; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Leptin; Lipogenesis; Mice; Mice, Obese; Muscle Fibers, Skeletal; Muscle, Skeletal; Phosphorylation; Rats; Reactive Oxygen Species | 2013 |
Effects of dietary history on energy metabolism and physiological parameters in C57BL/6J mice.
Understanding body weight regulation is essential to fight obesity. Mouse studies, using different types of diets, showed conflicting results in terms of body weight persistence after changing from an ad libitum high-fat diet to an ad libitum low-fat diet. In this study, we questioned specifically whether the energy content of the diet has a lasting effect on energy balance and body weight, using multiple switches and two purified diets with a different fat-to-sugar ratio, but otherwise identical ingredients. Young-adult obesity-prone male C57BL/6J mice were fed single or double switches of semi-purified diets with either 10 energy % (en%) fat (LF) or 40en% fat (HF), with starch replaced by fat, while protein content remained equal. After none, one or two dietary changes, energy metabolism was assessed at 5, 14 and 19 weeks. We observed no systematic continuous compensation in diet and energy intake when returning to LF after HF consumption. Body weight, white adipose tissue mass and histology, serum metabolic parameters, energy expenditure and substrate usage all significantly reflected the current diet intake, independent of dietary changes. This contrasts with studies that used diets with different ingredients and showed persistent effects of dietary history on body weight, suggesting diet-dependent metabolic set points. We conclude that body weight and metabolic parameters 'settle', based on current energetic input and output. This study also highlights the importance of considering the choice of diet in physiological and metabolic intervention studies. Topics: Adipose Tissue, White; Animals; Body Weight; Calorimetry; Diet, Fat-Restricted; Diet, High-Fat; Dietary Fats; Energy Intake; Energy Metabolism; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity | 2013 |
Anti‑obesity effects of Actinidia polygama extract in mice with high‑fat diet‑induced obesity.
Actinidia polygama has been used as a herbal folk medicine for treating pain, gout, rheumatoid arthritis and inflammation. In the present study, the anti‑obesity properties of Actinidia polygama extract (APE) were investigated in mice with high‑fat diet‑induced obesity. APE treatment of high‑fat diet (HFD)‑fed obese mice significantly reduced body weight, adipose tissue mass and serum triglyceride and leptin levels relative to the HFD‑fed mice. Food intake did not differ between the HFD and HFD+APE groups, although the food efficiency ratio (FER) was significantly decreased in the HFD+APE group compared with the HFD group. Histological examination showed that the sizes of the adipocytes were significantly smaller in the HFD+APE group compared with the HFD group. Serum levels of aspartate transaminase were significantly decreased in the HFD+APE mice compared with the HFD‑fed mice, but serum levels of alanine transaminase (ALT), blood urea nitrogen and creatinine were not significantly changed in the HFD+APE mice compared with the levels in the normal diet (ND)‑fed and HFD‑fed mice. These results suggest that APE may be useful for treating metabolic diseases, including obesity and hyperlipidemia, without toxic side‑effects. Topics: Actinidia; Adipose Tissue; Alanine Transaminase; Animals; Anti-Obesity Agents; Aspartate Aminotransferases; Blood Urea Nitrogen; Body Weight; Cell Size; Creatinine; Diet, High-Fat; Eating; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Plant Extracts; Triglycerides | 2013 |
Leptin: making it live up to its promise using natural products.
Topics: Animals; Betulinic Acid; Body Weight; Enzyme Inhibitors; Humans; Leptin; Male; Obesity; Orthosiphon; Pentacyclic Triterpenes; Plant Extracts; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Saussurea; Triterpenes | 2013 |
Combined treatment of betulinic acid, a PTP1B inhibitor, with Orthosiphon stamineus extract decreases body weight in high-fat-fed mice.
Leptin resistance is a common feature of obesity and is accompanied by hyperleptinemia. Although leptin sensitizers improve leptin resistance, they also decrease plasma leptin levels that attenuate the leptin-associated antiobesity effect. We hypothesized that the combinational treatment of leptin sensitizer and endogenous leptin expression stimulant would synergistically induce an antiobesity effect in high-fat-fed obese animals. Betulinic acid (BA) isolated from Saussurea lappa suppressed the hypothalamic protein tyrosine phosphatase 1B in mice and enhanced the antiobesity effect of leptin in obese rats. Ethanol extract of Orthosiphon stamineus (OS) induced leptin expressions in both 3T3-L1 adipocytes and mice in a dose-dependent manner. To evaluate our hypothesis, we treated obese mice induced by 6 weeks of high-fat-diet feeding with BA and OS for 2 weeks. Although BA or OS alone did not decrease body weight in obese mice, the combinational treatment of BA and OS decreased body weight significantly compared to either BA- or OS-treated obese mice. These results suggest that combinational treatment of BA and OS would be effective for the treatment of obesity. Topics: Animals; Betulinic Acid; Body Weight; Diet, High-Fat; Dietary Fats; Down-Regulation; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; NIH 3T3 Cells; Obesity; Orthosiphon; Pentacyclic Triterpenes; Plant Extracts; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Rats, Sprague-Dawley; Saussurea; Triterpenes | 2013 |
Taurine supplementation improves liver glucose control in normal protein and malnourished mice fed a high-fat diet.
Poor nutrition during the perinatal period is associated with an increased risk for metabolic syndrome in adulthood. Taurine (TAU) regulates β-cell function and glucose homeo-stasis. Here, we assessed the effects of TAU supplementation upon adiposity and glucose control in malnourished mice fed a high-fat diet (HFD).. Weaned male C57BL/6J mice were fed a control (14% protein - C) or a protein-restricted (6% protein - R) diet for 6 weeks. Afterwards, mice received or not an HFD for 8 weeks (CH and RH). Half of the HFDmice were supplemented with 5% TAU after weaning (CHT and RHT). Protein restriction led to typical malnutrition features. HFD increased body weight, adiposity, and led to hyperleptinemia, hyperphagia, glucose intolerance, and higher liver glucose output in RH and CH groups. Fasted R mice showed higher plasma adiponectin levels and increased phosphorylation of the AMP-activated protein kinase (p-AMPK) in the liver. These parameters were reduced in RH mice and increased p-AMPK persisted in RHT. TAU prevented obesity and improved glucose tolerance only in CHT, but liver glucose control was ameliorated in both supplemented groups. Better CHT liver glucose control was linked to increased Akt (thymoma viral proto-oncogene/protein kinase B) phosphorylation.. Malnourished mice fed an HFD developed obesity, glucose intolerance, and increased liver glucose output. TAU preserved only normal liver glucose control in RHT mice, an effect associated with increased liver p-AMPK content. Topics: Adiponectin; Adiposity; Amino Acids; AMP-Activated Protein Kinases; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Dietary Supplements; Glucose Intolerance; Leptin; Liver; Male; Malnutrition; Mice; Mice, Inbred C57BL; Phosphorylation; Proto-Oncogene Proteins c-akt; Taurine | 2013 |
Association of the leptin gene E2-169T>C and E3-299T>A mutations with carcass and meat quality traits of the Chinese Simmental-cross steers.
Leptin is a hormone affecting the regulation of body composition, energy balance, and meat quality in mammals. The objective of this study was to evaluate the association of novel single nucleotide polymorphisms in coding region for leptin gene with carcass and meat quality traits of Chinese Simmental-cross steers. Two SNPs (E2-169 T>C and E3-299 T>A) were genotyped on 135 crossbred bulls. The 45 traits being measured included dressing percentage, dressed weight, marbling score, muscle color score, backfat thickness, fatty acid content, etc. Statistical analysis revealed that two SNPs in the exon of leptin gene were associated with the carcass and meat quality traits. The C-bearing genotypes (CC or TC) of E2-169 T>C (C57R) showed higher dressed weight, thickness of loin, MCS, FCS, intramuscular fat content, and polyunsaturated fatty acid content (P<0.05). E3-299 >A(S100T) also showed a significant association with the carcass traits (dressing percentage, living QIB) and fatty acid content in Simmental-cross steers(P<0.05). Our findings suggested that polymorphisms in leptin might be one of the important genetic factors that influence carcass yield and meat quality in beef cattle, and it may be a useful marker for meat quality traits in future marker-assisted selection programs in beef cattle breeding and production. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Cattle; Gene Frequency; Genetic Variation; Genotype; Leptin; Meat; Muscle, Skeletal; Phenotype; Polymorphism, Single Nucleotide | 2013 |
Therapeutic assessment of cytochrome C for the prevention of obesity through endothelial cell-targeted nanoparticulate system.
Because the functional apoptosis-initiating protein, cytochrome C (CytC) is rapidly cleared from the circulation (t1/2 (half-life): 4 minutes), it cannot be used for in vivo therapy. We report herein on a hitherto unreported strategy for delivering exogenous CytC as a potential and safe antiobesity drug for preventing diet-induced obesity, the most common type of obesity in humans. The functional activity of CytC encapsulated in prohibitin (a white fat vessel-specific receptor)-targeted nanoparticles (PTNP) was evaluated quantitatively, as evidenced by the observations that CytC-loaded PTNP causes apoptosis in primary adipose endothelial cells in a dose-dependent manner, whereas CytC alone did not. The delivery of a single dose of CytC through PTNP into the circulation disrupted the vascular structure by the targeted apoptosis of adipose endothelial cells in vivo. Intravenous treatment of CytC-loaded PTNP resulted in a substantial reduction in obesity in high-fat diet (HFD) fed wild-type (wt) mice, as evidenced by the dose-dependent prevention of the percentage of increase in body weight and decrease in serum leptin levels. In addition, no detectable hepatotoxicity was found to be associated with this prevention. Thus, the finding highlights the promising potential of CytC for use as an antiobesity drug, when delivered through a nanosystem. Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Cholesterol; Cytochromes c; Diet, High-Fat; Drug Delivery Systems; Endothelial Cells; Immobilized Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Obesity; Prohibitins; Repressor Proteins; Triglycerides | 2013 |
Neonatal leptin exposure specifies innervation of presympathetic hypothalamic neurons and improves the metabolic status of leptin-deficient mice.
The paraventricular nucleus of the hypothalamus (PVH) consists of distinct functional compartments regulating neuroendocrine, behavioral, and autonomic activities that are involved in the homeostatic control of energy balance. These compartments receive synaptic inputs from neurons of the arcuate nucleus of the hypothalamus (ARH) that contains orexigenic agouti-related peptide (AgRP) and anorexigenic pro-opiomelanocortin (POMC) neuropeptides. The axon outgrowth from the ARH to PVH occurs during a critical postnatal period and is influenced by the adipocyte-derived hormone leptin, which promotes its development. However, little is known about leptin's role in specifying patterns of cellular connectivity in the different compartments of the PVH. To address this question, we used retrograde and immunohistochemical labeling to evaluate neuronal inputs onto sympathetic preautonomic and neuroendocrine neurons in PVH of leptin-deficient mice (Lep(ob)/Lep(ob)) exposed to a postnatal leptin treatment. In adult Lep(ob)/Lep(ob) mice, densities of AgRP- and α-melanocortin stimulating hormone (αMSH)-immunoreactive fibers were significantly reduced in neuroendocrine compartments of the PVH, but only AgRP were reduced in all regions containing preautonomic neurons. Moreover, postnatal leptin treatment significantly increased the density of AgRP-containing fibers and peptidergic inputs onto identified preautonomic, but not onto neuroendocrine cells. Neonatal leptin treatment neither rescued αMSH inputs onto neuroendocrine neurons, nor altered cellular ratios of inhibitory and excitatory inputs. These effects were associated with attenuated body weight gain, food intake and improved physiological response to sympathetic stimuli. Together, these results provide evidence that leptin directs cell type-specific patterns of ARH peptidergic inputs onto preautonomic neurons in the PVH, which contribute to normal energy balance regulation. Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Animals, Newborn; Body Temperature Regulation; Body Weight; Eating; Energy Metabolism; Female; gamma-Aminobutyric Acid; Glucose Tolerance Test; Glutamic Acid; Hypothalamus; Image Processing, Computer-Assisted; Immunohistochemistry; Leptin; Male; Mice; Mice, Knockout; Neurons; Neurosecretory Systems; Parasympathetic Nervous System; Peptides | 2013 |
Inhibition of leptin regulation of parasympathetic signaling as a cause of extreme body weight-associated asthma.
Impaired lung function caused by decreased airway diameter (bronchoconstriction) is frequently observed whether body weight is abnormally high or low. That these opposite conditions affect the airways similarly suggests that the regulation of airway diameter and body weight are intertwined. We show here that, independently of its regulation of appetite, melanocortin pathway, or sympathetic tone, leptin is necessary and sufficient to increase airway diameter by signaling through its cognate receptor in cholinergic neurons. The latter decreases parasympathetic signaling through the M(3) muscarinic receptor in airway smooth muscle cells, thereby increasing airway diameter without affecting local inflammation. Accordingly, decreasing parasympathetic tone genetically or pharmacologically corrects bronchoconstriction and normalizes lung function in obese mice regardless of bronchial inflammation. This study reveals an adipocyte-dependent regulation of bronchial diameter whose disruption contributes to the impaired lung function caused by abnormal body weight. These findings may be of use in the management of obesity-associated asthma. Topics: Animals; Asthma; Body Weight; Bronchi; Bronchoconstriction; Cholinergic Antagonists; Cholinergic Neurons; Diet, High-Fat; Inflammation; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Myocytes, Smooth Muscle; Obesity; Parasympathetic Nervous System; Receptor, Muscarinic M3; Signal Transduction | 2013 |
Astrocytic leptin-receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity.
To determine how astrocytic leptin signaling regulates the physiological response of mice to diet-induced obesity (DIO), we performed metabolic analyses and hypothalamic leptin signaling assays on astrocytic leptin-receptor knockout (ALKO) mice in which astrocytes lack functional leptin receptor (ObR) signaling. ALKO mice and wild-type (WT) littermate controls were studied at different stages of DIO with measurement of body wt, percent fat, metabolic activity, and biochemical parameters. When fed regular chow, the ALKO mice had similar body wt, percent fat, food intake, heat dissipation, respiratory exchange ratio, and activity as their WT littermates. There was no change in blood concentrations of triglyceride, soluble leptin receptor (sObR), mRNA for leptin and uncoupling protein 1 (UCP1) in adipose tissue, and insulin sensitivity. Unexpectedly, in response to a high-fat diet the ALKO mice had attenuated hyperleptinemia and sObR, a lower level of leptin mRNA in subcutaneous fat, and a paradoxical increase in UCP1 mRNA. Thus, ALKO mice did not show the worsening of obesity that occurs with normal WT mice and the neuronal ObR mutation that results in morbid obesity. The findings are consistent with a competing, counterregulatory model between neuronal and astrocytic leptin signaling. Topics: Adiposity; Animals; Astrocytes; Biomarkers; Blood Glucose; Body Weight; Diet, High-Fat; Disease Models, Animal; Energy Metabolism; Genotype; Hypothalamus; Insulin; Ion Channels; Leptin; Mice; Mice, Knockout; Mitochondrial Proteins; Motor Activity; Obesity; Phenotype; Receptors, Leptin; RNA, Messenger; Signal Transduction; Subcutaneous Fat; Time Factors; Triglycerides; Uncoupling Protein 1 | 2013 |
Female Nur77-deficient mice show increased susceptibility to diet-induced obesity.
Adipose tissue is essential in the regulation of body weight. The key process in fat catabolism and the provision of energy substrate during times of nutrient deprivation or enhanced energy demand is the hydrolysis of triglycerides and the release of fatty acids and glycerol. Nur77 is a member of the NR4A subfamily of nuclear receptors that plays an important metabolic role, modulating hepatic glucose metabolism and lipolysis in muscle. However, its endogenous role on white adipose tissue, as well as the gender dependency of these mechanisms, remains largely unknown. Male and female wild type and Nur77 deficient mice were fed with a high fat diet (45% calories from fat) for 4 months. Mice were analyzed in vivo with the indirect calorimetry system, and tissues were analyzed by real-time PCR and Western blot analysis. Female, but not male Nur77 deficient mice, gained more weight and fat mass when compared to wild type mice fed with high fat diet, which can be explained by decreased energy expenditure. The lack of Nur77 also led to a decreased pHSL/HSL ratio in white adipose tissue and increased expression of CIDEA in brown adipose tissue of female Nur77 deficient mice. Overall, these findings suggest that Nur77 is an important physiological modulator of lipid metabolism in adipose tissue and that there are gender differences in the sensitivity to deletion of the Nur77 signaling. The decreased energy expenditure and the actions of Nur77 on liver, muscle, brown and white adipose tissue contribute to the increased susceptibility to diet-induced obesity in females lacking Nur77. Topics: Adipose Tissue, White; Adiposity; Animals; Apoptosis Regulatory Proteins; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; Disease Susceptibility; Energy Metabolism; Fatty Acids, Nonesterified; Female; Gene Knockout Techniques; Homeostasis; Insulin; Leptin; Lipolysis; Liver; Male; Mice; Muscles; Nuclear Receptor Subfamily 4, Group A, Member 1; Obesity; Signal Transduction; Triglycerides | 2013 |
Perinatal bisphenol A exposure promotes hyperactivity, lean body composition, and hormonal responses across the murine life course.
The development of adult-onset diseases is influenced by perinatal exposure to altered environmental conditions. One such exposure, bisphenol A (BPA), has been associated with obesity and diabetes, and consequently labeled an obesogen. Using an isogenic murine model, we examined the effects of perinatal exposure through maternal diet to 50 ng (n=20), 50 μg (n=21), or 50 mg (n=18) BPA/kg diet, as well as controls (n=20) on offspring energy expenditure, spontaneous activity, and body composition at 3, 6, and 9 mo of age, and hormone levels at 9 and 10 mo of age. Overall, exposed females and males exhibited increased energy expenditure (P<0.001 and 0.001, respectively) throughout the life course. In females, horizontal and vertical activity increased (P=0.07 and 0.06, respectively) throughout the life course. Generally, body composition measures were not different throughout the life course in exposed females or males (all P>0.44), although body fat and weight decreased in exposed females at particular ages (all P<0.08). Milligram-exposed females had improved glucose, insulin, adiponectin, and leptin profiles (all P<0.10). Thus, life-course analysis illustrates that BPA is associated with hyperactive and lean phenotypes. Variability across studies may be attributable to differential exposure duration and timing, dietary fat and phytoestrogen content, or lack of sophisticated phenotyping across the life course. Topics: Adiponectin; Adipose Tissue; Aging; Animals; Benzhydryl Compounds; Body Composition; Body Weight; Energy Metabolism; Estrogens, Non-Steroidal; Female; Glucose; Insulin; Leptin; Male; Mice; Phenols; Pregnancy; Prenatal Exposure Delayed Effects | 2013 |
Interrelationships of nutrition, metabolic hormones and resumption of ovulation in multiparous suckled beef cows on subtropical pastures.
The effect of nutrition before and after calving on metabolic status and the resumption of ovulation postpartum was examined in multiparous sucked beef cows on subtropical pastures. At 6-7 months of gestation, Droughtmaster cows were randomly assigned on body weight (BW) and stage of gestation to two groups that received either standard subtropical pasture (SP, n = 7, 543 ± 12 kg BW) or improved pasture (IP, n = 7, 564 ± 12 kg BW). The two nutritional treatments were maintained after calving. Starting at 1 week after calving, cows were monitored for BW and body condition score (BCS, biweekly) and for circulating concentrations of insulin, glucose, IGF-1, GH and leptin (weekly). Ovarian follicular status was monitored weekly by trans-rectal ultrasonography. Fecal samples were obtained at 3-week intervals to ascertain percentage crude protein (%CP) and dry matter digestibility (DMD) of pastures. Crude protein and DMD were greater (P < 0.05) for cows on IP during the first 9 weeks after calving after which there were no differences between nutritional treatments. Cows on IP were heavier (P < 0.05) and had a greater (P < 0.01) BCS than cows on SP at 1 week after calving (585 ± 9 kg and 3.7 ± 0.2 BCS and 528 ± 21 kg and 2.3 ± 0.2 BCS, respectively). Cows on SP showed a gradual increase in BW and there were no differences in BW after approximately 7 weeks postpartum whilst BCS remained less for cows on SP. Plasma concentrations of insulin, glucose, IGF-1 and leptin were all greater (P < 0.01) for cows on IP compared with cows on SP, whilst GH did not differ. The diameter of the largest follicle did not differ between cows on IP and SP throughout the postpartum period. However, 7 of 7 cows on IP resumed ovulations between 12 and 15 weeks postpartum whilst only 1 of 7 cows on SP had resumed ovulation during the study. It is concluded from the findings that exposure of cows to IP and SP before and after calving resulted in two groups of cows with different metabolic homeostasis and that the greater circulating concentrations of insulin, glucose, IGF-1 and leptin promoted the earlier resumption of ovulation for cows on IP. Topics: Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Body Weight; Cattle; Female; Growth Hormone; Insulin; Insulin-Like Growth Factor I; Least-Squares Analysis; Leptin; Ovarian Follicle; Ovulation; Postpartum Period; Pregnancy; Queensland; Random Allocation; Ultrasonography | 2013 |
The brain subfornical organ mediates leptin-induced increases in renal sympathetic activity but not its metabolic effects.
The adipocyte-derived hormone leptin acts within the central nervous system to decrease food intake and body weight and to increase renal and thermogenic brown adipose tissue sympathetic nerve activity (SNA). Previous studies have focused on hypothalamic brain regions, although recent findings have identified leptin receptors (ObR) in a distributed brain network, including the circumventricular subfornical organ (SFO), a forebrain region devoid of a blood-brain barrier. We tested the hypothesis that ObR in the SFO are functionally linked to leptin-induced decreases in food intake and body weight and increases in SNA. SFO-targeted microinjections of an adenovirus encoding Cre-recombinase in ObR(flox/flox) mice resulted in selective ablation of ObR in the SFO. Interestingly, deletion of ObR in the SFO did not influence the decreases in either food intake or body weight in response to daily systemic or cerebroventricular administration of leptin. In line with these findings, reduction in SFO ObR did not attenuate leptin-mediated increases in thermogenic brown adipose tissue SNA. In contrast, increases in renal SNA induced by systemic or cerebroventricular administration of leptin were abolished in mice with SFO-targeted deletion of ObR. These results demonstrate that ObR in the SFO play an important role in leptin-induced renal sympathoexcitation, but not in the body weight, food intake, or brown adipose tissue SNA thermogenic effects of leptin. These findings highlight the concept of a distributed brain network of leptin action and illustrate that brain regions, including the SFO, can mediate distinct cardiovascular and metabolic responses to leptin. Topics: Adipose Tissue, Brown; Animals; Body Weight; Brain; Eating; Gene Silencing; Injections, Intraventricular; Kidney; Leptin; Male; Mice; Receptors, Leptin; Subfornical Organ; Sympathetic Nervous System; Thermogenesis | 2013 |
Seminal plasma adipokine levels are correlated with functional characteristics of spermatozoa.
To study adipokines as a potential link between obesity and male subfertility.. Cross-sectional study of subjects stratified into subgroups according to body mass index (BMI): normal-weight (18.50-24.99 kg/m(2)), overweight (25-29.99 kg/m(2)), and obese (>30 kg/m(2)).. Leipzig, Germany from 2007 to 2011.. Ninety-six male volunteers without spermatogenesis-associated diseases.. None.. Semen parameters, reproductive hormones in serum, and leptin, adiponectin, resistin, chemerin, progranulin, vaspin, and visfatin concentrations in serum and seminal plasma.. All measured adipokines were detectable in human seminal plasma. The levels of progranulin, visfatin, and vaspin were statistically significantly higher in seminal plasma than in serum. An increase in body weight was associated with decreased levels of seminal plasma progranulin. Additionally, overweight/obese men had statistically significantly lower progranulin levels in seminal plasma than normal weight men. Adiponectin and progranulin concentrations in seminal plasma statistically significantly positively correlated with sperm concentration, sperm count, and total normomorphic spermatozoa.. Adipokines are differently regulated in human male reproductive tract compared with the peripheral blood, and they could influence sperm functionality. Topics: Adipokines; Adiponectin; Adult; Body Weight; Chemokines; Cross-Sectional Studies; Cytokines; Fertility; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Overweight; Progranulins; Resistin; Semen; Serpins; Spermatozoa; Young Adult | 2013 |
Elevated serum leptin levels in nonobese patients with psoriasis.
Leptin, an adipocyte-derived hormone, has been shown to have several immunological effects similar to those of proinflammatory cytokines. The relationship between serum leptin, psoriasis, and obesity is still conflicted, and very few studies have investigated its role in skin diseases other than psoriasis.. To evaluate the possible relationship between serum leptin in nonobese patients with psoriasis and other randomly selected skin diseases.. Eighty subjects (40 patients with psoriasis, 20 patients with other randomly selected skin diseases, and 20 healthy controls) were included in the study. Fasting serum leptin levels of the study groups were examined by sandwich enzyme-linked immunosorbent assay.. Elevated serum leptin levels were detected in both nonobese patients with psoriasis (P=.004) and those with other randomly selected skin diseases (P=.05). Leptin levels failed to correlate to the Psoriasis Area and Severity Index score of psoriatic patients. Both sexes demonstrated comparable levels of serum leptin in psoriatic patients, while female patients suffering from other skin diseases showed higher levels of serum leptin than did males of the same group.. Leptin may play a role in the immunopathogenesis of psoriasis and other skin diseases, even in the absence of obesity as a cofactor. Topics: Adult; Aged; Body Mass Index; Body Weight; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Male; Middle Aged; Obesity; Psoriasis; Severity of Illness Index; Skin; Skin Diseases; Young Adult | 2013 |
Anti-obesity effect of Lactobacillus gasseri BNR17 in high-sucrose diet-induced obese mice.
Previously, we reported that Lactobacillus gasseri BNR17 (BNR17), a probiotic strain isolated from human breast milk, inhibited increases in body weight and adipocyte tissue weight in high-sucrose diet-fed Sprague-Dawley (SD) rats and reduced glucose levels in type 2 diabetes mice. In the current study, we conducted further experiments to extend these observations and elucidate the mechanism involved. C57BL/6J mice received a normal diet, high-sucrose diet or high-sucrose diet containing L. gasseri BNR17 (10(9) or 10(10) CFU) for 10 weeks. The administration of L. gasseri BNR17 significantly reduced the body weight and white adipose tissue weight regardless of the dose administered. In BNR17-fed groups, mRNA levels of fatty acid oxidation-related genes (ACO, CPT1, PPARα, PPARδ) were significantly higher and those of fatty acid synthesis-related genes (SREBP-1c, ACC) were lower compared to the high-sucrose-diet group. The expression of GLUT4, main glucose transporter-4, was elevated in BNR17-fed groups. L. gasseri BNR17 also reduced the levels of leptin and insulin in serum. These results suggest that the anti-obesity actions of L. gasseri BNR17 can be attributed to elevated expression of fatty acid oxidation-related genes and reduced levels of leptin. Additionally, data suggested the anti-diabetes activity of L. gasseri BNR17 may be to due elevated GLUT4 and reduced insulin levels. Topics: Adipose Tissue; Animals; Body Weight; Dietary Sucrose; Disease Models, Animal; Gene Expression Regulation; Humans; Insulin; Lactobacillus; Leptin; Liver; Male; Mice; Mice, Obese; Obesity; Probiotics; RNA, Messenger | 2013 |
Antioxidant treatment prevents the development of fructose-induced abdominal adipose tissue dysfunction.
In the present study, we tested the effect of OS (oxidative stress) inhibition in rats fed on an FRD [fructose-rich diet; 10% (w/v) in drinking water] for 3 weeks. Normal adult male rats received a standard CD (commercial diet) or an FRD without or with an inhibitor of NADPH oxidase, APO (apocynin; 5 mM in drinking water; CD-APO and FRD-APO). We thereafter measured plasma OS and metabolic-endocrine markers, AAT (abdominal adipose tissue) mass and cell size, FA (fatty acid) composition (content and release), OS status, LEP (leptin) and IRS (insulin receptor substrate)-1/IRS-2 mRNAs, ROS (reactive oxygen species) production, NADPH oxidase activity and LEP release by isolated AAT adipocytes. FRD-fed rats had larger AAT mass without changes in body weight, and higher plasma levels of TAG (triacylglycerol), FAs, TBARS (thiobarbituric acid-reactive substance) and LEP. Although no significant changes in glucose and insulin plasma levels were observed in these animals, their HOMA-IR (homoeostasis model assessment of insulin resistance) values were significantly higher than those of CD. The AAT from FRD-fed rats had larger adipocytes, higher saturated FA content, higher NADPH oxidase activity, greater ROS production, a distorted FA content/release pattern, lower insulin sensitivity together with higher and lower mRNA content of LEP and IRS-1-/2 respectively, and released a larger amount of LEP. The development of all the clinical, OS, metabolic, endocrine and molecular changes induced by the FRD were significantly prevented by APO co-administration. The fact that APO treatment prevented both changes in NADPH oxidase activity and the development of all the FRD-induced AAT dysfunctions in normal rats strongly suggests that OS plays an important role in the FRD-induced MS (metabolic syndrome) phenotype. Topics: Abdominal Fat; Acetophenones; Adipocytes; Animals; Antioxidants; Biomarkers; Body Weight; Eating; Fatty Acids; Fructose; Homeostasis; Leptin; Male; Metabolic Diseases; NADPH Oxidases; Oxidative Stress; Rats; Rats, Wistar; Sweetening Agents | 2013 |
Positive correlation between serum taurine and adiponectin levels in high-fat diet-induced obesity rats.
The purpose of this study was to investigate the relationship between serum taurine level and serum adiponectin or leptin levels in high-fat diet-induced obesity rats. Five-week-old male Sprague-Dawley rats were randomly divided into three groups for a period of 8 weeks (normal diet, N group; high-fat diet, HF group; high-fat diet + taurine, HFT group). Taurine was supplemented by dissolving in feed water (3% w/v), and the same amount of distilled water was orally administrated to N and HF groups. In serum, adiponectin level was higher in HFT group compared to HF group. The serum taurine level was negatively correlated with serum total cholesterol (TC) level and positively correlated with serum adiponectin level. These results suggest that dietary taurine supplementation has beneficial effects on total cholesterol and adiponectin levels in high-fat diet-induced obesity rats. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Leptin; Lipids; Male; Obesity; Organ Size; Rats; Rats, Sprague-Dawley; Taurine | 2013 |
Effects of late gestational high-fat diet on body weight, metabolic regulation and adipokine expression in offspring.
Gestational exposures such as dietary changes can alter offspring phenotype through epigenetic modifications and promote increased risk for specific diseases, such as metabolic syndrome. We hypothesized that high-fat diet (HFD) during late gestation would lead increased risk for insulin resistance and hyperlipidemia via associated epigenetic alterations in tissue adipocytokine genes.. Offspring mice of mothers fed a HFD during late gestation (HFDO) were weighed and their food intake measured weekly till age 20 weeks at which time glucose and insulin tolerance tests, plasma lipid and adipocytokine levels were assessed, as well as mRNA expression in visceral fat. Adipocytokine gene methylation levels in visceral fat, liver and muscle were also assayed.. HFDO mice had increased weight accrual and food intake, and exhibited insulin resistance, hyperlipidemia and hyperleptinemia, as well as hypoadiponectinemia. Furthermore, increased methylation of adiponectin and leptin receptor, and decreased methylation of leptin genes with unchanged glucagon-like peptide-1 methylation patterns emerged in HFDO mice.. Taken together, late gestational HFD induces increased risk of metabolic syndrome in the progeny, which is coupled with hypoadiponectinemia as well as with leptin resistance, and concomitant presence of selective tissue-based epigenetic changes among adipocytokine genes. Topics: Acetylation; Adiponectin; Animals; Animals, Newborn; Body Weight; Diet, High-Fat; Epigenesis, Genetic; Female; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Liver; Male; Metabolic Syndrome; Metabolism, Inborn Errors; Mice; Mice, Inbred C57BL; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Time Factors | 2013 |
Chronic vagus nerve stimulation reduces body fat, blood cholesterol and triglyceride levels in rats fed a high-fat diet.
There is growing evidence that vagus nerve stimulation (VNS) exerts a suppressive effect on both short- and long-term feeding in animal models. We previously showed that VNS with high-frequency (10 Hz) electrical impulses decreased food intake and body weight in rats. In the present study, we investigated the effect of VNS with a low frequency (1 Hz) on the serum lipid concentrations, feeding behavior and appetite in rats fed a high-fat diet. The levels of appetite-regulating peptides were also assessed. Adult male Wistar rats were subcutaneously implanted with a microstimulator (MS) and fed a high-fat diet throughout the entire study period (42 days). The left vagus nerve was stimulated subdiaphragmatically by rectangular electrical pulses (10 ms, 200 mV, 1 Hz, 12 h a day) generated by the MS. The daily food intake and body weight were measured each morning. At the end of the experiments, the serum glucose, cholesterol, triglycerides, low-density lipoproteins, high-density lipoproteins, ghrelin, leptin and nesfatin-1 concentrations were measured. The adipose tissue content was evaluated by the assessment of the weight of the epididymal fat pads. Chronic VNS significantly decreased food intake, body weight gain and epididymal fat pad weight. VNS also lowered the total plasma cholesterol concentrations and triglyceride levels. Finally, the serum concentrations of nesfatin-1 were elevated, leptin levels were decreased, and ghrelin levels remained unchanged after VNS. The study demonstrates that chronic electrical VNS exerts anorexigenic effects, lowering the blood concentration of lipids. Increased nesfatin-1 levels may contribute to these effects. Topics: Adipose Tissue; Adult; Animals; Body Weight; Cholesterol; Diet, High-Fat; Eating; Humans; Leptin; Male; Models, Animal; Obesity; Rats; Rats, Wistar; Triglycerides; Vagus Nerve; Vagus Nerve Stimulation; Weight Gain | 2012 |
Inhibition of soluble epoxide hydrolase reduces food intake and increases metabolic rate in obese mice.
This study evaluated the responses to soluble epoxide hydrolase (s-EH) inhibition, an essential enzyme in the metabolism of arachidonic acid, on food intake, body weight and metabolic parameters in mice fed a high fat-high fructose diet (HFD) for 10 weeks.. After 5 weeks of HFD, mice were divided into two groups: 1) s-EH inhibitor (AR9281, 200mg/kg/day by gavage twice daily), and 2) vehicle (0.3ml per gavage). Food intake, body weight, oxygen consumption (VO(2)), carbon dioxide production (VCO(2)), respiratory quotient (RQ), and motor activity were measured weekly for more 5 weeks. HFD increased body weight (37±1 vs. 26±1g), and plasma of glucose (316±8 vs. 188±27mg/dl), insulin (62.1±8.1 vs. 15.5±5.0μU/ml), and leptin levels (39.4±3.6 vs. 7.5±0.1ng/ml) while reducing VO(2), VCO(2) and motor activity. s-EH inhibition for 5 weeks decreased caloric intake by ~32% and increased VO(2) by ~17% (42.8±1.4 vs. 50.2±1.5ml/kg/min) leading to significant weight loss. Inhibition of s-EHi also caused significant reductions in plasma leptin levels and visceral fat content. Uncoupling protein 1 (UCP1) content in brown adipose tissue was also elevated by ~50% during s-EH inhibition compared to vehicle treatment.. These results suggest that s-EH inhibition with AR9281 promotes weight loss by reducing appetite and increasing metabolic rate, and that increased UCP1 content may contribute to the increase in energy expenditure. Topics: Adipose Tissue, Brown; Animals; Arachidonic Acid; Blood Glucose; Body Weight; Diet; Dietary Fats; Energy Intake; Energy Metabolism; Epoxide Hydrolases; Fructose; Hormones; Insulin; Ion Channels; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondrial Proteins; Obesity; Oxygen Consumption; Uncoupling Protein 1; Uncoupling Protein 3 | 2012 |
Angiotensin-converting enzyme inhibition reverses diet-induced obesity, insulin resistance and inflammation in C57BL/6J mice.
Angiotensin-converting enzyme (ACE) inhibition can reduce the body weight of mice maintained on a high-fat diet. The current study examined the effect of the ACE inhibitor, captopril (CAP), on the reversal of diet-induced obesity (DIO), insulin resistance and inflammation in mice.. DIO was produced in C57BL/6J male mice (n=30) by maintaining animals on a high-fat diet (w/w 21% fat) for 12 weeks. During the subsequent 12-week treatment period, the animals were allowed access to the high-fat diet and either water containing CAP (0.05 mg ml(-1)) or plain tap water (CON, control).. From the first week of treatment, food intake and body weight decreased in CAP-treated mice compared with CON mice. Both peripheral insulin sensitivity and hepatic insulin sensitivity were improved in CAP-treated mice compared with CON mice. CAP-treated mice had decreased absolute and relative liver and epididymal fat weights compared with CON mice. CAP-treated mice had higher plasma adiponectin and lower plasma leptin levels than CON mice. Relative to CON mice, CAP-treated mice had reduced adipose and skeletal muscle monocyte chemoattractant protein 1 (MCP-1), adipose interleukin-6 (IL-6), toll-like receptor 4 (TLR4) and uncoupling protein 2 (UCP2) mRNA expressions. Furthermore, CAP-treated mice had increased peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), long chain acyl-CoA dehydrogenase (LCAD), hormone sensitive lipase (HSL) and decreased lipoprotein lipase (LPL) mRNA expressions in the liver.. The results of the current study indicate that in mice with DIO, CAP treatment reduced food intake and body weight, improved insulin sensitivity and decreased the mRNA expression of markers of inflammation. Thus, CAP may be a viable treatment for obesity, insulin resistance and inflammation. Topics: Acyl-CoA Dehydrogenase, Long-Chain; Adiponectin; Adipose Tissue; Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Body Weight; Captopril; Chemokine CCL2; Diet, High-Fat; Gene Expression Regulation; Glucose Tolerance Test; Inflammation; Insulin Resistance; Interleukin-6; Ion Channels; Leptin; Lipid Metabolism; Lipoprotein Lipase; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Muscle, Skeletal; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Sterol Esterase; Toll-Like Receptor 4; Trans-Activators; Transcription Factors; Uncoupling Protein 2 | 2012 |
Hypocholesterolemic Effects of N-[(2-Hydroxy-3-N,N-Dimethylhexadecyl Ammonium)Propyl] Chitosan Chloride in High-Fat-Diet-Induced Rats.
In this paper, the potential hypocholesterolemic effect of N-[(2-hydroxy-3-N,N-dimethylhexadecyl ammonium)propyl] chitosan chloride (N-CQCs) was studied. In vivo hypocholesterolemic tests of N-CQCs were carried out to examine the effect on LDL, HDL, TC, leptin, FFA and SOD. The results showed that LDL, TC, leptin and FFA were decreased after supplementation with N-CQCs in the high-fat diet, preliminarily indicating that N-CQCs have a better hypocholesterolemic effect than chitosan. SOD was significantly elevated by N-CQCs compared with that of HF and HFC groups. N-CQCs increased antioxidant activity of SOD, indicating that N-CQCs regulated antioxidant enzyme activities and might reduced lipid peroxidation. Topics: Adipose Tissue; Animals; Anticholesteremic Agents; Body Weight; Chitosan; Diet, High-Fat; Feces; Leptin; Lipids; Male; Rats; Rats, Wistar; Superoxide Dismutase | 2012 |
Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain.
The hormones leptin and ghrelin act in apposition to one another in the regulation of body weight homeostasis. Interestingly, both leptin receptor expression and ghrelin receptor expression have been observed within many of the same nuclei of the central nervous system (CNS), suggesting that these hormones may act on a common population of neurons to produce changes in food intake and energy expenditure. In the present study we explored the extent of this putative direct leptin and ghrelin interaction in the CNS and addressed the question of whether a loss of ghrelin signaling would affect sensitivity to leptin. Using histological mapping of leptin receptor and ghrelin receptor expression, we found that cells containing both leptin receptors and ghrelin receptors are mainly located in the medial part of the hypothalamic arcuate nucleus. In contrast, coexpression was much less extensive elsewhere in the brain. To assess the functional consequences of this observed receptor distribution, we explored the effect of ghrelin receptor deletion on leptin sensitivity. In particular, the responses of ad libitum-fed, diet-induced obese and fasted mice to the anorectic actions of leptin were examined. Surprisingly, we found that deletion of the ghrelin receptor did not affect the sensitivity to exogenously administrated leptin. Thus, we conclude that ghrelin and leptin act largely on distinct neuronal populations and that ghrelin receptor deficiency does not affect sensitivity to the anorexigenic and body weight-lowering actions of leptin. Topics: Animals; Body Weight; Brain; Diet, High-Fat; Ghrelin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Obesity; Receptors, Ghrelin; Receptors, Leptin; Recombinant Fusion Proteins; RNA, Messenger | 2012 |
Abnormal leptin bioavailability in adolescent idiopathic scoliosis: an important new finding.
This was a cross-sectional study.. The present study aimed to explore the differences in leptin bioavailability between adolescent idiopathic scoliosis (AIS) and healthy age-matched girls in a Chinese Han population.. AIS is a common spinal deformity mainly occurring in girls during the peripubertal period. The development of scoliosis is related to relative anterior spinal overgrowth. AIS girls also have associated lower body mass index (BMI) and lower bone mineral status. Leptin, together with soluble leptin receptor (sOB-R), was shown to play an important role in the regulation of bone and energy metabolism in children. It was hypothesized that leptin and sOB-R are abnormal and associated with deranged growth and anthropometric phenotypes in AIS girls.. Serum leptin and sOB-R were measured together with documentation of anthropometric parameters and clinical data in 95 AIS girls and 46 healthy matched controls (age 11-16 years). Serum leptin and sOB-R concentrations were measured by enzyme-linked immunosorbent assay and correlated with the different measured parameters.. AIS girls had significantly lower BMI and longer arm span than healthy controls. AIS girls were found to have significantly higher sOB-R levels and lower free leptin index (FLI) after adjusting for age and body weight in multivariate regression analysis. Significant correlation was found between sOB-R, FLI, and curve severity in AIS girls.. This is the first study demonstrating the presence of abnormal leptin bioavailability in AIS girls that might play an important role in the etiopathogenesis of AIS. Further investigation is required to provide a better understanding of the underlying mechanisms, with the aim to explore the potential clinical application as a biomarker for predicting curve initiation or progression in AIS. Topics: Adolescent; Anthropometry; Body Height; Body Weight; Child; Cross-Sectional Studies; Female; Humans; Leptin; Receptors, Leptin; Scoliosis | 2012 |
Leptin levels are associated with decreased depressive symptoms in women across the weight spectrum, independent of body fat.
Leptin is anorexigenic, and levels are markedly decreased in women with low body weight and high in women with obesity. Ghrelin opposes leptin effects on appetite and is negatively associated with body mass index. These appetite-regulating hormones may have opposing effects on mood and stress pathways. Women with anorexia nervosa (AN), hypothalamic amenorrhoea (HA) and obesity are at increased risk of depression and anxiety. It is unknown whether dysregulation of leptin or ghrelin contributes to the development of depression and/or anxiety in these disorders. We investigated the relationship between leptin and ghrelin levels and symptoms of depression, anxiety and perceived stress in women across the weight spectrum.. Cross-sectional.. 64 women: 15 with AN, 12 normal-weight with HA, 17 overweight or obese (OB) and 20 normal-weight in good health (HC).. Fasting serum leptin and plasma ghrelin levels were measured. Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A) and the Perceived Stress Scale were administered.. Leptin levels were inversely associated with HAM-D, HAM-A and Perceived Stress scores. The negative relationships between leptin and severity of symptoms of both depression and anxiety remained significant after controlling for body fat or weight. There was no relationship between ghrelin and symptoms of depression or anxiety. Although ghrelin levels were positively associated with the degree of perceived stress, this relationship was not significant after controlling for body fat or weight.. Leptin may mediate depressive symptoms across the weight spectrum. Further investigation of the role of leptin in modulating mood will be important. Topics: Adipose Tissue; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Cross-Sectional Studies; Depression; Fasting; Female; Ghrelin; Humans; Leptin; Obesity | 2012 |
The temporal impact of chronic intermittent psychosocial stress on high-fat diet-induced alterations in body weight.
Chronic stress and diet can independently or in concert influence the body's homeostasis over time. Thus, it is crucial to investigate the interplay of these parameters to gain insight into the evolution of stress-induced metabolic and eating disorders.. C57BL/6J mice were subjected to chronic psychosocial (mixed model of social defeat and overcrowding) stress in combination with either a high- or low-fat diet for three or six weeks. To determine the evolution of stress and dietary effects, changes in body weight, caloric intake and caloric efficiency were determined as well as circulating leptin, insulin, glucose and corticosterone levels and social avoidance behaviour.. Exposure to stress for three weeks caused an increase in weight gain, in caloric intake and in caloric efficiency only in mice on a low-fat diet. However, after six weeks, only stressed mice on a high-fat diet displayed a pronounced inhibition of body weight gain, accompanied by reduced caloric intake and caloric efficiency. Stress decreased circulating leptin levels in mice on a low-fat diet after three weeks and in mice on a high-fat diet after three and six weeks of exposure. Plasma levels of insulin and markers of insulin resistance were blunted in mice on high-fat diet following six weeks of stress exposure. Social avoidance following chronic stress was present in all mice after three and six weeks.. This study describes the evolution of the chronic effects of social defeat/overcrowding stress in combination with exposure to high- or low-fat diet. Most importantly, we demonstrate that a six week chronic exposure to social defeat stress prevents the metabolic effects of high-fat diet, by inhibiting an increase in weight gain, caloric intake and efficiency and insulin resistance as well as in plasma leptin and insulin levels. This study highlights the importance of considering the chronic aspects of both parameters and their time-dependent interplay. Topics: Animals; Blood Glucose; Body Weight; Chronic Disease; Corticosterone; Crowding; Diet, High-Fat; Energy Intake; Insulin; Interpersonal Relations; Leptin; Male; Mice; Mice, Inbred C57BL; Social Dominance; Social Environment; Stress, Psychological; Weight Gain | 2012 |
Treatment with a constitutive androstane receptor ligand ameliorates the signs of preeclampsia in high-fat diet-induced obese pregnant mice.
Constitutive androstane receptor (CAR) has been reported to decrease insulin resistance, while obesity and insulin resistance may also be involved in the pathogenesis of preeclampsia. We examined whether a CAR ligand, 1,4-bis(2-(3,5-dichloropyridyloxy)) benzene (TCPOBOP), can ameliorate the signs of preeclampsia in high-fat diet (HFD)-induced obese pregnant mice to examine a possibility of CAR as a therapeutic target. We employed six groups including non-pregnant, HFD-fed or control diet-fed pregnant mice with or without TCPOBOP treatment (n=6). In HFD pregnant mice, insulin resistance increased with increasing expression of gluconeogenic and lipogenic genes and abnormal adipocytokine levels. TCPOBOP treatment, which was once-weekly intraperitoneal injections (0.5 mg/kg) and started at day 0.5 of pregnancy, improved glucose tolerance with significant changes of gluconeogenic, lipogenic and adipocytokine genes. HFD pregnant mice had hypertension and proteinuria, while TCPOBOP treatment ameliorated these signs. Our data suggested CAR might be a potential therapeutic target for obese preeclampsia patients with insulin resistance. Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Constitutive Androstane Receptor; Diet, High-Fat; Female; Gene Expression; Gluconeogenesis; Gonadal Steroid Hormones; Hydrocortisone; Insulin; Leptin; Lipogenesis; Male; Mice; Mice, Inbred ICR; Obesity; Pre-Eclampsia; Pregnancy; Pyridines; Receptors, Cytoplasmic and Nuclear | 2012 |
Variations in thermal physiology and energetics of the tree shrew (Tupaia belangeri) in response to cold acclimation.
Variations in environmental factors instigate significant changes in the physiology and behavior of animals, necessary for their survival. The present study investigated the hypothesis that ambient temperature is a cue capable of inducing changes in body mass, energy intake, and thermogenic capacity. Moreover, the current study determined the potential role of leptin in regulating adaptive thermogenesis in tree shrews (Tupaia belangeri). The tree shrew was chosen as the experimental animal as they inhabit a wide area of Asia and must acclimatize to the cold. Animals were subjected to either 5° C over 28 days to simulate cold acclimation, or maintained under the original climate of room temperature. At 28 days cold-acclimatized shrews had increased body mass by 9.41 g compared to controls. The increase in body mass was found primarily to be due to growth of the digestive organs, combined with significantly increased food intake. Under cold acclimation, uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) was significantly elevated, while serum leptin concentration was significantly depressed below control levels. Serum leptin concentration was negatively correlated with body mass, energy intake, and thermogenic capacity during cold acclimation. In summary, these findings indicate that tree shrews adjust energy intake, thermogenic capacity, and body reserves in response to the cold, and further suggest that circulating leptin may act as a key signaling protein to regulate these adaptations. Topics: Acclimatization; Adaptation, Physiological; Adipose Tissue, Brown; Animals; Body Weight; Cold Temperature; Eating; Energy Intake; Female; Ion Channels; Leptin; Male; Mitochondrial Proteins; Thermogenesis; Tupaia; Uncoupling Protein 1 | 2012 |
Effect of fermented Angelicae gigantis Radix on carbon tetrachloride-induced hepatotoxicity and oxidative stress in rats.
This study is aimed to evaluate the protective effect of fermented Angelicae gigantis Radix (AGR) with Monascus purpureus strain on carbon tetrachloride (CCl(4))-induced hepatotoxicity and oxidative stress in rats. The activities of liver marker enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and the levels of lipid peroxidation were increased when CCl(4) was treated but these parameters were significantly decreased by fermented AGR treatment. CCl(4) treatment exhibited decrease in serum concentrations of triglyceride, total cholesterol, HDL-cholesterol, and free fatty acids, and these were also decreased by fermented AGR administration. The level of serum leptin was significantly lower in fermented AGR administration than that in normal control group. CCl(4) treatment significantly increased the concentration of liver triglyceride. The current study observed significant elevations of the thiobarbituric acid-reactive substances (TBARS) levels in the liver homogenate, mitochondrial, and microsomal fractions of CCl(4) control group compared with normal control group. CCl(4) treatment resulted in a significant decrease in the levels of plasma and hepatic glutathione, but these reductions were significantly increased by fermented AGR administration. CCl(4) induced the marked hepatocytes necrosis and fatty accumulation around the central veins. Accordingly, fermented AGR may be an ideal candidate for the hepatoprotective effect in animal model. Topics: Adipose Tissue, White; Angelica; Animals; Body Weight; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Coumarins; Drinking; Eating; Enzymes; Fermentation; Glutathione; Leptin; Lipids; Liver; Male; Microsomes, Liver; Mitochondria, Liver; Monascus; Necrosis; Organ Size; Oxidative Stress; Phytotherapy; Plant Extracts; Plant Roots; Rats; Rats, Sprague-Dawley; Thiobarbituric Acid Reactive Substances; Zinc | 2012 |
Seasonal changes in body mass, energy intake and thermogenesis in Maximowiczi's voles (Microtus maximowiczii) from the Inner Mongolian grassland.
Small mammals inhabiting temperate and arctic regions exhibit annual adaptive adjustments in physiology, anatomy, and behavior. No data on the physiology of Maximowicz's voles (Microtus maximowiczii) are available at present. Here we examined the seasonal changes in body mass, food intake, thermogenic capacity, serum leptin and thyroid hormone levels in wild-captured individuals from Inner Mongolian grassland, China. We further examined the effects of photoperiod on these parameters. Energy intake, resting metabolic rate, nonshivering thermogenesis (NST), and serum tri-iodothyronine (T3) levels increased while serum leptin and body mass decreased in the cold seasons. Serum T3 levels were positively correlated with NST and uncoupling protein 1 (UCP1) contents in brown adipose tissue, and leptin levels were negatively correlated with energy intake and resting metabolic rate. Furthermore, laboratory data showed these changes could be induced by short photoperiod alone. Taken together, our results indicate that Maximowicz's voles can increase thermogenic capacity and energy intake to cope with cold stress. Serum leptin seems to be involved in the regulation of energy intake and changes in T3 level may be important for the variations in NST and/or UCP1. Short photoperiod can serve as a seasonal cue for the winter acclimatization of energy balance in free-living Maximowicz's voles. Topics: Adaptation, Physiological; Adipose Tissue, Brown; Analysis of Variance; Animals; Arvicolinae; Body Weight; China; Electron Transport Complex IV; Energy Metabolism; Ion Channels; Leptin; Mitochondrial Proteins; Photoperiod; Seasons; Thermogenesis; Uncoupling Protein 1 | 2012 |
Impact of perinatal prebiotic consumption on gestating mice and their offspring: a preliminary report.
To assess the impact of prebiotic supplementation during gestation and fetal and early neonatal life, gestating BALB/cj dam mice were fed either a control or a prebiotic (galacto-oligosaccharides-inulin, 9:1 ratio)-enriched diet throughout pregnancy and lactation, and allowed to nurse their pups until weaning. At the time of weaning, male offspring mice were separated from their mothers, weaned to the same solid diet as their dam and their growth was monitored until killed 48 d after weaning. Prebiotic treatment affected neither the body-weight gain nor the food intake of pregnant mice. In contrast, at the time of weaning, pups that had been nursed by prebiotic-fed dams had a higher body weight (11.0 (se 1.2) g) than pups born from control dams (9.8 (se 0.9) g). At 48 d after weaning, significantly higher values were observed for colon length and muscle mass in the offspring of prebiotic-fed dams (1.2 (se 0.1) cm/cm and 5.7 (se 1.8) mg/g, respectively), compared with control offspring (1.1 (se 0.1) cm/cm and 2.9 (se 0.9) mg/g, respectively), without any difference in spleen and stomach weight, or serum leptin concentration. The present preliminary study suggests that altering the fibre content of the maternal diet during both pregnancy and lactation enhances offspring growth, through an effect on intestinal and muscle mass rather than fat mass accretion. Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Colon; Dietary Supplements; Female; Galactose; Inulin; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Mice; Mice, Inbred BALB C; Oligosaccharides; Organ Size; Prebiotics; Pregnancy; Spleen; Stomach; Time Factors | 2012 |
Cold exposure down-regulates adiponutrin/PNPLA3 mRNA expression and affects its nutritional regulation in adipose tissues of lean and obese Zucker rats.
Adiponutrin/PNPLA3 is a protein highly produced in adipose tissue whose expression is under tight nutritional regulation. It possesses lipogenic/lipolytic capacity and, although adiponutrin polymorphisms are related to obesity, its physiological role is not clear. To help clarify its role, we studied the effect of acute cold exposure on adiponutrin mRNA expression in different adipose tissues of lean/obese Zucker rats subjected to feeding/fasting/refeeding. The effect of cold on the expression of key lipogenic enzymes and on uncoupling protein-1 (UCP1) was evaluated in selected adipose depots. Adiponutrin mRNA levels were also determined in the adipose tissue of isoprenaline-treated rats and in cultured adipocytes treated with noradrenaline, isoprenaline and a selective β3-adrenoceptor (AR) agonist. Adiponutrin expression was strongly down-regulated by cold in the different adipose depots in lean animals, while this down-regulation was impaired in obese rats. Adiponutrin pattern of expression in response to cold correlated positively with that of the lipogenic enzymes and negatively with UCP1 expression. Acute intraperitoneal administration of isoprenaline also produced a decrease in adiponutrin expression in adipose tissue. In vitro data suggest that adiponutrin's inhibitory effect could be mediated, at least in part, by the sympathetic system via β1/β2-AR. In addition, improvement in metabolic parameters related to obesity in cold-exposed animals was related to an improvement in adiponutrin nutritional regulation. Thus, cold inhibition of adiponutrin expression in adipose tissue (which correlates with the response of lipogenic enzymes) supports a physiological role for this protein in lipogenesis. Moreover, alterations in adiponutrin expression and regulation in adipose tissue are related to obesity. Topics: Adipocytes; Adipose Tissue; Animal Nutrition Sciences; Animals; Blood Glucose; Body Weight; Cells, Cultured; Cold Temperature; Disease Models, Animal; Gene Expression Regulation; Insulin; Insulin Resistance; Ion Channels; Isoproterenol; Leptin; Male; Membrane Proteins; Mice; Mitochondrial Proteins; Norepinephrine; Obesity; Rats; Rats, Zucker; Receptors, Adrenergic, beta-3; RNA, Messenger; Time Factors; Uncoupling Protein 1 | 2012 |
Altered sciatic nerve fiber morphology and endoneural microvessels in mouse models relevant for obesity, peripheral diabetic polyneuropathy, and the metabolic syndrome.
The morphology of sciatic nerves from leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice, both models for obesity, peripheral diabetic neuropathy, and the metabolic syndrome, has yet to be examined for changes in nerve fibers and in endoneural microvessels. Sciatic nerves from three groups of 4-month-old mice (WT C57BL6, ob/ob, and db/db) were investigated. In ultrathin sections, the thickness of myelin sheaths was significantly reduced in small, medium-sized, and large axons of db/db mice compared with WT mice. In ob/ob mice, only large fibers showed a decrease in myelin sheath thickness. The number of nonmyelinated nerve fibers was lower in ob/ob mice than in the db/db group. A thickened basal lamina of Schwann cells occurred in the ob/ob group only. In contrast, the basement membrane of endoneural microvessels was thickened in both obese groups. For this reason, laminin expression in Western blot analysis was lower in the db/db group than in the ob/ob one. Endoneural microvessels, which had been injected with fluorescein isothiocyanate, depicted signs of vasodilatation in the ob/ob and vasoconstriction in db/db mice. Endoneural vessels displayed two receptors of oxLDL. LOX-1 was strongly expressed in db/db mice, whereas TLR4 was at its maximum in the ob/ob group. We conclude that changes in nerve fibers and in endoneural microvessels are present in sciatic nerve of both mouse models of type 2 diabetes. Upregulation of oxLDL-dependent receptors in endoneural microvessels might be connected to different degrees of oxidative stress in severe diabetic db/db mice and in the mild diabetic ob/ob group. Topics: Analysis of Variance; Animals; Basement Membrane; Body Weight; CD36 Antigens; Diabetic Neuropathies; Disease Models, Animal; Laminin; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Obese; Microscopy, Electron, Transmission; Microvessels; Myelin Sheath; Obesity; Oxidative Stress; Receptors, Leptin; Scavenger Receptors, Class E; Schwann Cells; Sciatic Nerve; Thiobarbituric Acid Reactive Substances; Toll-Like Receptor 4; von Willebrand Factor | 2012 |
The effect of three-month pre-season preparatory period and short-term exercise on plasma leptin, adiponectin, visfatin, and ghrelin levels in young female handball and basketball players.
The aim of the study was to assess the effect of a 3-month pre-season preparatory period and shortterm moderate aerobic exercise and intensive fitness and speed exercise on adipokine and ghrelin levels in young female handball and basketball players.. Fifty healthy young female professional basketball and handball players were enrolled into the study before the opening of the season (after a 2-month holiday with no training or dietary restrictions). Serum estradiol and plasma leptin, adiponectin, visfatin, and ghrelin levels were determined at the beginning and the end of a 3-month period of moderate aerobic training. Plasma adipokines and ghrelin levels were additionally assessed after 2 h of moderate aerobic exercise or after intensive fitness and speed exercise training.. Long-term moderate aerobic exercise was followed by a significant decrease in plasma ghrelin and leptin levels (921±300 vs 575±572 pg/ml, p<0.001 and 16.4±15.6 vs 11.8±16.3 ng/ml, p<0.01, respectively); plasma adiponectin and visfatin remained unchanged. No changes were observed in plasma ghrelin and leptin levels after short-term moderate aerobic exercise or after intensive fitness and speed exercise. Plasma visfatin concentration increased significantly after short-term moderate aerobic exercise (22.1±8.7 vs 27.6±9.0 ng/ml, p<0.001), whilst adiponectin increased after intensive fitness and speed exercise (16.7±7.8 vs 21.0±9.8 μg/ml, p<0.001).. Regular moderate aerobic training in preparation for the match season is followed by a decline in circulating leptin and ghrelin levels even in athletes without body weight changes. Short-term intensive fitness and moderate aerobic exercise seem to modulate the production of different adipokines. Topics: Adiponectin; Adult; Basketball; Body Weight; Exercise; Female; Ghrelin; Humans; Leptin; Nicotinamide Phosphoribosyltransferase; Time Factors; Young Adult | 2012 |
Antiobesity effect of Tamarindus indica L. pulp aqueous extract in high-fat diet-induced obese rats.
Obesity and overweight are associated with atherosclerosis, fatty liver, hyperlipemia, diabetes mellitus, and various types of cancer. The global prevalence of overweight and obesity has reached epidemic proportions. Here, we investigated the effect of Tamarindus indica pulp aqueous extract (TIE) in diet-induced obese Sprague-Dawley rats. The animals were divided into five groups and labeled as follows: the normal control (NC) group received normal diet; the positive control (PC) group received high-fat diet; and the TIE 5, 25, and 50 groups, after the induction of obesity via a high-fat diet, received TIE at 5, 25, or 50 mg/kg orally for 10 weeks. It was observed that TIE decreased the levels of plasma total cholesterol, low-density lipoprotein (LDL), and triglyceride, and increased high-density lipoprotein (HDL), with the concomitant reduction of body weight. Moreover, TIE decreased plasma leptin and reduced fatty acid synthase (FAS) activity and enhanced the efficiency of the antioxidant defense system. TIE exhibits antiobesity effects, as indicated by a significant reduction in adipose tissue weights, as well as lowering the degree of hepatic steatosis in the obesity-induced rats. The extract possesses hepatoprotective activity, as it reversed the plasma liver enzymes level elevation prior to the high-fat diet. In conclusion, TIE improved obesity-related parameters in blood, liver, and adipose tissue in a rat model and suppressed obesity induced by a high-fat diet, possibly by regulating lipid metabolism and lowering plasma leptin and FAS levels. A dose-dependant effect of TIE is detected, where TIE at 50 mg/kg showed the most prominent effect, followed by TIE at 25 mg/kg and, subsequently, 5 mg/kg. Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Diet, High-Fat; Eating; Insulin; Leptin; Male; Obesity; Plant Extracts; Rats; Rats, Sprague-Dawley; Tamarindus | 2012 |
Obesity alters circadian behavior and metabolism in sex dependent manner in the volcano mouse Neotomodon alstoni.
The aim of the present study is to evaluate whether circadian locomotor activity, and the daily profile of plasma parameters related to metabolic syndrome (nutrients: glucose and triacylglycerides, and hormones: insulin and leptin), differ between male and female Neotomodon alstoni mice, both lean and obese. Young adult animals were captured in the field and kept at the laboratory animal facility. After 6 to 7 months feeding the animals ad libitum with a regular diet for laboratory rodents, 50-60% of mice became obese. Comparisons between sexes indicated that lean females were more active than males; however obese females reduced their nocturnal activity either in LD or DD, and advanced the phase of their activity-onset with respect to lights off. No differences in food intake between lean and obese mice, either during the day or night, were observed. Daily profiles of metabolic syndrome-related plasma parameters showed differences between sexes, and obesity was associated with increased values, especially leptin (500% in females and 273% in males) and insulin (150% in both females and males), as compared with lean mice. Our results indicate that lean mice display behavioral and endocrine differences between sexes, and obesity affects the parameters tested in a sex-dependent manner. The aforementioned leads us to propose N. alstoni, studied in captivity, could be an interesting model for the study of sex differences in the effects of obesity. Topics: Analysis of Variance; Animals; Blood Glucose; Body Weight; Circadian Rhythm; Disease Models, Animal; Eating; Female; Insulin; Leptin; Male; Mice; Motor Activity; Obesity; Sex Characteristics; Triglycerides | 2012 |
Increased food intake and changes in metabolic hormones in response to chronic sleep restriction alternated with short periods of sleep allowance.
Rodent models for sleep restriction have good face validity when examining food intake and related regulatory metabolic hormones. However, in contrast to epidemiological studies in which sleep restriction is associated with body weight gain, sleep-restricted rats show a decrease in body weight. This difference with the human situation might be caused by the alternation between periods of sleep restriction and sleep allowance that often occur in real life. Therefore, we assessed the metabolic consequences of a chronic sleep restriction protocol that modeled working weeks with restricted sleep time alternated by weekends with sleep allowance. We hypothesized that this protocol could lead to body weight gain. Male Wistar rats were divided into three groups: sleep restriction (SR), forced activity control (FA), and home cage control (HC). SR rats were subjected to chronic sleep restriction by keeping them awake for 20 h per day in slowly rotating drums. To model the human condition, rats were subjected to a 4-wk protocol, with each week consisting of a 5-day period of sleep restriction followed by a 2-day period of sleep allowance. During the first experimental week, SR caused a clear attenuation of growth. In subsequent weeks, two important processes occurred: 1) a remarkable increase in food intake during SR days, 2) an increase in weight gain during the weekends of sleep allowance, even though food intake during those days was comparable to controls. In conclusion, our data revealed that the alternation between periods of sleep restriction and sleep allowance leads to complex changes in food intake and body weight, that prevent the weight loss normally seen in continuous sleep-restricted rats. Therefore, this "week-weekend" protocol may be a better model to study the metabolic consequences of restricted sleep. Topics: Animals; Body Weight; Corticosterone; Eating; Energy Metabolism; Glucose; Insulin; Leptin; Male; Models, Animal; Rats; Rats, Wistar; Sleep; Sleep Deprivation; Time Factors | 2012 |
Glucose tolerance in response to a high-fat diet is improved by a high-protein diet.
Consumption of a high-fat (HF) diet results in insulin resistance and glucose intolerance. Weight loss is often recommended to reverse these metabolic alterations and the use of a high-protein (HP), low-carbohydrate diet is encouraged. In lean rats, consumption of a HP diet improves glycemic control. However, it is unknown whether this diet has a similar effectiveness in rodents with impaired glucose tolerance. Rats were fed a HF or a chow (CH) diet for 6 weeks and then switched to a HP diet or a CH or pair-fed (PF) to the amount of kcals consumed per day by the HP group. Following the diet switch, body weight gain was attenuated as compared to HF rats, and similar between HP, CH, and PF rats. Despite similar weight progression, HP and PF rats had a significant decrease in body fat after 2 weeks, as compared to HF rats. In contrast, CH rats did not show this effect. Glucose tolerance was attenuated more quickly in HP rats than in CH or PF rats. These results indicate that a HP diet may be more effective than a balanced diet for improving glycemic control in overweight individuals. Topics: Adipose Tissue; Animals; Body Weight; Diet, Carbohydrate-Restricted; Diet, High-Fat; Dietary Proteins; Energy Intake; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Glucose Intolerance; Glucose Tolerance Test; Insulin; Leptin; Male; Radioimmunoassay; Rats; Rats, Long-Evans; Weight Loss | 2012 |
Effects of high-fat diet on plasma lipids, adiposity, and inflammatory markers in ovariectomized C57BL/6 mice.
We hypothesized that a high-fat (HF) diet aggravates ovariectomy-related complications. To test this hypothesis, ovariectomized (OVX) mice were fed a HF diet, and we investigated the lipid metabolism, adipose tissue remodeling, adipokines, and inflammatory cytokines.. To investigate the situation in a mouse model of ovariectomy, OVX and SHAM C57BL/6 mice fed a HF diet (60% fat) or standard chow (SC, 10% fat) were monitored for 18 wk. We evaluated daily food intake and weekly body weight. Mice were killed at 30 wk of age. Blood samples and adipose tissue were collected for biochemical, histologic, and molecular analysis.. OVX groups showed atrophied uterus compared to the SHAM groups, ensuring the success of surgically induced menopause. Despite lower food intake, OVX-HF mice gained about 52% more weight and had heavier total body fats, especially in relation to ovarian fat pad (372%)-a visceral fat which is associated with increased pathogenicity in obesity, and showed larger adipocytes (30%) when compared to OVX-SC mice. Biochemical analysis showed that the OVX-HF mice had increased levels of serum total cholesterol (51%), greater serum triglycerides (158%), lower serum adiponectin (40%), and higher plasma leptin (323%) than OVX-SC mice. The obese group (OVX-HF) also had higher IL-6 levels than both SHAM-HF (241%) and OVX-SC mice (870%).. OVX C57BL/6 mice fed HF diet had greater adipose fat pad, larger adipocytes, and increased inflammatory markers, reinforcing the idea that a HF diet aggravates the complications of ovariectomy-associated inflammation. Topics: Adipokines; Adiponectin; Adipose Tissue; Adiposity; Animals; Biomarkers; Body Weight; Cholesterol; Diet, High-Fat; Dietary Fats; Female; Inflammation; Interleukin-6; Leptin; Lipid Metabolism; Mice; Mice, Inbred C57BL; Obesity; Ovariectomy; Triglycerides | 2012 |
Dietary sardine protein lowers insulin resistance, leptin and TNF-α and beneficially affects adipose tissue oxidative stress in rats with fructose-induced metabolic syndrome.
The present study aims at exploring the effects of sardine protein on insulin resistance, plasma lipid profile, as well as oxidative and inflammatory status in rats with fructose-induced metabolic syndrome. Rats were fed sardine protein (S) or casein (C) diets supplemented or not with high-fructose (HF) for 2 months. Rats fed the HF diets had greater body weight and adiposity and lower food intake as compared to control rats. Increased plasma glucose, insulin, HbA1C, triacylglycerols, free fatty acids and impaired glucose tolerance and insulin resistance was observed in HF-fed rats. Moreover, a decline in adipose tissues antioxidant status and a rise in lipid peroxidation and plasma TNF-α and fibrinogen were noted. Rats fed sardine protein diets exhibited lower food intake and fat mass than those fed casein diets. Sardine protein diets diminished plasma insulin and insulin resistance. Plasma triacylglycerol and free fatty acids were also lower, while those of α-tocopherol, taurine and calcium were enhanced as compared to casein diets. Moreover, S-HF diet significantly decreased plasma glucose and HbA1C. Sardine protein consumption lowered hydroperoxide levels in perirenal and brown adipose tissues. The S-HF diet, as compared to C-HF diet decreased epididymal hydroperoxides. Feeding sardine protein diets decreased brown adipose tissue carbonyls and increased glutathione peroxidase activity. Perirenal and epididymal superoxide dismutase and catalase activities and brown catalase activity were significantly greater in S-HF group than in C-HF group. Sardine protein diets also prevented hyperleptinemia and reduced inflammatory status in comparison with rats fed casein diets. Taken together, these results support the beneficial effect of sardine protein in fructose-induced metabolic syndrome on such variables as hyperglycemia, insulin resistance, hyperlipidemia and oxidative and inflammatory status, suggesting the possible use of sardine protein as a protective strategy against insulin resistance and related situations. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cytokines; Diet; Dietary Proteins; Eating; Fish Proteins; Fructose; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Male; Metabolic Syndrome; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha | 2012 |
Viscous dietary fiber reduces adiposity and plasma leptin and increases muscle expression of fat oxidation genes in rats.
Dietary interventions that reduce accumulation of body fat are of great interest. Consumption of viscous dietary fibers cause well-known positive metabolic effects, such as reductions in the postprandial glucose and insulin concentrations. However, their effect on body composition and fuel utilization has not been previously studied. To examine this, rats were fed a viscous nonfermentable dietary fiber, hydroxypropyl methylcellulose (HPMC), for 6 weeks. Body composition was measured by dual-energy X-ray absorptiometry (DXA) and fat pad weight. Plasma adipokines, AMP kinase activation, and enzyme and mRNA analysis of key regulators of energetics in liver and soleus muscle were measured. The HPMC diet significantly lowered percent body fat mass and increased percent lean body mass, compared to a cellulose-containing diet (no viscosity). Fasting leptin was reduced 42% and resistin 28% in the HPMC group compared to the cellulose group. Rats fed HPMC had greater activation of AMP kinase in liver and muscle and lower phosphoenolpyruvate carboxykinase (PEPCK) expression in liver. mRNA expression in skeletal muscle was significantly increased for carnitine palmitoyltransferase 1B (CPT-1B), PPARγ coactivator 1α, PPARδ and uncoupling protein 3 (UCP3), as was citrate synthase (CS) activity, in the HPMC group relative to the cellulose group. These results indicate that viscous dietary fiber preserves lean body mass and reduces adiposity, possibly by increasing mitochondrial biogenesis and fatty acid oxidation in skeletal muscle, and thus represents a metabolic effect of viscous fiber not previously described. Thus, viscous dietary fiber may be a useful dietary component to assist in reduction of body fat. Topics: Absorptiometry, Photon; Adiposity; AMP-Activated Protein Kinases; Animals; Body Weight; Citrate (si)-Synthase; Dietary Fats; Dietary Fiber; Ion Channels; Leptin; Lipid Peroxidation; Liver; Male; Mitochondrial Proteins; Muscle, Skeletal; PPAR gamma; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Uncoupling Protein 3 | 2012 |
Repeated gastric distension alters food intake and neuroendocrine profiles in rats.
The consumption of a large food bolus leads to stomach distension. Gastric distension potently signals the termination of a meal by stimulating gastric mechanoreceptors and activating neuroendocrine circuitry. The ability to terminate a meal is altered in disorders such as bulimia nervosa (BN), binge-eating disorder (BED) and certain subtypes of obesity in which large quantities of food are frequently ingested. When a large meal is consumed, the stomach is rapidly stretched. We modeled this rapid distension of the stomach in order to determine if the neuroendocrine abnormalities present in these disorders, including increased gastric capacit3y, leptin dysregulation, and alterations in neuropeptide Y (NPY), and proopiomelanocortin (POMC) expression, were influenced by the rapid stretch aspect of repeatedly consuming a large meal. To test the effects of repeated gastric distension (RGD) on neuroendocrine factors involved in energy homeostasis, a permanent intra-gastric balloon was implanted in rats, and briefly inflated daily for 4 weeks. Though body weights and daily food intakes remained equivalent in RGD and control rats, a significant delay in the onset of feeding was present during the first and second, but not the third and fourth weeks of inflations. Despite equivalent body weights and daily caloric consumption, RGD animals had significantly decreased leptin levels (p<0.05), and tended to have increased fasting arcuate NPY levels (p=0.08), which were suppressed more than control animals following food intake (control and RGD decreases from baseline were 184.95% and 257.42%, respectively). NPY expression in the nucleus of the solitary tract followed a similar pattern. These data demonstrate that the act of regularly distending the stomach can have effects on the regulation of energy balance that are independent from those related to caloric consumption, and may be related to disorders such as BN, BED, and certain types of obesity in which meal termination is impaired. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Bulimia; Eating; Energy Metabolism; Feeding Behavior; Gastric Balloon; Hyperphagia; Leptin; Male; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Long-Evans; Solitary Nucleus; Stomach | 2012 |
Leanness in postnatally nutritionally programmed rats is associated with increased sensitivity to leptin and a melanocortin receptor agonist and decreased sensitivity to neuropeptide Y.
Pups of normally nourished dams that are cross-fostered after birth to dams fed a low-protein (8% by weight) diet (postnatal low protein (PLP)) grow slower during the suckling period and remain small and lean throughout adulthood. At weaning, they have increased expression in the arcuate nucleus (ARC) of the hypothalamus of the orexigenic neuropeptide Y (NPY) and decreased expression of pro-opiomelanocortin, the precursor of anorexigenic melanocortins.. We investigated, using third ventricle administration, whether 3-month-old male PLP rats display altered sensitivity to leptin with respect to food intake, NPY and the melanocortin 3/4-receptor agonist MTII, and using in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR, whether the differences observed were associated with changes in the hypothalamic expression of NPY or the leptin receptor, NPY receptors and melanocortin receptors.. PLP rats were smaller and had reduced percentage body fat content and plasma leptin concentration compared with control rats. Leptin (5 μg) reduced food intake over 0-48 h more in PLP than control rats (P<0.05). Submaximal doses of NPY increased the food intake less in PLP rats than in controls, whereas submaximal doses of MTII reduced the food intake more in PLP rats. Maximal responses did not differ between PLP and control rats. Leptin and melanocortin-3 receptor (MC3R) expression were increased in both ARC and ventromedial hypothalamic nuclei in PLP animals compared with the controls. MC4R, NPY Y1R, Y5R and NPY expression were unchanged.. Postnatal undernourishment results in food intake in adult rats being more sensitive to reduction by leptin and melanocortins, and less sensitive to stimulation by NPY. We propose that this contributes to increased leptin sensitivity and resistance to obesity. Increased expression of ObRb and MC3R may partly explain these findings but other downstream mechanisms must also be involved. Topics: Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Body Weight; Disease Susceptibility; Eating; Gene Expression Regulation; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Wistar; Receptor, Melanocortin, Type 3; Thinness; Time Factors; Weight Gain | 2012 |
Pu-erh tea, green tea, and black tea suppresses hyperlipidemia, hyperleptinemia and fatty acid synthase through activating AMPK in rats fed a high-fructose diet.
Although green tea extract has been reported to suppress hyperlipidemia, it is unclear how tea extracts prepared from green, oolong, black and pu-erh teas modulate fatty acid synthase expression in rats fed on a high-fructose diet. In this animal study, we evaluated the hypolipidemic and hypoleptinemia effect of these four different tea leaves fed to male Wistar rats for 12 weeks. The results showed that a fructose-rich diet significantly elevated serum triacylglycerols, cholesterol, insulin, and leptin concentrations, as compared with those in the control group. Interestingly, consuming tea leaves for 12 weeks almost normalized the serum triacylglycerols concentrations. Again, rats fed with fructose/green tea and fructose/pu-erh tea showed the greatest reduction in serum TG, cholesterol, insulin and leptin levels. In contrast, serum cholesterol and insulin concentrations of the fructose/oolong tea-fed rats did not normalize. The relative epididymal adipose tissue weight was lower in all rats supplemented with tea leaves than those fed with fructose alone. There was molecular evidence of improved lipid homeostasis according to fatty acid synthase (FAS) protein expression. Furthermore, supplementation of green, black, and pu-erh tea leaves significantly decreased hepatic FAS mRNA and protein levels, and increased AMPK phosphorylation, compared with those of rats fed with fructose only. These findings suggest that the intake of green, black, and pu-erh tea leaves ameliorated the fructose-induced hyperlipidemia and hyperleptinemia state in part through the suppression of FAS protein levels and increased AMPK phosphorylation. Topics: Adipose Tissue; Alanine Transaminase; AMP-Activated Protein Kinases; Animals; Antioxidants; Aspartate Aminotransferases; Blood Glucose; Body Weight; Cholesterol; Diet; Dietary Supplements; Fatty Acid Synthases; Fructose; Hyperlipidemias; Insulin; Leptin; Lipid Metabolism; Liver; Male; Phosphorylation; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; RNA, Messenger; Tea; Triglycerides | 2012 |
Variations of plasma leptin in show horses during a work season.
Leptin is an adipocytokine mainly expressed by adipose tissue. Secretion of leptin in healthy animals is closely related to fat mass and metabolic activity. The aim of this study was to investigate plasma leptin variations, in relation to nutritional and exercise parameters in adult show horses during a work season. EDTA-blood samples were taken at rest from 37 Iberian horses. Body weight, body condition score and fat percentage determined by ultrasonic measurement of rump fat thickness were measured. Plasma leptin was determined with a multi-species RIA kit. Linear mixed effects model was used to assess relationship between plasma leptin and other biological parameters. Plasma leptin concentration was <12.6 ng/ml (mean = 2.8 ± 1.6 ng/ml) and was significantly higher during training periods (p < 0.0001) (4.5 ± 1.7 ng/ml) than in show periods (2.0 ± 1.1 ng/ml), despite a significant increase (p < 0.0001) in energy intake. The body weight remained almost constant. The plasma leptin concentrations were significantly affected by exercise (p < 0.0001), body weight (p = 0.04) and BCS (p < 0.0001), but were not affected by percentage of fat. In conclusion, the marked decrease in leptin values observed during a period of intense (i.e. excessive) exercise could result from an adaptation to cumulative alterations in energy balance, to exercise per se or to a combination of both. Topics: Animals; Body Composition; Body Weight; Energy Metabolism; Horses; Leptin; Male; Physical Conditioning, Animal | 2012 |
Effect of estrogen therapy on adipocytokines in ovariectomized-aged rats.
Obesity is a chronic disease that is characterized by excessive accumulation of body fat. The physiological changes associated with estrogen deprivation in menopause have a significant impact on total body fat and adipose tissue distribution. Adipocytokines, such as adiponectin and leptin are related to adipose tissue, and their levels are affected by estrogen. The aim of the present study was to investigate the alteration of adipocytokine levels with estrogen therapy.. Aged Wistar albino rats were divided into two main groups: control (C) and ovariectomized (OVX). Six months after ovariectomy, the ovariectomized group was divided into four subgroups: two ovariectomized groups received saline (OVX) and sesame oil (OVX+S.oil), and two groups received physiological dose (OVX+PhyE2) and pharmacological dose (OVX+PharmE2) estrogen (2 and 20µg/kg per day, respectively). Body weight was monitored weekly for 6weeks. Adiponectin, leptin and homocysteine levels were measured from blood samples before and after treatment.. Body weight increased in OVX, OVX+S.oil and OVX+PhyE2 over 6weeks (P<0.001). Adiponectin levels were significantly decreased in the OVX+S.oil and OVX+PhyE2 groups (P=0.017 and P=0.008, respectively). Leptin level was significantly decreased in the OVX+PharmE2 group (P=0.042). Homocysteine level was decreased in the OVX+S.oil group (P=0.037).. Adipocytokines may play a role in the pathogenesis of cancer or obesity-related complications in menopause. Estrogen therapy may reduce these complications by changing the levels of adipocytokines. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Estradiol; Female; Homocysteine; Leptin; Ovariectomy; Rats; Rats, Wistar | 2012 |
Neurological and stress related effects of shifting obese rats from a palatable diet to chow and lean rats from chow to a palatable diet.
Rats exposed to an energy rich, cafeteria diet overeat and become obese. The present experiment examined the neural and behavioural effects of shifting obese rats from this diet to chow and lean rats from chow to the cafeteria diet. Two groups of male Sprague Dawley rats (n=24) were fed either highly palatable cafeteria diet or regular chow (30% vs. 12% energy as fat) for 16 weeks. Half of each group (n=12) was then switched to the opposing diet while the remainder continued on their original diet. The effects of diet switch on the response to restraint stress were assessed and rats were euthanised nine days after diet reversal. After 16 weeks of cafeteria diet, rats were 27% heavier than controls. Rats switched from chow to cafeteria diet (Ch-Caf) became hyperphagic and had increased dopamine D1, D2 and tyrosine hydroxylase mRNA expression in the ventral tegmental area (VTA) compared to rats switched from cafeteria to chow (Caf-Ch). Caf-Ch rats were hypophagic with significant reductions in white (16%) and brown (32%) adipose tissue mass, plasma leptin (34%) and fasting glucose (22%) compared to rats remaining on the cafeteria diet (Caf-Caf). Caf-Caf rats had an elevated plasma corticosterone response to restraint stress compared to Ch-Caf rats indicating that acute but not chronic consumption of palatable cafeteria diet may protect against stress. Caf-Ch rats had increased corticotropin releasing hormone mRNA expression in the dorsal hypothalamus compared to Ch-Ch rats implying that removal of the palatable diet activated the HPA axis. The results were discussed in terms of the links between palatability of diet, obesity and stress. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Diet, High-Fat; Feeding Behavior; Hypothalamus; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Stress, Psychological; Tyrosine 3-Monooxygenase; Ventral Tegmental Area | 2012 |
Regulation of adiponectin secretion by soy isoflavones has implication for endocrine function of the testis.
Testicular Leydig cells are the predominant source of the male sex steroid hormone testosterone (T), which is required to maintain male fertility. There is now growing evidence that environmental stressors, including chemicals present in food, air and water, may affect energy balance. A relationship between energy balance and reproductive capacity has been proposed for a long time. In the present study, developmental exposures of male rats to soy isoflavones in the maternal diet from gestational day 12 to day 21 post-partum enhanced adiponectin expression in adipose tissue and increased serum adiponectin concentrations in adulthood. However, exposure to soy isoflavones caused a decrease in T production and expression of adiponectin and its receptor (adipoR2) in Leydig cells. In separate experiments, incubation of Leydig cells with recombinant adiponectin in the absence of isoflavones caused a decrease in T biosynthesis associated with diminished expression of the cholesterol transporter steroidogenic acute regulatory protein (StAR). Thus, chemical-induced alterations in serum adiponectin concentrations have implication for steroid hormone secretion. The results also imply that changes in adipose tissue metabolism occasioned by exposure to dietary estrogens, and perhaps other estrogenic agents, possibly contribute to deficiencies in reproductive capacity attributed to these compounds. Topics: Adiponectin; Adipose Tissue; Androgens; Animals; Blood Glucose; Blotting, Western; Body Weight; Cell Cycle Proteins; Cell Separation; Endocrine Glands; Estradiol; Glycine max; In Vitro Techniques; Insulin; Isoflavones; Leptin; Leydig Cells; Male; Rats; Rats, Long-Evans; Receptors, Estrogen; Testis; Testosterone | 2012 |
Switching from high-fat to low-fat diet normalizes glucose metabolism and improves glucose-stimulated insulin secretion and insulin sensitivity but not body weight in C57BL/6J mice.
Environmental factors such as a high-fat diet contribute to type 2 diabetes and obesity. This study examined glycemia, insulin sensitivity, and β-cell function after switching from a high-fat diet to a low-fat diet in mice.. C57BL/6J mice were fed a high-fat diet or low-fat diet for 18 months, after which mice on the high-fat diet either maintained this diet or switched to a low-fat diet for 4 weeks. Body weight and glucose and insulin responses to intraperitoneal glucose were determined. Insulin secretion (insulinogenic index: the 10-minute insulin response divided by the 10-minute glucose level) and insulin sensitivity (1 divided by basal insulin) were determined.. After 18 months on a high-fat diet, mice had glucose intolerance, marked hyperinsulinemia, and increased body weight compared to mice on a low-fat diet (P < 0.001). Switching from a high-fat diet to low-fat diet normalized glucose tolerance, reduced but not normalized body weight (P < 0.001), increased insulin secretion (248 ± 39 vs 141 ± 46 pmol/mmol; P = 0.028) and improved but not normalized insulin sensitivity (3.2 ± 0.1 vs 1.0 ± 0.1 [pmol/L]; P = 0.012).. Switching from a high-fat diet to low-fat diet normalizes glucose tolerance and improves but not normalizes insulin secretion and insulin sensitivity. These effects are more pronounced than the reduced body weight. Topics: Animals; Blood Glucose; Body Weight; Diet, Fat-Restricted; Diet, High-Fat; Fatty Acids, Nonesterified; Female; Glucose Intolerance; Glucose Tolerance Test; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Mice; Mice, Inbred C57BL; Recovery of Function; Time Factors | 2012 |
Silk and silkworm pupa peptides suppress adipogenesis in preadipocytes and fat accumulation in rats fed a high-fat diet.
The objective was to confirm the anti-obesity activity of a silk peptide (SP) and a silkworm pupa peptide (SPP) in rats fed a high-fat diet (HFD) and to elucidate their action mechanism(s) in a preadipocyte culture system.. In an in vitro mechanistic study, the differentiation and maturation of 3T3-L1 preadipocytes were stimulated with insulin (5 μg/mL), and effects of SP and SPP on the adipogenesis of mature adipocytes were assessed. In an in vivo anti-obesity study, male C57BL/6 mice were fed an HFD containing SP or SPP (0.3, 1.0, or 3.0%) for 8 weeks, and blood and tissue parameters of obesity were analyzed.. Hormonal stimulation of preadipocytes led to a 50-70% increase in adipogenesis. Polymerase chain reaction and Western blot analyses revealed increases in adipogenesis-specific genes (leptin and Acrp30) and proteins (peroxisome proliferator-activated receptor-γ and Acrp30). The hormone-induced adipogenesis and activated gene expression was substantially inhibited by treatment with SP and SPP (1-50 μg/mL). The HFD markedly increased body weight gain by increasing the weight of epididymal and mesenteric fat. Body and fat weights were significantly reduced by SP and SPP, in which decreases in the area of abdominal adipose tissue and the size of epididymal adipocytes were confirmed by magnetic resonance imaging and microscopic examination, respectively. Long-term HFD caused hepatic lipid accumulation and increased blood triglycerides and cholesterol, in addition to their regulatory factors Acrp30 and leptin. However, SP and SPP recovered the concentrations of Acrp30 and leptin, and attenuated steatosis.. SP and SPP inhibit the differentiation of preadipocytes and adipogenesis by modulating signal transduction pathways and improve HFD-induced obesity by reducing lipid accumulation and the size of adipocytes. Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adiponectin; Animals; Anti-Obesity Agents; Body Weight; Bombyx; Cell Differentiation; Diet, High-Fat; Insect Proteins; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Peptides; PPAR gamma; Pupa; Silk | 2012 |
Relationships among interleukin-6, tumor necrosis factor-α, adipokines, vitamin D, and chronic periodontitis.
The aim of this study is to explore relationships among serum adipokines, vitamin D, and clinical and microbial parameters of chronic periodontitis before and after treatment.. Weight, height, and smoking status were recorded for 56 patients with chronic periodontitis. Plaque, gingivitis, bleeding on probing, suppuration, probing depth, and clinical attachment level were measured at all teeth present. Subgingival biofilm samples from each tooth were analyzed for levels of 40 bacterial species using checkerboard DNA-DNA hybridization. Serum levels of interleukin-6 (IL-6), tumor necrosis factor-α, adiponectin, leptin, resistin, and vitamin D were measured at baseline. Sample collection was then performed in a subset of the population 6 months after therapy (n = 17). Serum samples were analyzed using enzyme-linked immunosorbent assay and immunoassays. Differences in clinical, microbial, and serum factors among groups were sought using the Mann-Whitney U test. Correlations among factors were evaluated using regression analysis. Effects of therapy were sought using the Wilcoxon signed rank test.. There were positive correlations between adiponectin/vitamin D and between IL-6/leptin, negative correlations between IL-6/vitamin D and leptin/vitamin D, but no associations between serum analytes and clinical or microbial parameters. Sex and body mass index were associated with levels of adipokines. Periodontal therapy improved clinical and microbiologic parameters but did not influence the levels of serum analytes.. Adipokines and IL-6 levels were affected by sex and body mass index. Serum analytes were not influenced by periodontal therapy. Topics: Adipokines; Adiponectin; Adult; Aged; Biofilms; Body Height; Body Mass Index; Body Weight; Chronic Periodontitis; Dental Plaque; Dental Plaque Index; Dental Scaling; Female; Follow-Up Studies; Humans; Interleukin-6; Leptin; Male; Middle Aged; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Resistin; Root Planing; Smoking; Tumor Necrosis Factor-alpha; Vitamin D; Young Adult | 2012 |
Hepatic endothelin-1 and endocannabinoids-dependent effects of hyperleptinemia in nonalcoholic steatohepatitis-cirrhotic rats.
Leptin, the ob gene product, is a protein released from adipocytes and has been detected in fibrotic and cirrhotic livers. Leptin in brain has an inhibitory effect on food intake. Nonalcoholic steatohepatitis (NASH) is characterized by hyperleptinemia. This study explores the possible mechanisms of hyperleptinemia in relation to increased intrahepatic resistance (IHR) and portal hypertension in NASH cirrhotic rats. NASH cirrhotic rats with hyperleptinemia were induced in Zucker (fa/fa) and lean rats by feeding the animals a high fat/methionine-choline-deficient (HF/MCD) diet with and without exogenous administration of recombinant leptin. Portal venous pressure (PVP), IHR, plasma and hepatic levels of various substances, histopathology of the liver, the hepatic hydroxyproline content, and the expression of various hepatic protein and messenger RNA (mRNA) were measured. Hepatic microcirculatory dysfunction and the vasoconstrictive response to endothelin-1 were also observed using a liver perfusion system and intravital microscopy. Finally, the effect of leptin on hepatic stellate cells (HSCs) was evaluated. Both in HF/MCD-Zucker and HF/MCD+leptin lean rats, significant hepatic fibrogenesis and cirrhosis, marked portal hypertension, microcirculatory dysfunction, an enhanced vasoconstrictive response to endothelin-1, and an increased IHR were found to be associated with higher levels of hepatic endothelin-1 and endocannabinoids, expression levels of the cannabinoid type 1 receptor, endothelin-1 type A receptor (ET(A) R), activator protein-1, transforming growth factor beta (TGF-β)(1), osteopontin, tumor necrosis factor alpha (TNF-α), leptin, and the leptin receptor (OBRb). Interestingly, acute incubation of leptin directly increases the expression of ET(A) R, OBRb and activator protein-1 in HSCs.. An HF/MCD diet and hyperleptinemia increase hepatic endocannabinoids production, promote hepatic fibrogenesis, enhance the hepatic vasoconstrictive response to endothelin-1, and aggravate hepatic microcirculatory dysfunction; these events subsequently increase IHR and portal hypertension in NASH cirrhotic rats. Topics: Animals; Biopsy, Needle; Body Weight; Cannabinoid Receptor Modulators; Diet, High-Fat; Disease Models, Animal; Disease Progression; Endocannabinoids; Endothelin-1; Fatty Liver; Hepatic Stellate Cells; Hypertension, Portal; Immunohistochemistry; Insulin Resistance; Kupffer Cells; Leptin; Liver; Microcirculation; Non-alcoholic Fatty Liver Disease; Random Allocation; Rats; Rats, Zucker; RNA, Messenger; Statistics, Nonparametric | 2012 |
Disruption of the chemokine-like receptor-1 (CMKLR1) gene is associated with reduced adiposity and glucose intolerance.
Adipose tissue secretes a variety of bioactive signaling molecules, termed adipokines, which regulate numerous biological functions including appetite, energy balance, glucose homeostasis, and inflammation. Chemerin is a novel adipokine that regulates adipocyte differentiation and metabolism by binding to and activating the G protein-coupled receptor, chemokine like receptor-1 (CMKLR1). In the present study, we investigated the impact of CMKLR1 deficiency on adipose development, glucose homeostasis, and inflammation in vivo. Herein we report that regardless of diet (low or high fat), CMKLR1(-/-) mice had lower food consumption, total body mass, and percent body fat compared with wild-type controls. CMKLR1(-/-) mice also exhibited decreased hepatic and white adipose tissue TNFα and IL-6 mRNA levels coincident with decreased hepatic dendritic cell infiltration, decreased adipose CD3+ T cells, and increased adipose natural killer cells. CMKLR1(-/-) mice were glucose intolerant compared with wild-type mice, and this was associated with decreased glucose stimulated insulin secretion as well as decreased skeletal muscle and white adipose tissue glucose uptake. Collectively these data provide compelling evidence that CMKLR1 influences adipose tissue development, inflammation, and glucose homeostasis and may contribute to the metabolic derangement characteristic of obesity and obesity-related diseases. Topics: Adiponectin; Adipose Tissue, White; Adiposity; Animals; Blood Glucose; Body Weight; Cytokines; Dietary Fats; Eating; Gene Expression Regulation; Glucaric Acid; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Liver; Mice; Mice, Knockout; Receptors, Chemokine; Receptors, G-Protein-Coupled | 2012 |
High fat diet affects reproductive functions in female diet-induced obese and dietary resistant rats.
The incidence of ovulatory disorders is common in obese animal models. The mechanism behind this effect is unclear. We hypothesised that a high-fat (HF) diet induces alterations in neuroendocrine mechanisms resulting in anovulation in diet-induced obese (DIO) animals. Adult female DIO and diet-resistant (DR) rats were fed either chow or a HF diet (45% calories from fat) for 6 weeks. Oestrous cyclicity and body weight were monitored regularly. At the end of treatment, rats were implanted with a jugular catheter to monitor luteinising hormone (LH) levels on the day of pro-oestrous. Rats were sacrificed on the next pro-oestrous, and their brains and ovaries were collected. Plasma from trunk blood was analysed for oestradiol and leptin concentrations. Ovaries were fixed and sectioned for histological analysis. Brains were removed, frozen and sectioned, and norepinephrine (NE) concentrations in discrete hypothalamic areas were measured using high-performance liquid chromatography with electrochemical detection. A HF diet exposure affected oestrous cyclicity in both DIO and DR rats, with the effect being more pronounced in DIO animals. HF diet exposure increased leptin levels in both DIO and DR rats. Oestradiol levels were low in the DIO-HF group. NE levels in the hypothalamus were unaffected by HF diet or genotype. A normal LH surge was observed in DR-Chow rats and LH levels were low in the remaining groups. These results lead to the conclusion that DIO rats have an inherently reduced reproductive capacity and exposure to a HF diet decreases it further. A reduction in oestradiol and LH surge levels could contribute to this effect; however, the underlying mechanisms need to be investigated further. Topics: Animals; Body Weight; Diet, High-Fat; Dietary Fats; Disease Resistance; Estradiol; Estrous Cycle; Female; Hypothalamus; Leptin; Norepinephrine; Obesity; Ovary; Rats; Reproduction; Thinness | 2012 |
Postweaning low-calcium diet promotes later-life obesity induced by a high-fat diet.
The aim of this study was to investigate the effects of a postweaning low-calcium diet on later obesity and explore the underlying mechanisms. Ninety-six male rats were weaned at 3 weeks of age, fed standard (STD: 0.50% calcium, n=48) and low-calcium (LC: 0.15% calcium, n=48) diets for 3 weeks, and then fed the standard diet for a 3-week washout period successively. Finally, the STD rats were divided into STD control and high-fat diet (HFD) groups, and the LC ones into LC control and LC+HFD (LCHF) groups. The STD and LC rats were fed the standard diet, while the HFD control and LCFD ones were fed a high-fat diet for 6 weeks to induce obesity. During the three feeding periods, adenosine-monophosphate-activated protein kinase (AMPK) and its responsive proteins phospho-acetyl-coA carboxylase, carnitine palmitoyltransferase 1 and uncoupling protein 3 were persistently down-regulated in the LC group (decreased by 18%, 24%, 18% and 20%, respectively) versus the STD group, and these effects were significantly more pronounced in the LCHFD group (decreased by 21%, 30%, 23% and 25%, respectively) than the HFD group by a later high-fat stimuli, causing more fat and body weight in adulthood. However, lipolysis enzymes, serum leptin, insulin and lipids were not significantly affected until the body weight and fat content changed at 15 weeks of age. The results suggest that the low-calcium diet after weaning promotes rat adult-onset obesity induced by high-fat diet, which might be achieved by programming expressions of genes involved in AMPK pathway. Topics: Acetyl-CoA Carboxylase; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Blood Glucose; Blotting, Western; Body Weight; Calcium, Dietary; Carnitine O-Palmitoyltransferase; Diet, High-Fat; Dietary Fats; Down-Regulation; Energy Intake; Fatty Acid Synthases; Female; Insulin; Ion Channels; Leptin; Lipase; Lipids; Liver; Male; Mitochondrial Proteins; Muscle, Skeletal; Obesity; Pregnancy; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sterol Esterase; Uncoupling Protein 3; Weaning | 2012 |
Early nutritional changes induce sexually dimorphic long-term effects on body weight gain and the response to sucrose intake in adult rats.
Long-term metabolic effects induced by early nutritional changes are suspected to differ between males and females, but few studies have analyzed both sexes simultaneously. We analyzed the consequences of neonatal nutritional changes on body weight (BW) and the adult response to a sucrose-enriched diet in both male and female rats. Litter size was manipulated at birth to induce over- and undernutrition (4 pups: L4; 12 pups: L12; 20 pups: L20). From 50 to 65 days of age, half of each group received a 33% sucrose solution instead of water. Serum leptin, insulin, and ghrelin levels were analyzed at day 65. At weaning, rats from L4 weighed more and those from L20 weighed less than controls (L12). Body weight was greater in L4 rats throughout the study and increased further compared with controls in adult life. L20 males ate less and gained less weight throughout the study, but L20 females had a significant catch-up in BW. Sucrose intake increased total energy consumption in all groups, but not BW gain, with L4 males and L4 and L20 females reducing weight gain. Yet, sucrose intake increased serum leptin levels, with this increase being significant in L4 and L20 males. Our results suggest that females are more capable than males of recuperating and maintaining a normal BW after reduced neonatal nutrition. Furthermore, increased sucrose intake does not increase BW, but could alter body composition as reflected by leptin levels, with the percentage of calories consumed in the form of sucrose being affected by sex and neonatal nutrition. Topics: Animals; Animals, Newborn; Body Weight; Dietary Carbohydrates; Energy Intake; Female; Ghrelin; Insulin; Leptin; Male; Malnutrition; Nutritional Status; Overnutrition; Rats; Sex Factors; Sucrose | 2012 |
Effects of neonatal castration and androgenization on sexual dimorphism in bone, leptin and corticosterone secretion.
This study investigated the role of neonatal sex steroids in rats on sexual dimorphism in bone, as well as on leptin and corticosterone concentrations throughout the lifespan. Castration of males and androgenization of females were used as models to investigate the role of sex steroids shortly after birth. Newborn Wistar rats were divided into four groups, two male groups and two female groups. Male pups were cryoanesthetized and submitted to castration or sham-operation procedures within 24 h after birth. Female pups received a subcutaneous dose of testosterone propionate (100 μg) or vehicle. Rats were euthanized at 20, 40, or 120 postnatal days. Body weight was also measured at 20, 40, and 120 days of age, and blood samples and femurs were collected. The length and thickness of the femurs were measured and the areal bone mineral density (areal BMD) was determined by dual-energy X-ray absorptiometry (DEXA). Biomechanical three-point bending testing was used to evaluate bone breaking strength, energy to fracture, and extrinsic stiffness. Blood samples were submitted to a biochemical assay to estimate calcium, phosphorus, alkaline phosphatase, leptin, and corticosterone levels. Weight gain, areal BMD and bone biomechanical properties increased rapidly with respect to age in all groups. In control animals, skeletal sexual dimorphism, leptin concentration, and dimorphic corticosterone concentration patterns were evident after puberty. However, androgen treatment induced changes in growth, areal BMD, and bone mass properties in neonatal animals. In addition, neonatally-castrated males had bone development and mechanical properties similar to those of control females. These results suggest that the exposure to neonatal androgens may represent at least one covariate that mediates dimorphic variation in leptin and corticosterone secretions. The study indicates that manipulation of the androgen environment during the critical period of sexual differentiation of the brain causes long-lasting changes in bone development, as well as serum leptin and corticosterone concentrations. In addition, this study provides useful models for the investigation of bone disorders induced by hypothalamic hypogonadism. Topics: Absorptiometry, Photon; Animals; Animals, Newborn; Biomechanical Phenomena; Biophysical Phenomena; Body Weight; Bone Density; Castration; Corticosterone; Female; Femur; Leptin; Male; Radioimmunoassay; Rats; Rats, Wistar; Sex Characteristics; Virilism | 2012 |
Elucidation of thrifty features in adult rats exposed to protein restriction during gestation and lactation.
Since the introduction of the thrifty phenotype hypothesis, the potential traits of thrift have been described in increasingly broad terms but biochemical and behavioral evidence of thrift has not been well demonstrated. The objective of our studies was to use a rodent model to identify features of thrift programmed by early life protein restriction. Robust programming of thrifty features requires a thrifty nutritional environment during the entire window of developmental plasticity. Therefore, pregnant rats were exposed to a low protein diet throughout the window of developmental plasticity spanning the period of gestation and lactation and its effects on energy acquisition, storage and expenditure in the adult offspring were examined. Maternal protein restriction reduced birth weight and produced long term reductions in body and organ weights in the offspring. Low protein offspring demonstrated an increased drive to seek food as evidenced by hyperphagia that was mediated by changes in plasma leptin and ghrelin levels. Hyperphagia was accompanied by increased efficiency in converting caloric intake into body mass. The higher feed efficiency was mediated by greater insulin sensitivity. Energy expenditure of low protein offspring in locomotion was not affected either in the light or dark phase. However, low protein offspring exhibited higher resting and basal metabolic rates as evidenced by higher core body temperature in the fed and fasted states. The increased thermogenesis was not mediated by thyroid hormones but by an increased sympathetic nervous system drive as reflected by a lower areal bone mineral density and bone mineral content and lower plasma adiponectin and triglyceride levels. Elevated thermogenesis in the low protein offspring possibly offsets the effects of hyperphagia, minimizes their chances of weight gain, and improves survivability. This constellation of metabolic features in the low protein offspring will maximize survival potential in a post natal environment of nutritional scarcity and constitute a thrifty phenotype. Topics: Adaptation, Physiological; Animals; Birth Weight; Body Composition; Body Temperature; Body Weight; Diet, Protein-Restricted; Energy Metabolism; Female; Ghrelin; Insulin Resistance; Lactation; Leptin; Motor Activity; Nutritional Physiological Phenomena; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Random Allocation; Rats; Thermogenesis | 2012 |
Ablation of neurons expressing agouti-related protein, but not melanin concentrating hormone, in leptin-deficient mice restores metabolic functions and fertility.
Leptin-deficient (Lep(ob/ob)) mice are obese, diabetic, and infertile. Ablation of neurons that make agouti-related protein (AgRP) in moderately obese adult Lep(ob/ob) mice caused severe anorexia. The mice stopped eating for 2 wk and then gradually recovered. Their body weight fell to within a normal range for WT mice, at which point food intake and glucose tolerance were restored to that of WT mice. Remarkably, both male and female Lep(ob/ob) mice became fertile. Ablation of neurons that express melanin-concentrating hormone (MCH) in adult Lep(ob/ob) mice had no effect on food intake, body weight, or fertility, but resulted in improved glucose tolerance. We conclude that AgRP-expressing neurons play a critical role in mediating the metabolic syndrome and infertility of Lep(ob/ob) mice, whereas MCH-expressing neurons have only a minor role. Topics: Agouti-Related Protein; Animals; Body Weight; Feeding Behavior; Fertility; Glucose; Glucose Tolerance Test; Homeostasis; Hypothalamic Hormones; Leptin; Melanins; Mice; Mice, Inbred C57BL; Mice, Obese; Neurons; Obesity; Pituitary Hormones; Survival Analysis | 2012 |
Gender-dependent consequences of chronic olanzapine in the rat: effects on body weight, inflammatory, metabolic and microbiota parameters.
Atypical antipsychotic drugs (AAPDs) such as olanzapine have a serious side effect profile including weight gain and metabolic dysfunction, and a number of studies have suggested a role for gender in the susceptibility to these effects. In recent times, the gut microbiota has been recognised as a major contributor to the regulation of body weight and metabolism. Thus, we investigated the effects of olanzapine on body weight, behaviour, gut microbiota and inflammatory and metabolic markers in both male and female rats.. Male and female rats received olanzapine (2 or 4 mg/kg/day) or vehicle for 3 weeks. Body weight, food and water intake were monitored daily. The faecal microbial content was assessed by 454 pyrosequencing. Plasma cytokines (tumour necrosis alpha, interleukin 8 (IL-8), interleuin-6 and interleukin 1-beta (IL-1β)) as well as expression of genes including sterol-regulatory element binding protein-1c and CD68 were analysed.. Olanzapine induced significant body weight gain in the female rats only. Only female rats treated with olanzapine (2 mg/kg) had elevated plasma levels of IL-8 and IL-1β, while both males and females had olanzapine-induced increases in adiposity and evidence of macrophage infiltration into adipose tissue. Furthermore, an altered microbiota profile was observed following olanzapine treatment in both genders.. This study furthers the theory that gender may impact on the nature of, and susceptibility to, certain side effects of antipsychotics. In addition, we demonstrate, what is to our knowledge the first time, an altered microbiota associated with chronic olanzapine treatment. Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antipsychotic Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Benzodiazepines; Biomarkers; Body Weight; Brain; Drinking; Eating; Female; Gene Expression; Ghrelin; Inflammation Mediators; Leptin; Liver; Locomotion; Male; Metagenome; Nuclear Proteins; Olanzapine; Rats; Rats, Sprague-Dawley; Sex Characteristics; Sterol Regulatory Element Binding Protein 1; Transcription Factors | 2012 |
Hindbrain leptin and glucagon-like-peptide-1 receptor signaling interact to suppress food intake in an additive manner.
The physiological control of feeding behavior involves modulation of the intake inhibitory effects of gastrointestinal satiation signaling via endogenous hindbrain leptin receptor (LepR) and glucagon-like-peptide-1 receptor (GLP-1R) activation.. Using a variety of dose-combinations of hindbrain delivered (4th intracerebroventricular; i.c.v.) leptin and the GLP-1R agonist exendin-4, experiments demonstrate that hindbrain LepR and GLP-1R signaling interact to control food intake and body weight in an additive manner. In addition, the maximum intake suppressive response that could be achieved by 4th i.c.v. leptin alone in non-obese rats (∼33%) was shown to be further suppressed when exendin-4 was co-administered. Importantly, it was determined that the interaction between hindbrain LepR signaling and GLP-1R signaling is relevant to endogenous food intake control, as hindbrain GLP-1R blockade by the selective antagonist exendin-(9-39) attenuated the intake inhibitory effects of hindbrain leptin delivery.. Collectively, the findings reported here show that hindbrain LepR and GLP-1R activation interact in at least an additive manner to control food intake and body weight. As evidence is accumulating that combination pharmacotherapies offer greater sustained food intake and body weight suppression in obese individuals when compared with mono-drug therapies or lifestyle modifications alone, these findings highlight the need for further examination of combined central nervous system GLP-1R and LepR signaling as a potential drug target for obesity treatment. Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Exenatide; Feeding Behavior; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Injections, Intraventricular; Leptin; Male; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Rhombencephalon; Signal Transduction; Venoms | 2012 |
Selective estrogen receptor modulator promotes weight loss in ovariectomized female rhesus monkeys (Macaca mulatta) by decreasing food intake and increasing activity.
The effect of hormone replacement therapy (HRT) on body weight in postmenopausal women is controversial, with studies reporting an increase, a decrease, and no change in body weight. To examine estrogen receptor actions on body weight, we investigated the effects of treatment with a selective estrogen receptor modulator (SERM) on body weight, food intake, and activity and metabolic rate in a nonhuman primate model. Eighteen ovariectomized female rhesus monkeys were treated with a nonsteroidal SERM (GSK232802A, 5 mg/kg po) for 3 mo. GSK232802A decreased lutenizing hormone (P < 0.0001) and follicle-stimulating hormone levels (P < 0.0001), consistent with the estrogenic action of the compound. GSK232802A treatment produced a small but sustained weight loss (4.6 ± 1.0%, P < 0.0001) and reduced adiposity (P < 0.0001), which was due at least in part to a suppression of food intake (3.6 ± 3.7%, P < 0.0001). Physical activity increased during the 3rd mo of treatment (P = 0.04). Baseline activity level and the change in activity due to treatment were correlated, with the most sedentary individuals exhibiting increased physical activity during the 1st mo of treatment (P = 0.02). Metabolic rate did not change (P = 0.58). These results indicate that GSK232802A treatment reduces body weight and adiposity in ovariectomized nonhuman primates by suppressing food intake and increasing activity, particularly in the most sedentary individuals. These findings suggest that SERM treatment may counteract weight gain in postmenopausal women. Topics: Alkaline Phosphatase; Animals; Body Composition; Body Fat Distribution; Body Weight; Eating; Energy Metabolism; Female; Leptin; Luteinizing Hormone; Macaca mulatta; Motor Activity; Ovariectomy; Selective Estrogen Receptor Modulators; Triiodothyronine; Weight Loss | 2012 |
Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice.
These preclinical studies aimed to 1) increase our understanding the dietary induction of nonalcoholic steatohepatitis (NASH), and, 2) further explore the utility and mechanisms of glucagon-like peptide-1 receptor (GLP-1R) agonism in NASH. We compared the effects of a high trans-fat (HTF) or high lard fat (HLF) diet on key facets of nonalcoholic fatty liver disease (NAFLD)/NASH in Lep(ob)/Lep(ob) and C57BL6J (B6) mice. Although HLF-fed mice experienced overall greater gains in weight and adiposity, the addition of trans-fat better mirrored pathophysiological features of NASH (e.g., hepatomegaly, hepatic lipid, and fibrosis). Administration of AC3174, an exenatide analog, and GLP-1R agonist to Lep(ob)/Lep(ob) and B6 ameliorated hepatic endpoints in both dietary models. Next, we assessed whether AC3174-mediated improvements in diet-induced NASH were solely due to weight loss in HTF-fed mice. AC3174-treatment significantly reduced body weight (8.3%), liver mass (14.2%), liver lipid (12.9%), plasma alanine aminotransferase, and triglycerides, whereas a calorie-restricted, weight-matched group demonstrated only modest nonsignificant reductions in liver mass (9%) and liver lipid (5.1%) relative to controls. Treatment of GLP-1R-deficient (GLP-1RKO) mice with AC3174 had no effect on body weight, adiposity, liver or plasma indices pointing to the GLP-1R-dependence of AC3174's effects. Interestingly, the role of endogenous GLP-1Rs in NASH merits further exploration as the GLP-1RKO model was protected from the deleterious hepatic effects of HTF. Our pharmacological data further support the clinical evaluation of the utility of GLP-1R agonists for treatment of NASH. Topics: Animals; Body Composition; Body Weight; Diet; Diet, Fat-Restricted; Diet, High-Fat; Endpoint Determination; Fatty Liver; Gene Expression; Glucagon-Like Peptide-1 Receptor; Hormones; Leptin; Lipids; Liver; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Non-alcoholic Fatty Liver Disease; Peptides; Receptors, Glucagon; Trans Fatty Acids; Weight Loss | 2012 |
Combination of fucoxanthin and conjugated linoleic acid attenuates body weight gain and improves lipid metabolism in high-fat diet-induced obese rats.
The present study investigated the effects of combined fucoxanthin (Fc) and conjugated linoleic acid (CLA) on high-fat diet-induced obese rats. Thirty five rats were divided into four groups, fed a high-fat diet (Control, 15% fat, wt/wt), supplemented with low Fc (FCL, 0.083 mg/kg/bw), high Fc (FCH, 0.167 mg/kg/bw) and FCL (0.083 mg/kg/bw) plus CLA (0.15 g/kg/bw) (FCL+CLA) for 52 d. Body weight and white adipose tissue (WAT) weight were significantly suppressed in FCL+CLA group than those in control group. WAT weight was also markedly attenuated in FCL and FCH groups. Accumulation of hepatic lipid droplets and the perirenal adipocyte size of FCL, FCH and FCL+CLA groups were diminished compared to control group. Serum total cholesterol level in FCH group, triacylglycerol and leptin levels in FCL, FCH and FCL+CLA groups, and glucose concentration in FCH and FCL+CLA groups were significantly decreased than those in control group. The mRNA expression of adiponectin, adipose triacylglycerol lipase, carnitine palmitoyltransferase 1A was remarkably up-regulated in FCL, FCH and FCL+CLA groups. These results suggest that Fc and FCL+CLA could reduce serum levels of triacylglycerol, glucose and leptin, and FCL+CLA could exert anti-obesity effects by regulating mRNA expression of enzymes related to lipid metabolism in WAT of diet-induced obesity rats. Topics: Adipocytes; Adiponectin; Adipose Tissue, White; Animals; Blood Glucose; Body Weight; Carnitine O-Palmitoyltransferase; Cholesterol; Diet, High-Fat; Dietary Fats; Gene Expression; Leptin; Linoleic Acids, Conjugated; Lipase; Lipid Metabolism; Liver; Male; Obesity; Rats; Rats, Sprague-Dawley; Triglycerides; Xanthophylls | 2012 |
Preadipocyte factor-1 concentrations in patients with anorexia nervosa: the influence of partial realimentation.
Preadipocyte factor-1 (Pref-1) is a member of epidermal growth-factor like family of proteins that regulates adipocyte and osteoblast differentiation. Experimental studies suggest that circulating Pref-1 levels may be also involved in the regulation of lipid and glucose metabolism and energy homeostasis. We hypothesized that alterations in Pref-1 levels may contribute to the ethiopathogenesis of anorexia nervosa or its underlying metabolic abnormalities. We measured Pref-1 concentrations and other hormonal, biochemical and anthropometric parameters in eighteen patients with anorexia nervosa and sixteen healthy women and studied the influence of partial realimentation of anorexia nervosa patients on these parameters. The mean duration of realimentation period was 46±2 days. At baseline, anorexia nervosa patients had significantly decreased body mass index, body weight, body fat content, fasting glucose, serum insulin, TSH, free T4, leptin and total protein. Partial realimentation improved these parameters. Baseline serum Pref-1 levels did not significantly differ between anorexia nervosa and control group (0.26±0.02 vs. 0.32±0.05 ng/ml, p=0.295) but partial realimentation significantly increased circulating Pref-1 levels (0.35±0.04 vs. 0.26±0.02 ng/ml, p<0.05). Post-realimentation Pref-1 levels significantly positively correlated with the change of body mass index after realimentation (r=0.49, p<0.05). We conclude that alterations in Pref-1 are not involved in the ethiopathogenesis of anorexia nervosa but its changes after partial realimentation could be involved in the regulation of adipose tissue expansion after realimentation. Topics: Adipose Tissue; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Calcium-Binding Proteins; Eating; Female; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Membrane Proteins; Young Adult | 2012 |
Endogenously determined restriction of food intake overcomes excitation-contraction uncoupling in JP45KO mice with aging.
The decline in muscular strength with age is disproportionate to the loss in total muscle mass that causes it. Knocking out JP45, an integral protein of the junctional face membrane of the skeletal muscle sarcoplasmic reticulum (SR), results in decreased expression of the voltage-gated Ca(2+) channel, Ca(v)1.1; excitation-contraction uncoupling (ECU); and loss of muscle force (Delbono et al., 2007). Here, we show that Ca(v)1.1 expression, charge movement, SR Ca(2+) release, in vitro contractile force, and sustained forced running remain stable in male JP45KO mice at 12 and 18 months. They also exhibit the level of ECU reported for 3-4-month mice (Delbono et al., 2007). No further decline at later ages was recorded. Preserved ECC was not related to increased expression of any protein that directly or indirectly interacts with JP45 at the triad junction. However, maintained muscle force and physical performance were associated with ablation of JP45 expression in the brain, spontaneous and significantly diminished food intake and less tendency toward obesity when exposed to a high-fat diet compared to WT. We propose that (1) endogenously generated restriction in food intake overcomes the deleterious effects of JP45 ablation on ECC and skeletal muscle force mainly through downregulation of neuropeptide-Y expression in the hypothalamic arcuate nucleus; and (2) the JP45KO mouse constitutes an invaluable model to examine the mechanisms controlling food intake as well as skeletal muscle function with aging. Topics: Aging; Animals; Body Weight; Calcium Channels, L-Type; Caloric Restriction; Diet, High-Fat; Eating; Hippocampus; Insulin; Leptin; Male; Membrane Proteins; Mice; Mice, Knockout; Muscle Contraction; Muscle Fibers, Skeletal; Muscle Strength; Muscle, Skeletal; Sarcoplasmic Reticulum | 2012 |
Amylin-leptin coadministration stimulates central histaminergic signaling in rats.
Combined amylin+leptin (AMN+LEP) can reduce diet induced obesity and is very effective in combating LEP resistance. The purpose of this study was to evaluate the effect of AMN+LEP on central histaminergic signaling in lean and obese rats. Male rats were administered LEP (300 μg/kg/d), AMN (100 μg/kg/d), AMN+LEP or vehicle (SAL, 0.9% normal saline), via a subcutaneous mini-osmotic pump or single injection (LEP, 300 μg/kg and AMN, 100 μg/kg) for acute studies. AMN+LEP administration increased expression of histamine H1 receptor (HIR) and histidine decarboxylase (HDC) mRNA in the hypothalamus. Increased levels of H1R were seen in arcuate (Arc) and ventromedial hypothalamus (VMH) as well as the area postrema (APOS) and nucleus of solitary tract (NTS) following AMN+LEP administration. APOS and NTS also showed expression of immediate early gene c-FOS in the hindbrain in AMN+LEP-treated rats. We confirmed previous evidence indicating that AMN+LEP increased STAT-3 protein phosphorylation in Arc and VMH. Finally, by in vivo microdialysis, we observed an increase in methyl HIS levels in the VMH of AMN, LEP and AMN+LEP-treated rats. Taken together, these observations are consistent with an important role that neuronal HIS may play in mediating the potent effects of AMN+LEP on food intake and body weight. Topics: Animals; Body Weight; Eating; Genes, fos; Histamine; Histidine Decarboxylase; Hypothalamus; Islet Amyloid Polypeptide; Leptin; Male; Methylhistidines; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Rhombencephalon; RNA, Messenger; Signal Transduction; Up-Regulation | 2012 |
Free-choice and no-choice high-fat diets affect striatal dopamine D2/3 receptor availability, caloric intake, and adiposity.
Different types of high-fat (HF) diets are used to study diet-induced obesity (DIO) in rodents and this has led to different phenotypes. This study assesses whether different HF diets differentially affect striatal dopamine D(2/3) receptor (DRD(2/3)) availability, as decreased striatal DRD(2/3) availability has been implicated in obesity in relation to reward deficiency for food. Thirty rats were randomized to either a free-choice HF diet (HF-choice), a premixed HF diet (HF-no-choice), or a standard chow diet for 28 days. Striatal DRD(2/3) was measured using (123)I-IBZM storage phosphor imaging at day 29. DRD(2/3) availability was significantly decreased in the dorsal striatum in the HF-choice rats compared to chow rats, but not in HF-no-choice rats. Additionally, caloric intake of the HF-choice rats was significantly higher than that of HF-no-choice rats and serum leptin and percentage abdominal fat store weight of total body weight were significantly higher in the HF-choice rats compared to chow rats. These preliminary results suggest that the choice element in HF diets, which is possibly related to the motivational aspects of eating, leads to overconsumption and to a distinct state of obesity. These results are relevant for future studies on DIO when considering choice of diet type. Topics: Adiposity; Animals; Body Weight; Choice Behavior; Corpus Striatum; Diet, High-Fat; Energy Intake; Feeding Behavior; Hyperphagia; Intra-Abdominal Fat; Leptin; Male; Motivation; Obesity; Random Allocation; Rats; Rats, Wistar; Receptors, Dopamine D2; Reward | 2012 |
Body weight impact on puberty: effects of high-calorie diet on puberty onset in female rhesus monkeys.
Secular trends toward a declining age at puberty onset with correlated changes in body weight have been reported in economically advanced countries. This has been attributed to excess calorie intake along with reduced physical activity in children. However, because the timing of puberty in humans is also influenced by other factors, such as genetic traits, living conditions, geographical location, and environmental chemicals, it is difficult to distinguish the effect of diet and body size from other factors in a human population. Here we report that feeding juvenile female rhesus monkeys born and raised at the Wisconsin National Primate Research Center with a high-calorie diet results in acceleration of body growth and precocious menarche. The monkeys fed a high-calorie diet also had an elevated body mass index. The most significant treatment effects on circulating hormones were increased leptin and IGF-I levels throughout the experiment. The findings of this study suggest the importance of close monitoring of juvenile feeding behaviors as an important intervention to reduce the prevalence of precocious development and metabolic diseases in adulthood. Topics: Aging; Animals; Body Mass Index; Body Weight; Energy Intake; Female; Insulin-Like Growth Factor I; Leptin; Macaca mulatta; Menarche; Models, Animal; Ovulation; Sexual Maturation; Time Factors | 2012 |
Effects of ileal interposition on glucose metabolism in obese rats with diabetes.
Ileal interposition (IT), in which the distal ileum is transposed isoperistaltically into the proximal jejunum, is considered as a procedure for metabolic or antidiabetes surgery. Our aim was to study the effects of IT on glycemic control, fat metabolism, and hormonal changes in obese rats with spontaneous diabetes.. Animals were divided into either an IT or a sham (SH) group. They underwent an oral glucose tolerance test (OGTT) before and 4 and 8 weeks after the operation. All animals were killed 10 weeks after operation for analyses of tissue weight (liver, pancreas, epididymal fat, brown fat), immunoblotting of uncoupling protein-1 (UCP1) protein in brown adipose tissue (BAT), and fasting plasma levels of glucose, insulin, glucagon-like peptide (GLP)-1, peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), and leptin.. Body weight increased postoperatively in both groups compared with preoperative weight, but it did not differ between the 2 groups. Eight weeks postoperatively, integrated blood glucose levels during the OGTT were decreased in IT compared with SH (P < .05). Fasting plasma levels of insulin, GLP-1, and GIP did not differ between the 2 groups, but PYY levels were higher in the IT animals (P < .01). The weight of epididymal and BATs, homeostasis model assessment insulin resistance, and fasting plasma leptin levels were decreased in the IT group (P < .05). Expression of UCP1 was higher in IT than SH animals (P < .05).. These results suggest that IT improves glucose and lipid metabolism by decreasing insulin resistance and epididymal fat, and increased expression of UCP1 in BAT might be among the mechanisms responsible. Topics: Adipose Tissue, Brown; Animals; Body Weight; Comorbidity; Diabetes Mellitus; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Ileum; Insulin Resistance; Ion Channels; Jejunum; Leptin; Lipid Metabolism; Male; Mitochondrial Proteins; Obesity; Peptide YY; Rats, Inbred OLETF; Uncoupling Protein 1 | 2012 |
In vivo effects of leptin on lymphocyte subpopulations in mice.
Leptin, a hormone-cytokine mainly produced by the adipose tissue, has pleitropic effects on many biological system including metabolic, endocrine, and immune system. Although it is well known that leptin controls food intake on hypothalamic regions of brain, the role of leptin in hematopoietic and immune processes has been mainly investigated with in vitro and transgenic mouse studies. The aim of this study was to investigate the effects of peripheral leptin on lymphocyte subpopulation. Initially forty male Swiss albino mice were divided into five groups. Mice in group I (Control) were given serum physiologic (SP) and group L100, group L250, group L500, and group L1000 were given 100, 250, 500 and 1000 μg/kg/day recombinant mouse leptin, respectively. Leptin or SP was injected subcutaneously for the next 6 days. Daily food/water intake was recorded for each group. At the end of the study, whole blood samples (500 μl) were obtained via intracardiac punction in anesthetized mice. Leptin levels and lymphocyte subpopulations in blood samples were analyzed. We show that no in vivo dose-dependent effect of leptin is existed on lymphocyte subpopulations count in mice. Treatment of mice with high-dose leptin led to increase only CD4+ cells (P<0.05). In addition, high-dose leptin slightly increased CD3+ cells but this was not statistically confirmed (P=0.08). Notably, it was found that leptin caused insignificant changes on body weight and food intake in normal body weight mice. The data support that high-dose leptin has proliferative effect on CD4+ cells in vivo. However, more in vivo study needs to be examined to clarify how leptin affect lymphocyte subpopulations. Topics: Animals; Antigens, CD; Body Weight; Cell Survival; Cells, Cultured; Cytokines; Eating; Humans; Immunophenotyping; Leptin; Lymphocyte Activation; Lymphocyte Count; Lymphocyte Subsets; Male; Mice | 2012 |
Sympathetic overactivity precedes metabolic dysfunction in a fructose model of glucose intolerance in mice.
Consumption of high levels of fructose in humans and animals leads to metabolic and cardiovascular dysfunction. There are questions as to the role of the autonomic changes in the time course of fructose-induced dysfunction. C57/BL male mice were given tap water or fructose water (100 g/l) to drink for up to 2 mo. Groups were control (C), 15-day fructose (F15), and 60-day fructose (F60). Light-dark patterns of arterial pressure (AP) and heart rate (HR), and their respective variabilities were measured. Plasma glucose, lipids, insulin, leptin, resistin, adiponectin, and glucose tolerance were quantified. Fructose increased systolic AP (SAP) at 15 and 60 days during both light (F15: 123 ± 2 and F60: 118 ± 2 mmHg) and dark periods (F15: 136 ± 4 and F60: 136 ± 5 mmHg) compared with controls (light: 111 ± 2 and dark: 117 ± 2 mmHg). SAP variance (VAR) and the low-frequency component (LF) were increased in F15 (>60% and >80%) and F60 (>170% and >140%) compared with C. Cardiac sympatho-vagal balance was enhanced, while baroreflex function was attenuated in fructose groups. Metabolic parameters were unchanged in F15. However, F60 showed significant increases in plasma glucose (26%), cholesterol (44%), triglycerides (22%), insulin (95%), and leptin (63%), as well as glucose intolerance. LF of SAP was positively correlated with SAP. Plasma leptin was correlated with triglycerides, insulin, and glucose tolerance. Results show that increased sympathetic modulation of vessels and heart preceded metabolic dysfunction in fructose-consuming mice. Data suggest that changes in autonomic modulation may be an initiating mechanism underlying the cluster of symptoms associated with cardiometabolic disease. Topics: Animals; Baroreflex; Blood Glucose; Blood Pressure; Body Weight; Disease Models, Animal; Fructose; Glucose Intolerance; Heart Rate; Insulin; Insulin Resistance; Leptin; Lipids; Male; Mice; Sympathetic Nervous System | 2012 |
Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice.
Leptin action on its receptor (LEPR) stimulates energy expenditure and reduces food intake, thereby lowering body weight. One leptin-sensitive target cell mediating these effects on energy balance is the proopiomelano-cortin (POMC) neuron. Recent evidence suggests that the action of leptin on POMC neurons regulates glucose homeostasis independently of its effects on energy balance. Here, we have dissected the physiological impact of direct leptin action on POMC neurons using a mouse model in which endogenous LEPR expression was prevented by a LoxP-flanked transcription blocker (loxTB), but could be reactivated by Cre recombinase. Mice homozygous for the Lepr(loxTB) allele were obese and exhibited defects characteristic of LEPR deficiency. Reexpression of LEPR only in POMC neurons in the arcuate nucleus of the hypothalamus did not reduce food intake, but partially normalized energy expenditure and modestly reduced body weight. Despite the moderate effects on energy balance and independent of changes in body weight, restoring LEPR in POMC neurons normalized blood glucose and ameliorated hepatic insulin resistance, hyperglucagonemia, and dyslipidemia. Collectively, these results demonstrate that direct leptin action on POMC neurons does not reduce food intake, but is sufficient to normalize glucose and glucagon levels in mice otherwise lacking LEPR. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Energy Metabolism; Female; Glucagon; Glucose; Homeostasis; Homozygote; Hypothalamus; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Neurons; Pro-Opiomelanocortin; Receptors, Leptin | 2012 |
Arginine nutrition and fetal brown adipose tissue development in diet-induced obese sheep.
The global incidence of human obesity has more than doubled over the past three decades. An ovine model of obesity was developed to determine effects of maternal obesity and arginine supplementation on maternal, placental, and fetal parameters of growth, health, and well being. One-hundred-twenty days prior to embryo transfer, ewes were fed either ad libitum (n = 10) to induce obesity or 100% National Research Council-recommended nutrient requirements (n = 10) as controls. Embryos from superovulated ewes with normal body condition were transferred to the uterus of control-fed and obese ewes on day 5.5 post-estrus to generate genetically similar singleton pregnancies. Beginning on day 100 of gestation, obese ewes received intravenous administration of saline or L-arginine-HCl three times daily (81 mg arginine/kg body weight/day) to day 125, whereas control-fed ewes received saline. Fetal growth was assessed at necropsy on day 125. Maternal obesity increased (1) percentages of maternal and fetal carcass lipids and (2) concentrations of leptin, insulin, glucose, glutamate, leucine, lysine and threonine in maternal plasma while reducing (1) concentrations of progesterone, glycine and serine in maternal plasma and (2) amniotic and allantoic fluid volumes. Administration of L-arginine to obese ewes increased arginine and ornithine concentrations in maternal and fetal plasma, amniotic fluid volume, protein content in maternal carcass, and fetal brown adipose tissue (+60%), while reducing maternal lipid content and circulating leptin levels. Fetal or placental weight did not differ among treatments. Results indicate that arginine treatment beneficially reduces maternal adiposity and enhances fetal brown adipose tissue development in obese ewes. Topics: Adipose Tissue, Brown; Administration, Intravenous; Animals; Arginine; Blood Glucose; Body Weight; Diet; Female; Fetal Development; Fetus; Gestational Age; Insulin; Leptin; Nutritional Status; Obesity; Pregnancy; Sheep, Domestic; Single Embryo Transfer | 2012 |
Metabolic effects of estrogen substitution in combination with targeted exercise training on the therapy of obesity in ovariectomized Wistar rats.
Postmenopausal women tend to have a higher risk in developing obesity and thus metabolic syndrome. Recently we could demonstrate that physical activity and estrogen replacement are effective strategies to prevent the development of nutritional induced obesity in an animal model. The aim of this study was to determine the combined effects of estrogen treatment and exercise training on already established obesity. Therefore ovariectomized (OVX) and sham-operated (SHAM) female Wistar rats were exposed to a high fat diet for ten months. After this induction period obese SHAM and OVX rats either remained sedentary or performed treadmill training for six weeks. In addition OVX rats were treated with 17β-Estradiol (E(2)) alone, or in combination with training. Before and after intervention effects on lipid and glucose metabolism were investigated. Training resulted in SHAM and OVX rats in a significant decrease of body weight, subcutaneous and visceral body fat, size of adipocytes and the serum levels of leptin, cholesterol, low-density lipoprotein and triglycerides. In OVX animals E(2) treatment resulted in similar effects. Often the combination of E(2) treatment and training was most effective. Analysis of the respiratory quotient indicates that SHAM animals had a better fat burning capacity than OVX rats. There was a tendency that training in SHAM animals and E(2) treatment in OVX animals could improve this capacity. Analysis of glucose metabolism revealed that obese SHAM animals had higher glucose tolerance than OVX animals. Training improved glucose tolerance in SHAM and OVX rats, E(2) treatment in OVX rats. The combination of both was most effective. Our results indicate that even after a short intervention period of six weeks E(2) treatment and exercise training improve parameters related to lipid as well as glucose metabolism and energy expenditure in a model of already established obesity. In conclusion a combination of hormone replacement therapy and exercise training could be a very effective strategy to encourage the therapy of diet-induced obesity and its metabolic consequences in postmenopausal women. Topics: Animals; Body Weight; Diet, High-Fat; Estrogens; Female; Intra-Abdominal Fat; Leptin; Obesity; Ovariectomy; Physical Conditioning, Animal; Rats; Rats, Wistar | 2012 |
Reproductive and metabolic phenotype of a mouse model of PCOS.
Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women in their reproductive age, is characterized by both reproductive and metabolic features. Recent studies in human, nonhuman primates, and sheep suggest that hyperandrogenism plays an important role in the development of PCOS. We investigated whether chronic dihydrotestosterone (DHT) exposure in mice reproduces both features of PCOS. Such a model would allow us to study the mechanism of association between the reproductive and metabolic features in transgenic mice. In this study, prepubertal female mice received a 90 d continuous release pellet containing the nonaromatizable androgen DHT or vehicle. At the end of the treatment period, DHT-treated mice were in continuous anestrous, their ovaries contained an increased number of atretic follicles, with the majority of atretic antral follicles having a cyst-like structure. Chronic DHT-exposed mice had significantly higher body weights (21%) than vehicle-treated mice. In addition, fat depots of DHT-treated mice displayed an increased number of enlarged adipocytes (P < 0.003). Leptin levels were elevated (P < 0.013), adiponectin levels were diminished (P < 0.001), and DHT-treated mice were glucose intolerant (P < 0.001). In conclusion, a mouse model of PCOS has been developed showing reproductive and metabolic characteristics associated with PCOS in women. Topics: Adiponectin; Animals; Body Weight; Dihydrotestosterone; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Humans; Immunohistochemistry; Insulin; Leptin; Lipid Metabolism; Luteinizing Hormone; Mice; Mice, Inbred C57BL; Ovarian Follicle; Ovary; Phenotype; Polycystic Ovary Syndrome; Reproduction; Reverse Transcriptase Polymerase Chain Reaction | 2012 |
Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response.
Autophagy is a catabolic cellular process involving the degradation of the cell's own components. Although the role of autophagy of diverse tissues in body metabolism has been investigated, the importance of autophagy in hypothalamic proopiomelanocortin (POMC) neurons, key regulators of energy balance, has not been addressed. The role of autophagy in leptin sensitivity that is critical for the control of body weight and appetite has also not been investigated. We produced mice with specific deletion of autophagy-related 7 (Atg7), an essential autophagy gene, in hypothalamic POMC neurons (Atg7(ΔPOMC) mice). Atg7 expression was deficient in the arcuate nucleus of the hypothalamus of Atg7(ΔPOMC) mice. p62, a specific substrate of autophagy, accumulated in the hypothalamus of Atg7(ΔPOMC) mice, which colocalized with ubiquitin. Atg7(ΔPOMC) mice had increased body weight due to increased food intake and decreased energy expenditure. Atg7(ΔPOMC) mice were not more prone to diet-induced obesity compared with control mice but more susceptible to hyperglycemia after high-fat diet. The ability of leptin to suppress fasting-elicited hyperphagia and weight gain during refeeding was attenuated in Atg7(ΔPOMC) mice. Deficient autophagy did not significantly affect POMC neuron number but impaired leptin-induced signal transducer and activation of transcription 3 activation. Our findings indicate a critical role for autophagy of POMC neurons in the control of energy homeostasis and leptin signaling. Topics: Animals; Appetite Regulation; Autophagy; Autophagy-Related Protein 7; Body Weight; Disease Models, Animal; Eating; Energy Metabolism; Gene Deletion; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Microtubule-Associated Proteins; Neurons; Obesity; Pro-Opiomelanocortin; Signal Transduction | 2012 |
Role of GABA release from leptin receptor-expressing neurons in body weight regulation.
It is well established that leptin regulates energy balance largely through isoform B leptin receptor-expressing neurons (LepR neurons) in the brain and that leptin activates one subset of LepR neurons (leptin-excited neurons) while inhibiting the other (leptin-inhibited neurons). However, the neurotransmitters released from LepR neurons that mediate leptin action in the brain are not well understood. Previous results demonstrate that leptin mainly acts on γ-aminobutyric acid (GABA)ergic neurons to reduce body weight, and that leptin activates proopiomelanocortin neuron activity by reducing GABA release onto these neurons, suggesting a body weight-promoting role for GABA released from leptin-inhibited neurons. To directly examine the role of GABA release from LepR neurons in body weight regulation, mice with disruption of GABA release specifically from LepR neurons were generated by deletion of vesicular GABA transporter in LepR neurons. Interestingly, these mice developed mild obesity on chow diet and were sensitive to diet-induced obesity, which were associated with higher food intake and lower energy expenditure. Moreover, these mice showed blunted responses in both food intake and body weight to acute leptin administration. These results demonstrate that GABA plays an important role in mediating leptin action. In combination with the previous studies that leptin reduces GABA release onto proopiomelanocortin neurons through leptin-inhibited neurons and that disruption of GABA release from agouti gene-related protein neurons, one subset of LepR-inhibited neurons, leads to a lean phenotype, our results suggest that, under our experimental conditions, GABA release from leptin-excited neuron dominates over leptin-inhibited ones. Topics: Animals; Body Weight; Eating; Energy Metabolism; gamma-Aminobutyric Acid; Leptin; Mice; Mice, Transgenic; Neurons; Obesity; Receptors, Leptin; Vesicular Inhibitory Amino Acid Transport Proteins | 2012 |
Low-carbohydrate high-fat diets in combination with daily exercise in rats: effects on body weight regulation, body composition and exercise capacity.
The aim of the current investigation was to examine the effects of consuming a low-carbohydrate high-fat diet (LC-HFD) in combination with daily exercise on body weight, body composition, endocrine control of the energy balance system and exercise capacity in adolescent and mature rats.. Adolescent (n=23) and mature rats (n=16) were maintained on either a standard chow diet (CH) or a LC-HFD for a period of ten days prior to daily exercise training for 21 days in forced running wheel system. At the end of the 21 day training sessions all rats took part in an exercise performance test where time to exhaustion was measured.. Rats maintained on the LC-HFD demonstrated a significant lack of body weight gain (p<0.05) compared to CH maintained rats, despite equicaloric intake and performing identical amounts of daily exercise. Body composition was significantly altered in the LC-HFD rats (p<0.05) with increased body fat (p<0.01). Leptin concentrations were higher (p<0.05) and IGF-I concentrations were lower (p<0.01) in the LC-HFD fed rats. Exercise performance was not diminished in the LC-HFD group despite the higher fat mass. Both groups irrespective of age performed equally as well in the time to exhaustion test (p>0.05).. Maintenance on the LC-HFD in combination with forced daily exercise did not impact exercise capacity (total distance and meters per minute). Additionally consumption of an extreme LC-HFD in combination with daily exercise resulted in significantly less body weight gain but increased fat mass. When combined with daily exercise this diet clearly had a negative impact on body composition, but did not affect exercise capacity. Topics: Adipose Tissue; Age Factors; Animals; Body Composition; Body Weight; Diet, Carbohydrate-Restricted; Diet, High-Fat; Dietary Carbohydrates; Dietary Fats; Energy Intake; Energy Metabolism; Feces; Insulin-Like Growth Factor I; Leptin; Lipids; Male; Nitrogen; Physical Conditioning, Animal; Rats; Rats, Wistar | 2012 |
Long-term consequences of feed restriction during late pregnancy in goats on feeding behavior and emotional reactivity of female offspring.
Feed restriction during pregnancy can have detrimental effects on offspring development both during the juvenile period and during adult life. Long-term effects of maternal feed restriction during the last third of pregnancy on growth, metabolism and behavior of female kids, with a focus on feeding behavior and emotional reactivity, were studied in goats. Female kids born to control (CONT, n=17) or born to feed restricted goats (REST, n=15) were artificially reared and monitored from birth to 24 months of age. Maternal feeding restriction globally reduced live weight (P<0.001) and body condition score (P=0.02) of REST compared to CONT offspring. Females from the REST group had a higher daily feed intake (P=0.05) and tended to eat more rapidly (P=0.09) than females from the CONT group at 12 months of age. One year later, REST goats still ate more than CONT goats (P=0.05). Glucose metabolism did not appear to be modified as no differences were observed in glucose or insulin responses to an intravenous glucose tolerance test. No differences in time budget were found at 12 months of age. However, the HPA axis response to an ACTH injection was greater in REST than in CONT goats: higher peak cortisol concentration (P=0.02) and a greater area under the curve were found (P=0.01) at 14 months of age. In conclusion, maternal feed restriction during late pregnancy modified both feeding behavior and the stress physiology of female offspring for up to 2 years of age. However, the changes observed were small. Topics: Adrenocorticotropic Hormone; Age Factors; Animals; Body Weight; Eating; Emotions; Feeding Behavior; Female; Food Deprivation; Glucose Tolerance Test; Goats; Hydrocortisone; Hypothalamo-Hypophyseal System; Leptin; Maternal Nutritional Physiological Phenomena; Pituitary-Adrenal System; Pregnancy; Pregnancy Complications; Stress, Psychological | 2012 |
Leptins and leptin receptor expression in the goldfish (Carassius auratus). Regulation by food intake and fasting/overfeeding conditions.
Leptin is a hormone involved in feeding and body weight regulation in vertebrates, but the relationship between energy status and leptin has not been clearly established in fish. The aim of this study was to investigate in a teleost, the goldfish (Carassius auratus), the tissue expression pattern of two leptins (gLep-aI and gLep-aII) and leptin receptor (gLepR); and the effect of feeding on expression of these genes. Leptin system expression in goldfish was firstly analyzed in fish under overfeeding (2 weeks) or fasting (1 week), and secondly, at different postfeeding times (0, 3, 6, 9 and 12h). Goldfish has two Lep-a paralog genes, gLep-aI was widely expressed in central and peripheral tissues, whereas gLep-aII was preferentially expressed in brain. This different distribution pattern of leptins suggests that they can play different physiological roles in goldfish. The gLepR mRNA was ubiquitous expressed, with the highest expression in the telencephalon and hypothalamus. No significant differences in the leptin system expression were found among control, overfed and fasting groups, suggesting an apparent lack of correlation between nutritional status and leptin system in goldfish. Hepatic expression of gLep-aI significantly increased 9h after feeding time, while hypothalamic leptin system expression did not change after feeding. In summary, leptin in goldfish could signal short-term changes in food intake, as postprandial satiety, but seems to be independent of fasting/overfeeding conditions in this teleost. The widespread distribution of leptins and leptin receptor in goldfish strongly supports that this hormone may have pleitropic actions in fish. Topics: Animals; Body Weight; Eating; Fasting; Female; Gene Expression Regulation; Genetic Pleiotropy; Goldfish; Hypothalamus; Leptin; Liver; Male; Organ Specificity; Overnutrition; Protein Isoforms; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Telencephalon | 2012 |
High-fat diet-induced reduction of peroxisome proliferator-activated receptor-γ coactivator-1α messenger RNA levels and oxidative capacity in the soleus muscle of rats with metabolic syndrome.
Animal models of type 2 diabetes exhibit reduced peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) messenger RNA (mRNA) levels, which are associated with decreased oxidative capacity, in skeletal muscles. In contrast, animal models with metabolic syndrome show normal PGC-1α mRNA levels. We hypothesized that a high-fat diet decreases PGC-1α mRNA levels in skeletal muscles of rats with metabolic syndrome, reducing muscle oxidative capacity and accelerating metabolic syndrome or inducing type 2 diabetes. We examined mRNA levels and fiber profiles in the soleus muscles of rats with metabolic syndrome (SHR/NDmcr-cp [cp/cp]; CP) fed a high-fat diet. Five-week-old CP rats were assigned to a sedentary group (CP-N) that was fed a standard diet (15.1 kJ/g, 23.6% protein, 5.3% fat, and 54.4% carbohydrates) or a sedentary group (CP-H) that was fed a high-fat diet (21.6 kJ/g, 23.6% protein, 34.9% fat, and 25.9% carbohydrates) and were housed for 10 weeks. Body weight, energy intake, and systolic blood pressure were higher in the CP-H group than in the CP-N group. Nonfasting glucose, triglyceride, total cholesterol, and leptin levels were higher in the CP-H group than in the CP-N group. There was no difference in insulin levels between the CP-N and CP-H groups. Muscle PGC-1α mRNA levels and succinate dehydrogenase activity were lower in the CP-H group than in the CP-N group. We concluded that a high-fat diet reduces PGC-1α mRNA levels and oxidative capacity in skeletal muscles and accelerates metabolic syndrome. Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Fats; Energy Intake; Insulin; Leptin; Male; Metabolic Syndrome; Muscle, Skeletal; Oxidation-Reduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma; Rats; Rats, Inbred Strains; RNA-Binding Proteins; RNA, Messenger; Sedentary Behavior; Succinate Dehydrogenase; Transcription Factors; Triglycerides | 2012 |
Study of the leptin levels and its gene polymorphisms in patients with idiopathic short stature and growth hormone deficiency.
Leptin levels may regulate fat metabolism, skeletal growth, and puberty. Leptin gene variants affect risk of obesity, cancer, but their effect on onset of growth hormone deficiency (GHD) and idiopathic short stature (ISS) is unknown. We tested the hypothesis that the phenotype of GHD and ISS may be associated with polymorphism in the leptin gene. The prevalence of a single nucleotide polymorphism (SNP) in the leptin gene (LEP) promoter at -2548 and the leptin and insulin growth factor-1 (IGF-1) concentrations in GHD and ISS were compared to those of healthy controls. IGF-1 and leptin concentrations were significantly lower in both the GHD and ISS groups than in the control group. The ISS and GHD groups had a significantly different distribution of SNP alleles at the LEP -2548 (P = 0.010). Individuals with LEP -2548A/G or G/G genotype in ISS group (47.5%) showed a significantly lower weight and body mass index (BMI) (but not leptin levels) than individuals carrying the A/A genotype (52.5%). LEP -2548A/A in GHD patients (65.8%) was associated with lower weight, BMI, leptin concentrations than those of individuals carrying the A/G or G/G genotype (34.2%). These data suggest that the LEP -2548A polymorphism may associate with the weight and BMI of the children with ISS and GHD. Topics: Age Determination by Skeleton; Age Factors; Body Height; Body Mass Index; Body Weight; Child; Dwarfism; Female; Gene Frequency; Growth Disorders; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Male; Polymorphism, Single Nucleotide | 2012 |
Effects of leptin treatment and Western diet on wheel running in selectively bred high runner mice.
The role of leptin in regulating physical activity is varied. The behavioral effects of leptin signaling depend on the type of activity and the animal's physiological state. We used mice from lines selectively bred for high voluntary wheel running to further study how leptin regulates volitional exercise. Mice from four replicate high runner (HR) lines typically run ~3-fold more revolutions per day than those from four non-selected control (C) lines. HR mice have altered dopamine function and differences from C in brain regions known to be important in leptin-mediated behavior. Furthermore, male HR mice have been found to dramatically increase running when administered Western diet, an effect possibly mediated through leptin signaling. Male mice from generation 61 (representing three HR lines and one C line) were allowed wheel access at 24 days of age and given either Western diet (high in fat and with added sucrose) or standard chow. After four weeks, Western diet significantly increased circulating leptin, insulin, C-peptide, gastric inhibitory polypeptide, and inflammatory hormone resistin concentrations in HR mice (C mice not measured). Western diet increased running in HR mice, but did not significantly affect running in C mice. During the fifth week, all mice received two days of intra-peritoneal sham injections (physiological saline) followed by three days of murine recombinant leptin injections, and then another six days of sham injections. Leptin treatment significantly decreased caloric intake (adjusted for body mass) and body mass in all groups. Wheel running significantly increased with leptin injections in HR mice (fed Western or standard diet), but was unaffected in C mice. Whether Western diet and leptin treatment stimulate wheel running in HR mice through the same physiological pathways awaits future study. These results have implications for understanding the neural and endocrine systems that control locomotor activity, food consumption, and body weight, and how they may vary with genetic background. Topics: Animals; Body Weight; C-Peptide; Diet, High-Fat; Dietary Fats; Energy Intake; Gastric Inhibitory Polypeptide; Insulin; Leptin; Male; Mice; Mice, Inbred Strains; Motor Activity; Recombinant Proteins; Resistin | 2012 |
TrkB receptor signaling in the nucleus tractus solitarius mediates the food intake-suppressive effects of hindbrain BDNF and leptin.
Brain-derived neurotrophic factor (BDNF) and TrkB receptor signaling contribute to the central nervous system (CNS) control of energy balance. The role of hindbrain BDNF/TrkB receptor signaling in energy balance regulation is examined here. Hindbrain ventricular BDNF suppressed body weight through reductions in overall food intake and meal size and by increasing core temperature. To localize the neurons mediating the energy balance effects of hindbrain ventricle-delivered BDNF, ventricle subthreshold doses were delivered directly to medial nucleus tractus solitarius (mNTS). mNTS BDNF administration reduced food intake significantly, and this effect was blocked by preadministration of a highly selective TrkB receptor antagonist {[N2-2-2-Oxoazepan-3-yl amino]carbonyl phenyl benzo (b)thiophene-2-carboxamide (ANA-12)}, suggesting that TrkB receptor activation mediates hindbrain BDNF's effect on food intake. Because both BDNF and leptin interact with melanocortin signaling to reduce food intake, we also examined whether the intake inhibitory effects of hindbrain leptin involve hindbrain-specific BDNF/TrkB activation. BDNF protein content within the dorsal vagal complex of the hindbrain was increased significantly by hindbrain leptin delivery. To assess if BDNF/TrkB receptor signaling acts downstream of leptin signaling in the control of energy balance, leptin and ANA-12 were coadministered into the mNTS. Administration of the TrkB receptor antagonist attenuated the intake-suppressive effects of leptin, suggesting that mNTS TrkB receptor activation contributes to the mediation of the anorexigenic effects of hindbrain leptin. Collectively, these results indicate that TrkB-mediated signaling in the mNTS negatively regulates food intake and, in part, the intake inhibitory effects of leptin administered into the NTS. Topics: Animals; Azepines; Benzamides; Body Weight; Brain-Derived Neurotrophic Factor; Drug Interactions; Eating; Energy Metabolism; Fourth Ventricle; Injections, Intraventricular; Leptin; Male; Melanocortins; Obesity; Rats; Rats, Sprague-Dawley; Receptor, trkB; Signal Transduction; Solitary Nucleus | 2012 |
Systemic leptin administration in supraphysiological doses maintains bone mineral density and mechanical strength despite significant weight loss.
The effects of leptin on bone are controversial. Although in vitro studies have shown that leptin stimulates osteoblast differentiation and mineralization and inhibits osteoclastogenesis, some rodent studies have shown that leptin administered centrally might result in decreased bone formation. In the present study we have investigated the skeletal effects of supraphysiological concentrations of leptin administered sc to rats. Female Fischer rats were given leptin 100 μg/d, 200 μg/d, or saline by continuous infusion for 9 wk. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry, bone microarchitecture was analyzed by micro-computed tomography, and biomechanical properties were tested by three-point bending experiments. At the end of the study, the body weight was significantly lower in rats receiving leptin compared with controls (-10.8% and -12.0% in low- and high-dose leptin groups, respectively). The high-dose leptin group also significantly lost weight compared with baseline. The plasma leptin concentration was 14- and 33-fold increased in the low- and high-dose groups, respectively. No significant differences in femoral BMD were observed. Whole-body BMD was significantly lower in the low-dose leptin group, whereas there was no difference between the high-dose leptin group and the control. Mechanical strength and microarchitecture were similar in the high-dose and the control group. The low-dose group, however, had decreased cortical volume in the femoral metaphysis, lowered bone strength, and altered moment of inertia. In conclusion, leptin given at very high doses maintains BMD, microarchitecture, and mechanical strength in female rats, despite a significant decrease in body weight. Topics: Animals; Body Weight; Bone Density; Female; Femur; Leptin; Rats; Rats, Inbred F344; Weight Loss | 2012 |
Pre- and postnatal calorie restriction perturbs early hypothalamic neuropeptide and energy balance.
Energy balance is regulated by circulating leptin concentrations and hypothalamic leptin receptor (ObRb) signaling via STAT3 but is inhibited by SOCS3 and PTP1B. Leptin signaling enhances anorexigenic neuropeptides and receptor (POMC, MC3-R, MC4-R) activation while suppressing orexigenic neuropeptides (NPY, AgRP). We investigated in a sex-specific manner the early (PN2) and late (PN21) postnatal hypothalamic mechanisms in response to intrauterine (IUGR), postnatal (PNGR), and combined (IPGR) calorie and growth restriction. At PN2, both male and female IUGR were hypoleptinemic, but hypothalamic leptin signaling in females was activated as seen by enhanced STAT3. In addition, increased SOCS3 and PTP1B supported early initiation of leptin resistance in females that led to elevated AgRP but diminished MC3-R and MC4-R. In contrast, males demonstrated leptin sensitivity seen as a reduction in PTP1B and MC3-R and MC4-R with no effect on neuropeptide expression. At PN21, with adequate postnatal caloric intake, a sex-specific dichotomy in leptin concentrations was seen in IUGR, with euleptinemia in males indicative of persisting leptin sensitivity and hyperleptinemia in females consistent with leptin resistance, both with normal hypothalamic ObRb signaling, neuropeptides, and energy balance. In contrast, superimposition of PNGR upon IUGR (IPGR) led to diminished leptin concentrations with enhanced PTP1B and an imbalance in arcuate nuclear NPY/AgRP and POMC expression that favored exponential hyperphagia and diminished energy expenditure postweaning. We conclude that IUGR results in sex-specific leptin resistance observed mainly in females, whereas PNGR and IPGR abolish this sex-specificity, setting the stage for acquiring obesity after weaning. Topics: Age Factors; Agouti-Related Protein; Analysis of Variance; Animals; Animals, Newborn; Body Weight; Caloric Restriction; Drinking; Eating; Energy Intake; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation, Developmental; Hypothalamus; Injections, Intraventricular; Leptin; Male; Milk; Neuropeptide Y; Neuropeptides; Pregnancy; Prenatal Exposure Delayed Effects; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Respiratory Physiological Phenomena; RNA, Messenger; Sex Factors; Signal Transduction; STAT3 Transcription Factor | 2012 |
Reduced serotonin reuptake transporter (SERT) function causes insulin resistance and hepatic steatosis independent of food intake.
Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes. Topics: Animals; Body Weight; Eating; Enzyme Activation; Fatty Liver; Glucose Intolerance; Hypertrophy; Insulin; Insulin Resistance; Islets of Langerhans; JNK Mitogen-Activated Protein Kinases; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscles; Mutation; Obesity; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Serotonin Plasma Membrane Transport Proteins | 2012 |
Leptin resistance in vagal afferent neurons inhibits cholecystokinin signaling and satiation in diet induced obese rats.
The gastrointestinal hormone cholecystokinin (CCK) plays an important role in regulating meal size and duration by activating CCK1 receptors on vagal afferent neurons (VAN). Leptin enhances CCK signaling in VAN via an early growth response 1 (EGR1) dependent pathway thereby increasing their sensitivity to CCK. In response to a chronic ingestion of a high fat diet, VAN develop leptin resistance and the satiating effects of CCK are reduced. We tested the hypothesis that leptin resistance in VAN is responsible for reducing CCK signaling and satiation.. Lean Zucker rats sensitive to leptin signaling, significantly reduced their food intake following administration of CCK8S (0.22 nmol/kg, i.p.), while obese Zucker rats, insensitive to leptin, did not. CCK signaling in VAN of obese Zucker rats was reduced, preventing CCK-induced up-regulation of Y2 receptor and down-regulation of melanin concentrating hormone 1 receptor (MCH1R) and cannabinoid receptor (CB1). In VAN from diet-induced obese (DIO) Sprague Dawley rats, previously shown to become leptin resistant, we demonstrated that the reduction in EGR1 expression resulted in decreased sensitivity of VAN to CCK and reduced CCK-induced inhibition of food intake. The lowered sensitivity of VAN to CCK in DIO rats resulted in a decrease in Y2 expression and increased CB1 and MCH1R expression. These effects coincided with the onset of hyperphagia in DIO rats.. Leptin signaling in VAN is required for appropriate CCK signaling and satiation. In response to high fat feeding, the onset of leptin resistance reduces the sensitivity of VAN to CCK thus reducing the satiating effects of CCK. Topics: Animals; Body Weight; Cells, Cultured; Cholecystokinin; Diet, High-Fat; Eating; Leptin; Male; Neurons, Afferent; Obesity; Phenotype; Rats; Rats, Sprague-Dawley; Rats, Zucker; Satiation; Signal Transduction; Vagus Nerve | 2012 |
Long term metabolic impact of high protein neonatal feeding: a preliminary study in male rat pups born with a low birth weight.
Nutrition received in early life may impact adult health. The aim of the study was to determine whether high protein feeding in neonatal period would have long term metabolic effects in an animal model of low birth weight infants.. Male rat pups born from dams receiving a low protein diet during gestation were separated from their mothers, and equipped with gastrostomy tubes to receive as their sole feeding a milk formula of either adequate protein (AP; n = 14; 8.7 g protein/dL; total energy: 155 kcal/100 g), or high protein content (HP; n = 14; 13.0 g protein/dL; total energy: 171 kcal/100 g) between the 7th (D7) and 21st day (D21) of life. Rats were then weaned to standard chow until sacrificed at adulthood.. At D18, HP feeding was associated with higher estimated rates of protein turnover (p = 0.007) and synthesis (p = 0.051), as assessed using l-[U-(13)C]valine infusion. HP milk feeding in early life was associated with an increase in weight gain from puberty through adulthood, along with an increase in food intake, serum insulin (179 ± 58 vs. 55 ± 7 pmol/L; means ± SE), pancreatic β-cell number, plasma triglycerides (95 ± 8 vs. 73 ± 9 mg/dL), serum leptin (9.7 ± 1.0 vs. 5.5 ± 1.2 ng/mL), mesenteric fat mass, and adipocyte size.. In an animal model of low birth weight infants, high protein neonatal feeding may have a lasting effect on fat and glucose metabolism, potentially leading to "metabolic syndrome" in adulthood. Topics: Adipose Tissue; Animals; Animals, Newborn; Blood Glucose; Body Weight; Diet; Dietary Proteins; Energy Intake; Female; Hormones; Leptin; Lipid Metabolism; Male; Pancreas; Rats; Rats, Sprague-Dawley; Valine | 2012 |
Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin.
Mutations in the Bdnf gene, which produces transcripts with either short or long 3' untranslated regions (3' UTRs), cause human obesity; however, the precise role of brain-derived neurotrophic factor (BDNF) in the regulation of energy balance is unknown. Here we show the relationship between Bdnf mRNA with a long 3' UTR (long 3' UTR Bdnf mRNA), leptin, neuronal activation and body weight. We found that long 3' UTR Bdnf mRNA was enriched in the dendrites of hypothalamic neurons and that insulin and leptin could stimulate its translation in dendrites. Furthermore, mice harboring a truncated long Bdnf 3' UTR developed severe hyperphagic obesity, which was completely reversed by viral expression of long 3' UTR Bdnf mRNA in the hypothalamus. In these mice, the ability of leptin to activate hypothalamic neurons and inhibit food intake was compromised despite normal activation of leptin receptors. These results reveal a novel mechanism linking leptin action to BDNF expression during hypothalamic-mediated regulation of body weight, while also implicating dendritic protein synthesis in this process. Topics: 3' Untranslated Regions; Age Factors; Analysis of Variance; Animals; Body Weight; Brain-Derived Neurotrophic Factor; Cells, Cultured; Dendrites; Disease Models, Animal; Energy Metabolism; Female; Gene Expression Regulation; Green Fluorescent Proteins; Humans; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Neurons; Obesity; Proto-Oncogene Proteins c-fos; Receptor, Insulin; Receptor, trkB; RNA, Messenger; Signal Transduction; Transduction, Genetic | 2012 |
Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals.
In mammals, leptin regulates food intake and energy balance mainly through the activation of LepRb in the hypothalamus, and estrogen has a leptin-like effect in the hypothalamic control of metabolism. However, it remains to be elucidated how estrogen signaling is intertwined with the leptin pathway. We show here that Shp2, a nonreceptor tyrosine phosphatase, acts to integrate leptin and estrogen signals. The expression of a dominant-active mutant (Shp2(D61A)) in forebrain neurons conferred female, but not male, transgenic mice resistance to high-fat diet (HFD)-induced obesity and liver steatosis, accompanied by improved insulin sensitivity and glucose homeostasis. Fed with either HFD or regular chow food, Shp2(D61A) female mice showed dramatically enhanced leptin sensitivity. Microinjection of Shp2(D61A)-expressing adeno-associated virus into mediobasal hypothalamus elicited a similar antiobese effect in female mice. Biochemical analyses showed a physical association of Shp2 with estrogen receptor alpha, which is necessary for the synergistic and persistent activation of Erk by leptin and estrogen. Together, these results elucidate a mechanism for the direct cross talk of leptin and estrogen signaling and offer one explanation for the propensity of postmenopausal women to develop obesity. Topics: Animals; Body Weight; Diet, High-Fat; Energy Metabolism; Estrogen Receptor alpha; Estrogens; Female; Hypothalamus; Leptin; Male; Mice; Mice, Transgenic; Mutation; Neurons; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Receptors, Leptin; Sex Factors; Signal Transduction | 2012 |
Effects of a high-fat diet exposure in utero on the metabolic syndrome-like phenomenon in mouse offspring through epigenetic changes in adipocytokine gene expression.
The links between obesity in parents and their offspring and the role of genes and a shared environment are not completely understood. Adipocytokines such as leptin and adiponectin play important roles in glucose and lipid metabolism. Therefore, we examined whether the offspring from dams exposed to a high-fat diet during pregnancy (OH mice) exhibited hypertension, insulin resistance, and hyperlipidemia along with epigenetic changes in the expression of adipocytokine genes. OH mice were significantly heavier than the offspring of dams exposed to a control diet during pregnancy (OC mice) from 14 wk of age after an increased caloric intake from 8 wk. OH mice exhibited higher blood pressure and worse glucose tolerance than the OC mice at 24 wk. Total triglyceride and leptin levels were significantly higher and the adiponectin level was significantly lower in OH compared with OC mice at 12 wk of age. This was associated with changes in leptin and adiponectin expression in white adipose tissue. There were lower acetylation and higher methylation levels of histone H3 at lysine 9 of the promoter of adiponectin in adipose tissues of OH mice at 2 wk of age as well as at 12 and 24 wk of age compared with OC mice. In contrast, methylation of histone 4 at lysine 20 in the leptin promoter was significantly higher in OH compared with OC mice. Thus, exposure to a high-fat diet in utero might cause a metabolic syndrome-like phenomenon through epigenetic modifications of adipocytokine, adiponectin, and leptin gene expression. Topics: Acetylation; Adiponectin; Adipose Tissue; Animals; Animals, Newborn; Blood Pressure; Body Weight; Diet, High-Fat; Energy Intake; Epigenesis, Genetic; Female; Gene Expression; Glucose Tolerance Test; Histones; Insulin; Leptin; Male; Metabolic Syndrome; Methylation; Mice; Mice, Inbred ICR; Pregnancy; Prenatal Exposure Delayed Effects; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Triglycerides | 2012 |
Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity.
α-Melanocyte-stimulating hormone (α-MSH) is a critical regulator of energy metabolism. Prolyl carboxypeptidase (PRCP) is an enzyme responsible for its degradation and inactivation. PRCP-null mice (PRCP(gt/gt)) showed elevated levels of brain α-MSH, reduced food intake, and a leaner phenotype compared with wild-type controls. In addition, they were protected against diet-induced obesity. Here, we show that PRCP(gt/gt) animals have improved metabolic parameters compared with wild-type controls under a standard chow diet (SD) as well as on a high-fat diet (HFD). Similarly to when they are exposed to SD, PRCP(gt/gt) mice exposed to HFD for 13 wk showed a leaner phenotype due to decreased fat mass, increased energy expenditure, and locomotor activity. They also showed improved insulin sensitivity and glucose tolerance compared with WT controls and a significant reduction in fasting glucose levels. These improvements occured before changes in body weight and composition were evident, suggesting that the beneficial effect of PRCP ablation is independent of the adiposity levels. In support of a reduced gluconeogenesis, liver PEPCK and G-6-Pase mRNA levels were reduced significantly in PRCP(gt/gt) compared with WT mice. A significant decrease in liver weight and hepatic triglycerides were also observed in PRCP(gt/gt) compared with WT mice. Altogether, our data suggest that PRCP is an important regulator of energy and glucose homeostasis since its deletion significantly improves metabolic parameters in mice exposed to both SD and HFD. Topics: Animals; Body Composition; Body Weight; Carboxypeptidases; Diet, High-Fat; Energy Metabolism; Fatty Acids; Gene Deletion; Gluconeogenesis; Glucose; Glucose Tolerance Test; Homeostasis; Hormones; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Organ Size; Real-Time Polymerase Chain Reaction | 2012 |
Response of gut hormones after implantation of a reversible gastric restrictive device in different animal models.
Variable responses of gut hormones have been observed after bariatric procedures. The aim of the present study was to evaluate the ghrelin, glucagon-like peptide 1 (GLP-1), and leptin levels in nonobese canine and obese rat models after weight loss owing to a reversible gastric restriction (RGR) device.. Mongrel dogs and obese Zucker rats were submitted to either surgical implantation or a sham operation and were followed up for 6 wk. The serum fasting ghrelin, GLP-1, and leptin levels in dogs were measured using enzyme-linked immunosorbent assay before and after surgical implantation and after implant removal. The protein expression of mucosa ghrelin, GLP-1, and leptin in the dog and rat stomach were measured using Western blotting.. The RGR implant in dogs and rats resulted in a significant decrease in food intake and body weight. In the nonobese dog, the serum ghrelin level and mucosa ghrelin expression were significantly increased after surgical implantation (P < 0.05) and tended to recover after implant removal. In the obese rat, mucosa ghrelin expression decreased by about 27% (P = 0.06) 6 wk after implantation. A lower serum leptin level in dogs and lower mucosa leptin expression in dogs and rats was observed after surgical implantation compared with the sham procedure (P < 0.05). The RGR implant had no influence on the serum GLP-1 level in dogs or mucosa GLP-1 expression in either animal model.. Our results showed that ghrelin levels are downregulated with short-term RGR implantation in obese rats but upregulated in nonobese dogs, implying that the energy balance could be an important determinant of ghrelin level. The marked suppression of leptin in both animal models might contribute to the weight-reducing effect of the RGR implant. Topics: Animals; Body Weight; Disease Models, Animal; Dogs; Energy Metabolism; Gastric Mucosa; Gastroplasty; Ghrelin; Glucagon-Like Peptide 1; Leptin; Obesity; Rats; Rats, Zucker; Weight Loss | 2012 |
Beneficial effects by intake of Euphausiacea pacifica on high-fat diet-induced obesity.
Obesity is a major health problem showing increased incidence in developed and developing countries. We examined the effect of Euphausia pacifica (E. pacifica) (Pacific Krill) on high-fat diet (HFD)-induced obesity in C57BL/6 mice. No significant differences were observed in average food intake between the HFD and HFD with E. pacifica group, or the low-fat diet (LFD) and LFD with E. pacifica group for 18 weeks. The increased ratio of body weight in the HFD containing E. pacifica group was significantly reduced, being 10% lower than that with HFD group in the 18th week (HFD, 298.6±18.8% vs. HFD with E. pacifica, 267.8±16.2%; p<0.05), while the ratio for the LFD containing E. pacifica group was reduced by 4% compared with LFD group (LFD, 244.2±11.6% vs. LFD with E. pacifica, 234.1±18.0%). There were no effects of E. pacifica on total cholesterol levels in serum and liver, whereas the supplement of E. pacifica tended to decrease triglyceride levels in the HFD groups. The leptin level in serum was significantly decreased in the HFD group (p<0.01) by E. pacifica. The adipocyte area (1926±1275 μm(2)) in the HFD containing E. pacifica group was significantly reduced by 20% (p<0.001) compared with the HFD group. These results suggested that E. pacifica supplementation in the diet is beneficial for the prevention of HFD-induced obesity. Topics: Adipocytes; Animals; Body Weight; Cholesterol; Complex Mixtures; Diet, High-Fat; Eating; Euphausiacea; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Triglycerides | 2012 |
Platycodon grandiflorum modifies adipokines and the glucose uptake in high-fat diet in mice and L6 muscle cells.
Obesity and diabetes have become the most common human health problems worldwide. Obesity's contribution to type 2 diabetes might be due to dysregulation of adipokines and glucose uptake.. In this study, we performed in-vivo and in-vitro studies to evaluate the effects of Platycodon grandiflorum extract (PGE) on adipokines and glucose uptake. Before study, platycodin D concentrations were analysed by HPLC in PGE prepared in water, in 50% ethanol and in 80% ethanol, and we selected the 80% ethanol extract as the PGE for this study based on the HPLC results.. We found that inclusion of PGE in the high-fat diet (HFD) markedly attenuated food intake, body weight, epididymal fat weight, adipocyte size and blood glucose levels by the oral glucose tolerance test in mice, and maintained serum levels of adiponectin, resistin, leptin, fructosamine and triglycerides. Gene expression analysis revealed that PGE up-regulated adiponectin, and down-regulated TNF-α and leptin in fat tissue. In L6 muscle cells in vitro, PGE increased insulin-stimulated glucose uptake.. We conclude that PGE may improve obesity in mice fed an HFD and glucose uptake in L6 muscle cells by modifying adipokines, and could offer clinical benefits as a supplement to treat obesity and diabetes. Topics: Adipocytes; Adipokines; Adiponectin; Animals; Blood Glucose; Body Weight; Cell Line; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Diet, High-Fat; Energy Intake; Fructosamine; Gene Expression; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Leptin; Male; Mice; Mice, Inbred ICR; Muscle Cells; Obesity; Phytotherapy; Plant Extracts; Platycodon; Resistin; Saponins; Triglycerides; Triterpenes; Tumor Necrosis Factor-alpha | 2012 |
Involvement of doublecortin-expressing cells in the arcuate nucleus in body weight regulation.
Hypothalamic functions, including feeding behavior, show a high degree of plasticity throughout life. Doublecortin (DCX) is a marker of plasticity and neuronal migration expressed in the hypothalamus. Therefore, we wanted to map the fate of DCX(+) cells in the arcuate nucleus (ARC) of the hypothalamus. For this purpose, we generated a BAC transgenic mouse line that expresses the inducible recombinase CreER(T2) under control of the DCX locus. Crossing this line with the Rosa26 or Ai14 reporter mouse lines, we found reporter(+) cells in the ARC upon tamoxifen treatment. They were born prenatally and expressed both DCX and the plasticity marker TUC-4. Immediately after labeling, reporter(+) cells had an enlarged soma that normalized over time, suggesting morphological remodeling. Reporter(+) cells expressed β-endorphin and BSX, neuronal markers of the feeding circuit. Furthermore, leptin treatment led to phosphorylation of STAT3 in reporter(+) cells in accordance with the concept that they are part of the feeding circuits. Indeed, we found a negative correlation between the number of reporter(+) cells and body weight and epididymal fat pads. Our data suggest that DCX(+) cells in the ARC represent a cellular correlate of plasticity that is involved in controlling energy balance in adult mice. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Doublecortin Domain Proteins; Doublecortin Protein; Energy Metabolism; Female; Gene Expression; Homeodomain Proteins; Immunohistochemistry; Leptin; Male; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Nerve Tissue Proteins; Neuronal Plasticity; Neurons; Neuropeptides; Phosphorylation; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor | 2012 |
Association of leptin genotypes with beef cattle characteristics.
A single nucleotide polymorphism (C/T) in bovine leptin, resulting in an arginine to cysteine amino acid substitution (p.Arg25Cys), has previously been shown to have an impact on carcass characteristics. Given the significant energetic relationship between fat and animal efficiency, further evaluation of this SNP across larger animal populations is warranted. Of the total number of 136 286 genotyped cattle in this study, 92 112 and 53 189 were analysed for backfat and body weight measurements, respectively. Results showed a significant positive relationship (P < 0.0001) between the T allele frequency and animal backfat, with TT, CT and CC animals having estimates of 6.79 ± 0.02, 6.49 ± 0.01 and 6.28 ± 0.01 mm, respectively. Calculations using rate of backfat accretion showed that animals with CC genotypes would require more days to reach 12 mm of backfat (45 days) than animals with CT (42 days) and TT (38 days) genotypes. Animal weight was also shown to be positively associated (P < 0.0001) with genotype, as animals of the TT, CT and CC genotypes weighed 484.2 ± 0.7, 488.0 ± 0.5 and 487.3 ± 0.6 kg, respectively, further underscoring the effects of this SNP on key market cattle characteristics. Topics: Adipose Tissue; Animals; Body Weight; Cattle; Female; Genotype; Leptin; Male; Polymerase Chain Reaction; Polymorphism, Single Nucleotide | 2012 |
Metabolic effects of a stabilizing peptide fusion protein of leptin in normal mice.
Leptin is a protein hormone produced by adipocytes. It is secreted into the blood stream and plays a key role in regulating body energy homeostasis by inhibiting feeding behavior followed by decreased body weight. Because protein aggregation is a major problem in therapeutic proteins, we previously demonstrated that a stabilizing peptide (SP) fusion protein of leptin (SP-leptin) appeared to resist aggregation induced by agitation, freezing/thawing, or heat stress. In this study, we fused mouse leptin with the stabilizing peptide and compared the biological activities of leptin and SP-leptin in vivo using a male C57Bl mouse model and ex vivo using MCF7 breast cancer cell lines. Each group of mice was treated with saline, leptin, and SP-leptin for 20 days and the differences in body weight, food intake, abdominal fat contents, and TG concentration were measured. The SP-leptin appeared to decrease the body weight and food intake in male C57Bl mice more significantly than wild type leptin, and the SP-leptin treated MCF7 cells displayed better cell proliferation than leptin. As a consequence of decreased body weight, the SP-leptin treated mouse group showed decreased abdominal fat contents and low triglyceride (TG) concentration. Moreover, the SP-leptin treated mouse group had fewer lipid droplets in liver and reduced lipid droplet size when analyzed by Oil red O and H & E staining. These results demonstrated that SP-leptin is more effective than wild type leptin in normal mice in lowering their body weight and fat contents in the abdominal region, the serum, and the liver. Topics: Abdominal Fat; Adiposity; Animals; Body Weight; Cell Line, Tumor; Feeding Behavior; Humans; Leptin; Lipids; Liver; Male; Metabolic Networks and Pathways; Mice; Mice, Inbred C57BL; Peptides; Protein Stability; Recombinant Fusion Proteins | 2012 |
The influence of reproductive physiology and nutrient supply on the periparturient relaxation of immunity to the gastrointestinal nematode Trichostrongylus colubriformis in Merino ewes.
A pen experiment was conducted to investigate the interaction of early-weaning and nutrient supply on the periparturient relaxation of immunity to the gastrointestinal nematode (GIN) Trichostrongylus colubriformis in Merino ewes. Mixed-age pregnant and non-pregnant (dry) ewes were infected with 8,000 T. colubriformis L(3)/week, and fed either a high or low quality diet. Following parturition, lambs were either removed from their mothers at 2 days of age or allowed to continue suckling. Systemic immunity began to wane during late pregnancy with circulating eosinophils and plasma total antibody (Ab) levels declining from day -37 (relative to the midpoint of lambing) and day -24, respectively. Pregnant ewes fed the low quality diet exhibited an increasing faecal worm egg count (WEC) from day -24 and had higher intestinal worm burdens on day 13, whereas ewes fed the high quality diet had a delayed transient rise in WEC of lower magnitude. Dry and early-weaned ewes remained highly resistant to T. colubriformis at all times. In the post-lambing/lactation period, ewes fed the high quality diet had higher levels of local total Ab and numbers of goblet cells (GC) in the small intestine on days 13 and 41. Lactating/suckled ewes had a lower anti-parasite local immune response as indicated by reduced titres of total Ab, IgG(1), IgM and IgA and lower numbers of mucosal mast cells (MMC), globule leukocytes (GL) and GC in small intestinal tissue compared to their dry and early-weaned counterparts. Early-weaning resulted in rapid recovery of blood eosinophils and total Ab. On day 13 post-lambing, titres of total Ab, IgG(1), IgM, IgA and IgE, and numbers of MMC and GL were greater than those measured in dry and suckled ewes. When fed the high quality diet, ewes had a higher dry matter (DM) intake, maternal weight, fat score, greater fat depth and eye muscle depth, birthed heavier lambs that had higher growth rates, and produced more milk. The physiological status of pregnancy resulted in a higher DM intake but lower measures of fat depth and eye muscle depth, and suckling led to an increase in DM intake but a reduction in body weight and fat score through mobilisation of fat and muscle reserves. Despite the marked effect of diet quality on production traits, some inconsistencies were observed between body composition and apparent parasite resistance, measured by WEC and worm counts, suggesting that the nutritional influence was not necessarily always mediated through chan Topics: Animals; Antibodies, Helminth; Blood Cell Count; Body Composition; Body Weight; Diet; Feces; Female; Lactation; Leptin; Parasite Egg Count; Peripartum Period; Pregnancy; Random Allocation; Reproduction; Sheep; Sheep Diseases; Trichostrongylosis; Trichostrongylus | 2012 |
Effects of leptin replacement alone and with exendin-4 on food intake and weight regain in weight-reduced diet-induced obese rats.
Weight loss in obese humans produces a relative leptin deficiency, which is postulated to activate potent orexigenic and energy conservation mechanisms to restrict weight loss and promote weight regain. Here we determined whether leptin replacement alone or with GLP-1 receptor agonist exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced diet-induced obese (DIO) rats. Forty percent restriction in daily intake of a high-fat diet in DIO rats for 4 wk reduced body weight by 12%, body fat by 29%, and plasma leptin by 67% and normalized leptin sensitivity. When food restriction ended, body weight, body fat, and plasma leptin increased rapidly. Daily administration of leptin [3-h intraperitoneal (ip) infusions (4 nmol·kg(-1)·h(-1))] at onset and end of dark period for 3 wk did not attenuate hyperphagia and weight regain, nor did it affect mean daily meal sizes or meal numbers. Exendin-4 (50 pmol·kg(-1)·h(-1)) infusions during the same intervals prevented postrestriction hyperphagia and weight regain by normalizing meal size. Coadministration of leptin and exendin-4 did not reduce body weight more than exendin-4 alone. Instead, leptin began to attenuate the inhibitory effects of exendin-4 on food intake, meal size, and weight regain by the end of the second week of administration. Plasma leptin in rats receiving leptin was sevenfold greater than in rats receiving vehicle and 17-fold greater than in rats receiving exendin-4. Together, these results do not support the hypothesis that leptin replacement alone or with exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced DIO rats. Topics: Animals; Body Composition; Body Fat Distribution; Body Weight; Caloric Restriction; Dose-Response Relationship, Drug; Eating; Exenatide; Glucagon-Like Peptide-1 Receptor; Hyperphagia; Leptin; Male; Obesity; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Venoms; Weight Gain; Weight Loss | 2012 |
The anorectic effect of CNTF does not require action in leptin-responsive neurons.
Leptin resistance is a feature of obesity that poses a significant therapeutic challenge. Any treatment that is effective to reduce body weight in obese patients must overcome or circumvent leptin resistance, which promotes the maintenance of excess body fat in obese individuals. Ciliary neurotrophic factor (CNTF) is unique in its ability to reduce food intake and body weight in obese, leptin-resistant humans and rodents. Although attempts to use CNTF as an obesity therapy failed due to the development of neutralizing antibodies to the drug, efforts to understand mechanisms for CNTF's anorectic effects provide an opportunity to develop new drugs for leptin-resistant individuals. CNTF and leptin share several structural, anatomic, and signaling properties, but it is not understood whether or how the two cytokines might interact to affect energy balance. Here, we conditionally deleted the CNTF receptor (CNTFR) subunit, CNTFRα, in cells expressing leptin receptors. We found that CNTFR signaling in leptin-responsive neurons is not required for endogenous maintenance of energy balance and is not required for the anorectic response to exogenous administration of a CNTF agonist. These results indicate that despite anatomical overlap for CNTF and leptin action, CNTF appears to act within a distinct neuronal population to elicit its potent anorectic effect. Topics: Animals; Appetite Depressants; Body Weight; Ciliary Neurotrophic Factor; Ciliary Neurotrophic Factor Receptor alpha Subunit; Diet, High-Fat; Eating; Energy Metabolism; Female; Immunohistochemistry; Leptin; Male; Mice; Mice, Knockout; Mice, Transgenic; Neurons; Paraventricular Hypothalamic Nucleus; Phosphorylation; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor | 2012 |
Lys656Asn polymorphism of leptin receptor, leptin levels and insulin resistance in patients with non alcoholic fatty liver disease.
Some studies have pointed to a role of leptin and insulin resistance in pathogenesis of non alcoholic fatty liver disease (NAFLD). The aim of our study was to investigate the influence of Lys656Asn polymorphism LEPR gene on the histological changes, insulin resistance and leptin levels in overweight patients.. A population of 76 patients with NAFLD was recruited in a cross sectional study. A biochemical analysis of serum was measured. Genotype of LEPR gene Lys656Asn was studied.. Nineteen patients (25%) had the genotype Lys656Asn and 4 patients genotype Asn656Asn (mutant type group) and 53 patients (69.7%) Lys656Lys (wild type group). Body mass index, weight, fat mass, waist circumference, waist to hip ratio, glucose levels and HOMA-IR were higher in mutant than wild type group. LEPR polymorphism is in any way related with liver lesions. The multivariate analysis adjusted by age, sex, BMI and genotype showed an independently association of lobular inflammation 4.19 (CI95%: 1.37-12.77), portal inflammation 1.97 (CI95%: 1.05-3.74) and steatosis 9.23 (CI95%: 1.47-57.83) with HOMA. Liver steatosis was associated with leptin levels (1.09 (CI95%: 1.06-1.18)), too.. Lys656Asn polymorphism of LEPR gene is associated with obesity parameters, insulin resistance and glucose levels in patients with NAFLD. In logistic regression analysis, only insulin resistance was associated with portal inflammation), lobular inflammation and steatosis; liver steatosis was related with leptin levels, too. Topics: Adult; Anthropometry; Biopsy; Blood Glucose; Body Weight; Cholesterol; DNA; Fatty Liver; Female; Genotype; Humans; Insulin Resistance; Leptin; Liver; Male; Middle Aged; Overweight; Polymorphism, Genetic; Receptors, Leptin; Risk Factors; Sample Size; Triglycerides | 2012 |
Subjective and biological weight-related parameters in adolescents and young adults with schizophrenia spectrum disorder under clozapine or olanzapine treatment.
Administration of atypical antipsychotics often induces significant weight gain and metabolic changes. Little is known about subjective weight-related parameters in adolescent patients. Therefore, this cross-sectional, explorative study aimed to assess these parameters and their relationship with biological weight-related parameters.. 74 patients (mean age: 19.9 [SD ± 2.3] years; 66.2% male) with schizophrenia under clozapine or olanzapine treatment were examined. Subjective well-being, eating behavior, body perception and social functioning were assessed, using the Three-Factor-Eating-Questionnaire, FKB-20 Body Perception Questionnaire, Subjective Well-being under Neuroleptics, Short Form and Global Assessment of Functioning. Patients' biological weight-related parameters were measured as well. Gender differences as well as associations between subjective and biological weight-related parameters were evaluated.. Female patients reported significantly worse negative body appraisal and physical functioning than males. An elevated BMI was associated with impaired physical functioning in females and with negative body appraisal and hunger in males.. In our sample of young patients with schizophrenia unter treatment with atypical antipsychotics, an elevated BMI was associated with impaired physical functioning and negative body appraisal, respectively. Bearing in mind the high risk of obesity in this population, the mentioned impairments should be accounted for, especially in terms of compliance and quality of life. Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Body Image; Body Mass Index; Body Weight; Clozapine; Cross-Sectional Studies; Feeding Behavior; Female; Ghrelin; Humans; Hunger; Leptin; Male; Obesity; Olanzapine; Physical Fitness; Schizophrenia; Schizophrenic Psychology; Sex Factors; Social Adjustment; Young Adult | 2012 |
Potential effects of lignan-enriched flaxseed powder on bodyweight, visceral fat, lipid profile, and blood pressure in rats.
The potential effects of secoisolariciresinol diglucoside lignan-enriched flaxseed powder (LEFP) on bodyweight, visceral fat, lipid profile, adipokines, and blood pressure were investigated using rats, divided into four groups (n=8); a normal control diet (NC), a normal control diet with 0.02% LEFP (NCL), a high-fat and high-fructose diet (HFD), or a high-fat and high-fructose diet with 0.02% LEFP (HFDL). Liver, heart, kidney, adipose tissues, and blood were collected following 12-weeks on the diets. The average body weight of the HFD group was significantly higher than those of the NC, NCL, and the HFDL groups (P<0.05). Also, the average weights of kidneys from the HFD and HFDL groups was higher than those of the NC and NCL groups (P<0.05), although not significantly different in the weights of livers and hearts. The visceral fat weight was significantly higher in rats in the HFD group, but notably reduced in the HFDL fed rats (P<0.05). Accordingly, plasma leptin increased significantly in rats fed the HFD diet, higher than rats fed the HFDL diet. Also, the rats in the HFDL group showed improved lipid profile, compared to the rats in the HFD group (P<0.05). Furthermore, a significant reduction in blood pressure was observed in the rats of the HFDL group compared to the HFD group (P<0.05). These data suggest that the LEFP supplementation may provide beneficial effects such as the reduction of bodyweight and fat accumulation, the lipid profile improvement, and blood pressure control. Topics: Animals; Blood Pressure; Body Weight; Butylene Glycols; Diet, High-Fat; Dietary Fats; Dietary Sucrose; Flax; Food, Fortified; Fructose; Glucosides; Heart; Intra-Abdominal Fat; Kidney; Leptin; Lipids; Liver; Male; Organ Size; Rats; Rats, Sprague-Dawley; Seeds | 2012 |
Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21.
The identification of leptin as a mediator of body weight regulation provided much initial excitement for the treatment of obesity. Unfortunately, leptin monotherapy is insufficient in reversing obesity in rodents or humans. Recent findings suggest that amylin is able to restore leptin sensitivity and when used in combination with leptin enhances body weight loss in obese rodents and humans. However, as the uniqueness of this combination therapy remains unclear, we assessed whether co-administration of leptin with other weight loss-inducing hormones equally restores leptin responsiveness in diet-induced obese (DIO) mice. Accordingly, we report here the design and characterization of a series of site-specifically enhanced leptin analogs of high potency and sustained action that, when administered in combination with exendin-4 or fibroblast growth factor 21 (FGF21), restores leptin responsiveness in DIO mice after an initial body weight loss of 30%. Using either combination, body weight loss was enhanced compared with either exendin-4 or FGF21 monotherapy, and leptin alone was sufficient to maintain the reduced body weight. In contrast, leptin monotherapy proved ineffective when identical weight loss was induced by caloric restriction alone over a comparable time. Accordingly, we find that a hypothalamic counter-regulatory response to weight loss, assessed using changes in hypothalamic agouti related peptide (AgRP) levels, is triggered by caloric restriction, but blunted by treatment with exendin-4. We conclude that leptin re-sensitization requires pharmacotherapy but does not appear to be restricted to a unique signaling pathway. Our findings provide preclinical evidence that high activity, long-acting leptin analogs are additively efficacious when used in combination with other weight-lowering agents. Topics: Animals; Body Weight; Diet; Drug Combinations; Exenatide; Fibroblast Growth Factors; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Models, Molecular; Obesity; Peptides; Polyethylene Glycols; Venoms | 2012 |
Estrogen improved metabolic syndrome through down-regulation of VEGF and HIF-1α to inhibit hypoxia of periaortic and intra-abdominal fat in ovariectomized female rats.
Metabolic syndrome (MBS), a cluster of metabolic abnormalities and visceral fat accumulation, increases cardiovascular risks in postmenopausal women. In addition to visceral fat, perivascular adipose tissue has been recently found to play an important role in vascular pathophysiology. Hence, the present study investigates the effects of estrogen on both intra-abdominal fat (visceral fat) and periaortic fat (perivascular fat) accumulation as well as hypoxia in ovariectomized female rats. Female rats were divided into sham operation, ovariectomy and ovariectomy with 17β-estradiol supplementation groups. Twelve weeks later, we found that estrogen improved MBS via reducing body weight gain, the weight of periaortic and intra-abdominal fat, hepatic triglyceride, and total serum cholesterol levels. Estrogen also increased insulin sensitivity through restoring glucose and serum leptin levels. For periaortic fat, western blot showed estrogen inhibited hypoxia by reducing the levels of VEGF and HIF-1α, which is consistent with the results from immunohistochemical staining. The correlation analysis indicated that perivascular fat had a positive correlation with body weight, intra-abdominal fat or serum total cholesterol, but a negative correlation with insulin sensitivity index. For intra-abdominal fat, real-time fluorescent RT-PCR showed estrogen improved fat dysfunction via reducing the levels of relative leptin, MCP-1 but increasing adiponectin mRNA. Estrogen reduced the levels of VEGF and HIF-1α to inhibit hypoxia but restored the levels of PPARγ and Srebp-1c, which are important for lipid capacity function of intra-abdominal fat. These results demonstrated estrogen improved MBS through down-regulating VEGF and HIF-1α to inhibit hypoxia of periaortic and intra-abdominal fat in ovariectomized female rats. Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Chemokine CCL2; Cholesterol; Down-Regulation; Estrogens; Female; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Liver; Metabolic Syndrome; Organ Size; Ovariectomy; PPAR gamma; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Triglycerides; Uterus; Vascular Endothelial Growth Factor A | 2012 |
Shift of circadian feeding pattern by high-fat diets is coincident with reward deficits in obese mice.
Recent studies provide evidence that high-fat diets (HF) trigger both i) a deficit of reward responses linked to a decrease of mesolimbic dopaminergic activity, and ii) a disorganization of circadian feeding behavior that switch from a structured meal-based schedule to a continuous snacking, even during periods normally devoted to rest. This feeding pattern has been shown to be a cause of HF-induced overweight and obesity. Our hypothesis deals with the eventual link between the rewarding properties of food and the circadian distribution of meals. We have investigated the effect of circadian feeding pattern on reward circuits by means of the conditioned-place preference (CPP) paradigm and we have characterized the rewarding properties of natural (food) and artificial (cocaine) reinforcers both in free-feeding ad libitum HF mice and in HF animals submitted to a re-organized feeding schedule based on the standard feeding behavior displayed by mice feeding normal chow ("forced synchronization"). We demonstrate that i) ad libitum HF diet attenuates cocaine and food reward in the CPP protocol, and ii) forced synchronization of feeding prevents this reward deficit. Our study provides further evidence that the rewarding impact of food with low palatability is diminished in mice exposed to a high-fat diet and strongly suggest that the decreased sensitivity to chow as a positive reinforcer triggers a disorganized feeding pattern which might account for metabolic disorders leading to obesity. Topics: Adipose Tissue; Animals; Body Weight; Circadian Rhythm; Cocaine; Diet, High-Fat; Feeding Behavior; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Reward | 2012 |
Relationship of insulin, glucose, leptin, IL-6 and TNF-α in human breast milk with infant growth and body composition.
Numerous appetite, growth, obesity-related hormones and inflammatory factors are found in human breast-milk, but there is little evidence on their relationship with infant body composition. OBJECTVIE: The purpose of the present cross-sectional pilot study was to assess the cross-sectional associations of appetite-regulating hormones and growth factors (leptin, insulin and glucose) and inflammatory factors (interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α)) in human breast-milk with infant size, adiposity, and lean tissue at 1-month of age in healthy term infants.. Human breast-milk was collected from nineteen exclusively breast-feeding mothers using one full breast expression between 8:00 and 10:00 a.m. The milk was then mixed, aliquoted, stored at -80°C and then centrifuged to remove the milk fat, prior to analyses using commercially available immunoassay kits; milk analytes were natural log transformed prior to analysis. Infant body composition was assessed using a Lunar iDXA v11-30.062 scanner (Infant whole body analysis enCore 2007 software, GE, Fairfield, CT).. Maternal pre-pregnancy BMI was positively associated with milk leptin concentration (P = 0.0027), and so maternal-BMI-adjusted Spearman correlations were examined between breast-milk analytes and infant growth and body composition variables. As previously reported, greater milk leptin was associated with lower BMIZ (BMI-for-age z-score based on WHO 2006 growth charts; r = -0.54, P = 0.03). Glucose was positively associated with relative weight (r = 0.6, P = 0.01), and both fat and lean mass (0.43-0.44, P < 0.10). Higher concentrations of milk insulin were associated with lower infant weight, relative weight, and lean mass (r = -0.49-0.58, P < 0.06). Higher milk IL-6 was associated with lower relative weight, weight gain, percent fat, and fat mass (r = -0.55-0.70, P < 0.03 for all), while higher TNF-α was associated with lower lean mass (r = -0.58, P = 0.05), but not measures of adiposity.. These preliminary data suggest for the first time that in the first months of life, breast-milk concentrations of insulin, glucose, IL-6 and TNF-α, in addition to leptin, may be bioactive and differentially influence the accrual of fat and lean body mass. Topics: Absorptiometry, Photon; Adiposity; Body Height; Body Mass Index; Body Weight; Breast Feeding; Child Development; Cross-Sectional Studies; Female; Glucose; Humans; Infant; Infant, Newborn; Insulin; Interleukin-6; Leptin; Maternal Nutritional Physiological Phenomena; Milk, Human; Oklahoma; Pilot Projects; Pregnancy; Tumor Necrosis Factor-alpha | 2012 |
Protective potentials of wild rice (Zizania latifolia (Griseb) Turcz) against obesity and lipotoxicity induced by a high-fat/cholesterol diet in rats.
The study evaluates the protective potentials of wild rice against obesity and lipotoxicity induced by a high-fat/cholesterol diet in rats. In addition to the rats of low-fat diet group, others animals were exposed to a high-fat/cholesterol diet condition for 8 weeks. The city diet (CD) is based on the diet consumed by urban residents in modern China, which is rich in fat/cholesterol and high in carbohydrates from white rice and processed wheat starch. The chief source of dietary carbohydrates of wild rice diet (WRD) is from Chinese wild rice and other compositions are the same with CD. Rats fed CD showed elevated body and liver organ weights, lipid profiles, free fatty acids (FFA) and leptin comparable with rats fed high-fat/cholesterol diet (HFD) known to induce obesity and hyperlipidaemia in this species. However, rats consuming WRD suppressed the increase of lipid droplets accumulation, FFA, and leptin, and the decrease of lipoprotein lipase and adipose triglyceride lipase. Meanwhile, WRD prevented high-fat/cholesterol diet-induced elevation in protein expression of sterol-regulatory element binding protein-1c, and gene expression of fatty acid synthase and acetyl-CoA carboxylase. These findings indicate that wild rice as a natural food has the potentials of preventing obesity and liver lipotoxicity induced by a high-fat/cholesterol diet in rats. Topics: Animals; Base Sequence; Blotting, Western; Body Weight; Cholesterol, Dietary; Dietary Fats; DNA Primers; Feeding Behavior; Leptin; Lipids; Liver; Male; Obesity; Organ Size; Oryza; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction | 2012 |
Energy metabolism, thermogenesis and body mass regulation in tree shrew (Tupaia belangeri) during subsequent cold and warm acclimation.
Environmental cues play important roles in the regulation of an animal's physiology and behavior. The purpose of the present study was to test the hypothesis that ambient temperature is a cue to induce adjustments in body mass, energy intake and thermogenic capacity, associated with changes in serum leptin levels in tree shrews (Tupaia belangeri). We found that tree shrews increased basal metabolic rate (BMR), energy intake and subsequently showed a significant decrease in body mass after being returned to warm ambient temperature. Uncoupling protein 1 (UCP1) content in brown adipose tissue (BAT) increased during cold acclimation and reversed after rewarming. The trend of energy intake increased during cold acclimation and decreased after rewarming; the trend of energy intake during cold acclimation was contrary to the trend of energy intake during rewarming. Further, serum leptin levels were negatively correlated with body mass. Together, these data supported our hypothesis that ambient temperature was a cue to induce changes in body mass and metabolic capacity. Serum leptin, as a starvation signal in the cold and satiety signal in rewarming, was involved in the processes of thermogenesis and body mass regulation in tree shrews. Topics: Acclimatization; Adipose Tissue, Brown; Animals; Basal Metabolism; Body Weight; Electron Transport Complex IV; Energy Intake; Energy Metabolism; Ion Channels; Leptin; Liver; Mitochondria, Liver; Mitochondrial Proteins; Thermogenesis; Tupaiidae; Uncoupling Protein 1 | 2012 |
The evaluation of estradiol and leptin action on the activity of the somatotropic and gonadotropic axes in peripubertal female rats.
Available data suggest that estrogens and leptin play a role in the control of the pubertal process. In humans and some mammal species the increase of the activity of gonadotropic axis accompanies the decrease in the rate of growth at puberty. The effect of 17β-estradiol and/or leptin administration on the somatotropic and gonadotropic axes was studied using prepubertal female rats as an animal model.. Prepubertal female rats received estradiol/saline, estradiol/leptin, oil/leptin or oil/saline (vehicles) respectively. The changes of growth rate, and serum 17β-estradiol, leptin, GH, IGF-I and gonadotropins levels as well as LHRH and estrogen receptor (ER) concentrations in the medial basal hypothalamus (MBH) and the pituitary were determined. All hormones concentrations were measured by radioimmunoassay and ER by radioligand methods .. In estradiol and/or leptin treated animals noticeable reduction of rate of growth was found. The decrease of growth in response to estradiol treatment accompanied the increase GH level and the decrease of IGF-I concentration in the circulation. Both hormones operating together activated reproductive axis, what was manifested by a significant increase of LHRH abundant in the hypothalamus as well as elevated LH and FSH levels in the circulation. In these rats a significant decrease of the estrogen receptor concentrations in the pituitary was observed.. The role of estradiol and leptin in the control of growth and reproduction seems to overlap only partially. Estradiol plays a significant role in the activation of the reproductive axis, and leptin takes part as a permissive factor in pubertal process. Topics: Animals; Body Weight; Estradiol; Female; Follicle Stimulating Hormone; Gonadotrophs; Gonadotropin-Releasing Hormone; Growth Hormone; Hypothalamus; Insulin-Like Growth Factor I; Leptin; Luteinizing Hormone; Pituitary Gland; Rats; Rats, Wistar; Receptors, Estrogen; Sexual Maturation; Somatotrophs | 2012 |
Juvenile, but not adult exposure to high-fat diet impairs relational memory and hippocampal neurogenesis in mice.
Increased consumption of high-fat diet (HFD) leads to obesity and adverse neurocognitive outcomes. Childhood and adolescence are important periods of brain maturation shaping cognitive function. These periods could consequently be particularly sensitive to the detrimental effects of HFD intake. In mice, juvenile and adulthood consumption of HFD induce similar morphometric and metabolic changes. However, only juvenile exposure to HFD abolishes relational memory flexibility, assessed after initial radial-maze concurrent spatial discrimination learning, and decreases neurogenesis. Our results identify a critical period of development covering adolescence with higher sensitivity to HFD-induced hippocampal dysfunction at both behavioral and cellular levels. Topics: Age Factors; Animals; Blood Glucose; Body Weight; Corticosterone; Dentate Gyrus; Diet, High-Fat; Discrimination Learning; Doublecortin Domain Proteins; Energy Intake; Hippocampus; Immunoenzyme Techniques; Leptin; Lipids; Male; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Nerve Tissue Proteins; Neurogenesis; Neuropeptides; Overweight; Spatial Behavior | 2012 |
Resistance to obesity by repression of VEGF gene expression through induction of brown-like adipocyte differentiation.
Adipose tissues are classified into white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is responsible for energy storage, and malfunction is associated with obesity. BAT, on the contrary, consumes fat to generate heat through uncoupling mitochondrial respiration and is important in body weight control. Vascular endothelial growth factor (VEGF)-A is the founding member of the VEGF family and has been found highly expressed in adipose tissue. A genetic mouse model of an inducible VEGF (VEGF-A) repression system was used to study VEGF-regulated energy metabolism in WAT. VEGF-repressed mice demonstrated lower food efficiency, lower body weight, and resistance to high-fat diet-induced obesity. Repression of VEGF expression caused morphological and molecular changes in adipose tissues. VEGF repression induced brown-like adipocyte development in WAT, up-regulation of BAT-specific genes including PRDM16, GATA-1, BMP-7, CIDEA, and UCP-1 and down-regulation of leptin, a WAT-specific gene. VEGF repression up-regulated expression of VEGF-B and its downstream fatty acid transport proteins. Relative levels of VEGF/VEGF-B may be important switches in energy metabolism and of pharmaceutical significances. Topics: Adipocytes; Adipogenesis; Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Cell Differentiation; Female; Gene Expression Profiling; Gene Expression Regulation; Inflammation; Leptin; Male; Mice; Mice, Transgenic; Microscopy, Fluorescence; Models, Genetic; Obesity; Phenotype; Vascular Endothelial Growth Factor A | 2012 |
Cimicifuga racemosa and its triterpene-saponins prevent the Metabolic Syndrome and deterioration of cartilage in the knee joint of ovariectomized rats by similar mechanisms.
An unphysiologic accumulation of fat cells in many parts of the body including abdomen and joints results in increased production of pro-inflammatory cytokines which have adverse effects on serum lipids, glucose and on joint cartilage. The special extract of Cimicifuga racemosa CR BNO 1055 was shown to reduce the size of the abdominal fat depot. It was therefore tempting to test whether this extract, its saponin and its unpolar and polar fractions S- and R-fraction respectively (no quotation) also reduce fat depots and fat cell accumulation in a fat depot located in the lower hind leg (called paratibial fat depot = PFD), in joint fat pads (in the knee joint this is called Hoffa's fat pad) that occur in response to ovariectomy and whether this was accompanied by reduced serum lipids, glucose and improved cartilage features in the knee joint.. Rats (n = 10/group) were ovariectomized (ovx) and fed with CR BNO 1055, S- or R-fraction containing food (average intake 8.2, or 2.05 or 7.07 mg/day/animal) for 4 weeks. Ovx rats kept under no additive-containing food served as controls. The sizes of the PFD, of Hoffa's fat pad and of the cartilage thickness of the knee joints were determined by quantitative computer tomography and histomorphometrically. In the serum cholesterol, leptin and glucose levels were measured.. High load with fat tissue in the PFD and in the knee joints was present in the ovx rats. Treatment with CR BNO 1055 and its S-fraction reduced fat load of both, Hoffa's fat pad and of the PFD significantly and this resulted in reduced body weight which was significant under CR BNO 1055. Fat load in the PFD correlated significantly with the height of serum leptin and cholesterol. The fat load in the knee joint correlated inversely with the size of knee cartilage tissue.. High fat load of the body increases following ovx and this causes increased serum leptin, cholesterol and glucose levels. Following ovx the size of Hoffa's fat pad increases also significantly and this has adverse effects on knee cartilage tissue. Therefore, increased fat tissue in joints appears to belong to the Metabolic Syndrome. This effect can be largely prevented by CR BNO 1005 and its S- but not by its R-fraction. Hence, the saponins in CR BNO 1055 may be useful in preventing the Metabolic Syndrome and osteoarthritis. Topics: Adipocytes; Animals; Body Weight; Cartilage, Articular; Cholesterol; Cimicifuga; Female; Hindlimb; Leptin; Metabolic Syndrome; Ovariectomy; Plant Extracts; Rats; Rats, Sprague-Dawley; Saponins; Triterpenes | 2012 |
A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity.
The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT(1a)R(-/-)), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT(1a)R(-/-) vs. AT(1a)R(+/+) mice. ICV leptin in rats increased AT(1a)R and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT(1a)R mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake. Topics: Adipose Tissue; alpha-MSH; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Brain; Captopril; Corticotropin-Releasing Hormone; Eating; Gene Deletion; Leptin; Losartan; Male; Mice; Mice, Inbred C57BL; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Sympathetic Nervous System | 2012 |
Role of the blood-brain barrier in the evolution of feeding and cognition.
The blood-brain barrier (BBB) regulates the blood-to-brain passage of gastrointestinal hormones, thus informing the brain about feeding and nutritional status. Disruption of this communication results in dysregulation of feeding and body weight control. Leptin, which crosses the BBB to inform the CNS about adiposity, provides an example. Impaired leptin transport, especially coupled with central resistance, results in obesity. Various substances/conditions regulate leptin BBB transport. For example, triglycerides inhibit leptin transport. This may represent an evolutionary adaptation in that hypertriglyceridemia occurs during starvation. Inhibition of leptin, an anorectic, during starvation could have survival advantages. The large number of other substances that influence feeding is explained by the complexity of feeding. This complexity includes cognitive aspects; animals in the wild are faced with cost/benefit analyses to feed in the safest, most economical way. This cognitive aspect partially explains why so many feeding substances affect neurogenesis, neuroprotection, and cognition. The relation between triglycerides and cognition may be partially mediated through triglyceride's ability to regulate the BBB transport of cognitively active gastrointestinal hormones such as leptin, insulin, and ghrelin. Topics: Adiposity; Animals; Biological Transport; Blood-Brain Barrier; Body Weight; Brain; Cognition; Feeding Behavior; Gastrointestinal Hormones; Ghrelin; Humans; Insulin; Leptin; Mice; Triglycerides | 2012 |
Leucine improves glucose and lipid status in offspring from obese dams, dependent on diet type, but not caloric intake.
Previously, we showed that offspring from obese rat dams were hyperphagic, with increased adiposity, hyperlipidaemia and glucose intolerance associated with increased orexigenic neuropeptide expression after fasting. Mammalian target of rapamycin (mTOR) can inhibit food intake through a hypothalamic action. As we previously showed that maternal obesity down-regulated hypothalamic mTOR, in the present study, we hypothesised that dietary leucine supplementation would activate hypothalamic mTOR to reduce food intake, thus limiting metabolic disorders in offspring from obese dams, regardless of postweaning diet. Obesity was induced in Sprague-Dawley females by high-fat diet (HFD) for 5 weeks before mating, throughout gestation and lactation. Male pups from HFD-fed mothers were weaned onto chow or HFD; within each dietary group, half were supplied with leucine via drinking water (1.5%) versus water control for 10 weeks. Those from chow-fed mothers were fed chow and water. Maternal obesity led to increased adiposity in chow-fed offspring. Postweaning HFD consumption exaggerated adiposity, hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. Supplementation with leucine doubled leucine intake and increased hypothalamic mTOR activation; however, appetite regulation was not affected. A reduction in blood lipid levels was observed in offspring regardless of diet, as well as improved glucose tolerance in HFD-fed rats. In HFD-fed rats, up-regulated carnitine palmitoyl-transferase-1 and peroxisome-proliferator-activated receptor-γ coactivator-1α in muscle and glucose transporter 4 in fat suggested that leucine improved peripheral fat oxidation and glucose transport. Leucine is able to improve peripheral glucose and lipid metabolism independent of appetite and weight regulation, suggesting its potential application in the management of metabolic disorders. Topics: Animals; Appetite; Blotting, Western; Body Weight; Diet; Energy Intake; Fatty Acids, Nonesterified; Female; Glucose; Glucose Tolerance Test; Hypothalamus; Insulin; Leptin; Leucine; Lipid Metabolism; Muscle, Skeletal; Obesity; Organ Size; Pregnancy; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Signal Transduction; TOR Serine-Threonine Kinases; Triglycerides | 2012 |
Diagnostic criteria for gestational diabetes: who decides?
Topics: Adiposity; Birth Weight; Body Weight; Female; Glucose Intolerance; Humans; Leptin; Lipids; Pregnancy | 2012 |
Effect of maternal weight, adipokines, glucose intolerance and lipids on infant birth weight among women without gestational diabetes mellitus.
The delivery of excess maternal nutrients to the fetus is known to increase the risk of macrosomia, even among infants of women without gestational diabetes mellitus. With the current obesity epidemic, maternal adiposity and its associated effects on circulating adipokines and inflammatory proteins may now have a greater impact on fetal growth. We sought to evaluate the independent effects of maternal glycemia, lipids, obesity, adipokines and inflammation on infant birth weight.. We included 472 women who underwent an oral glucose tolerance test in late pregnancy and were found not to have gestational diabetes; 104 (22.0%) had gestational impaired glucose tolerance. We also measured fasting levels of insulin, low-and high-density lipoprotein cholesterol, triglycerides, leptin, adiponectin and C-reactive protein. Obstetric outcomes were assessed at delivery.. The mean birth weight was 3481 g (standard deviation 493 g); 68 of the infants were large for gestational age. On multiple linear regression analysis, positive determinants of birth weight were length of gestation, male infant, weight gain during pregnancy up to the time of the oral glucose tolerance test, body mass index (BMI) before pregnancy and impaired glucose tolerance in pregnancy. Leptin, adiponectin and C-reactive protein levels were each negatively associated with birth weight. On logistic regression analysis, the significant metabolic predictors of having a large-for-gestational-age infant were BMI before pregnancy (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.05-1.27, per 1 kg/m(2) increase), weight gain during pregnancy up to the time of the oral glucose tolerance test (OR 1.12, 95% CI 1.05-1.19, per 1 kg increase) and leptin level (OR 0.50, 95% CI 0.30-0.82, per 1 standard deviation change).. Among women without gestational diabetes, maternal adiposity and leptin levels were the strongest metabolic determinants of having a large-for-gestational-age infant rather than glucose intolerance and lipid levels. Topics: Adipokines; Adiposity; Adult; Birth Weight; Body Mass Index; Body Weight; C-Reactive Protein; Female; Fetal Macrosomia; Glucose Intolerance; Humans; Leptin; Lipids; Logistic Models; Mothers; Pregnancy | 2012 |
The gender- and fat depot-specific regulation of leptin, resistin and adiponectin genes expression by progesterone in rat.
Progesterone affects lipid metabolism in adipose tissue and influences fat distribution in human. The aim of the study was to analyze the effect of progesterone on rat body and fat mass and on expression of genes encoding adipokines involved in the regulation of energy homeostasis. The results presented here indicate that progesterone administration to females caused increase in body and inguinal white adipose tissue mass. The increase of inguinal white adipose tissue mass is associated with the hypertrophy of adipocyte. The same dose of progesterone caused increase of its circulating concentration in males, however it barely reached the value observed in non-treated control females and did not have any effect on body and fat mass. The elevated circulating progesterone concentration was associated with an approximately 6- and 2-fold increase of leptin and resistin mRNA level respectively, and 2-fold decrease of adiponectin mRNA level only in inguinal white adipose tissue of females. RU 486, specific antagonist of progesterone receptor, abolished the effect of progesterone on the adipokine mRNA level in inguinal adipose tissue. In males, the elevated circulating progesterone concentration showed no effects on leptin, resistin or adiponectin mRNA level in inguinal, retroperitoneal or epididymal adipose tissue. Moreover, the results presented in this paper demonstrate a relatively high level of progesterone receptor mRNA in inguinal white adipose tissue of females, which was down-regulated in response to progesterone administration. In retroperitoneal adipose tissue of control females progesterone receptor mRNA level was approximately 3-fold lower as compared to inguinal adipose tissue. In inguinal, epididymal and retroperitoneal white adipose tissue of males progesterone receptor mRNA was hardly detected. Our results suggest that depot- and sex-dependent responsiveness of adipose tissue to the pharmacological dose of progesterone is controlled by both circulating concentration of progesterone and the white adipose tissue progesterone receptor level. Topics: Adiponectin; Adipose Tissue, White; Animals; Body Weight; Female; Gene Expression Regulation; Hormone Antagonists; Leptin; Male; Mifepristone; Progesterone; Rats; Receptors, Progesterone; Resistin; RNA, Messenger; Sex Characteristics | 2012 |
Developmental plasticity in thyroid function primed by maternal hyperleptinemia in early lactation: a time-course study in rats.
Pups whose mothers were leptin-treated during the last 3 days of lactation have thyroid dysfunction at adulthood. However, there was no report about leptin treatment in the first days of life or about its action on thyroid function during development. Here, we evaluated the effects of maternal leptin treatment on the first 10 days of lactation upon thyroid function of the offspring at 21, 30, and 180 days old. At birth, lactating Wistar rats were divided into: Leptin (Lep) - leptin-treated (8 μg/100 g of body weight, s.c.) for the first 10 days of lactation and Control (C, saline-treated). Mothers were killed at the end of lactation and their offspring at 21, 30, and 180 days old. Triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), and leptin levels in serum and milk were measured. Liver mitochondrial glycerolphosphate dehydrogenase (mGPD) activity was determined. Significant differences had p<0.05. At the end of lactation, Lep mothers had higher milk T3 (+ 30%), while their offspring had higher serum T3 (+ 20%) and TSH (+ 84%). At 30 days-old, Lep offspring showed lower TSH ( - 48%), T3 ( - 20%), and mGPDm ( - 42%). At 180 days-old, Lep group presented hyperleptinemia (1.4-fold increase), higher serum T3 (+ 22%), and lower mGPD activity ( - 57%). Maternal hyperleptinemia on lactation causes hypothyroidism in the pups at 30 days, which may program for higher serum T3 at adulthood. In conclusion, maternal hyperleptinemia during lactation, that is common in obese mothers, may have an impact in future disease development, such as thyroid dysfunction. Topics: Animals; Body Weight; Feeding Behavior; Female; Glycerolphosphate Dehydrogenase; Growth and Development; Lactation; Leptin; Male; Mice; Milk; Mitochondria, Liver; Rats; Rats, Wistar; Thyroid Function Tests; Thyroid Gland; Thyroxine; Time Factors; Triiodothyronine | 2012 |
Experimental hyperthyroidism decreases gene expression and serum levels of adipokines in obesity.
To analyze the influence of hyperthyroidism on the gene expression and serum concentration of leptin, resistin, and adiponectin in obese animals.. Male Wistar rats were randomly divided into two groups: control (C)-fed with commercial chow ad libitum-and obese (OB)-fed with a hypercaloric diet. After group characterization, the OB rats continued receiving a hypercaloric diet and were randomized into two groups: obese animals (OB) and obese with 25 μg triiodothyronine (T(3))/100 BW (OT). The T(3) dose was administered every day for the last 2 weeks of the study. After 30 weeks the animals were euthanized. Samples of blood and adipose tissue were collected for biochemical and hormonal analyses as well as gene expression of leptin, resistin, and adiponectin.. T(3) treatment was effective, increasing fT(3) levels and decreasing fT(4) and TSH serum concentration. Administration of T(3) promotes weight loss, decreases all fat deposits, and diminishes serum levels of leptin, resistin, and adiponectin by reducing their gene expression.. Our results suggest that T(3) modulate serum and gene expression levels of leptin, resistin, and adiponectin in experimental model of obesity, providing new insights regarding the relationship between T(3) and adipokines in obesity. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Disease Models, Animal; Gene Expression Regulation; Homeostasis; Hyperthyroidism; Leptin; Male; Obesity; Random Allocation; Rats; Rats, Wistar; Resistin; Thyrotropin; Thyroxine; Triiodothyronine | 2012 |
Rapid onset of renal sympathetic nerve activation in rabbits fed a high-fat diet.
Hypertension and elevated sympathetic drive result from consumption of a high-calorie diet and deposition of abdominal fat, but the etiology and temporal characteristics are unknown. Rabbits instrumented for telemetric recording of arterial pressure and renal sympathetic nerve activity (RSNA) were fed a high-fat diet for 3 weeks then control diet for 1 week or control diet for 4 weeks. Baroreflexes and responses to air-jet stress and hypoxia were determined weekly. After 1 week of high-fat diet, caloric intake increased by 62%, accompanied by elevated body weight, blood glucose, plasma insulin, and leptin (8%, 14%, 134%, and 252%, respectively). Mean arterial pressure, heart rate, and RSNA also increased after 1 week (6%, 11%, and 57%, respectively). Whereas mean arterial pressure and body weight continued to rise over 3 weeks of high-fat diet, heart rate and RSNA did not change further. The RSNA baroreflex was attenuated from the first week of the diet. Excitatory responses to air-jet stress diminished over 3 weeks of high-fat diet, but responses to hypoxia were invariant. Resumption of a normal diet returned glucose, insulin, leptin, and heart rate to control levels, but body weight, mean arterial pressure, and RSNA remained elevated. In conclusion, elevated sympathetic drive and impaired baroreflex function, which occur within 1 week of consumption of a high-fat, high-calorie diet, appear integral to the rapid development of obesity-related hypertension. Increased plasma leptin and insulin may contribute to the initiation of hypertension but are not required for maintenance of mean arterial pressure, which likely lies in alterations in the response of neurons in the hypothalamus. Topics: Adiposity; Analysis of Variance; Animals; Baroreflex; Blood Glucose; Blood Pressure; Body Weight; Diet, High-Fat; Dietary Fats; Heart Rate; Hypertension; Insulin; Kidney; Leptin; Male; Obesity; Rabbits; Sympathetic Nervous System; Time Factors | 2012 |
FOXO1 in the ventromedial hypothalamus regulates energy balance.
The transcription factor FOXO1 plays a central role in metabolic homeostasis by regulating leptin and insulin activity in many cell types, including neurons. However, the neurons mediating these effects and the identity of the molecular targets through which FOXO1 regulates metabolism remain to be defined. Here, we show that the ventral medial nucleus of the hypothalamus (VMH) is a key site of FOXO1 action. We found that mice lacking FOXO1 in steroidogenic factor 1 (SF-1) neurons of the VMH are lean due to increased energy expenditure. The mice also failed to appropriately suppress energy expenditure in response to fasting. Furthermore, these mice displayed improved glucose tolerance due to increased insulin sensitivity in skeletal muscle and heart. Gene expression profiling and sequence analysis revealed several pathways regulated by FOXO1. In addition, we identified the nuclear receptor SF-1 as a direct FOXO1 transcriptional target in the VMH. Collectively, our data suggest that the transcriptional networks modulated by FOXO1 in VMH neurons are key components in the regulation of energy balance and glucose homeostasis. Topics: Animals; Body Composition; Body Weight; Catecholamines; Cells, Cultured; Diet, High-Fat; Energy Metabolism; Female; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Profiling; Glucose; Insulin Resistance; Ion Channels; Leptin; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Organ Specificity; Oxygen Consumption; Phenotype; Steroidogenic Factor 1; Transcription, Genetic; Uncoupling Protein 1; Ventromedial Hypothalamic Nucleus | 2012 |
Central leptin and insulin administration modulates serum cytokine- and lipoprotein-related markers.
In most obese patients there is an inflammatory state characterized by lipid abnormalities, hyperleptinemia and hyperinsulinemia.. The objective was to identify mechanisms involved in leptin's role in the attenuation of the response to insulin using a proteomic approach.. We studied the serum proteomic profile of rats treated by central leptin infusion followed by an injection of insulin. We analyzed the relationship between these proteins and serum cytokine and apolipoprotein levels.. Out of 81 protein spots, intensity differences were found in 11, corresponding to 5 proteins: three isoforms of α1 macroglobulin; three of haptoglobin and serum amyloid P component-precursor. All of these are acute-phase proteins involved in inflammation and are correlated with cytokine levels. Additionally, two apolipoprotein E and two apolipoprotein A1 isoforms were identified and were found to correlate with LDL and HDL.. Our results indicate that increased leptin and insulin levels change these circulating proteins, thus promoting systemic inflammation and changing lipid metabolism. Topics: Animals; Body Weight; Cytokines; Electrophoresis, Gel, Two-Dimensional; Enzyme-Linked Immunosorbent Assay; Insulin; Leptin; Lipoproteins; Male; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA, Messenger; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization | 2012 |
The effect of chronic immobilization stress on leptin signaling in the ovariectomized (OVX) rat.
Previous studies have shown that both 17β-estradiol (E2) treatment and chronic stress may attenuate post-OVX weight gain in the female rat. However, the interaction between E2 and stress is unclear. This study examined the effect of E2 treatment and chronic immobilization stress on body weight. Adult OVX Sprague-Dawley rats were randomly assigned to one of four treatment groups in a 2X2 factorial design examining hormone treatment [vehicle (VEH) or E2, sc] and stress (no stress vs stress 60 min/day for 22 days). After 22 days, E2 significantly inhibited weight gain and food intake in OVX rats. In contrast, chronic stress reduced body weight only in control OVX animals but did not affect food intake. E2 reduced circulating leptin levels in non-stressed animals, but not in animals subjected to chronic immobilization. Western blot analysis indicated that E2 treatment increased leptin receptor (Ob-Rb) expression in the medial basal hypothalamus (MBH); however, this treatment also increased suppressor of cytokine signaling 3 (SOCS3), which is an inhibitor of leptin signaling. Chronic immobilization stress blunted the E2-induced increase in Ob-Rb and SOCS3 levels. These results suggest that chronic stress counteracts E2 effects on leptin signaling in the MBH without altering body weight. Topics: Animals; Blotting, Western; Body Weight; Brain Chemistry; Corticosterone; Drug Implants; Eating; Enzyme-Linked Immunosorbent Assay; Estradiol; Female; Hypothalamo-Hypophyseal System; Hypothalamus, Middle; Leptin; Ovariectomy; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Restraint, Physical; Signal Transduction; STAT3 Transcription Factor; Stress, Psychological; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins | 2012 |
p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on food intake.
The PI3K-AKT, mTOR-p70S6 kinase and AMPK pathways play distinct and critical roles in metabolic regulation. Each pathway is necessary for leptin's anorexigenic effects in the hypothalamus. Here we show that these pathways converge in an integrated phosphorylation cascade to mediate leptin action in the hypothalamus. We identify serine(491) on α2AMPK as the site of convergence and show that p70S6 kinase forms a complex with α2AMPK, resulting in phosphorylation on serine(491). Blocking α2AMPK-serine(491) phosphorylation increases hypothalamic AMPK activity, food intake, and body weight. Serine(491) phosphorylation is necessary for leptin's effects on hypothalamic α2AMPK activity, neuropeptide expression, food intake, and body weight. These results identify an inhibitory AMPK kinase, p70S6 kinase, and demonstrate that AMPK is a substrate for mTOR-p70S6 kinase. This discovery has broad biologic implications since mTOR-p70S6 kinase and AMPK have multiple, fundamental and generally opposing cellular effects that regulate metabolism, cell growth, and development. Topics: Adenylate Kinase; Agouti-Related Protein; Animals; Body Weight; Cell Line; Eating; Hypothalamus; Leptin; Male; Mice; Mice, Knockout; Phosphatidylinositol 3-Kinases; Phosphorylation; Pro-Opiomelanocortin; Protein Processing, Post-Translational; Protein Subunits; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Serine; Signal Transduction | 2012 |
Effect of electroacupuncture on leptin resistance in rats with diet-induced obesity.
In the present study, the effects of electroacupuncture (EA) on body weight and sensitivity of leptin in diet-induced obese rats were examined and the underlying mechanisms were explored. After feeding with high-fat (HIF) diet for 12 weeks, the diet-induced obese rats received electroacupuncture stimulation three times per week for four weeks. The expression of the leptin receptor in the hypothalamus was measured using immunohistochemistry. The plasma leptin was detected with ELISA. The leptin and leptin receptor mRNA was examined with real-time PCR. Results showed that electroacupuncture treatment led to a reduction of body weight, decrease in the plasma leptin levels, and an increase in leptin receptor expression in the hypothalamus. Our results suggested that regulating the expression of leptin and the leptin receptor might be one of the molecular mechanisms underlying the reduction of body weight in diet-induced obese rats by electroacupuncture treatment. Topics: Animals; Body Weight; Diet, High-Fat; Electroacupuncture; Hypothalamus; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Leptin; RNA, Messenger | 2012 |
The effect of sleep apnea and insomnia on blood levels of leptin, insulin resistance, IP-10, and hydrogen sulfide in type 2 diabetic patients.
Sleep deficits associated with sleep apnea and insomnia increase the risk of vascular inflammation and insulin resistance. This study examined the hypothesis that inflammation markers are higher in those diabetic patients who experience sleep deficits compared with those without any history of a sleep disorder.. Fasting blood was obtained after written informed consent, and sleep disorder histories were obtained from type 2 diabetic patients (n=81) attending clinics of the Louisiana State University Health Sciences Center.. There was a significant correlation between body weight and leptin, and leptin in turn was significantly correlated with 10-kDa interferon-γ-induced protein (IP-10) levels and insulin resistance in type 2 diabetic patients. Fasting blood levels of leptin, IP-10, and insulin resistance were significantly elevated in patients with sleep deficits compared with diabetics with normal sleep patterns. There were no differences in glycosylated hemoglobin (HbA1c) or fasting glucose in patients with sleep deficits compared with those with normal sleep patterns. Sleep deficits increase circulating levels of leptin, IP-10, and insulin resistance compared to levels seen in patients with diabetes who reported no difficulty with sleep. Patients with sleep apnea had significantly lower hydrogen sulfide (H(2)S) levels compared with patients with normal sleep patterns or patients with insomnia. Low levels of circulating H(2)S could contribute to higher vascular inflammation in patients with sleep apnea.. These results suggest that sleep apnea is associated with a decrease in circulating H(2)S and sleep disorders increase the risk of inflammation and insulin resistance, which can contribute to the increased risk of vascular disease in subjects with type 2 diabetes. Topics: Adult; Body Weight; Case-Control Studies; Chemokine CXCL10; Diabetes Mellitus, Type 2; Female; Humans; Hydrogen Sulfide; Insulin Resistance; Leptin; Male; Middle Aged; Sleep Apnea Syndromes; Sleep Initiation and Maintenance Disorders | 2012 |
Green tea polyphenols benefits body composition and improves bone quality in long-term high-fat diet-induced obese rats.
This study investigates the effects of green tea polyphenols (GTPs) on body composition and bone properties along with mechanisms in obese female rats. Thirty-six 3-month-old Sprague Dawley female rats were fed either a low-fat (LF) or a high-fat (HF) diet for 4 months. Animals in the LF diet group continued on an LF diet for additional 4 months, whereas those in the HF diet group were divided into 2 groups: with GTP (0.5%) or without in drinking water, in addition to an HF diet for another 4 months. Body composition, femur bone mass and strength, serum endocrine and proinflammatory cytokines, and liver glutathione peroxidase (GPX) protein expression were determined. We hypothesized that supplementation of GTP in drinking water would benefit body composition, enhance bone quality, and suppress obesity-related endocrines in HF diet-induced obese female rats and that such changes are related to an elevation of antioxidant capacity and a reduction of proinflammatory cytokine production. After 8 months, compared with the LF diet, the HF diet increased percentage of fat mass and serum insulin-like growth factor I and leptin levels; reduced percentage of fat-free mass, bone strength, and GPX protein expression; but had no effect on bone mineral density and serum adiponectin levels in the rats. Green tea polyphenol supplementation increased percentage of fat-free mass, bone mineral density and strength, and GPX protein expression and decreased percentage of fat mass, serum insulin-like growth factor I, leptin, adiponectin, and proinflammatory cytokines in the obese rats. This study shows that GTP supplementation benefited body composition and bone properties in obese rats possibly through enhancing antioxidant capacity and suppressing inflammation. Topics: Adiponectin; Adipose Tissue; Animals; Antioxidants; Body Composition; Body Weight; Bone Density; Cytokines; Diet, High-Fat; Dietary Supplements; Drinking Water; Energy Intake; Female; Glutathione Peroxidase; Insulin-Like Growth Factor I; Leptin; Muscle, Skeletal; Obesity; Polyphenols; Rats; Rats, Sprague-Dawley; Tea | 2012 |
Effects of ambient temperature on adaptive thermogenesis during maintenance of reduced body weight in mice.
We showed previously that, at ambient room temperature (22°C), mice maintained at 20% below their initial body weight by calorie restriction expend energy at a rate below that which can be accounted for by the decrease of fat and fat-free mass. Food-restricted rodents may become torpid at subthermoneutral temperatures, a possible confounding factor when using mice as human models in obesity research. We examined the bioenergetic, hormonal, and behavioral responses to maintenance of a 20% body weight reduction in singly housed C57BL/6J +/+ and Lep(ob) mice housed at both 22°C and 30°C. Weight-reduced high-fat-fed diet mice (HFD-WR) showed similar quantitative reductions in energy expenditure-adjusted for body mass and composition-at both 22°C and 30°C: -1.4 kcal/24 h and -1.6 kcal/24 h below predicted, respectively, and neither group entered torpor. In contrast, weight-reduced Lep(ob) mice (OB-WR) housed at 22°C became torpid in the late lights-off period (0200-0500) but did not when housed at 30°C. These studies indicate that mice with an intact leptin axis display similar decreases in "absolute" energy expenditure in response to weight reduction at both 22°C and 30°C ambient temperature. More importantly, the "percent" decrease in total energy expenditure observed in the HFD-WR compared with AL mice is much greater at 30°C (-19%) than at 22°C (-10%). Basal energy expenditure demands are ∼45% lower in mice housed at 30°C vs. 22°C, since the mice housed at thermoneutrality do not allocate extra energy for heat production. The higher total energy expenditure of mice housed at 22°C due to these increased thermogenic demands may mask physiologically relevant changes in energy expenditure showing that ambient temperature must be carefully considered when quantifying energy metabolism in both rodents and humans. Topics: Adaptation, Physiological; Animals; Body Composition; Body Weight; Caloric Restriction; Diet, High-Fat; Energy Intake; Energy Metabolism; Leptin; Mice; Temperature; Thermogenesis; Weight Loss | 2012 |
Analysis of adipose tissues and stromal vascular cells in a murine arthritis model.
Changes in body composition in rheumatoid arthritis (RA), including a reduction in skeletal muscle mass and the accumulation of visceral fat, have been identified, and the interaction between immune abnormality and metabolic disorders has received much attention. The effect of a high-fat (HF) diet and the role of adipose tissue in an arthritis model were investigated.. The effect of an HF diet on the histopathology of joints in murine type II collagen-induced arthritis (CIA) was evaluated. The morphology and adipokine production of adipose tissues were analyzed, and macrophages in the stromal vascular fraction (SVF) were counted by flow cytometry. Serum adipokine levels were measured by ELISA.. Significant exacerbation of joint destruction and aggravated pathological conditions were observed in CIA mice that were fed an HF diet. However, the boundary length of adipose tissue tended to decrease and the levels of adipokines (leptin and adiponectin) were lowered by the induction of arthritis. In HF/CIA mice, nevertheless, the production of MCP-1 in adipose tissues and the accumulation of macrophages in the SVF were significantly higher than CON/CIA group. The serum leptin/adiponectin (L/A) ratio was positively correlated with the number of macrophages in the SVF and MCP-1 production by adipose tissue, particularly in the CIA group.. Functional alterations of adipose tissues could be originated from HF diet during developing arthritis. An abnormal activation of macrophages and an increased production of MCP-1 in adipose tissues might be both involved in joint destruction and inflammation. Topics: Adiponectin; Animals; Arthritis, Experimental; Blood Vessels; Body Weight; Collagen Type II; Diet, High-Fat; Edema; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Inflammation; Intra-Abdominal Fat; Joints; Leptin; Male; Mice; Mice, Inbred DBA; Severity of Illness Index; Spleen; Stromal Cells | 2012 |
Effects of glucose-6-phosphate dehydrogenase deficiency on the metabolic and cardiac responses to obesogenic or high-fructose diets.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common human enzymopathy that affects cellular redox status and may lower flux into nonoxidative pathways of glucose metabolism. Oxidative stress may worsen systemic glucose tolerance and cardiometabolic syndrome. We hypothesized that G6PD deficiency exacerbates diet-induced systemic metabolic dysfunction by increasing oxidative stress but in myocardium prevents diet-induced oxidative stress and pathology. WT and G6PD-deficient (G6PDX) mice received a standard high-starch diet, a high-fat/high-sucrose diet to induce obesity (DIO), or a high-fructose diet. After 31 wk, DIO increased adipose and body mass compared with the high-starch diet but to a greater extent in G6PDX than WT mice (24 and 20% lower, respectively). Serum free fatty acids were increased by 77% and triglycerides by 90% in G6PDX mice, but not in WT mice, by DIO and high-fructose intake. G6PD deficiency did not affect glucose tolerance or the increased insulin levels seen in WT mice. There was no diet-induced hypertension or cardiac dysfunction in either mouse strain. However, G6PD deficiency increased aconitase activity by 42% and blunted markers of nonoxidative glucose pathway activation in myocardium, including the hexosamine biosynthetic pathway activation and advanced glycation end product formation. These results reveal a complex interplay between diet-induced metabolic effects and G6PD deficiency, where G6PD deficiency decreases weight gain and hyperinsulinemia with DIO, but elevates serum free fatty acids, without affecting glucose tolerance. On the other hand, it modestly suppressed indexes of glucose flux into nonoxidative pathways in myocardium, suggesting potential protective effects. Topics: Acetylglucosamine; Aconitate Hydratase; Adiponectin; Animals; Body Weight; Citrate (si)-Synthase; Diet; Echocardiography; Electrophoresis, Polyacrylamide Gel; Female; Fructose; Glucose Tolerance Test; Glucosephosphate Dehydrogenase; Glucosephosphate Dehydrogenase Deficiency; Gonads; Heart; Humans; Insulin; Leptin; Mice; Mice, Inbred C3H; Obesity; Oxidative Stress; Triglycerides | 2012 |
Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance.
Obesity-related leptin resistance manifests in loss of leptin's ability to reduce appetite and increase energy expenditure. Obesity is also associated with increased activity of the endocannabinoid system, and CB(1) receptor (CB(1)R) inverse agonists reduce body weight and the associated metabolic complications, although adverse neuropsychiatric effects halted their therapeutic development. Here we show that in mice with diet-induced obesity (DIO), the peripherally restricted CB(1)R inverse agonist JD5037 is equieffective with its brain-penetrant parent compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance, even though it does not occupy central CB(1)R or induce related behaviors. Appetite and weight reduction by JD5037 are mediated by resensitizing DIO mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes and increasing leptin clearance via the kidney. Thus, inverse agonism at peripheral CB(1)R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance. Topics: Adipocytes; Animals; Anti-Obesity Agents; Body Weight; Drug Inverse Agonism; Drug Resistance; Fatty Liver; Insulin Resistance; Leptin; Mice; Molecular Structure; Obesity; Pyrazoles; Receptor, Cannabinoid, CB1; Regression Analysis; Sulfonamides | 2012 |
Leptin deficiency contributes to the pathogenesis of alcoholic fatty liver disease in mice.
White adipose tissue (WAT) secretes adipokines, which critically regulate lipid metabolism. The present study investigated the effects of alcohol on adipokines and the mechanistic link between adipokine dysregulation and alcoholic fatty liver disease. Mice were fed alcohol for 2, 4, or 8 weeks to document changes in adipokines over time. Alcohol exposure reduced WAT mass and body weight in association with hepatic lipid accumulation. The plasma adiponectin concentration was increased at 2 weeks, but declined to normal at 4 and 8 weeks. Alcohol exposure suppressed leptin gene expression in WAT and reduced the plasma leptin concentration at all times measured. There is a highly positive correlation between plasma leptin concentration and WAT mass or body weight. To determine whether leptin deficiency mediates alcohol-induced hepatic lipid dyshomeostasis, mice were fed alcohol for 8 weeks with or without leptin administration for the last 2 weeks. Leptin administration normalized the plasma leptin concentration and reversed alcoholic fatty liver. Alcohol-perturbed genes involved in fatty acid β-oxidation, very low-density lipoprotein secretion, and transcriptional regulation were attenuated by leptin. Leptin also normalized alcohol-reduced phosphorylation levels of signal transducer Stat3 and adenosine monophosphate-activated protein kinase. These data demonstrated for the first time that leptin deficiency in association with WAT mass reduction contributes to the pathogenesis of alcoholic fatty liver disease. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; CCAAT-Enhancer-Binding Protein-alpha; Ethanol; Fatty Liver, Alcoholic; Gene Expression Regulation; Hepatocyte Nuclear Factor 1-alpha; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Organ Size; PPAR alpha | 2012 |
Neurochemical characterization of body weight-regulating leptin receptor neurons in the nucleus of the solitary tract.
The action of peripherally released leptin at long-form leptin receptors (LepRb) within the brain represents a fundamental axis in the regulation of energy homeostasis and body weight. Efforts to delineate the neuronal mediators of leptin action have recently focused on extrahypothalamic populations and have revealed that leptin action within the nucleus of the solitary tract (NTS) is critical for normal appetite and body weight regulation. To elucidate the neuronal circuits that mediate leptin action within the NTS, we employed multiple transgenic reporter lines to characterize the neurochemical identity of LepRb-expressing NTS neurons. LepRb expression was not detected in energy balance-associated NTS neurons that express cocaine- and amphetamine-regulated transcript, brain-derived neurotrophic factor, neuropeptide Y, nesfatin, catecholamines, γ-aminobutyric acid, prolactin-releasing peptide, or nitric oxide synthase. The population of LepRb-expressing NTS neurons was comprised of subpopulations marked by a proopiomelanocortin-enhanced green fluorescent protein (EGFP) transgene and distinct populations that express proglucagon and/or cholecystokinin. The significance of leptin action on these three populations of NTS neurons was assessed in leptin-deficient Ob/Ob mice, revealing increased NTS proglucagon and cholecystokinin, but not proopiomelanocortin, expression. These data provide new insight into the appetitive brainstem circuits engaged by leptin. Topics: Animals; Body Weight; Brain-Derived Neurotrophic Factor; Cholecystokinin; Energy Metabolism; gamma-Aminobutyric Acid; Leptin; Mice; Mice, Transgenic; Neurons; Neuropeptide Y; Phosphorylation; Pro-Opiomelanocortin; Proglucagon; Prolactin-Releasing Hormone; Receptors, Leptin; Solitary Nucleus; STAT3 Transcription Factor | 2012 |
Metabolic effects of intermittent hypoxia in mice: steady versus high-frequency applied hypoxia daily during the rest period.
Intermittent hypoxia (IH) is a frequent occurrence in sleep and respiratory disorders. Both human and murine studies show that IH may be implicated in metabolic dysfunction. Although the effects of nocturnal low-frequency intermittent hypoxia (IH(L)) have not been extensively examined, it would appear that IH(L) and high-frequency intermittent hypoxia (IH(H)) may elicit distinct metabolic adaptations. To this effect, C57BL/6J mice were randomly assigned to IH(H) (cycles of 90 s 6.4% O(2) and 90 s 21% O(2) during daylight), IH(L) (8% O(2) during daylight hours), or control (CTL) for 5 wk. At the end of exposures, some of the mice were subjected to a glucose tolerance test (GTT; after intraperitoneal injection of 2 mg glucose/g body wt), and others were subjected to an insulin tolerance test (ITT; 0.25 units Humulin/kg body wt), with plasma leptin and insulin levels being measured in fasting conditions. Skeletal muscles were harvested for GLUT4 and proliferator-activated receptor gamma coactivator 1-α (PGC1-α) expression. Both IH(H) and IH(L) displayed reduced body weight increases compared with CTL. CTL mice had higher basal glycemic levels, but GTT kinetics revealed marked differences between IH(L) and IH(H), with IH(L) manifesting the lowest insulin sensitivity compared with either IH(H) or CTL, and such findings were further confirmed by ITT. No differences emerged in PGC1-α expression across the three experimental groups. However, while cytosolic GLUT4 protein expression remained similar in IH(L), IH(H), and CTL, significant decreases in GLUT4 membrane fraction occurred in hypoxia and were most pronounced in IH(L)-exposed mice. Thus IH(H) and IH(L) elicit differential glucose homeostatic responses despite similar cumulative hypoxic profiles. Topics: Adaptation, Physiological; Animals; Body Weight; Circadian Rhythm; Glucose Transporter Type 4; Hypoxia; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Models, Animal; Muscle, Skeletal; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rest; Time Factors; Trans-Activators; Transcription Factors | 2012 |
A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin.
We previously demonstrated that animals fed a high-fat (HF) diet for 10 weeks developed insulin resistance and behavioural inflexibility. We hypothesised that intervention with metformin would diminish the HF-feeding-evoked cognitive deficit by improving insulin sensitivity.. Rats were trained in an operant-based matching and non-matching to position task (MTP/NMTP). Animals received an HF (45% of kJ as lard; n = 24), standard chow (SC; n = 16), HF + metformin (144 mg/kg in diet; n = 20) or SC + metformin (144 mg/kg in diet; n = 16) diet for 10 weeks before retesting. Body weight and plasma glucose, insulin and leptin were measured. Protein lysates from various brain areas were analysed for alterations in intracellular signalling or production of synaptic proteins.. HF-fed animals developed insulin resistance and an impairment in switching task contingency from matching to non-matching paradigm. Metformin attenuated the insulin resistance and weight gain associated with HF feeding, but had no effect on performance in either MTP or NMTP tasks. No major alteration in proteins associated with insulin signalling or synaptic function was detected in response to HF diet in the hypothalamus, hippocampus, striatum or cortex.. Metformin prevented the metabolic but not cognitive alterations associated with HF feeding. The HF diet protocol did not change basal insulin signalling in the brain, suggesting that the brain did not develop insulin resistance. These findings indicate that HF diet has deleterious effects on neuronal function over and above those related to insulin resistance and suggest that weight loss may not be sufficient to reverse some damaging effects of poor diet. Topics: Alzheimer Disease; Animals; Behavior, Animal; Body Weight; Brain; Cognition Disorders; Conditioning, Operant; Dietary Fats; Disease Models, Animal; Hormones; Hypoglycemic Agents; Insulin Resistance; Leptin; Male; Metformin; Nerve Tissue Proteins; Rats; Rats, Wistar; Signal Transduction; Treatment Failure | 2012 |
Cafeteria diet-induced obesity plus chronic stress alter serum leptin levels.
Obesity is a disease that has become a serious public health issue worldwide, and chronic stressors, which are a problem for modern society, cause neuroendocrine changes with alterations in food intake. Obesity and chronic stress are associated with the development of cardiovascular diseases and metabolic disorders. In this study, a rat model was used to evaluate the effects of a hypercaloric diet plus chronic restraint stress on the serum leptin and lipids levels and on the weight of specific adipose tissue (mesenteric, MAT; subcutaneous, SAT and visceral, VAT). Wistar rats were divided into the following 4 groups: standard chow (C), hypercaloric diet (HD), stress plus standard chow (S), and stress plus hypercaloric diet (SHD). The animals in the stress groups were subjected to chronic stress (placed inside a 25 cm × 7 cm plastic tube for 1h per day, 5 days per week for 6 weeks). The following parameters were evaluated: the weight of the liver, adrenal glands and specific adipose tissue; the delta weight; the Lee index; and the serum levels of leptin, corticosterone, glucose, total cholesterol, and triglycerides. The hypercaloric diet induced obesity in rats, increasing the Lee index, weight, leptin, triglycerides, and cholesterol levels. The stress decreased weight gain even in animals fed a hypercaloric diet but did not prevent a significant increase in the Lee index. However, an interaction between the independent factors (hypercaloric diet and stress) was observed, which is demonstrated by the increased serum leptin levels in the animals exposed to both protocols. Topics: Adipose Tissue; Animals; Body Weight; Corticosterone; Diet; Disease Models, Animal; Energy Intake; Leptin; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Liver; Obesity; Organ Size; Rats; Rats, Wistar; Restraint, Physical; Stress, Physiological | 2012 |
Creation and preliminary characterization of a leptin knockout rat.
Leptin, a cytokine-like hormone secreted mainly by adipocytes, regulates various pathways centered on food intake and energy expenditure, including insulin sensitivity, fertility, immune system, and bone metabolism. Here, using zinc finger nuclease technology, we created the first leptin knockout rat. Homozygous leptin null rats are obese with significantly higher serum cholesterol, triglyceride, and insulin levels than wild-type controls. Neither gender produced offspring despite of repeated attempts. The leptin knockout rats also have depressed immune system. In addition, examination by microcomputed tomography of the femurs of the leptin null rats shows a significant increase in both trabecular bone mineral density and bone volume of the femur compared with wild-type littermates. Our model should be useful for many different fields of studies, such as obesity, diabetes, and bone metabolism-related illnesses. Topics: Animals; Body Weight; Bone Density; Cholesterol; Eating; Energy Metabolism; Femur; Insulin; Leptin; Obesity; Phenotype; Rats; Rats, Transgenic; Triglycerides; Zinc Fingers | 2012 |
Maternal pregravid weight is the primary determinant of serum leptin and its metabolic associations in pregnancy, irrespective of gestational glucose tolerance status.
Several previous studies have investigated circulating levels of the adipokine leptin in relation to gestational diabetes mellitus (GDM). However, these studies have yielded markedly conflicting results, including increased, decreased, and unchanged leptin levels in women with GDM as compared with their peers.. We sought to evaluate the metabolic determinants of serum leptin in a well-characterized cohort reflecting the full spectrum of glucose intolerance in pregnancy.. Metabolic characterization, including oral glucose tolerance test (OGTT) and measurement of serum leptin, insulin, lipids, adiponectin, and C-reactive protein, was performed in 817 pregnant women. The OGTT identified 198 women with GDM, 142 with gestational impaired glucose tolerance, and 477 with normal glucose tolerance.. Median leptin (ng/ml) did not differ between the normal glucose tolerance (33.7), gestational impaired glucose tolerance (36.3), and GDM (36.4) groups (P = 0.085). On univariate correlation analysis, leptin was most strongly associated with prepregnancy body mass index (BMI) (r = 0.54, P < 0.0001), fasting insulin (r = 0.60, P < 0.0001), and C-reactive protein (r = 0.38, P < 0.0001) but only weakly associated with area under the glucose curve (AUC(glucose)) on the OGTT (r = 0.10, P = 0.0066). On multiple linear regression analysis, the strongest independent determinant of leptin was prepregnancy BMI (t = 11.55, P < 0.0001), whereas AUC(glucose) was not a significant predictor (t = -0.95, P = 0.34). Furthermore, although its respective associations with fasting insulin, triglycerides, and adiponectin varied across tertiles of prepregnancy BMI, leptin was not significantly associated with AUC(glucose) in any BMI tertile.. Pregravid BMI, rather than gestational glucose tolerance, is the primary determinant of serum leptin concentration in pregnancy. Topics: Adiponectin; Adult; Blood Glucose; Body Weight; C-Reactive Protein; Diabetes, Gestational; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Pregnancy | 2012 |
Fat-reducing effects of dehydroepiandrosterone involve upregulation of ATGL and HSL expression, and stimulation of lipolysis in adipose tissue.
Dehydroepiandrosterone (DHEA) reduces body fat in rodents and humans, and increases glycerol release from isolated rat epididymal adipocytes and human visceral adipose tissue explants. It suggests that DHEA stimulates triglyceride hydrolysis in adipose tissue; however, the mechanisms underlying this action are still unclear. We examined the effects of DHEA on the expression of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), the key enzymes of lipolysis, in rat epididymal white adipose tissue (eWAT). Male Wistar rats were fed a diet containing 0.6% DHEA for 2 weeks and eWAT was analyzed for mRNA and protein expression of ATGL and HSL, as well as mRNA expression of peroxisome proliferator-activated receptor γ 2 (PPARγ2) and its downstream target fatty acid translocase (FAT). Glycerol release from eWAT explants and serum free fatty acids (FFA) were also measured. Rats that received DHEA gained less weight, had 23% lower eWAT mass and 31% higher serum FFA levels than controls. Cultured explants of eWAT from DHEA-treated rats released 81% more glycerol than those from control rats. DHEA administration upregulated ATGL mRNA (1.62-fold, P<0.05) and protein (1.78-fold, P<0.05) expression as well as augmented HSL mRNA levels (1.36-fold, P<0.05) and Ser660 phosphorylation of HSL (2.49-fold, P<0.05). PPARγ2 and FAT mRNA levels were also increased in DHEA-treated rats (1.61-fold, P<0.05 and 2.16-fold, P<0.05; respectively). Moreover, ATGL, HSL, and FAT mRNA levels were positively correlated with PPARγ2 expression. This study demonstrates that DHEA promotes lipid mobilization in adipose tissue by increasing the expression and activity of ATGL and HSL. The effects of DHEA appear to be mediated, at least in part, via PPARγ2 activation, which in turn upregulates ATGL and HSL gene expression. Topics: Adipose Tissue; Animals; Body Weight; Dehydroepiandrosterone; Epididymis; Fatty Acids, Nonesterified; Gene Expression Regulation, Enzymologic; Glycerol; Intra-Abdominal Fat; Leptin; Lipase; Lipolysis; Male; Phosphorylation; PPAR gamma; Rats; Rats, Wistar; RNA, Messenger; Sterol Esterase; Time Factors; Up-Regulation | 2012 |
[D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, augments the effects of orally delivered exenatide and pramlintide acetate on energy balance and glycemic control in insulin-resistant male C57BLK/6-m db/db mice.
The escalation predicted for the incidence of both type 2 diabetes mellitus and obesity has prompted investigators to search for additional pharmacotherapeutic approaches to their treatment. Two of these approaches, combination pharmacotherapy and utilization of leptin-related bioactive synthetic peptides as anti-diabetes/anti-obesity agents, were used in the present study. Exenatide or pramlintide acetate was reconstituted in dodecyl maltoside (DDM) in the absence or presence of [D-Leu-4]-OB3, and delivered orally by gavage to insulin-resistant male C57BLK/6-m db/db mice twice daily for 14 days. Body weight gain, food and water intake, blood glucose, and serum insulin levels were measured. Mice given DDM alone for 14 days were 19.7% heavier than they were at the beginning of the study, while oral delivery of exenatide or [D-Leu-4]-OB3 in DDM reduced body weight gain to only 13.9% and 11.5%, respectively, of initial body weight. Mice receiving exenatide and [D-Leu-4]-OB3 were 4.2% lighter than they were at the beginning of the study. In another study, Intravail® treated control mice gained 38.2% of their initial body weight, while mice receiving pramlintide acetate or [D-Leu-4]-OB3 were only 26.8% and 25.4% heavier, respectively, at the end of the study, Co-administration of pramlintide acetate and [D-Leu-4]-OB3 did not further enhance the effect of pramlintide acetate on body weight gain. Food intake was reduced by exenatide, pramlintide acetate, and [D-Leu-4]-OB3 alone, and co-delivery with [D-Leu-4]-OB3 did not induce a further decrease. Water intake was not affected by exenatide, pramlintide acetate, or [D-Leu-4]-OB3 alone, but co-delivery of exenatide or pramlintide acetate with [D-Leu-4]-OB3 resulted in a significant reduction in water intake. Oral delivery of exenatide or pramlintide acetate in DDM significantly lowered blood glucose levels by 20.4% and 30.2%, respectively. Co-delivery with [D-Leu-4]-OB3 further reduced blood glucose by 38.3% and 50.5%, respectively. A concentration-dependent increase in serum insulin was observed in response to increasing concentrations of exenatide, and [D-Leu-4]-OB3 slightly reduced the insulin response to exenatide at all concentrations tested. Increasing concentrations of pramlintide acetate alone did not elevate serum insulin, and when given in combination with [D-Leu-4]-OB3, serum insulin levels fell below those of DDM-treated control mice. Our data indicate that (1) exenatide and pramlintide acetate, curren Topics: Administration, Oral; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Drug Combinations; Drug Synergism; Eating; Energy Metabolism; Exenatide; Glucosides; Hypoglycemic Agents; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Peptide Fragments; Peptides; Venoms | 2012 |
Weight homeostasis & its modulators in hyperthyroidism before & after treatment with carbimazole.
Hyperthyroidism is associated with increased food intake, energy expenditure and altered body composition. This study was aimed to evaluate the role of adipocytokines in weight homeostasis in patients with hyperthyroidism.. Patients (n=27, 11men) with hyperthyroidism (20 Graves' disease, 7 toxic multinodular goiter) with mean age of 31.3±4.2 yr and 28 healthy age and body mass index (BMI) matched controls were studied. They underwent assessment of lean body mass (LBM) and total body fat (TBF) by dual energy X-ray absorptiometer (DXA) and blood sample was taken in the fasting state for measurement of leptin, adiponectin, ghrelin, insulin, glucose and lipids. Patients were re-evaluated after 3 months of treatment as by that time all of them achieved euthyroid state with carbimazole therapy.. The LBM was higher (P<0.001) in healthy controls as compared to hyperthyroid patients even after adjustment for body weight (BW), whereas total body fat was comparable between the two groups. Serum leptin levels were higher in patients with hyperthyroidism than controls (22.3±3.7 and 4.1±0.34 ng/ml, P<0.001), whereas adiponectin levels were comparable. Plasma acylated ghrelin was higher in patients than in controls (209.8±13.3 vs 106.2±8.2 pg/ml, P<0.05). Achievement of euthyroidism was associated with significant weight gain (P<0.001) and significant increase in lean body mass (P<0.001). The total body fat also increased but insignificantly from 18.4±1.8 to 19.9±1.8 kg. There was significant decrease (P<0.05) in serum leptin and acylated ghrelin but adiponectin levels remained unaltered after treatment. Serum leptin positively correlated with TBF and this correlation persisted even after adjustment for BW, BMI, gender and age (r=0.62, P=0.001). However, serum leptin and acylated ghrelin did not correlate with the presence or absence of hyperphagia.. Patients with hyperthyroidism predominantly had decreased lean body mass which increased after achievement of euthyroidism with carbimazole. The hyperphagia and the alterations in weight homeostasis associated with hyperthyroidism were independent of circulating leptin and ghrelin levels. Topics: Adipose Tissue; Adult; Antithyroid Agents; Body Composition; Body Weight; Carbimazole; Energy Metabolism; Ghrelin; Humans; Hyperphagia; Hyperthyroidism; Leptin; Male; Thyroid Hormones | 2012 |
Brain structure predicts risk for obesity.
The neurobiology of obesity is poorly understood. Here we report findings of a study designed to examine the differences in brain regional gray matter volume in adults recruited as either Obese Prone or Obese Resistant based on self-identification, body mass index, and personal/family weight history. Magnetic resonance imaging was performed in 28 Obese Prone (14 male, 14 female) and 25 Obese Resistant (13 male, 12 female) healthy adults. Voxel-based morphometry was used to identify gray matter volume differences between groups. Gray matter volume was found to be lower in the insula, medial orbitofrontal cortex and cerebellum in Obese Prone, as compared to Obese Resistant individuals. Adjusting for body fat mass did not impact these results. Insula gray matter volume was negatively correlated with leptin concentration and measures of hunger. These findings suggest that individuals at risk for weight gain have structural differences in brain regions known to be important in energy intake regulation, and that these differences, particularly in the insula, may be related to leptin. Topics: Adult; Body Mass Index; Body Weight; Brain; Cerebellum; Cerebral Cortex; Energy Intake; Family; Female; Humans; Hunger; Leptin; Magnetic Resonance Imaging; Male; Obesity; Organ Size; Risk Factors; Satiety Response; Social Control, Informal | 2012 |
Anti-obesity effect of kimchi fermented with Weissella koreensis OK1-6 as starter in high-fat diet-induced obese C57BL/6J mice.
In this study, we investigated the anti-obesity effects of kimchi (Korean traditional fermented vegetable) fermented either without starter culture or with a specific starter culture, Weissella koreensis OK1-6.. C57BL/6J mice were divided into four groups (n = 7); normal diet, HF (high-fat diet), HF-KC (high-fat diet containing 3% kimchi manufactured without starter) and HF-KCO (high-fat diet containing 3% kimchi manufactured with the starter culture W. koreensis OK1-6). After 12 weeks of dietary intervention, the mice were killed, and serum and tissue samples were examined. Serum and hepatic lipid profile, insulin, leptin concentration and expression level of lipid anabolic genes like peroxisome proliferator-activated receptor γ, stearoyl-CoA desaturase-1, liver X receptor α and SREBP2 were significantly decreased (<0.05) along with body and epididymal fat pad weight in the HF-KCO group compared with the HF-KC and HF group.. These results suggested that kimchi fermented with the starter W. koreensis OK1-6 has anti-obesity effects in HF-induced obese mice.. These results may contribute to nutraceutical and food industries in developing functional food and probiotics based therapies for the treatment and prevention of obesity. Topics: Adipose Tissue; Animals; Body Weight; Brassica; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Fermentation; Food Microbiology; Insulin; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; PPAR gamma; Weissella | 2012 |
Prepro-thyrotropin releasing hormone expressing neurons in the juxtaparaventricular region of the lateral hypothalamus are activated by leptin and altered by prenatal glucocorticoid exposure.
The neuropeptide thyrotropin-releasing hormone (TRH) is recognized to play an important role in controlling energy balance through direct effects on the CNS, although mechanisms explaining the phenomenon are poorly understood. To begin to understand the effects of TRH on CNS control of energy balance, we first mapped neurons expressing the TRH precursor peptide, prepro-TRH (ppTRH) in the paraventricular nucleus of the rat hypothalamus and the surrounding regions. We identified a population of ppTRH-expressing neurons in the juxtaparaventricular region of the lateral hypothalamus (LHAjp) which were stimulated by the satiety signal leptin (2.5μg/kg, IP). Using a model of fetal glucocorticoid (GC) exposure in which pregnant rats were treated with the synthetic GC dexamethasone (DEX) during gestational days 18-21, it was observed that such exposure resulted in reduced numbers of ppTRH-ir neurons in the LHAjp in adult male and female rats, and was accompanied by increased food intake. Our data provide further insight into the biological role of the LHAjp, as well as the potential involvement of TRH neurons within this region in metabolic disease associated with fetal glucocorticoid exposure. Topics: Analysis of Variance; Animals; Animals, Newborn; Body Weight; Dexamethasone; Eating; Female; Glucocorticoids; Hypothalamus; Leptin; Male; Neurons; Pregnancy; Prenatal Exposure Delayed Effects; Protein Precursors; Rats; Sex Factors; Thyrotropin-Releasing Hormone | 2012 |
Hormone resistance in diabetes and obesity: insulin, leptin, and FGF21.
This an edited transcript of the Lee E. Farr Lecture given by Dr. Jeffrey Flier on May 8, 2012, at the culmination of the annual Student Research Day at the Yale School of Medicine. In this presentation, Dr. Flier discusses his and his wife's research on insulin, leptin, and FGF21 in the context of his reflections upon his life's work and his advice for young investigators. Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus; Diet, Ketogenic; Fatty Liver; Fibroblast Growth Factors; Humans; Insulin; Insulin Resistance; Leptin; Mice; Mice, Knockout; Obesity | 2012 |
Synthesis and biological evaluation of 5-benzylidenepyrimidine-2,4,6(1H,3H,5H)-trione derivatives for the treatment of obesity-related nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD), one of chronic liver diseases, seems to be rising as the obesity epidemic continues. In this study, 54 novel (thio)barbituric acid derivatives have been synthesized and evaluated for pharmacological activity. 7h exhibited potent glucose-lowering effects on insulin-resistant HepG2 cells and regulated adiponectin and leptin expression in 3T3-L1 adipocytes. Oral administration of 7h at 25 mg kg(-1) day(-1) for 4 weeks improved the progression of high fat diet-induced NAFLD by reducing the weight of body, liver, and fat, as well as modulating serum levels of fasting glucose, insulin, triglycerides, LDL-c, ALT, adiponectin and hepatic contents of triglycerides, total cholesterol. H&E stainings revealed that 7h blocked fat deposition in liver and the increase of adipocyte number and size in adipose tissues from NAFLD. Furthermore, treatment with 7h alleviated the obese clinical symptoms, recovered serum biomarkers to appropriate ranges, and improved glucose tolerance by OGTT and IGTT in DIO mice. Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Alanine Transaminase; Animals; Barbiturates; Body Weight; Cholesterol; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Female; Glucose; Glucose Tolerance Test; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Tissue Distribution; Triglycerides | 2012 |
An obligate role of oxytocin neurons in diet induced energy expenditure.
Oxytocin neurons represent one of the major subsets of neurons in the paraventricular hypothalamus (PVH), a critical brain region for energy homeostasis. Despite substantial evidence supporting a role of oxytocin in body weight regulation, it remains controversial whether oxytocin neurons directly regulate body weight homeostasis, feeding or energy expenditure. Pharmacologic doses of oxytocin suppress feeding through a proposed melanocortin responsive projection from the PVH to the hindbrain. In contrast, deficiency in oxytocin or its receptor leads to reduced energy expenditure without feeding abnormalities. To test the physiological function of oxytocin neurons, we specifically ablated oxytocin neurons in adult mice. Our results show that oxytocin neuron ablation in adult animals has no effect on body weight, food intake or energy expenditure on a regular diet. Interestingly, male mice lacking oxytocin neurons are more sensitive to high fat diet-induced obesity due solely to reduced energy expenditure. In addition, despite a normal food intake, these mice exhibit a blunted food intake response to leptin administration. Thus, our study suggests that oxytocin neurons are required to resist the obesity associated with a high fat diet; but their role in feeding is permissive and can be compensated for by redundant pathways. Topics: Animals; Body Weight; Diet, High-Fat; Dietary Fats; Eating; Energy Intake; Energy Metabolism; Homeostasis; Injections, Intraperitoneal; Leptin; Male; Mice; Mice, Transgenic; Neurons; Obesity; Oxytocin; Paraventricular Hypothalamic Nucleus | 2012 |
Female heterozygous (+/fa) Zucker rats as a novel leptin-related mammary carcinogenesis model.
The homozygous mutant fatty Zucker rat (fa/fa) is the prominent model for the research of obesity, one of the most well-known risk factor of postmenopausal mammary cancer. But the usage as a mammary gland carcinogenesis model is considered to be restricted due to the hypoplasia of mammary gland. In the present study, to find the validity of heterozygous mutant (+/fa) lean Zucker rats as a new leptin-related mammary carcinogenesis model, we examined whether the number of terminal end buds of mammary gland, the serum biochemistry, leptin concentration in serum and adipose tissue are changed in 7-week-old female +/+, +/fa and fa/fa rats, and whether these changes and leptin, TNF-α and VEGF mRNA expression in adipose tissue of +/+ and +/fa rats are influenced by 10% corn oil diet for 5 weeks. We confirmed that mild hyperleptinemia was more pronounced in 7-week-old +/fa as compared with wild type (+/+) and hypoplasia of mammary glands characterized by fewer numbers of terminal end buds in fa/fa was not observed in +/fa. With 10% corn oil diet, leptin mRNA expression in adipose tissue showed increasing tendency both in +/fa and +/+. Comparing with +/+, adipose tissue in +/fa treated with 10% corn oil diet was found to be significantly increased in the concentration of leptin protein and tended to be elevated expression of TNF-α mRNA. These results suggest that +/fa with 10% corn oil diet may be a useful model for investigation of the participation of leptin and TNF-α in mammary gland carcinogenesis. Topics: Adipose Tissue; Animals; Body Weight; Corn Oil; Diet; Disease Models, Animal; Female; Leptin; Liver; Mammary Neoplasms, Animal; Obesity; Organ Size; Rats; Rats, Zucker; RNA, Messenger; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A | 2012 |
Maternal supplementation with an excess of different fat sources during pregnancy and lactation differentially affects feeding behavior in offspring: putative role of the leptin system.
This study investigates the lasting effects of maternal supplementation with different fat sources during pregnancy and lactation on feeding behavior and energy homeostasis of their offspring, and its relation to hypothetical effects in the development of main central structures involved in leptin signaling.. Offspring of dams supplemented with olive oil, butter, or margarine during late pregnancy and lactation were fed with normal fat (NF) diet until 4-month-old, and then with NF or high fat (HF) diet until 6-month-old. Results showed that 21-day-old margarine group pups presented a higher cell number in the arcuate nucleus (ARC) (females) and higher hypothalamic ObRb/SOCS3 mRNA ratio (males). In adulthood, and under HF diet, they displayed a lower body weight (both genders) and body fat (males) than the butter group, a lower preference for fat food (both genders), and lower leptin levels than the olive oil (both genders) and butter (males) groups.. Maternal supplementation with different fat sources during the perinatal period may affect the development of hypothalamic structures and hence predisposition to obesity. Margarine, compared with other fats, may program the offspring for increased leptin sensitivity and a lower preference for fat food, thus providing relative protection against body weight gain in adulthood, particularly under an obesogenic environment. Topics: Adipose Tissue; Animals; Animals, Newborn; Blood; Body Weight; Butter; Diet, High-Fat; Dietary Fats; Dietary Supplements; Energy Metabolism; Feeding Behavior; Female; Hypothalamus; Lactation; Leptin; Male; Margarine; Maternal Nutritional Physiological Phenomena; Olive Oil; Plant Oils; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar | 2012 |
Cytosolic malic enzyme 1 (ME1) mediates high fat diet-induced adiposity, endocrine profile, and gastrointestinal tract proliferation-associated biomarkers in male mice.
Obesity and associated hormonal disturbances are risk factors for colon cancer. Cytosolic Malic Enzyme (ME1) generates NADPH used for lipogenesis in gastrointestinal (GI), liver and adipose tissues. We have reported that inclusion of soy protein isolate (SPI) in the diet lowered body fat content and colon tumor incidence of rats fed AIN-93G diet, while others have demonstrated SPI inhibition of rat hepatic ME1 expression. The present study examined the individual and combined effects of dietary SPI and absence of ME1 on: 1) serum concentrations of hormones implicated in colon cancer development, 2) expression of lipogenic and proliferation-associated genes in the mouse colon and small intestine, and 3) liver and adipose expression of lipogenic and adipocytokine genes that may contribute to colon cancer predisposition.. Weanling wild type (WT) and ME1 null (MOD-1) male mice were fed high-fat (HF), iso-caloric diets containing either casein (CAS) or SPI as sole protein source for 5 wks. Somatic growth, serum hormone and glucose levels, liver and adipose tissue weights, GI tissue parameters, and gene expression were evaluated.. The MOD-1 genotype and SPI-HF diet resulted in decreases in: body and retroperitoneal fat weights, serum insulin, serum leptin, leptin/adiponectin ratio, adipocyte size, colon mTOR and cyclin D1 mRNA abundance, and jejunum FASN mRNA abundance, when compared to WT mice fed CAS-HF. Regardless of diet, MOD-1 mice had reductions in liver weight, liver steatosis, and colon crypt depth, and increases in adipose tissue expression of IRS1 and IRS2, compared to WT mice. SPI-HF diet reduced ME1 gene expression only in retroperitoneal fat.. Data suggest that the pharmacological targeting of ME1 or the inclusion of soy protein in the diet may provide avenues to reduce obesity and its associated pro-tumorigenic endocrine environment and improve insulin sensitivity, potentially disrupting the obesity-colon cancer connection. Topics: Adipocytes; Adiposity; Animals; Body Weight; Diet, High-Fat; Gastrointestinal Tract; Insulin; Leptin; Malate Dehydrogenase; Male; Mice; Mice, Mutant Strains; Soybean Proteins | 2012 |
[Effect of bisphenol A exposure during early development on body weight and glucose metabolism of female filial rats].
To investigate the effect of bisphenol A (BPA) exposure during early development on body weight and glucose metabolism of female filial rats.. Pregnant Sprague-Dawley rats were exposed by drinking water containing 1 microg/ml BPA from the 6th day of gestation to the end of lactation. Body weight of female pups was measured on born, during lactation and after weaning. The levels of fasting blood glucose, insulin and leptin, the weight of liver and kidney and peri-gonadal and peri-renal adipose tissue were measured, and the organ and adipose tissue coefficients were calculated.. Compared with the control pubs, the body weight of pups in BPA-exposed group was significantly higher at born and after weaning, the virginal and gonadal adipose tissue coefficient was significantly higher, and the levels of fasting blood glucose, serum insulin were increased but leptin decreased.. BPA exposure during early development could increase the body weight and result in insulin resistance. The decrease of serum leptin resulted from BPA exposure maybe one of reasons related to obesity and insulin resistance. Topics: Adipose Tissue; Animals; Benzhydryl Compounds; Body Weight; Breast Feeding; Female; Glucose; Insulin; Insulin Resistance; Lactation; Leptin; Obesity; Phenols; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Weaning | 2012 |
Plasma leptin concentrations during the reproductive cycle in the native Thai chicken (Gallus domesticus).
Plasma leptin concentrations were investigated during the reproductive cycle in the native Thai chicken. The plasma leptin concentration was high during non-laying (0.69±0.15ng/ml), lowered to a minimum concentration during egg laying (0.07±0.02ng/ml), and gradually increased during egg incubation and rearing of the chicks (0.53±0.22 and 0.74±0.29ng/ml, respectively). However, the differences were not significant. Incubating chickens that were deprived of their nests for 3 weeks showed a significant decrease in plasma leptin concentrations (0.29±0.04ng/ml, P<0.05) compared to those of their corresponding incubating controls (0.77±0.08ng/ml). Similarly, plasma leptin concentration of chickens that were deprived of their chicks for 4 weeks was significantly lower (0.09±0.11ng/ml, P<0.05), when compared to those of chickens that rearing their chicks (0.71±0.18ng/ml). These findings taken together with the results that the low plasma leptin concentrations were observed in chickens having relatively greater ovary and oviduct weights led to the suggestion that circulating leptin concentrations are associated with the reproductive states of the birds, especially the ovarian activity (i.e. ovarian steroid hormone concentrations) in the native Thai chicken, a tropical and continuous breeding species. Topics: Animals; Body Weight; Chickens; Female; Leptin; Male; Organ Size; Ovary; Oviducts; Reproduction | 2012 |
Serum ghrelin level and TNF-α/ghrelin ratio in patients with previous myocardial infarction.
Studies investigating serum ghrelin level in atherosclerosis yielded contradictory results. Interaction of ghrelin with adipocytokines is obscure in cardiovascular diseases. We undertook this study to determine which molecules influence ghrelin level and to see whether post-myocardial infarction (MI) patients have decreased ghrelin levels.. In this cross-sectional study, acyl-ghrelin concentration was determined by radioimmunoassay in sera of 171 patients (ages 62 ± 6 years, mean ± SD) with previous MI and 81 age-matched referent subjects. We evaluated the associations of ghrelin with insulin, adiponectin, leptin, resistin, fetuin-A and tumor necrosis factor-alpha (TNF-α).. Patients had lower ghrelin levels compared to referent subjects (240.55 ± 59.33 vs. 337.96 ± 30.75 pg/mL, p <0.001) even after excluding diabetic and obese patients (240.63 ± 54.08 vs. 337.96 ± 30.75, p <0.001). In multivariate analysis, insulin (β = -0.327, p <0.001) and adiponectin (β = 0.301, p <0.001) determined ghrelin level (R(2) = 0.199, p <0.001). There was no association between ghrelin and TNF-α levels. In discriminant analysis using ghrelin, adiponectin, leptin, fetuin-A, resistin and TNF-α, the structure matrix revealed ghrelin and TNF-α as strongest predictors for belonging to the patient group (0.760 and -0.569, respectively). Using these two parameters, 89.7% of cases were correctly classified. Subjects with high TNF-α/ghrelin ratio had 11.25 times higher chance for belonging to the patient group (95% CI 5.80-21.80; χ(2) (1) = 215.6, p <0.001). Acylated ghrelin levels are decreased in patients with coronary atherosclerosis, independently of body weight and the presence of type 2 diabetes mellitus. Ghrelin level is determined by elevated insulin and decreased adiponectin levels. Ghrelin alone or in combination with TNF-α may prove to be a novel indicator of coronary atherosclerosis. Topics: Adiponectin; Aged; alpha-2-HS-Glycoprotein; Atherosclerosis; Blood Glucose; Body Weight; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Ghrelin; Humans; Insulin; Leptin; Male; Middle Aged; Myocardial Infarction; Resistin; Tumor Necrosis Factor-alpha | 2012 |
Metabolic effects of chronic sleep restriction in rats.
Chronic partial sleep loss is associated with obesity and metabolic syndrome in humans. We used rats with lesions in the ventrolateral preoptic area (VLPO), which spontaneously sleep about 30% less than intact rats, as an animal model to study the consequences of chronic partial sleep loss on energy metabolism.. Adult male Sprague-Dawley rats (300-365 g).. We ablated the VLPO in rats using orexin-B-saporin and instrumented them with electrodes for sleep recordings. We monitored their food intake and body weight for the next 60 days and assessed their sleep-wake by 24-h EEG/EMG recordings on day 20 and day 50 post-surgery. On day 60, after blood samples were collected for metabolic profiling, the animals were euthanized and the brains were harvested for histological confirmation of the lesion site.. VLPO-lesioned animals slept up to 40% less than sham-lesioned rats. However, they showed slower weight gain than sham-lesioned controls, despite having normal food intake. An increase in plasma ghrelin and a decrease in leptin levels were observed, whereas plasma insulin levels remained unaffected. As expected from leaner animals, plasma levels of glucose, cholesterol, triglycerides, and C-reactive protein were reduced in VLPO-lesioned animals.. Chronic partial sleep loss did not lead to obesity or metabolic syndrome in rats. This finding raises the question whether adverse metabolic outcomes associated with chronic partial sleep loss in humans may be due to factors other than short sleep, such as circadian disruption, inactivity, or diet during the additional waking hours. Topics: Animals; Blood Glucose; Body Weight; C-Reactive Protein; Energy Metabolism; Ghrelin; Insulin; Leptin; Lipids; Male; Metabolic Syndrome; Obesity; Rats; Sleep Deprivation; Weight Gain | 2012 |
Evaluation of appetite-stimulating hormones in prepubertal children with epilepsy during topiramate treatment.
We investigated the mechanism of topiramate-related appetite loss and exposed its relationship to body weight, body mass index, body fat index, and serum insulin, lipid, leptin, neuropeptide-Y, cortisol, ghrelin, and adiponectin levels. Twenty children with epilepsy were evaluated at baseline and months 3 and 6 of treatment. Their body fat index, leptin, and neuropeptide-Y levels significantly decreased at month 3, whereas significant decreases occurred in body weight, body mass index, body fat index, neuropeptide-Y, cholesterol, and cortisol levels of patients at month 6 compared with baseline. Weight loss during topiramate treatment was attributed to loss of appetite and reduced food intake caused by reductions in neuropeptide-Y. To the best of our knowledge, this study is the first to describe reductions in neuropeptide-Y with topiramate use in humans. Topics: Adiponectin; Adiposity; Anticonvulsants; Appetite; Body Mass Index; Body Weight; Child; Epilepsy; Female; Fructose; Ghrelin; Humans; Insulin; Leptin; Male; Neuropeptide Y; Topiramate | 2012 |
Peroxisome deficient aP2-Pex5 knockout mice display impaired white adipocyte and muscle function concomitant with reduced adrenergic tone.
Peroxisomes are essential for intermediary lipid metabolism, but the role of these organelles has been primarily studied in the liver. We recently generated aP2-Pex5 conditional knockout mice that due to the nonselectivity of the aP2 promoter, not only had dysfunctional peroxisomes in the adipose tissue but also in the central and peripheral nervous system, besides some other tissues. Peroxisomes were however intact in the liver, heart, pancreas and muscle. Surprisingly, these mice not only showed dysfunctional white adipose tissue with increased fat mass and reduced lipolysis but also the skeletal muscle was affected including impaired shivering thermogenesis, reduced motor performance and increased insulin resistance. Non-shivering thermogenesis by brown adipose tissue was not altered. Strongly reduced levels of plasma adrenaline and to a lesser extent noradrenaline, impaired expression of catecholamine synthesizing enzymes in the adrenal medulla and reversal of all pathologies after administration of the β-agonist isoproterenol indicated that β-adrenergic signaling was reduced. Based on normal white adipose and muscle function in Nestin-Pex5 and Wnt-Pex5 knockout mice respectively, it is unlikely that peroxisome absence from the central and peripheral nervous system caused the phenotype. We conclude that peroxisomal metabolism is necessary to maintain the adrenergic tone in mice, which in turn determines metabolic homeostasis. Topics: Adipocytes, White; Adipose Tissue, White; Animals; Body Weight; Fatty Acid-Binding Proteins; Inflammation; Insulin; Leptin; Mice; Mice, Knockout; Muscle, Skeletal; Muscles; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Phenotype; Receptors, Cytoplasmic and Nuclear; Shivering; Signal Transduction; Sympathetic Nervous System; Thermogenesis | 2012 |
Maternal deprivation exacerbates the response to a high fat diet in a sexually dimorphic manner.
Maternal deprivation (MD) during neonatal life has diverse long-term effects, including affectation of metabolism. Indeed, MD for 24 hours during the neonatal period reduces body weight throughout life when the animals are maintained on a normal diet. However, little information is available regarding how this early stress affects the response to increased metabolic challenges during postnatal life. We hypothesized that MD modifies the response to a high fat diet (HFD) and that this response differs between males and females. To address this question, both male and female Wistar rats were maternally deprived for 24 hours starting on the morning of postnatal day (PND) 9. Upon weaning on PND22 half of each group received a control diet (CD) and the other half HFD. MD rats of both sexes had significantly reduced accumulated food intake and weight gain compared to controls when raised on the CD. In contrast, when maintained on a HFD energy intake and weight gain did not differ between control and MD rats of either sex. However, high fat intake induced hyperleptinemia in MD rats as early as PND35, but not until PND85 in control males and control females did not become hyperleptinemic on the HFD even at PND102. High fat intake stimulated hypothalamic inflammatory markers in both male and female rats that had been exposed to MD, but not in controls. Reduced insulin sensitivity was observed only in MD males on the HFD. These results indicate that MD modifies the metabolic response to HFD intake, with this response being different between males and females. Thus, the development of obesity and secondary complications in response to high fat intake depends on numerous factors. Topics: Animals; Animals, Newborn; Blood Glucose; Body Weight; Diet, High-Fat; Eating; Environment; Female; Insulin; Leptin; Male; Maternal Deprivation; Neuropeptide Y; Obesity; Rats; Rats, Wistar; Sex Characteristics; Triglycerides; Weaning; Weight Gain | 2012 |
Helicobacter pylori colonization ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism.
There is an inverse secular trend between the incidence of obesity and gastric colonization with Helicobacter pylori, a bacterium that can affect the secretion of gastric hormones that relate to energy homeostasis. H. pylori strains that carry the cag pathogenicity island (PAI) interact more intimately with gastric epithelial cells and trigger more extensive host responses than cag(-) strains. We hypothesized that gastric colonization with H. pylori strains differing in cag PAI status exert distinct effects on metabolic and inflammatory phenotypes.. To test this hypothesis, we examined metabolic and inflammatory markers in db/db mice and mice with diet-induced obesity experimentally infected with isogenic forms of H. pylori strain 26695: the cag PAI wild-type and its cag PAI mutant strain 99-305. H. pylori colonization decreased fasting blood glucose levels, increased levels of leptin, improved glucose tolerance, and suppressed weight gain. A response found in both wild-type and mutant H. pylori strain-infected mice included decreased white adipose tissue macrophages (ATM) and increased adipose tissue regulatory T cells (Treg) cells. Gene expression analyses demonstrated upregulation of gastric PPAR γ-responsive genes (i.e., CD36 and FABP4) in H. pylori-infected mice. The loss of PPAR γ in immune and epithelial cells in mice impaired the ability of H. pylori to favorably modulate glucose homeostasis and ATM infiltration during high fat feeding.. Gastric infection with some commensal strains of H. pylori ameliorates glucose homeostasis in mice through a PPAR γ-dependent mechanism and modulates macrophage and Treg cell infiltration into the abdominal white adipose tissue. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; CD36 Antigens; Enzyme-Linked Immunosorbent Assay; Fatty Acid-Binding Proteins; Flow Cytometry; Gastric Mucosa; Gene Expression Profiling; Genomic Islands; Ghrelin; Helicobacter Infections; Helicobacter pylori; Homeostasis; Insulin; Leptin; Macrophages; Mice; Obesity; PPAR gamma; T-Lymphocytes, Regulatory | 2012 |
Incorporation of conjugated linoleic acid into brain lipids is not necessary for conjugated linoleic acid-induced reductions in feed intake or body fat in mice.
Dietary conjugated linoleic acid (CLA) causes reduced feed intake (FI) and body fat (BF). It is unknown, though, if CLA incorporation into tissues, alterations in serum hormones, and/or appetite-regulating neuropeptides are involved. We hypothesized that CLA incorporation into brain lipids would be correlated with changes in appetite-regulating neuropeptide expression and reductions in FI and BF. Male mice (n = 150; 9 weeks old, ICR) received the control diet ad libitum (CON), 2% CLA diet ad libitum (CLA), or control diet pair-fed to the intake of CLA-fed mice for 1, 2, 3, 5, or 7 days. Both FI and body weight were measured daily, and a BF index was calculated. Liver, adipose, and brain fatty acids; serum insulin, leptin, and peptide YY; and arcuate nucleus neuropeptide Y, agouti-related protein, and α-melanocyte-stimulating hormone protein were determined. Mice fed CLA ate less (P < .05) than did the CON on days 1, 2, 3, and 7 but were leaner (P < .05) only on day 7. Mice that received the control diet pair-fed to the intake of CLA-fed mice did not differ in BF from the CON. By days 1 and 2, CLA isomers were incorporated into the liver and adipose but not in the brain. Insulin was increased in CLA-fed mice on days 5 and 7, and leptin was decreased on day 7. Peptide YY and the neuropeptides did not differ. Tissue CLA was not correlated with FI, body weight, or BF but was positively correlated with insulin and negatively correlated with leptin. The reduction in FI is not sufficient to cause the reduction in BF, and tissue CLA accumulation does not appear to be required. Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Appetite Regulation; Body Weight; Brain; Diet; Dietary Fats; Energy Intake; Feeding Behavior; Insulin; Leptin; Linoleic Acids, Conjugated; Liver; Mice; Mice, Inbred ICR; Neuropeptides; Peptide YY | 2012 |
Anti-obesity effects of onion extract in Zucker diabetic fatty rats.
Anti-obesity effects of onion extract were determined in obesity and diabetes-prone Zucker diabetic fatty rats by measuring the efficacy of markers concerned with diabetes and obesity. Body and adipose tissue weights in 5% of onion extract-fed group were found to be significantly lower than the control group without onion extract. Fasting blood glucose and HOMA-IR levels were also improved, although the serum insulin and leptin levels did not show any remarkable difference. Serum triglyceride and free fatty acid levels in both the 3% and 5%-fed group were found to be reduced compared to the control group. Additionally the feeding of the onion extract increased the glucose tolerance. These results suggest that dietary onion extract is beneficial for improving diabetes by decreasing lipid levels. We also examined differentiation ability of rat white preadipocyte cells using the onion extract and its sulfur-containing components. Cycloalliin, S-methyl-L-cysteine, S-propyl-L-cysteine sulfoxide, dimethyl trisulfide, especially S-methyl-L-cysteine sulfoxide were reported to be effective in inhibiting formation of oil drop in the cells, suggesting that these compounds may be involved in the anti-obesity effect of the onion extract. Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cell Line; Diabetes Mellitus; Fatty Acids, Nonesterified; Glucose Intolerance; Hypolipidemic Agents; Insulin; Insulin Resistance; Leptin; Male; Obesity; Onions; Phytotherapy; Plant Extracts; Rats; Rats, Zucker; Triglycerides | 2012 |
Metabolic alterations and increased liver mTOR expression precede the development of autoimmune disease in a murine model of lupus erythematosus.
Although metabolic syndrome (MS) and systemic lupus erythematosus (SLE) are often associated, a common link has not been identified. Using the BWF1 mouse, which develops MS and SLE, we sought a molecular connection to explain the prevalence of these two diseases in the same individuals. We determined SLE- markers (plasma anti-ds-DNA antibodies, splenic regulatory T cells (Tregs) and cytokines, proteinuria and renal histology) and MS-markers (plasma glucose, non-esterified fatty acids, triglycerides, insulin and leptin, liver triglycerides, visceral adipose tissue, liver and adipose tissue expression of 86 insulin signaling-related genes) in 8-, 16-, 24-, and 36-week old BWF1 and control New-Zealand-White female mice. Up to week 16, BWF1 mice showed MS-markers (hyperleptinemia, hyperinsulinemia, fatty liver and visceral adipose tissue) that disappeared at week 36, when plasma anti-dsDNA antibodies, lupus nephritis and a pro-autoimmune cytokine profile were detected. BWF1 mice had hyperleptinemia and high splenic Tregs till week 16, thereby pointing to leptin resistance, as confirmed by the lack of increased liver P-Tyr-STAT-3. Hyperinsulinemia was associated with a down-regulation of insulin related-genes only in adipose tissue, whereas expression of liver mammalian target of rapamicyn (mTOR) was increased. Although leptin resistance presented early in BWF1 mice can slow-down the progression of autoimmunity, our results suggest that sustained insulin stimulation of organs, such as liver and probably kidneys, facilitates the over-expression and activity of mTOR and the development of SLE. Topics: Animals; Antibodies, Antinuclear; Biomarkers; Body Weight; Cytokines; Disease Models, Animal; Feeding Behavior; Female; Gene Expression Regulation; Humans; Insulin; Intra-Abdominal Fat; Leptin; Liver; Lupus Erythematosus, Systemic; Metabolic Syndrome; Mice; Proteinuria; TOR Serine-Threonine Kinases; Triglycerides | 2012 |
Effects of neonatal overfeeding on juvenile and adult feeding and energy expenditure in the rat.
Overfeeding during perinatal life leads to an overweight phenotype that persists throughout the juvenile stage and into adulthood, however, the mechanism(s) underlying this effect are poorly understood. We hypothesized that obesity due to neonatal overfeeding is maintained by changes in energy expenditure and that these changes differ between males and females. We investigated feeding, physical activity, hormonal and metabolic alterations that occur in adult rats made obese by having been nursed in small litters (SL) compared with those from control litters (CL). There were no differences in absolute food intake between the groups, and juvenile and adult SL rats ate less chow per gram body weight than the CL did in the dark (active) phase. Juvenile, but not adult SL rats did have reduced whole body energy expenditure, but there were no differences between the groups by the time they reached adulthood. Adult SL females (but not males) had reduced brown adipose tissue (BAT) temperatures compared with CL in the first half of the dark phase. Our results indicate a persistent overweight phenotype in rats overfed as neonates is not associated with hyperphagia at any stage, but is reflected in reduced energy expenditure into the juvenile phase. The reduced dark phase BAT activity in adult SL females is not sufficient to reduce total energy expenditure at this stage of life and there is an apparently compensatory effect that prevents SL and CL from continuing to diverge in weight that appears between the juvenile and adult stages. Topics: Adipose Tissue, Brown; Animals; Animals, Newborn; Body Composition; Body Weight; Eating; Energy Metabolism; Female; Hormones; Hyperphagia; Leptin; Male; Motor Activity; Obesity; Overnutrition; Random Allocation; Rats; Rats, Wistar; Time | 2012 |
Effects of enriched environment on COX-2, leptin and eicosanoids in a mouse model of breast cancer.
Cyclooxygenase-2 (COX-2) and adipokines have been implicated in breast cancer. This study investigated a possible link between COX-2 and adipokines in the development of mammary tumors. A model of environmental enrichment (EE), known to reduce tumor growth was used for a syngeneic murine model of mammary carcinoma. 3-week-old, female C57BL/6 mice were housed in standard environment (SE) or EE cages for 9 weeks and transplanted orthotopically with syngeneic EO771 adenocarcinoma cells into the right inguinal mammary fat pad. EE housing influenced mammary gland development with a decrease in COX-2 expressing cells and enhanced side-branching and advanced development of alveolar structures of the mammary gland. Tumor volume and weight were decreased in EE housed mice and were associated with a reduction in COX-2 and Ki67 levels, and an increase in caspase-3 levels. In tumors of SE mice, high COX-2 expression correlated with enhanced leptin detection. Non-tumor-bearing EE mice showed a significant increase in adiponectin levels but no change in those of leptin, F(2)-isoprostanes, PGF(2α), IL-6, TNF-α, PAI-1, and MCP-1 levels. Both tumor-bearing groups (SE and EE housing) had increased resistin, IL-6, TNF-α, PAI-1 and MCP-1 levels irrespective of the different housing environment demonstrating higher inflammatory response due to the presence of the tumor. This study demonstrates that EE housing influenced normal mammary gland development and inhibited mammary tumor growth resulting in a marked decrease in intratumoral COX-2 activity and an increase in the plasma ratio of adiponectin/leptin levels. Topics: Adipokines; Adiponectin; Animals; Body Composition; Body Weight; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 2; Eicosanoids; Environment; Female; Humans; Immunohistochemistry; Inflammation; Ki-67 Antigen; Leptin; Mammary Neoplasms, Animal; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Time Factors | 2012 |
Antiobesity effect of Safoof Mohazzil, a polyherbal formulation, in cafeteria diet induced obesity in rats.
Obesity is reaching epidemic proportions all over the world yet it lacks adequate treatment. Most of the drugs have failed either due to ineffectiveness or adverse effects. Complementary and alternative system of medicine is being used since ancient times. However, many of them have not been tested for efficacy and safety using modern scientific methods. Therefore, the antiobesity effect of Safoof Mohazzil, a polyherbal formulation, was evaluated in cafeteria diet induced obesity in female Sprague Dawley rats. Animals weighing 100-150 g were divided into four groups (n = 8) i.e. standard pellet diet, cafeteria diet control, cafeteria diet + Safoof Mohazzil and standard pellet diet plus Safoof Mohazzil. The formulation was administered orally at a dose of 1 g/kg/day for 14 weeks. At the end of study, cafeteria diet significantly increased body weight, Lee's index, lipid profile (cholesterol and triglycerides), insulin and leptin levels as compared to standard pellet diet control group. Fourteen week treatment with Safoof Mohazzil significantly prevented the increase in body weight, Lee's index, lipid profile, insulin and leptin levels as compared to cafeteria diet control group without affecting food and water intake. Safoof Mohazzil had no adverse effect on hepatic transaminases, locomotor activity and motor coordination. The study provides evidence for antiobesity effect of Safoof Mohazzil. Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Disease Models, Animal; Drinking; Eating; Female; Leptin; Motor Activity; Obesity; Plant Preparations; Rats; Rats, Sprague-Dawley | 2012 |
The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression.
Metformin demonstrates anorectic effects in vivo and inhibits neuropeptide Y expression in cultured hypothalamic neurons. Here we investigated the mechanisms implicated in the modulation of feeding by metformin in animals rendered obese by long-term high-fat diet (diet-induced obesity [DIO]) and in animals resistant to obesity (diet resistant [DR]). Male Long-Evans rats were kept on normal chow feeding (controls) or on high-fat diet (DIO, DR) for 6 months. Afterward, rats were treated 14 days with metformin (75 mg/kg) or isotonic sodium chloride solution and killed. Energy efficiency, metabolic parameters, and gene expression were analyzed at the end of the high-fat diet period and after 14 days of metformin treatment. At the end of the high-fat diet period, despite higher leptin levels, DIO rats had higher levels of hypothalamic neuropeptide Y expression than DR or control rats, suggesting a central leptin resistance. In DIO but also in DR rats, metformin treatment induced significant reductions of food intake accompanied by decreases in body weight. Interestingly, the weight loss achieved by metformin was correlated with pretreatment plasma leptin levels. This effect was paralleled by a stimulation of the expression of the leptin receptor gene (ObRb) in the arcuate nucleus. These data identify the hypothalamic ObRb as a gene modulated after metformin treatment and suggest that the anorectic effects of the drug are potentially mediated via an increase in the central sensitivity to leptin. Thus, they provide a rationale for novel therapeutic approaches associating leptin and metformin in the treatment of obesity. Topics: Agouti-Related Protein; Animals; Blood Glucose; Body Weight; Eating; Humans; Hypoglycemic Agents; Hypothalamus; Insulin; Leptin; Male; Metformin; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Random Allocation; Rats; Rats, Long-Evans; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA; Statistics, Nonparametric | 2011 |
Postnatal early overfeeding induces hypothalamic higher SOCS3 expression and lower STAT3 activity in adult rats.
Postnatal early overnutrition (EO) is a risk factor for future obesity and metabolic disorders. Rats raised in small litters (SLs) develop overweight, hyperphagia, hyperleptinemia, hyperinsulinemia and hypertension when adults. As obesity is related to hyperleptinemia, leptin resistance and metabolic syndrome, we aimed to investigate body composition, plasma hormone levels, glucose tolerance and the leptin signaling pathway in hypothalamus from early overfed animals at weaning and adulthood. To induce postnatal EO, we reduced litter size to three pups/litter (SL), and the groups with normal litter size (10 pups/litter) were used as control. Rats had free access to standard diet and water postweaning. Body weight and food intake were monitored daily, and offspring were killed at 21 (weaning) and 180 days old (adulthood). Postnatal EO group had higher body weight and total and visceral fat mass at both periods. Lean mass and serum high-density lipoprotein cholesterol (HDL-C) were higher at 21 days and lower at 180 days. Small litter rats presented higher levels of globulins at both periods, while albumin levels were higher at weaning and lower at adulthood. There was higher leptin, insulin and glucose serum concentrations at 21 days old, while no glucose intolerance was observed in adulthood. Leptin signaling pathway was unaffected at weaning. However, postnatal EO induced lower JAK2 and p-STAT3, and higher SOCS3 expression in adult animals, indicating central leptin resistance in adulthood. In conclusion, postnatal EO induces obesity, higher total and visceral fat mass, lower HDL-C and central leptin resistance in adult life. Topics: Animals; Body Composition; Body Weight; Cholesterol, HDL; Eating; Female; Hypothalamus; Insulin; Intra-Abdominal Fat; Leptin; Litter Size; Male; Obesity; Overnutrition; Rats; Rats, Wistar; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Weaning | 2011 |
BMI and metabolic profile in patients with prolactinoma before and after treatment with dopamine agonists.
Hyperprolactinemia might be related to weight gain, metabolic syndrome (MS), and insulin resistance (IR). Treatment with dopamine agonist (DA) has been shown to reduce body weight and improve metabolic parameters. The objectives of this study were to determine the prevalence of obesity, overweight, MS, and IR in patients with prolactinoma before and after therapy with DA and to evaluate the relation between prolactin (PRL), body weight, fat distribution, leptin levels, IR, and lipid profile before treatment. In addition, we investigated the correlation of the reduction in PRL levels with weight loss and metabolic profile improvement. Twenty-two patients with prolactinoma completed 6 months of treatment with DA. These patients were submitted to clinical (BMI, waist circumference, blood pressure (BP)), laboratory evaluation (leptin, glucose, low-density lipoprotein (LDL)-cholesterol, and triglyceride (TG) levels) and abdominal computed tomography (CT) before and after treatment. The statistical analyses were done by nonparametric tests. At the beginning of the study, the prevalence of obesity, overweight, MS, and IR was 45, 27, 27, and 18%, respectively. After 6 months of treatment with DA, PRL levels normalized, but no significant difference in BMI was observed. However, there was a significant decrease on homeostasis model assessment of insulin resistance (HOMA(IR)) index, glucose, LDL-cholesterol, and TG levels. This study suggests a possible involvement of prolactinoma on the prevalence of obesity. We should consider that DA may be effective on improving metabolic parameters, and we speculate that a period longer than 6 months of treatment is necessary to conclude whether this drug can interfere in the body weight of patients with prolactinoma. Topics: Adult; Aftercare; Aged; Blood Glucose; Body Composition; Body Mass Index; Body Weight; Bromocriptine; Cabergoline; Cholesterol, HDL; Cholesterol, LDL; Dopamine Agonists; Ergolines; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Metabolome; Middle Aged; Obesity; Prevalence; Prolactinoma; Waist Circumference; Weight Gain; Young Adult | 2011 |
Gastrodia elata Blume water extracts improve insulin resistance by decreasing body fat in diet-induced obese rats: vanillin and 4-hydroxybenzaldehyde are the bioactive candidates.
Insulin resistance is a common symptom of metabolic diseases such as obesity, type 2 diabetes and hyperlipidemia.. We investigated whether Gastrodia elata Blume water extract(GEB), containing phenolic compounds, had a beneficial action on insulin resistance in male Sprague-Dawley rats fed a high fat diet(HFD) and determined how this effect was produced. In addition, the bioactive candidates involved were identified.. Rats fed HFD were daily administered with 0.3 g GEB(GEB-L), 1 g GEB(GEB-H), or 1 g cellulose(control) per kg body weight for 8 weeks, while rats in the fourth group were fed a low fat diet(LFD). In vitro study, 4 major components of GEB were tested for their impact on fat accumulation.. Rats in the control group exhibited a higher weight gain of epididymal and retroperitoneal fat pads than those fed LFD, while GEB prevented such an increment in a dose-dependent manner. GEB-H significantly decreased energy intake partly through potentiating STAT3 phosphorylation and attenuating AMPK phosphorylation in the hypothalamus. GEB-H also increased energy expenditure with the increase in fat oxidation. GEB-H increased whole body glucose disposal rates and decreased hepatic glucose output compared to the control. Among the major components of GEB, 4-hydroxybenzaldehyde and vanillin decreased triglyceride accumulation by modulating the expression of genes involved in fat metabolism in 3T3-L1 adipocytes. They increased insulin-stimulated glucose uptake to reduce insulin resistance.. GEB-H, mainly as a result of the action of 4-hydroxybenzaldehyde and vanillin, reduces insulin resistance by decreasing fat accumulation in adipocytes by activating fat oxidation and potentiating leptin signaling in diet-induced obese rats. Topics: Adenylate Kinase; Adipose Tissue; Animals; Benzaldehydes; Body Weight; Cell Line; Diet, Fat-Restricted; Dietary Fats; Energy Intake; Energy Metabolism; Gastrodia; Glucose Tolerance Test; Hypothalamus; Insulin; Insulin Resistance; Leptin; Male; Mice; Obesity; Plant Extracts; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor | 2011 |
The influence of overweight and obesity on longitudinal trends in maternal serum leptin levels during pregnancy.
Maternal obesity influences a number of metabolic factors that can affect the course of pregnancy. Among these factors, leptin plays an important role in energy metabolism and fetal development during pregnancy. Our objective was to estimate the influence of maternal overweight/obesity on variation in the maternal serum leptin profile during pregnancy. In a prospective cohort of 143 adult gravidas with singleton pregnancies presenting for general prenatal care, we measured serum leptin levels at 6-10, 10-14, 16-20, 22-26, and 32-36 weeks' gestation. The longitudinal effects of maternal prepregnancy BMI, categorized as nonoverweight (≤ 26.0 kg/m(2)) and overweight/obese (>26.0 kg/m(2)), on serum leptin concentration were analyzed using linear mixed models. Overweight/obese women had significantly higher serum leptin concentrations than their nonoverweight counterparts throughout pregnancy (P < 0.01). Although these concentrations increased significantly across gestation for both groups, the rate of increase was significantly smaller for overweight/obese women (P < 0.05). To investigate whether these differences merely reflected differences in weight-gain patterns between the two groups, we examined an index of leptin concentration per unit body weight (leptin (ng/ml)/weight (kg)). Overweight/obese women had a significantly higher index throughout pregnancy (P < 0.01). However, although this index increased significantly across pregnancy for nonoverweight women, it actually decreased significantly for overweight/obese women (P < 0.01). Our results suggest that factors other than fat mass alone influence leptin concentrations in overweight/obese women compared to normal-weight women during pregnancy. Such factors may contribute to differences in the intrauterine environment and its influence on pregnancy outcomes in the two groups. Topics: Adult; Body Mass Index; Body Weight; Cohort Studies; Female; Gestational Age; Humans; Leptin; Linear Models; Longitudinal Studies; Obesity; Overweight; Pregnancy; Pregnancy Outcome; Pregnancy Trimesters; Prospective Studies; Thinness | 2011 |
The act of voluntary wheel running reverses dietary hyperphagia and increases leptin signaling in ventral tegmental area of aged obese rats.
To test the hypothesis that exercise increases central leptin signaling, and thus reduces dietary weight gain in an aged obese model, we assessed the effects of voluntary wheel running (WR) in 23-month-old F344×BN rats fed a 60% high-fat (HF) diet for 3 months. After 2 months on the HF diet, half of the rats were provided access to running wheels for 2 weeks while the other half remained sedentary. Following the removal of the wheels, physical performance was evaluated, and 4 weeks later leptin signaling was assessed in hypothalamus and VTA after an acute bout of WR. Introduction of a HF diet led to prolonged hyperphagia (63.9 ± 7.8 kcal/day on chow diet vs. 88.1 ± 8.2 kcal/day on high-fat diet (when food intake stabilized), p < 0.001). As little as 9 (ranging to 135) wheel revolutions per day significantly reduced caloric consumption of HF food (46.8 ± 11.2 kcal/day) to a level below that on chow diet (63.9 ± 7.8 kcal/day, p < 0.001). After 2 weeks of WR, body weight was significantly reduced (7.9 ± 2.1% compared with prerunning weight, p < 0.001), and physical performance (latency to fall from an incline plane) was significantly improved (p = 0.04). WR significantly increased both basal (p = 0.04) and leptin-stimulated (p = 0.001) STAT3 phosphorylation in the ventral tegmental area (VTA), but not in the hypothalamus. Thus, in aged dietary obese rats, the act but not the extent of voluntary WR is highly effective in reversing HF consumption, decreasing body weight, and improving physical performance. It appears to trigger a response that substitutes for the reward of highly palatable food that may be mediated by increased leptin signaling in the VTA. Topics: Age Factors; Aging; Animals; Body Weight; Dietary Fats; Disease Models, Animal; Feeding Behavior; Hyperphagia; Leptin; Male; Obesity; Physical Conditioning, Animal; Random Allocation; Rats; Rats, Inbred F344; Sensitivity and Specificity; Signal Transduction; Ventral Tegmental Area | 2011 |
Chronic stress, energy balance and adiposity in female rats.
Stress preferentially increases the consumption of high fat foods in women, suggesting the interaction of these two factors may disproportionately predispose women toward excess weight gain. In the present study, female rats were exposed to a chronic high fat or chow diet and were exposed to 4weeks of chronic variable stress (CVS) or served as home cage controls. Control females exposed to a high fat diet displayed many symptoms of the metabolic syndrome including increased body weight gain, total and visceral adiposity and insulin and leptin concentrations relative to all groups. However, CVS-high fat, CVS chow and control chow groups had similar body weight gain and caloric efficiency. This finding suggests that CVS increases energy expenditure much more in females exposed to a high fat diet relative to those fed a standard chow diet. The CVS-high fat group had increased adiposity and increased circulating leptin and insulin concentrations, despite the fact that their body weight did not differ from the controls. These results underscore the importance of assessing the degree of adiposity, rather than body weight alone, as an index of overall metabolic health. Overall, the data indicate that in female rats, chronic stress prevents high fat diet related increases in body weight, but does not prevent high fat diet induced increases in adiposity when compared to chow-fed females. Topics: Adiposity; Animals; Blood Glucose; Body Weight; Corticosterone; Dietary Fats; Energy Intake; Energy Metabolism; Female; Insulin; Leptin; Rats; Rats, Long-Evans; Stress, Psychological | 2011 |
Puberty is delayed in male mice with dextran sodium sulfate colitis out of proportion to changes in food intake, body weight, and serum levels of leptin.
In boys, inflammatory bowel disease often results in delayed puberty associated with decreased bone mineral density and decreased linear growth. Our goal was to investigate whether pubertal timing and levels of leptin differed between prepubertal male mice with colitis and food-restricted (FR) mice maintained at a similar weight. We induced colitis in 32-d-old male mice using dextran sodium sulfate (DSS), resulting in 10 d of worsening colitis. We followed up these mice for separation of the prepuce from the glans penis as a marker of pubertal progression. Compared with free-feeding control mice, DSS and FR mice had significantly lower weight on d 7-10 of treatment. DSS mice had later puberty than control and FR mice. DSS mice also had smaller testes, lower FSH levels, increased systemic cytokines, and increased colonic inflammation by histology. Leptin levels were similar between DSS and FR mice, whereas both had decreases in leptin compared with controls. We conclude that DSS colitis causes delayed puberty in sexually immature male mice beyond what is seen among FR mice of similar weight, food intake, and leptin levels. These experiments provide support for the hypothesis that pubertal delay in colitis is influenced by factors beyond poor weight gain alone. Topics: Analysis of Variance; Animals; Body Weight; Colitis; Dextran Sulfate; Enzyme-Linked Immunosorbent Assay; Follicle Stimulating Hormone; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Puberty, Delayed; Radioimmunoassay; Testis; Testosterone | 2011 |
F2-isoprostanes and adiposity in older adults.
We examined whether a systemic marker of oxidative stress, F(2)-isoprostanes (F(2)-IPs), was associated with total and regional adiposity, adipocytokines, and change in adiposity. Using data from 726 participants enrolled in the Health, Aging, and Body Composition (Health ABC) study, F(2)-IPs and adipocytokines were measured from baseline plasma samples. Total adiposity was measured by whole-body dual-energy X-ray absorptiometry and regional adiposity by abdominal and thigh computed tomography scans at baseline and 5-year follow-up. ANOVA models were estimated to examine associations between F(2)-IP tertiles and baseline adiposity and changes in body composition. Median F(2)-IPs was 54.3 pg/ml; women had significantly higher levels than men (61.5 vs. 48.9 pg/ml, P < 0.001). F(2)-IPs were associated with higher levels of adiponectin, leptin, and tumor necrosis factor-α (TNF-α). Positive associations were found between F(2)-IPs and all measures of total and regional adiposity among women. In linear regression models, adipocytokines mediated associations among women. Over 5 years of follow-up, women in the highest vs. lowest F(2)-IP tertile exhibited significant loss of weight (lowest tertile: -1.1 kg, highest tertile: -2.7 kg, P < 0.05). In conclusion, F(2)-IPs were associated with measures of total and regional adiposity in women alone and these associations were partially explained by adipocytokines. F(2)-IPs predicted loss of total adiposity over time among women. Topics: Absorptiometry, Photon; Adiponectin; Adipose Tissue; Adiposity; Aged; Analysis of Variance; Body Composition; Body Mass Index; Body Weight; F2-Isoprostanes; Female; Follow-Up Studies; Humans; Insulin; Leptin; Male; Tumor Necrosis Factor-alpha | 2011 |
High-carbohydrate high-fat diet–induced metabolic syndrome and cardiovascular remodeling in rats.
The prevalence of metabolic syndrome including central obesity, insulin resistance, impaired glucose tolerance, hypertension, and dyslipidemia is increasing. Development of adequate therapy for metabolic syndrome requires an animal model that mimics the human disease state. Therefore, we have characterized the metabolic, cardiovascular, hepatic, renal, and pancreatic changes in male Wistar rats (8-9 weeks old) fed on a high-carbohydrate, high-fat diet including condensed milk (39.5%), beef tallow (20%), and fructose (17.5%) together with 25% fructose in drinking water; control rats were fed a cornstarch diet. During 16 weeks on this diet, rats showed progressive increases in body weight, energy intake, abdominal fat deposition, and abdominal circumference along with impaired glucose tolerance, dyslipidemia, hyperinsulinemia, and increased plasma leptin and malondialdehyde concentrations. Cardiovascular signs included increased systolic blood pressure and endothelial dysfunction together with inflammation, fibrosis, hypertrophy, increased stiffness, and delayed repolarization in the left ventricle of the heart. The liver showed increased wet weight, fat deposition, inflammation, and fibrosis with increased plasma activity of liver enzymes. The kidneys showed inflammation and fibrosis, whereas the pancreas showed increased islet size. In comparison with other models of diabetes and obesity, this diet-induced model more closely mimics the changes observed in human metabolic syndrome. Topics: Abdominal Fat; Animals; Body Weight; Diabetes Mellitus, Experimental; Dietary Carbohydrates; Dietary Fats; Energy Intake; Fructose; Glucose Intolerance; Humans; Hypertension; Inflammation; Insulin Resistance; Leptin; Liver; Male; Metabolic Syndrome; Obesity; Random Allocation; Rats; Rats, Wistar; Ventricular Remodeling | 2011 |
Association between the FTO rs9939609 polymorphism and leptin in European adolescents: a possible link with energy balance control. The HELENA study.
We examined the association between the FTO rs9939609 polymorphism and serum leptin concentrations in adolescents. The FTO rs9939609 polymorphism was genotyped, and fasting serum leptin and insulin were measured in 655 European adolescents (365 females) aged 14.6 ± 1.2 years. We measured weight, height, triceps and subscapular skinfolds and waist circumference, and body fat percentage was calculated. Sex, pubertal status, center, physical activity (accelerometry), total or central adiposity and serum insulin concentrations were entered as confounders in the analyses. The minor A allele of the FTO rs9939609 was significantly associated with higher serum leptin concentrations independently of potential confounders including adiposity (+3.9 ng ml(-1) per risk allele (95% confidence interval: 2.0, 5.9); adjusted P < 0.001). These findings could link the FTO gene with serum leptin and consequently with the control of energy balance. Leptin could be a possible intermediary contributing to the association between the FTO rs9939609 polymorphism and adiposity. Topics: Adiposity; Adolescent; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Body Mass Index; Body Weight; Energy Intake; Energy Metabolism; Female; Genotype; Humans; Leptin; Male; Motor Activity; Nutrition Surveys; Polymorphism, Genetic; Proteins; Sex Distribution; Waist Circumference; White People | 2011 |
Leptin augments cerebral hemodynamic reserve after three-vessel occlusion: distinct effects on cerebrovascular tone and proliferation in a nonlethal model of hypoperfused rat brain.
The adipocytokine leptin has distinct functions regulating vascular tone, inflammation, and collateral artery growth. Arteriogenesis is an inflammatory process and provides a mechanism to overcome the effects of vascular obstruction. We, therefore, tested the effects of leptin in hypoperfused rat brain (three-vessel occlusion). Systemic leptin administration for 1 week after occlusion surgery increased cerebral hemodynamic reserve similar to granulocyte-macrophage colony-stimulating factor (GM-CSF), as indicated by improved CO(2) reactivity (vehicle 0.53%±0.26% versus leptin 1.05%±0.6% per mm Hg arterial pCO(2), P<0.05). Infusion of microspheres under maximal vasodilation failed to show a positive effect of leptin on cerebral perfusion (vehicle 64.9%±4.5% versus leptin 66.3%±7.0%, occluded/nonoccluded hemisphere). Acute treatment with GM-CSF led to a significant increased CO(2) reactivity and cerebral perfusion (79.2%±8.1% versus 64.9%±4.5%, P<0.05). Vasoconstrictive response of isolated rat carotid artery rings, after phenylephrine was attenuated at 24 hours following preincubation with leptin, was unaffected by removal of endothelium but abrogated by coculture with N-(omega)-nitro-L-arginine methylester, pointing toward an inducible nitric oxide synthase-mediated mechanism. In chronic cerebral hypoperfusion, acute leptin treatment restored the hemodynamic reserve of the cerebral vasculature through its effects on vascular tone, while leaving vascular outward remodeling unaffected. Our results, for the first time, reveal a protective role of leptin on vascular function in hemodynamically compromised brain tissue. Topics: Animals; Anterior Cerebral Artery; Body Weight; Carbon Dioxide; Carotid Arteries; Cell Proliferation; Cerebrovascular Circulation; Cerebrovascular Disorders; Granulocyte-Macrophage Colony-Stimulating Factor; Hemodynamics; Leptin; Male; Monocytes; Muscle Tonus; Muscle, Smooth, Vascular; Neovascularization, Physiologic; Nitric Oxide Synthase Type II; Oxygen Consumption; Phenylephrine; Posterior Cerebral Artery; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents | 2011 |
Intracerebroventricular leptin administration differentially alters cardiac energy metabolism in mice fed a low-fat and high-fat diet.
Leptin directly acts on peripheral tissues and alters energy metabolism in obese mice. It also has acute beneficial effects on these tissues via its hypothalamic action. However, it is not clear what effect chronic intracerebroventrical (ICV) leptin administration has on cardiac energy metabolism. We examined the effects of chronic ICV leptin on glucose and fatty acid metabolism in isolated working hearts from high-fat-fed and low-fat-fed mice. Mice were fed a high-fat (60% calories from fat) or low-fat (10% calories from fat) diet for 8 weeks before ICV leptin (5 [mu]g/d) for 7 days. In low-fat-fed mice, leptin increased glucose oxidation rates in isolated working hearts when compared with control [203 +/- 21 vs. 793 +/- 93 nmol[middle dot](g dry weight)-1[middle dot]min-1]. In high-fat-fed mice leptin inhibited fatty acid oxidation [476 +/- 73 vs. 251 +/- 38 nmol[middle dot](g[middle dot]dry[middle dot]wt)-1[middle dot]min-1]. The increase in glucose oxidation in low-fat-fed mice was accompanied by increased pyruvate dehydrogenase activity. In high-fat-fed mice, leptin increased cardiac malonyl coenzyme A levels, secondary to a decrease in malonyl coenzyme A decarboxylase expression. These results suggest that ICV leptin alters cardiac energy metabolism opposite to its peripheral effects and that these effects differ depending on energy substrate supply to the mice. Topics: Animals; Body Weight; Carboxy-Lyases; Dietary Fats; Energy Intake; Energy Metabolism; Glucose; Hypothalamus; Infusions, Intraventricular; Leptin; Lipid Metabolism; Male; Malonyl Coenzyme A; Mice; Mice, Inbred C57BL; Mice, Obese; Myocardium; Obesity; Oxidation-Reduction; Random Allocation | 2011 |
Leptin regulates energy balance and motivation through action at distinct neural circuits.
Overconsumption of calorically dense foods contributes substantially to the current obesity epidemic. The adiposity hormone leptin has been identified as a potential modulator of reward-induced feeding. The current study asked whether leptin signaling within the lateral hypothalamus (LH) and midbrain is involved in effort-based responding for food rewards and/or the modulation of mesolimbic dopamine.. The contribution of endogenous leptin signaling for food motivation and mesolimbic dopamine tone was examined after viral-mediated reduction of the leptin receptor within LH and midbrain neurons in male rats.. Knockdown of leptin receptors selectively in the LH caused increased body weight, caloric consumption, and body fat in rats maintained on a calorically dense diet. Knockdown of leptin receptors selectively in midbrain augmented progressive ratio responding for sucrose and restored high-fat, diet-induced suppression of dopamine content in the nucleus accumbens.. In summary, endogenous leptin signaling in the hypothalamus restrains the overconsumption of calorically dense foods and the consequent increase in body mass, whereas leptin action in the midbrain regulates effort-based responding for food rewards and mesolimbic dopamine tone. These data highlight the ability of leptin to regulate overconsumption of palatable foods and food motivation through pathways that mediate energy homeostasis and reward, respectively. Topics: Animals; Body Weight; Brain; Conditioning, Operant; Dietary Fats; Dopamine; Energy Metabolism; Green Fluorescent Proteins; Leptin; Male; Motivation; Neural Pathways; Rats; Rats, Long-Evans; Receptors, Leptin; RNA, Small Interfering; STAT3 Transcription Factor | 2011 |
Obesity/hyperleptinemic phenotype adversely affects hippocampal plasticity: effects of dietary restriction.
Epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese and there is a growing appreciation that obesity affects the functional integrity of the central nervous system (CNS). We recently developed a lentivirus (LV) vector that produces an insulin receptor (IR) antisense RNA sequence (IRAS) that when injected into the hypothalamus selectively decreases IR signaling in hypothalamus, resulting in increased body weight, peripheral adiposity and plasma leptin levels. To test the hypothesis that this obesity/hyperleptinemic phenotype would impair hippocampal synaptic transmission, we examined short term potentiation (STP) and long term potentiation (LTP) in the hippocampus of rats that received the LV-IRAS construct or the LV-Control construct in the hypothalamus (hypo-IRAS and hypo-Con, respectively). Stimulation of the Schaffer collaterals elicits STP that develops into LTP in the CA1 region of hypo-Con rats; conversely, hypo-IRAS rats exhibit STP that fails to develop into LTP. To more closely examine the potential role of hyperleptinemia in these electrophysiological deficits, hypo-IRAS were subjected to mild food restriction paradigms that would either: 1) prevent the development of the obesity phenotype; or 2) reverse an established obesity phenotype in hypo-IRAS rats. Both of these paradigms restored LTP in the CA1 region and reversed the decreases in the phosphorylated/total ratio of GluA1 Ser845 AMPA receptor subunit expression observed in the hippocampus of hypo-IRAS rats. Collectively, these data support the hypothesis that obesity impairs hippocampal synaptic transmission and support the hypothesis that these deficits are mediated through the impairment of hippocampal leptin activity. Topics: Adiposity; Animals; Area Under Curve; Autoradiography; Body Weight; Corticosterone; Disease Models, Animal; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Food Deprivation; Hippocampus; Hypothalamus; In Vitro Techniques; Insulin; Leptin; Long-Term Potentiation; Male; Obesity; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Receptors, AMPA; RNA, Antisense; Serine | 2011 |
Npc1 haploinsufficiency promotes weight gain and metabolic features associated with insulin resistance.
A recent population-based genome-wide association study has revealed that the Niemann-Pick C1 (NPC1) gene is associated with early-onset and morbid adult obesity. Concurrently, our candidate gene-based mouse growth study performed using the BALB/cJ NPC1 mouse model (Npc1) with decreased Npc1 gene dosage independently supported these results by suggesting an Npc1 gene-diet interaction in relation to early-onset weight gain. To further investigate the Npc1 gene in relation to weight gain and metabolic features associated with insulin resistance, we interbred BALB/cJ Npc1(+/-) mice with wild-type C57BL/6J mice, the latter mouse strain commonly used to study aspects of diet-induced obesity and insulin resistance. This breeding produced a hybrid (BALB/cJ-C57BL/6J) Npc1(+/-) mouse model with increased susceptibility to weight gain and insulin resistance. The results from our study indicated that these Npc1(+/-) mice were susceptible to increased weight gain characterized by increased whole body and abdominal adiposity, adipocyte hypertrophy and hepatic steatosis in the absence of hyperphagia. Moreover, these Npc1(+/-) mice developed abnormal metabolic features characterized by impaired fasting glucose, glucose intolerance, hyperinsulinemia, hyperleptinemia and dyslipidemia marked by an increased concentration of cholesterol and triacylglycerol associated with low-density lipoprotein and high-density lipoprotein. The overall results are consistent with a unique Npc1 gene-diet interaction that promotes both weight gain and metabolic features associated with insulin resistance. Therefore, the NPC1 gene now represents a previously unrecognized gene involved in maintaining energy and metabolic homeostasis that will contribute to our understanding concerning the current global epidemic of obesity and type 2 diabetes mellitus. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Diet; Disease Models, Animal; Fatty Liver; Haploinsufficiency; Humans; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Leptin; Magnetic Resonance Imaging; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Niemann-Pick C1 Protein; Proteins; Triglycerides; Weight Gain | 2011 |
Novel porcine housekeeping genes for real-time RT-PCR experiments normalization in adipose tissue: assessment of leptin mRNA quantity in different pig breeds.
The main function of adipose tissue is energy storage and production of various cytokines and hormones, such as leptin. Leptin is a protein hormone synthesized and secreted by adipose tissue. The expression of leptin is strongly dependent on growth and luteinizing hormones, which play an important role in the brain-pituitary axis. The concentration of leptin in blood plasma increases with age and obesity and is associated with the level of leptin mRNA in adipose tissue. Selection of appropriate internal control gene (ICG) for normalization of quantitative PCR data for genes of interest is critical for interpretation of results. The estimation of leptin mRNA is important in the research on regulation of feed intake and metabolic and energy balance. Therefore, the objective of this study was to evaluate the stability of mRNA expression for a number of candidate housekeeping genes in the porcine backfat tissue across different breeds. In our study we used a freeware computer program (geNorm) to evaluate the most stable among eight ICG genes (β-actin, hypoxanthine phosphoribosyltransferase 1, TATA binding protein, glyceraldehyde-3-phosphate dehydrogenase, ornithine decarboxylase antizyme 1, 60S ribosomal protein L27, 40S ribosomal protein S29, eukaryotic elongation factor (1) in 90 mRNA samples of backfat tissue. In the study we used three breeds differing in muscling: Polish Large White (n=30), Polish Landrace (n=30) and Pietrain (n=30). The results showed that the three most stable genes were ornithine decarboxylase antizyme 1 (OAZ1), 60S ribosomal protein L27 (RPL27) and β-actin (M=0.579, 0.602 and 0.607, respectively). In order to evaluate the abundance of leptin mRNA, the two most stable genes were used. The highest level of mRNA expression was obtained for PL and the lowest for Pietrain pigs. These results confirmed previous studies which showed that pigs with lean carcass were characterized by a lower level of leptin transcript compared to pigs with large fat deposit. Moreover, we analyzed relationship between C3469T Lep polymorphism and level of leptin mRNA, but did not find significant associations. Our study provides a new panel of housekeeping genes for normalization of the expression of a gene of interest in adipose tissue. Topics: Actins; Animals; Body Weight; Diet; Female; Gene Expression Regulation; Leptin; Polymorphism, Single Nucleotide; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal Proteins; RNA, Messenger; Species Specificity; Subcutaneous Fat, Abdominal; Sus scrofa | 2011 |
Weight loss induced by rimonabant is associated with an altered leptin expression and hypothalamic leptin signaling in diet-induced obese mice.
This study investigates the molecular mechanisms and the center-periphery cross talk underlying the anti-obesity effect of the cannabinoid receptor 1 (CB(1)) antagonist/inverse agonist rimonabant in diet-induced obese (DIO) mice exposed to a 31 days chronic treatment with the drug. Present data showed a significant and stable weight loss both in animals treated with rimonabant 10mg/kg by oral gavage exposed to a high fat diet (SRFD) and in vehicle treated mice switched to a regular chow (VEND) with respect to vehicle fat diet fed mice (VEFD). Caloric intake was significantly lowered in SRFD and VEND during the first two and four days, respectively, then reaching the VEFD consume throughout the treatment. The drop of body weight was accompanied by leptin mRNA decrease in visceral fat tissue both in VEND and SRFD, as revealed by Real time PCR analysis. No difference in CB(1) mRNA receptor expression in hypothalamus and in visceral fat tissue among groups was observed. Leptin receptors were decreased in the hypothalamus of SRFD but not of VEND mice. Moreover, in SRFD and VEND mice the expression of orexigenic genes Neuropeptide Y and Agouti Related Protein (AGRP) was increased, while anorexigenic ones, Pro-OpioMelanoCortin (POMC) and Cocaine-and-Amphetamine-Regulated Transcript (CART) displayed no alteration in any group. This data contribute to clarify the molecular basis of the anti-obesity properties of rimonabant, underlying the role of the peripheral modulators which affect central circuits involved in the regulation of food intake and energy homeostasis. Topics: Analysis of Variance; Animals; Body Weight; Diet; Disease Models, Animal; Gene Expression Regulation; Hypothalamus; Leptin; Mice; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; Signal Transduction | 2011 |
High-fat diets impair spatial learning in the radial-arm maze in mice.
It has been suggested that hyperglycemia and insulin resistance triggered by energy-dense diets can account for hippocampal damage and deficits of cognitive behaviour. We wonder if the impairment of learning and memory processes detected in diet-induced obese (DIO) mice is linked to diet composition itself. With this purpose we have evaluated learning performance in mice undergoing a short-term high-fat (HF) treatment, which leads to a pre-obese state characterized by increased adiposity without significant changes of glucose and insulin plasma levels. C57BL/6J mice were fed either a HF (45 kcal% from fat) or control diet (10 kcal% from fat) during 8 weeks. Learning performance was evaluated by using the four-arm baited version of the eight-arm radial maze test (RAM). Mice were trained to learn the RAM protocol and then memory was tested at different time-points. Time spent to consume food placed in baited arms and errors committed to find them were measured in all sessions. DIO mice significantly spent more time in learning the task and made a greater number of errors than controls. Moreover, retention tests revealed that both working and total memory errors were also more numerous in DIO mice. The current results show that short-term DIO impairs spatial learning and suggest that impairment of hippocampal learning elicited by HF diets might be perceptible before metabolic alterations linked to obesity develop. Topics: Adiposity; Analysis of Variance; Animals; Body Weight; Diet; Dietary Fats; Eating; Insulin; Leptin; Male; Maze Learning; Mice; Obesity; Radioimmunoassay; Space Perception; Spatial Behavior | 2011 |
Development and characterization of high affinity leptins and leptin antagonists.
Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin. Topics: Amino Acid Substitution; Animals; Body Weight; Eating; HEK293 Cells; Humans; Leptin; Male; Mice; Mutagenesis; Mutation, Missense; Polyethylene Glycols; Protein Binding; Receptors, Leptin | 2011 |
Effects of leptin infusion during peak lactation on food intake, body composition, litter growth, and maternal neuroendocrine status in female Brandt's voles (Lasiopodomys brandtii).
During lactation, female small mammals frequently reduce their fat reserves to very low levels. The function of this reduction is unclear, as calculations suggest that the contribution of the withdrawn energy from fat to the total energy balance of lactation is trivial. An alternative hypothesis is that reducing fat leads to a reduction in circulating adipokines, such as leptin, that play a role in stimulating the hyperphagia of lactation. We investigated the role of circulating leptin in lactation by repleting leptin levels using miniosmotic pumps during the last 7 days of lactation in Brandt's voles (Lasiopodomys brandtii), a model small wild mammal we have extensively studied in the context of lactation energy demands. Repletion of leptin resulted in a dose-dependent reduction of body mass and food intake in lactating voles. Comparisons to nonreproducing individuals suggests that the reduced leptin in lactation, due to reduced fat stores, may account for ∼16% of the lactational hyperphagia. Reduced leptin in lactation may, in part, cause lactational hyperphagia via stimulatory effects on hypothalamic orexigenic neuropeptides (neuropeptide Y and agouti-related peptide) and inhibition of the anorexigenic neuropeptide (proopiomelanocortin). These effects were reversed by the experimental repletion of leptin. There was no significant effect of leptin treatment on daily energy expenditure, milk production or pup growth, but leptin repletion did result in a reversal of the suppression of uncoupling protein-1 levels in brown adipose tissue, indicating an additional role for reducing body fat and leptin during peak lacation. Topics: Adipose Tissue; Adipose Tissue, Brown; Agouti-Related Protein; Animal Structures; Animals; Animals, Suckling; Arvicolinae; Body Composition; Body Weight; Eating; Energy Intake; Energy Metabolism; Female; Gene Expression; Hypothalamus; Ion Channels; Lactation; Leptin; Liver; Mitochondrial Proteins; Neuropeptide Y; Neurosecretory Systems; Organ Size; Pro-Opiomelanocortin; Uncoupling Protein 1 | 2011 |
A high-protein neonatal formula induces a temporary reduction of adiposity and changes later adipocyte physiology.
The high-protein content of formula offered to low-birth weight babies is suspected to increase the risk of obesity later in life. This study assesses the immediate and subsequent effects of a protein intake in excess during suckling on hormonal and metabolic status and adipose tissue features in a porcine model of intrauterine growth restriction. Piglets were fed milk replacers formulated to provide an adequate (AP) or a high (HP) protein supply from day 2 to day 28. A subset of piglets was killed at day 28. After weaning, the remaining piglets had free access to the same solid high-fat diet until day 160. From day 2 to day 28, HP piglets had a greater daily weight gain (P < 0.05). Relative weight of perirenal adipose tissue (PAT), adipocyte mean diameters, activities of lipogenic enzymes in PAT and subcutaneous adipose tissue (SCAT), and leptinemia were lower (P < 0.05) in HP piglets than in AP piglets. Genes related to glucose utilization and lipid anabolism in PAT and SCAT were (P < 0.05) or tended (P < 0.1) to be downregulated in HP piglets. At day 160, adipocytes were enlarged, whereas lipogenic rates in adipocytes were reduced (P < 0.05) in SCAT of HP compared with AP pigs. Percent body fat, mRNA levels of genes controlling lipid metabolism, and plasma concentrations of hormones and metabolites were similar in HP and AP pigs. In conclusion, a HP neonatal formula induced a temporary reduction of adiposity and changed adipocyte physiology at peripubertal age. Topics: Adipocytes; Adipose Tissue; Adiposity; Animals; Animals, Newborn; Body Composition; Body Weight; Carbohydrate Metabolism; Dietary Proteins; DNA; Eating; Enzymes; Fatty Acid Synthases; Female; Food, Formulated; Gene Expression; Glucose; Insulin; Leptin; Lipid Metabolism; Lipids; Malate Dehydrogenase; Male; Proteins; Sus scrofa | 2011 |
Ablation of Sax2 gene expression prevents diet-induced obesity.
Regulation of energy homeostasis is mainly mediated by factors in the hypothalamus and the brainstem. Understanding these regulatory mechanisms is of great clinical relevance in the treatment of obesity and related diseases. The homeobox gene Sax2 is expressed predominantly in the brainstem, in the vicinity of serotonergic neurons, and in the ventral neural tube starting during early development. Previously, we have shown that the loss of function of the Sax2 gene in mouse causes growth retardation starting at birth and a high rate of postnatal lethality, as well as a dramatic metabolic phenotype. To further define the role of Sax2 in energy homeostasis, age-matched adult wild-type, Sax2 heterozygous and null mutant animals were exposed to a high-fat diet. Although food uptake among the different groups was comparable, Sax2 null mutants fed a high-fat diet exhibited a significantly lower weight gain compared to control animals. Unlike their counterparts, Sax2 null mutants did not develop insulin resistance and exhibited significantly lower leptin levels under both standard chow and high-fat diet conditions. Furthermore, neuropeptide Y, an important regulator of energy homeostasis, was significantly decreased in the forebrain of Sax2 null mutants on a high-fat diet. These data strongly suggest a critical role for Sax2 gene expression in diet-induced obesity. Sax2 gene expression may be required to allow the coordinated crosstalk of factors involved in the maintenance of energy homeostasis, possibly regulating the transcription of specific factors involved in energy balance. Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Blood Glucose; Body Temperature; Body Weight; Brain; Dietary Fats; Eating; Energy Metabolism; Female; Gene Expression; Glycogen; Heterozygote; Homeodomain Proteins; Insulin; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Neuropeptide Y; Nuclear Proteins; Obesity; Pro-Opiomelanocortin; Serotonin; Sex Characteristics; Transcription Factors | 2011 |
Blood pressure characteristics of female spontaneously diabetic Torii-Lepr(fa) rats.
Blood pressure in female SDT-fa/fa rats was periodically investigated at ages 8, 16, and 24 weeks. Furthermore, an insulin therapy was performed for 5 weeks in the female rats at age 11 weeks, and the change of blood pressure was examined. In addition to obesity, hyperglycemia, hyperinsulinemia, and hyperlipidemia, hyperleptinemia and increased urinary angiotensinogen level were observed during the experimental period. Blood pressure was elevated at ages 8 and 16 weeks, but that at 24 weeks was comparable to that in Sprague-Dawley (SD) rats. Heart rate was decreased from age 8 to 24 weeks. Insulin therapy induced good glycemic control and improvement of hyperlipidemia, but the blood pressure was not reduced. Blood pressure in female SDT-fa/fa rats was elevated temporarily. The blood pressure was not decreased by insulin treatment. SDT-fa/fa rat is a useful model to investigate the relation between diabetes mellitus and hypertension. Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Diabetes Mellitus; Female; Insulin; Leptin; Rats; Rats, Sprague-Dawley; Triglycerides | 2011 |
Body weight decreases induced by estradiol in female rhesus monkeys are dependent upon social status.
Gonadal steroids regulate appetite and thus body weight. In addition, continuous exposure to stressors negatively influences appetite through circuits likely distinct from those of gonadal steroids. The occurrence of adverse metabolic consequences due to chronic exposure to psychosocial stressors is twice as frequent in women as men, implicating a role for ovarian hormones, estradiol (E2) and progesterone (P4), in modulating stress-induced changes in appetite. Using social subordination in female macaques as a model of social stress, the current study tested the hypothesis that subordinate females would lose more weight during E2 treatment and gain less weight during P4 administration than dominant females. Because polymorphisms in the gene encoding the serotonin transporter (5HTT; SCL6A4) are known to alter responsivity to stress, we hypothesized that weight loss during E2 administration would be greatest in females with the short variant (s-variant) allele of 5HTT. Dominant females were significantly heavier than subordinate animals throughout the study, a result consistent with previous accounts of food intake when animals are fed a low-fat, high-fiber diet. Females with the s-variant 5HTT genotype weighed significantly less than l/l animals. Dominant animals lost significantly more weight than subordinate animals during E2 treatment. Administration of P4 blocked the weight-reducing effects of E2 in all females, regardless of social status. These data provide evidence that social subordination modulates the influence of ovarian steroid hormones on body weight in female rhesus monkeys independent of 5HTT genotype. Given the prosocial effects of these steroids, future studies are necessary to determine whether status differences in E2-induced weight loss are due to diminished food intake and or increases in energy expenditure and how the change in energy availability during E2 treatments relates to a female's motivation to interact with conspecifics. Topics: Alleles; Animals; Body Weight; Eating; Estradiol; Female; Genotype; Leptin; Macaca mulatta; Ovariectomy; Polymorphism, Genetic; Progesterone; Radioimmunoassay; Serotonin Plasma Membrane Transport Proteins; Social Dominance; Social Environment; Stress, Psychological | 2011 |
Central infusion of leptin does not increase AMPK signaling in skeletal muscle of sheep.
In sheep, central leptin infusion reduces food intake and increases energy expenditure in adipose tissue and skeletal muscle. The mechanisms for these peripheral effects of central leptin in sheep are not known but, on the basis of rodent studies, may involve AMPK. In mice, central leptin acutely increases both skeletal muscle AMPK activation and glucose uptake. Thus, to investigate whether these effects exist in higher-order mammals, ovariectomized Corriedale ewes (n = 4 per group) received a continuous lateral ventricular infusion (60 μl/h) of either leptin (50 μg/h) or artificial cerebrospinal fluid (aCSF; CON) for 8 days. Tritiated glucose (3-(3)H-glucose) was infused intravenously for calculation of whole body glucose turnover during both acute (6 h) and chronic (7-8 days) leptin/aCSF infusion. Muscle biopsies were also obtained. Leptin infusion reduced (P < 0.05) food intake and body weight, and it also increased plasma epinephrine concentration at 6 h and 7 days, suggesting increased sympathetic nerve activity. Despite this, and in contrast to rodent studies, central leptin infusion did not increase skeletal muscle AMPKα Thr(172) phosphorylation or ACCβ Ser(221) phosphorylation. Surprisingly, the glucose rate of appearance (glucose Ra) and rate of disappearance (glucose Rd) were reduced by both acute and chronic leptin infusion. Direct infusion of the AMPK activator 5-aminoimidazole-4-carboxyamide-ribonucleoside (AICAR) into the femoral artery increased skeletal muscle AMPK phosphorylation. In conclusion, although central leptin infusion in sheep caused the predicted reduction in food intake and increases plasma epinephrine concentration, it had no effect on AMPK activation in skeletal muscle and actually reduced glucose disposal. This suggests that there are species differences in the peripheral responses to central leptin infusion. Topics: Acetyl-CoA Carboxylase; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animal Structures; Animals; Blood Glucose; Body Weight; Catecholamines; Eating; Fatty Acids, Nonesterified; Female; Glycerol; Glycogen; Growth Hormone; Hydrocortisone; Hypoglycemic Agents; Infusions, Intra-Arterial; Infusions, Intraventricular; Insulin; Leptin; Liver; Muscle, Skeletal; Ovariectomy; Phosphorylation; Protein Subunits; Ribonucleotides; Sheep; Signal Transduction; Subcutaneous Fat | 2011 |
Role of adiponectin in the development of high fat diet-induced metabolic abnormalities in mice.
The adipokine adiponectin is decreased in severe obesity and is inversely associated with adipose mass. Adiponectin is associated with insulin sensitivity and cardioprotection. Obesity frequently results in the development of a "cardiometabolic syndrome" characterized by increased circulating insulin and leptin, and cardiac hypertrophy and dysfunction. This study examined if adiponectin-deficiency affects the development of metabolic and cardiac abnormalities in response to modest obesity. Mice were studied under normal conditions and with mild cardiac pressure-overload induced by abdominal aortic banding. After surgery, wild type and adiponectin-deficient mice were fed a high-fat diet for 8 weeks (45% energy from fat vs. 10%). In wild type mice the high-fat diet increased fat and whole body mass, which corresponded with elevated circulating insulin and leptin and a decrease the glucose/insulin ratio. On the other hand, in adiponectin-deficient mice the high-fat diet had less impact on body mass and no effect on fat mass, insulin, leptin, or glucose/insulin. There was modest cardiac hypertrophy with aortic banding, but no cardiac dysfunction or effects of adiponectin deficiency or diet. The results suggest that the increase in adipose mass, leptin and insulin induced by a high fat diet is dependent on adiponectin. The lack of accelerated cardiac hypertrophy and dysfunction in the adiponectin-deficient mice subjected to aortic banding and the high-fat diet suggest that adiponectin may not play a major role in protecting the heart during the early stages of diet-induced obesity. Topics: Adiponectin; Adipose Tissue; Animals; Blood Pressure; Body Weight; Cardiovascular Diseases; Dietary Fats; Disease Models, Animal; Female; Humans; Insulin; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity | 2011 |
Combined amylin-leptin treatment lowers blood pressure and adiposity in lean and obese rats.
To examine the cardiovascular effects of combined amylin (AMN) and leptin (LEP) treatment in lean and obese rats.. Rats were instrumented for telemetry and given LEP (300 μg kg(-1) day(-1)), AMN (100 μg kg(-1) day(-1)), AMN+LEP or vehicle (VEH; 0.9% normal saline) via a subcutaneous mini-osmotic pump for 7 days. The VEH group was subdivided into ad libitum fed and pair-fed to the amount of food AMN+LEP animals ate daily. Rats were housed in metabolic chambers for analysis of cardiovascular physiology and metabolism.. Male Fisher 344 × Brown Norway (FBNF1; Harlan; age=3-5 months; n=72) rats were placed on standard rodent chow (LEAN, n=41) or moderately high-fat diet (OBESE; n=31) to produce obesity.. AMN+LEP potently reduced food intake (LEAN: 57% OBESE: 59%) and abdominal fat mass (LEAN: 56% OBESE: 41%). Pair-fed rats displayed bradycardia and metabolic suppression. In contrast, AMN+LEP increased heart rate and oxygen consumption above levels in LEP or AMN-treated rats. LEP reduced blood pressure in both lean and obese rats but AMN had no effect. LEP-induced reductions in blood pressure were not altered by AMN+LEP treatment. Thus, AMN+LEP treatment decreased food intake, body fat and blood pressure in lean and obese rats.. We conclude that the potent anti-adiposity actions of AMN+LEP are due in part to prevention of the bradycardia and metabolic suppression typically observed with negative energy balance. Furthermore, the hypotensive actions of peripheral LEP treatment are observable in spite of the potent AMN+LEP activation of anorexic and thermogenic mechanisms in the central nervous system. Topics: Adiposity; Animals; Blood Pressure; Body Weight; Dietary Fats; Eating; Energy Metabolism; Heart Rate; Islet Amyloid Polypeptide; Leptin; Male; Rats; Rats, Inbred F344 | 2011 |
Ghrelin, leptin and adiponectin as possible predictors of the hedonic value of odors.
Several lines of evidence point to a close relationship between the hormones of energy homeostasis and the olfactory system. Examples are the localization of leptin and adiponectin receptors in the olfactory system or increased activation of brain regions related to the palatability and the hedonic value of food in response to food pictures after application of ghrelin. In this preliminary study, we tested in 31 subjects (17 male and 14 female) if and to what extent the peripheral blood concentrations of "satiety" hormones, such as leptin, adiponectin, and ghrelin (acyl and total), are correlated with the self-ratings of odor pleasantness and with the objective olfactory and gustatory ability. The hedonic values of some odors were found to be differently rated between donors depending on gender and body weight. The concentrations of leptin, adiponectin and total ghrelin were significantly associated with the hedonic value of pepper black oil, but failed to show significant correlations for 5 other odors tested. Except for a significant association between leptin and odor identification, hormone concentrations were not linked to the abilities of smell and taste. Peripheral adipokines and gut hormones may alter the perception and pleasantness of specific odors, presumably either directly through their receptors in the olfactory system or indirectly through central interfaces between the regulation systems of olfaction, appetite control, memory and motivation. Topics: Adiponectin; Adult; Appetite Regulation; Body Weight; Brain; Energy Metabolism; Feeding Behavior; Female; Ghrelin; Humans; Leptin; Male; Memory; Motivation; Obesity; Odorants; Olfactory Pathways; Piper nigrum; Plant Oils; Predictive Value of Tests; Satiation; Sex Factors; Smell; Taste; Taste Perception | 2011 |
Leptin reduces hyperactivity in an animal model for anorexia nervosa via the ventral tegmental area.
Hyperactivity in anorexia nervosa (AN) is associated with low plasma leptin levels and negatively impacts on disease outcome. Using an animal model that mimics features of AN including food-restriction induced hyperlocomotion, we demonstrate that central leptin injections in the lateral ventricle and local injections of leptin into the ventral tegmental area (VTA) suppress running wheel activity. The results support that falling levels of leptin, that accompany caloric restriction, result in increased activity levels because of decreased leptin signaling in the VTA, part of the mesolimbic reward system. Topics: Animals; Anorexia Nervosa; Body Weight; Disease Models, Animal; Eating; Female; Hyperkinesis; Infusions, Intraventricular; Insulin; Leptin; Motor Activity; Rats; Rats, Wistar; Ventral Tegmental Area | 2011 |
Plasma leptin and mRNA expression of lipogenesis and lipolysis-related factors in bovine adipose tissue around parturition.
The objective was to study changes in plasma leptin concentration parallel to changes in the gene expression of lipogenic- and lipolytic-related genes in adipose tissue of dairy cows around parturition. Subcutaneous fat biopsies were taken from 27 dairy cows in week 8 antepartum (a.p.), on day 1 postpartum (p.p.) and in week 5 p.p. Blood samples were assayed for concentrations of leptin and non-esterified fatty acids (NEFA). Subcutaneous adipose tissue was analysed for mRNA abundance by real-time qRT-PCR encoding for leptin, adiponectin receptor 1 (AdipoR1), adiponectin receptor 2 (AdipoR2), hormones-sensitive lipase (HSL), perilipin (PLIN), lipoprotein lipase (LPL), acyl-CoA synthase long-chain family member 1 (ACSL1), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN) and glycerol-3-phosphate dehydrogenase 2 (GPD2). Body weight and body condition score of the cows were lower after parturition than before parturition. The calculated energy balance was negative in week 1 and 5 p.p., with higher negative energy balance in week 1 p.p. compared with that in week 5 p.p. On day 1 p.p., highest concentrations of NEFA (353.3 μmol/l) were detected compared with the other biopsy time-points (210.6 and 107.7 μmol/l, in week 8 a.p., and week 5 p.p. respectively). Reduced plasma concentrations of leptin during p.p. when compared with a.p. would favour increasing metabolic efficiency and energy conservation for mammary function and reconstitution of body reserves. Lower mRNA abundance of ACC and FASN expression on day 1 p.p. compared with other biopsy time-points suggests an attenuation of fatty acid synthesis in subcutaneous adipose tissue shortly after parturition. Gene expression of AdipoR1, AdipoR2, HSL, PLIN, LPL, ACSL1 and GPD2 was unchanged over time. Topics: Adipose Tissue; Animals; Body Weight; Cattle; Energy Metabolism; Fatty Acids, Nonesterified; Female; Gene Expression Regulation; Leptin; Lipogenesis; Lipolysis; Parturition; Pregnancy; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2011 |
Traits of the metabolic syndrome alter corpulent obesity in LAN, SHR and DSS rats: behavioral and metabolic interactions with adrenalectomy.
Obesity results from a complex interaction of genes with environmental factors. Our experimental design compared obesity in three rat strains with the corpulent (cp) mutation. The three strains included Lister and Albany NIH (LAN) rats, Spontaneously Hypertensive Rats (SHR) and Dahl Salt Sensitive (DSS) rats that were congenically bred. The strains were selected because of different reported metabolic complications generally clustered with obesity, and defined as the metabolic syndrome. Body weight, food intake, carcass composition, plasma hormones and hypothalamic expression of Y5 receptors were assessed in obese (cp) and lean (wt) rats after adrenalectomy (ADX) or sham surgeries. Plasma corticosterone in sham-operated wtDSS and cpDSS were significantly higher (approx. 165ng/ml) than that in cpLAN and cpSHR (~77 and 68ng/ml respectively). All cp groups had a higher % carcass fat than wt groups. The % carcass fat was greater in cpDSS>cpLAN>cpSHR but plasma leptin was greatest in cpLAN>cpSHR>cpDSS. Hypothalamic expression of the Y5R after ADX resulted in a phenotype×surgery interaction since Y5R expression was slightly increased in cp rats and slightly decreased in wt rats. The strain with greatest number of metabolic syndrome traits, SHR, was not the fattest of the strains and had little response to ADX. The strains with fewer metabolic syndrome traits LAN and DSS had more extreme obesities which were attenuated after ADX. The results of the current experiment provide evidence that the corpulent mutation is not fully characterized in one strain. Topics: Adipose Tissue; Adrenalectomy; Analysis of Variance; Animals; Behavior, Animal; Body Composition; Body Weight; Corticosterone; Disease Models, Animal; Eating; Hypothalamus; Leptin; Male; Metabolic Diseases; Obesity; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Receptors, Neuropeptide Y; RNA, Messenger; Time Factors | 2011 |
Effects of long-term intraperitoneal injection of thyrotropin-releasing hormone (TRH) on aging- and obesity-related changes in body weight, lipid metabolism, and thyroid functions.
Adult adipose mice, high fat diet-fed (HFD) mice, anterior hypothalamus-lesioned obese mice and genetically obese mice, were injected daily with thyrotropin releasing hormone (TRH). The treatment provoked a mobilization of triglycerides in the peripheral blood, a decrease of leptin and a loss of body weight. The weight loss did not depend on TSH-mediated stimulation of thyroid hormone secretion with consequent metabolic hyperthyroidism. The levels of blood cholesterol were not affected or even suppressed. Even at a very high dosage TRH did not affect the obesity of genetically obese mice. The ubiquitous tripeptide TRH may thus constitute a key element in the hormone-controlled regulation of body weight and fat stores in the adult and aging body. Topics: Aging; Animals; Body Weight; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Female; Injections, Intraperitoneal; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Models, Animal; Obesity; Thyroid Gland; Thyrotropin-Releasing Hormone; Thyroxine; Triglycerides; Triiodothyronine | 2011 |
Leptin expression and leptin receptor gene polymorphisms in growth hormone deficiency patients.
Growth hormone deficiency (GHD) patients have lower weight, height, bone age, insulin-like growth factor 1 (IGF-1) levels, GH levels, fat metabolism and skeletal growth. The association of leptin with GHD characteristics and the effect of gene variants of leptin on GHD are unknown. Our aim was to examine the association of circulating leptin levels and common genetic variants in leptin (LEP) and leptin receptor (LEPR) genes with anthropometric measures, circulating hormone concentrations and GHD. A case control study of 125 GHD cases and 159 control subjects were characterized for bone age, body mass index (BMI), height, weight, leptin, IGF-1, GH and their genotype at the leptin promoter G-2548A, and LEPR variants, K109R and Q223R, at Chung Shan Medical University Hospital. Leptin levels were significantly associated with lower bone age, weight and BMI in GHD patients. Leptin levels were also significantly associated with reduced IGF-1 levels in girls but not boys in both groups. The frequency of LEPR223 [A/G or A/A] genotype was significantly higher than the LEPR223 G/G genotype in the GHD group. The LEPR223 [A/G or A/A] genotype was significantly associated with increased weight and BMI in the control group, but not in the GHD group. In conclusion, the GHD group carried a significantly higher frequency of the LEPR [G/A or A/A] genotype and of the A allele (LEPR223R). The LEPR223R polymorphism affected weight and BMI in control, but not in GHD patients, suggesting that the effect of LEPR223 [A/G or A/A] genotype was counteracted by other factor(s) in GHD patients. Topics: Adolescent; Age Determination by Skeleton; Alleles; Body Mass Index; Body Weight; Case-Control Studies; Chi-Square Distribution; Child; Female; Gene Frequency; Genotype; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leptin; Linkage Disequilibrium; Male; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Leptin; Thyroxine | 2011 |
Leptin-independent programming of adult body weight and adiposity in mice.
Low birth weight and rapid postnatal weight gain are independent and additive risk factors for the subsequent development of metabolic disease. Despite an abundance of evidence for these associations, mechanistic data are lacking. The hormone leptin has received significant interest as a potential programming factor, because differences in the profile of leptin in early life have been associated with altered susceptibility to obesity. Whether leptin alone is a critical factor for programming obesity has, until now, remained unclear. Using the leptin-deficient ob/ob mouse, we show that low birth weight followed by rapid catch-up growth during lactation (recuperated offspring) leads to a persistent increase in body weight in adult life, both in wild-type and ob/ob animals. Furthermore, recuperated offspring are hyperphagic and epididymal fat pad weights are significantly increased, reflecting greater adiposity. These results show definitively that factors other than leptin are crucial in the programming of energy homeostasis in this model and are powerful enough to alter adiposity in a genetically obese strain. Topics: Adiposity; Animals; Body Weight; Eating; Enzyme-Linked Immunosorbent Assay; Female; Leptin; Lipids; Male; Mice; Mice, Mutant Strains | 2011 |
Mechanical-tactile stimulation (MTS) during neonatal stress prevents hyperinsulinemia despite stress-induced adiposity in weanling rat pups.
Stress in early life negatively influences growth quality through perturbations in body composition including increased fat mass. At term (40 weeks) preterm infants have greater fat mass and abdominal visceral adipose tissue than term-born infants. Mechanical-tactile stimulation (MTS) attenuates the stress response in preterm infants and rodents. We tested the hypothesis that MTS, administered during an established model of neonatal stress, would decrease stress-driven adiposity and prevent associated metabolic imbalances in rat pups. Pups received one of three treatments from postnatal days 5 to P9: Neonatal Stress (Stress; n=20) = painful stimulus and hypoxic/hyperoxic challenge during 60 min of maternal separation; MTS (n=20) = neonatal stress+10 min of MTS; or Control (n=20). Body weight, DXA whole body fat mass (g), MRI subcutaneous and visceral adipose tissue, and fasting adiponectin, leptin, glucose, insulin, and corticosterone were measured at weaning (P21). Stress and MTS weight gain (g/d) were accelerated following neonatal stress with greater fat mass, abdominal subcutaneous adipose tissue, serum adiponectin, leptin, and fasting glucose at weaning (P21). Male Stress and MTS pups had greater visceral adipose tissue depot. Male and female Stress pups were hyperinsulinemic. In summary, neonatal stress compromised body composition by increasing fat mass and abdominal subcutaneous adipose tissue depot, and in males, visceral adipose tissue depot. Importantly, MTS prevented hyperinsulinemia despite of stress-induced adiposity. We conclude that MTS during neonatal stress has the potential to minimize metabolic consequences associated with stress-driven perturbations in fat mass and abdominal adipose depots. Topics: Absorptiometry, Photon; Adiponectin; Animals; Animals, Newborn; Blood Glucose; Body Composition; Body Weight; Corticosterone; Female; Hyperinsulinism; Intra-Abdominal Fat; Leptin; Magnetic Resonance Imaging; Male; Rats; Rats, Sprague-Dawley; Stress, Physiological; Touch | 2011 |
Treatment with a melanocortin agonist improves abnormal lipid metabolism in streptozotocin-induced diabetic mice.
Impairments in leptin-melanocortin signaling are associated with insulin-deficient diabetes and leptin treatment has been shown to be effective in reversing hyperglycemia in animal models of type 1 diabetes. Therefore, we hypothesized that enhanced central melanocortin signaling reverses the metabolic impairments associated with type 1 diabetes. To address this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with daily intracerebroventricular injection of MTII, a melanocortin agonist, for 11days. STZ-induced hyperglycemia and glucose intolerance were not improved by MTII treatment. MTII treatment did not alter expression levels of genes encoding gluconeogenic enzymes including glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), in the liver of diabetic mice. Skeletal muscle and white adipose tissue glucose transporter 4 (GLUT4) mRNA levels were not altered by MTII treatment in diabetic mice. In contrast, serum nonesterified fatty acid (NEFA) levels were significantly increased in STZ-induced diabetic mice compared to non-diabetic control mice and MTII treatment significantly reduced serum NEFA levels in diabetic mice. MTII treatment also significantly reduced expression levels of hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) mRNA in white adipose tissue of diabetic mice without a significant change in serum insulin levels. Expression levels of lipoprotein lipase (LPL) and fatty acid translocase (FAT/CD36) mRNA in white adipose tissue and skeletal muscle were not changed by MTII treatment. These data suggest that central melanocortin signaling regulates lipid metabolism and that enhancing central melanocortin signaling is effective in reversing abnormal lipid metabolism, but not carbohydrate metabolism, at least partly by reducing lipolysis in type 1 diabetes. Topics: alpha-MSH; Animals; Blood Glucose; Body Weight; Child; Diabetes Mellitus, Experimental; Eating; Humans; Insulin; Leptin; Lipid Metabolism; Male; Melanocortins; Mice; Mice, Inbred C57BL; Triglycerides | 2011 |
Leptin does not influence surfactant synthesis in fetal sheep and mice lungs.
In the fetus, leptin in the circulation increases at late gestation and likely influences fetal organ development. Increased surfactant by leptin was previously demonstrated in vitro using fetal lung explant. We hypothesized that leptin treatment given to fetal sheep and pregnant mice might increase surfactant synthesis in the fetal lung in vivo. At 122-124 days gestational age (term: 150 days), fetal sheep were injected with 5 mg of leptin or vehicle using ultrasound guidance. Three and a half days after injection, preterm lambs were delivered, and lung function was studied during 30-min ventilation, followed by pulmonary surfactant components analyses. Pregnant A/J mice were given 30 or 300 mg of leptin or vehicle by intraperitoneal injection according to five study protocols with different doses, number of treatments, and gestational ages to treat. Surfactant components were analyzed in fetal lung 24 h after the last maternal treatment. Leptin injection given to fetal sheep increased fetal body weight. Control and leptin-treated groups were similar in lung function (preterm newborn lamb), surfactant components pool sizes (lamb and fetal mice), and expression of genes related to surfactant synthesis in the lung (fetal mice). Likewise, saturated phosphatidylcholine and phospholipid were normal in mice lungs with absence of circulating leptin (ob/ob mice) at all ages. These studies coincided in findings that neither exogenously given leptin nor deficiency of leptin influenced fetal lung maturation or surfactant pool sizes in vivo. Furthermore, the key genes critically required for surfactant synthesis were not affected by leptin treatment. Topics: Animals; Animals, Newborn; Body Weight; Female; Fetus; Gene Expression Regulation, Developmental; Leptin; Lung; Mice; Mice, Obese; Organ Size; Phosphatidylcholines; Pregnancy; Pulmonary Surfactant-Associated Proteins; Sheep | 2011 |
The effect of Helicobacter pylori and economic status on growth parameters and leptin, ghrelin, and insulin-like growth factor (IGF)-I concentrations in children.
It was suggested that gastric colonization with Helicobacter pylori (H. pylori) was associated with suboptimal nutrition and growth in childhood. Furthermore, several studies indicated a relationship between H. pylori colonization and alterations in the circulating levels of growth-related molecules (GRM). Accordingly, in this study, we investigate the effect of H. pylori infection on GRMs and on the growth of healthy school children, taking into consideration the effect of their economic status (ES) and anthropometric indices of their parents.. To acquire sociodemographic and anthropometric nutritional parameters and to detect H. pylori-specific serum IgG antibodies and growth-related molecules, we evaluated a total of 473 children attending four different primary and secondary schools in Istanbul. Subsequently, we assessed the effect of H. pylori on growth-related parameters (weight for age SDS, height for age SDS, BMI SDS, TSF, and waist-to-hip ratio) and on GRMs (leptin, ghrelin, and insulin-like growth factor-1 (IGF-1)), controlling for age, gender, family income, household crowding (HC), breastfeeding, maternal and paternal BMI SDS, and midparental height SDS with complex statistical models.. Of the 473 children (275 F/198 M, age 6-15 years; mean: 10.3 ± 0.1 years), 161 (34%) were H. pylori-positive. The prevalence of H. pylori was significantly higher in lower economic status (ES) groups, in children living in crowded houses, and in older age groups. Using simple statistical models, we did not find any significant associations between H. pylori infection and the growth parameters. However, in complex models for height for age SDS and for weight for age SDS, there was a significant interaction between H. pylori infection status and ES. Whereas in H. pylori-positive subjects, mid-income family children were both taller and heavier than the low-income group, there was no such an association in H. pylori-negative subjects. Among biochemical parameters, only ghrelin levels were associated with H. pylori infection in all models. Leptin levels were associated with HC in girls, whereas none of the parameters was significantly associated with leptin levels in boys. For IGF-1 levels, for boys, age and maternal BMI, and for girls, age and HC were significantly associated with IGF-1 levels.. We suggest that H. pylori may impair growth significantly only in susceptible children where unfavorable socioeconomic conditions facilitate its action, probably through mechanisms, at least in part, involving growth-related molecules. Topics: Adolescent; Anthropometry; Antibodies, Bacterial; Body Height; Body Mass Index; Body Weight; Child; Female; Ghrelin; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Insulin-Like Growth Factor I; Leptin; Male; Schools; Socioeconomic Factors; Students; Turkey | 2011 |
Effects of tobacco smoke exposure during lactation on nutritional and hormonal profiles in mothers and offspring.
Exposure to tobacco smoke is related to changes in energy balance regulation and several endocrine dysfunctions. Previously, we showed that maternal nicotine (the main addictive compound of tobacco) exposure exclusively during lactation affects biochemical profiles in mothers, milk, and pups. As the possible consequences for mothers and offspring of maternal smoking during lactation are still unknown, we evaluated the effects of tobacco smoke exposure on nutritional, biochemical, and hormonal parameters in dams and pups at weaning. After 72 h from birth, lactating rats were divided into two groups: smoke-exposed (S) in a cigarette-smoking machine, 4 × 1 h per day throughout the lactation period without pups; control (C), rats were treated the same as the experimental group but exposed to filtered air. Dams and pups were killed at weaning (21 days of lactation). Body weight and food intake were evaluated. Milk, blood, visceral fat, adrenal, and carcass were collected. S dams showed hyperprolactinemia (+50%), hypoinsulinemia (-40%), hypoleptinemia (-46%), as well as lower triglycerides (-53%) and very low-density lipoprotein cholesterol (-50%). Milk of S dams had higher lactose (+52%) and triglycerides (+78%). S pups presented higher body protein (+17%), lower total (-24%) and subcutaneous fat contents (-25%), hypoglycemia (-11%), hyperinsulinemia (+28%), hypocorticosteronemia (-40%), lower adrenal catecholamine content (-40%), hypertriglyceridemia (+34%), higher high-density lipoprotein cholesterol (+16%), and lower low-density lipoprotein cholesterol (-45%). In conclusion, tobacco smoke exposure leads to changes in nutritional, biochemical, and hormonal parameters in dams and, passively through the milk, may promote several important metabolic disorders in the progeny. Topics: Adiponectin; Analysis of Variance; Animals; Animals, Newborn; Body Composition; Body Weight; Corticosterone; Eating; Female; Insulin; Lactation; Leptin; Lung; Milk; Prolactin; Radioimmunoassay; Rats; Rats, Wistar; Tobacco Smoke Pollution; Weaning | 2011 |
Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice.
In addition to its role in reproduction, estradiol-17β is critical to the regulation of energy balance and body weight. Estrogen receptor α-null (Erα-/-) mutant mice develop an obese state characterized by decreased energy expenditure, decreased locomotion, increased adiposity, altered glucose homeostasis, and hyperleptinemia. Such features are reminiscent of the propensity of postmenopausal women to develop obesity and type 2 diabetes. The mechanisms by which ERα signaling maintains normal energy balance, however, have remained unclear. Here we used knockin mice that express mutant ERα that can only signal through the noncanonical pathway to assess the role of nonclassical ERα signaling in energy homeostasis. In these mice, we found that nonclassical ERα signaling restored metabolic parameters dysregulated in Erα-/- mutant mice to normal or near-normal values. The rescue of body weight and metabolic function by nonclassical ERα signaling was mediated by normalization of energy expenditure, including voluntary locomotor activity. These findings indicate that nonclassical ERα signaling mediates major effects of estradiol-17β on energy balance, raising the possibility that selective ERα agonists may be developed to reduce the risks of obesity and metabolic disturbances in postmenopausal women. Topics: Animals; Body Weight; Eating; Energy Metabolism; Estrogen Receptor alpha; Female; Homeostasis; Humans; Leptin; Mice; Mice, Knockout; Mice, Obese; Motor Activity; Obesity; Signal Transduction; STAT3 Transcription Factor | 2011 |
Increased adiposity programmed by catch-up growth: requirement for leptin signals?
Topics: Adiposity; Animals; Body Weight; Eating; Female; Leptin; Lipids; Male; Mice; Mice, Mutant Strains | 2011 |
The transcriptomic profiles of adipose tissues are modified by feed deprivation in lactating goats.
A major function of ruminant adipose tissue is to store lipids for use in productive functions. Body fat mobilization is required during periods of negative energy balance such as lactation or undernutrition. Until now, gene expression profiling of ruminant adipose tissue in response to nutritional restriction has not been performed. To gain a better understanding of the molecular mechanisms in adipose tissue in response to dietary factors, microarray analysis was used to compare the effects of two extreme nutritional conditions (control diet vs. 48-h feed deprivation) in the omental and perirenal adipose tissues of lactating goats (Capra hircus). We observed the altered expression of 456 and 199 genes in omental and perirenal adipose tissues, respectively. Similar biological processes were altered by feed deprivation in these two sites, although twice as many genes were differentially expressed in the omental than in the perirenal adipose tissue. Taken together, the transcriptional changes involved in lipid metabolism (decreased lipid synthesis and triglyceride storage capacity as well as increased fatty acid oxidation) were consistent with reduced energy deposition in goat adipose tissues in response to a 48-h fast. An inflammatory state of the adipose tissue was observed following the 48-h fast. Topics: Adipose Tissue; Animal Feed; Animals; Body Weight; Fasting; Female; Gene Expression Profiling; Gene Expression Regulation; Goats; Insulin; Lactation; Leptin; Lipid Metabolism | 2011 |
Neonatal leptin administration alters regional brain volumes and blocks neonatal growth restriction-induced behavioral and cardiovascular dysfunction in male mice.
Premature delivery is often complicated by neonatal growth restriction (GR) and neurodevelopmental impairment. Because global overnutrition increases the risk of adult metabolic syndrome, we sought a targeted intervention. Premature delivery and perinatal GR decrease circulating levels of the neurotrophic hormone leptin. We hypothesized that leptin supplementation would normalize the outcomes of mice with incipient neonatal GR. Pups were fostered into litters of 6 or 12 to elicit divergent growth patterns. Pups in each litter received injections of saline or leptin from d 4 to 14. At 4 mo, mice underwent tail cuff blood pressure measurement, behavioral testing, and MRI. Mice fostered in litters of 12 had decreased weanling weights and leptin levels. Neonatal leptin administration normalized plasma leptin levels without influencing neonatal growth. Leptin replacement also normalized the hypertension, stress-linked immobility, conditioned fear, and amygdala enlargement seen in neonatal growth restricted male mice. In control males, neonatal leptin administration led to hypothalamic enlargement, without overt neurocardiovascular alterations. Female mice were less susceptible to the effects of neonatal GR or leptin supplementation. In conclusion, the effects of neonatal leptin administration are modulated by concurrent growth and gender. In growth restricted male mice, physiologic leptin replacement improves adult neurocardiovascular outcomes. Topics: Age Factors; Aging; Amygdala; Animals; Animals, Newborn; Behavior, Animal; Blood Pressure; Body Weight; Cardiovascular System; Conditioning, Psychological; Fear; Female; Hypertension; Injections, Intraperitoneal; Leptin; Litter Size; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Motor Activity; Organ Size; Phenotype; Sex Factors | 2011 |
Maternal obesity eliminates the neonatal lamb plasma leptin peak.
A neonatal peak in rodent plasma leptin plays a central role in regulating development of the hypothalamic appetite control centres. Maternal obesity lengthens and amplifies the peak in altricial rodent species. The precise timing and characteristics of the neonatal leptin peak have not been established in offspring of either normal or obese mothers in any precocial species. We induced obesity by feeding female sheep for 60 days before conception, and throughout pregnancy and parturition with 150% of the diet consumed by control ewes fed to National Research Council recommendations.We have reported that mature offspring of obese sheep fed similarly exhibited increased appetite, weight gain and obesity in response to ad libitum feeding at 19 months of age. We observed a leptin peak in lambs of control ewes between days 6 and 9 of postnatal life, earlier than reported in rodents. This peak was not present in lambs born to obese ewes. The leptin peak in lambs born to control ewes was not clearly related to any changes in plasma cortisol, insulin, triiodothyronine, IGF-1 or glucose. However, there was a significant increase in cortisol at birth in lambs born to obese ewes related to an increase in leptin in the first day of life. We conclude that the increased cortisol seen in lambs of obese sheep plays a role in disrupting the normal peak of leptin in lambs born to obese ewes thereby predisposing them to increased appetite and weight gain in later life. Topics: Animals; Animals, Newborn; Biomarkers; Birth Weight; Body Weight; Female; Hydrocortisone; Leptin; Obesity; Pregnancy; Pregnancy Complications; Sheep | 2011 |
Systemic but not central nervous system nitric oxide synthase inhibition exacerbates the hypertensive effects of chronic melanocortin-3/4 receptor activation.
We examined whether systemic or central nervous system (CNS) inhibition of nitric oxide synthase exacerbates the cardiovascular responses of chronic CNS melanocortin 3/4 receptor activation. Sprague-Dawley rats implanted with telemetry probes, venous catheters, and intracerebroventricular (ICV) cannulae were divided in 3 groups. After control measurements, the NO synthase inhibitor L-NAME was infused (10 μg/kg/min intravenous) for 17 days and, starting on day 7 of L-NAME infusion, the melanocortin 3/4 receptor agonist melanotan II (MTII; 10 ng/hr; group 1) or saline vehicle (group 2) was infused ICV for 10 days. A third group not treated with L-NAME also received MTII ICV. Melanocortin 3/4 receptor activation caused a greater increase in mean arterial pressure (MAP) and heart rate in rats treated with intravenous L-NAME (35 ± 6 mm Hg and 56 ± 8 bpm) than L-NAME plus vehicle or MTII alone (22 ± 5 and 9 ± 2 mm Hg, and 26 ± 14 and 27 ± 5 bpm), despite a 58% and 50% reduction in food intake during the first 6 days of MTII infusion. To test if the amplified pressor response to MTII after L-NAME was attributable to a reduction in nitric oxide availability in the brain, we also infused L-NAME directly into the CNS alone or in combination with MTII. ICV infusion of L-NAME plus MTII caused only ≈ 10 mm Hg increase in MAP with no change in heart rate, similar to the effects of ICV infusion of MTII alone, whereas ICV infusion of L-NAME alone had no effect on MAP. These results suggest that reduction in peripheral, but not CNS, nitric oxide production augments MAP sensitivity to CNS melanocortin 3/4 receptor activation. Topics: alpha-MSH; Analysis of Variance; Animals; Blood Glucose; Body Weight; Catheters, Indwelling; Eating; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Hypertension; Insulin; Leptin; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Telemetry | 2011 |
Early weaning causes undernutrition for a short period and programmes some metabolic syndrome components and leptin resistance in adult rat offspring.
Maternal malnutrition during lactation programmes for overweight and central leptin resistance in adulthood. The inhibition of lactation by maternal treatment with bromocriptine (a prolactin inhibitor) programmes for obesity, hyperleptinaemia and leptin resistance. Here, we evaluated the short- and long-term effects of early weaning (EW) on body-weight regulation, leptin signalling, and hormone and lipid profiles in rats offspring. Lactating rats were separated into two groups: EW--dams were wrapped with a bandage to interrupt the lactation in the last 3 d of lactation; control--dams whose pups had free access to milk during all lactation (21 d). Data were significant at P < 0·05. At weaning, EW pups presented lower body weight (-10%), length (-4%), visceral fat (-40%), total fat (-30%), serum leptin (-73%), glycaemia (-10%), serum insulin (-20%) and insulin resistance index (IRI; -30 %), but higher total body protein content (+40%). At 180 d, EW offspring showed hyperphagia, higher length (+3%), body weight (+8%), visceral and total fat (+36 and 84%), serum TAG (+96%), glycaemia (+15%), leptinaemia (+185%) and IRI (+29%); however, they showed lower total protein content (-23%), leptin:body fat ratio (41%), prolactinaemia (-38%) and adiponectinaemia (-59%). Despite unchanged leptin receptor (OB-R) and signal transducer and activator of transcription 3 (STAT3), they displayed lower hypothalamic janus tyrosine kinase 2, phosphorylated STAT3 and a higher suppressor of cytokine signalling 3 levels, suggesting a central leptin resistance. Adult rats that were early weaned displayed higher adiposity, insulin resistance and dyslipidaemia, which are related to metabolic syndrome development. Our model reinforces the idea that neonatal malnutrition caused by shortening of the lactation period is important for metabolic programming of future diseases. Topics: Aging; Animals; Blood Glucose; Body Composition; Body Size; Body Weight; Eating; Female; Genes, Homeobox; Hypothalamus; Lactation; Leptin; Male; Malnutrition; Maternal Nutritional Physiological Phenomena; Metabolic Syndrome; Rats; Signal Transduction; Time Factors; Weaning | 2011 |
Perinatal lack of maternal IL-6 promotes increased adiposity during adulthood in mice.
The perinatal environment appears important in establishing metabolic phenotypes in adulthood. Mice deficient in IL-6 (IL-6(-/-)) tend to develop mature-onset obesity, but it is unknown whether perinatal exposure to IL-6 produced by the dam influences the metabolism of adult offspring. To address this issue, we monitored IL-6(-/-) offspring of IL-6(-/-) or IL-6(+/-) dams, as well as wild-type (WT) mice. At adult age, IL-6(-/-) mice weighed significantly more and had more body fat than WT mice, regardless of maternal genotype, and had lower insulin sensitivity. This phenotype was more pronounced in IL-6(-/-) offspring of IL-6(-/-) dams, because they gained weight significantly faster than IL-6(-/-) offspring of IL-6(+/-) dams and had more body fat and higher serum leptin levels at an earlier age. The leptin content was 2-fold higher in milk from IL-6(-/-) than WT dams. However, cross-fostering IL-6(-/-) mice with WT dams did not alter body weight, body composition, or adipocyte size at adult age compared with IL-6(-/-) mice fostered by IL-6(-/-) dams. Conversely, WT mice fostered by IL-6(-/-) dams weighed significantly more than those fostered by WT dams and had more body fat, larger adipocytes, and altered hypothalamic gene expression. We conclude that body fat of adult mice can be increased by perinatal exposure to factors affected by lack of maternal IL-6. Topics: Adipocytes; Adiposity; Animals; Body Composition; Body Weight; Enzyme-Linked Immunosorbent Assay; Female; Glucose Clamp Technique; Hypothalamus; Interleukin-6; Leptin; Male; Mice; Mice, Mutant Strains; Milk; Pregnancy; RNA, Messenger | 2011 |
Upregulation of growth signaling and nutrient transporters in cotyledons of early to mid-gestational nutrient restricted ewes.
Multiparous ewes received 100% (control, C, n = 13) or 50% (nutrient restricted, NR, n = 14) of NRC dietary requirements from d28-d78 of gestation. On d78, 5 C and 6 NR ewes were necropsied. The remaining 8 C and 8 NR ewes were fed to 100% of NRC from d78-d135 and necropsied. Maternal blood was collected at both necropsies and at weekly intervals for assay of glucose, insulin and leptin. Fetal blood was collected at d78 and d135 necropsies for assay of glucose and lipids. Cotyledonary (COT) tissue was evaluated for protein and mRNA expression [fatty acid transporter (FATP)1, FATP4, CD36, glucose transporter (GLUT)1 and GLUT3], mRNA expression only [placenta fatty acid binding protein (FABPpm) and lipoprotein lipase (LPL)], or expression of phosphorylated and total protein forms [AMP kinase (AMPK)α, acetyl-CoA carboxylase (ACC), extracellular signal-regulated kinase (Erk)1/2, mammalian target of rapamycin (mTOR) and protein kinase B (Akt)]. On d78, but not d135, placental and fetal weights were reduced (P < 0.05) in NR vs. C ewes. Maternal circulating glucose, insulin and leptin levels were decreased in NR vs. C ewes on d78 (P < 0.05) but similar at d135. Fetal blood glucose and triglyceride levels were lower in NR vs. C ewes (P < 0.05) on d78, but similar on d135. On d78, GLUT1, FATP4, CD36 mRNA and protein expression levels, FABPpm mRNA level, and leptin protein level were all increased (P < 0.05) in COT of NR vs. C ewes. AMPK, ACC, and Erk1/2 activities were also increased (P < 0.05) in NR vs. C COT on d78. In contrast, only FATP4 was increased (P < 0.05) at both the mRNA and protein levels in COT of NR realimented vs. C ewes on d135. These data demonstrate placental adaptation to maternal NR through increasing nutrient transporter production and growth signaling activity. Topics: Animals; Blood Glucose; Blotting, Western; Body Weight; CD36 Antigens; Fatty Acid Transport Proteins; Fatty Acid-Binding Proteins; Female; Fetal Weight; Fetus; Food Deprivation; Glucose Transporter Type 1; Glucose Transporter Type 4; Insulin; Leptin; Male; Placenta; Pregnancy; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sheep; Signal Transduction; Up-Regulation | 2011 |
Inactivation of the Rcan2 gene in mice ameliorates the age- and diet-induced obesity by causing a reduction in food intake.
Obesity is a serious international health problem that increases the risk of several diet-related chronic diseases. The genetic factors predisposing to obesity are little understood. Rcan2 was originally identified as a thyroid hormone-responsive gene. In the mouse, two splicing variants that harbor distinct tissue-specific expression patterns have been identified: Rcan2-3 is expressed predominately in the brain, whereas Rcan2-1 is expressed in the brain and other tissues such as the heart and skeletal muscle. Here, we show that Rcan2 plays an important role in the development of age- and diet-induced obesity. We found that although the loss of Rcan2 function in mice slowed growth in the first few weeks after birth, it also significantly ameliorated age- and diet-induced obesity in the mice by causing a reduction in food intake rather than increased energy expenditure. Rcan2 expression was most prominent in the ventromedial, dorsomedial and paraventricular hypothalamic nuclei governing energy balance. Fasting and refeeding experiment showed that only Rcan2-3 mRNA expression is up-regulated in the hypothalamus by fasting, and loss of Rcan2 significantly attenuates the hyperphagic response to starvation. Using double-mutant (Lep(ob/ob) Rcan2(-/-)) mice, we were also able to demonstrate that Rcan2 and leptin regulate body weight through different pathways. Our findings indicate that there may be an Rcan2-dependent mechanism which regulates food intake and promotes weight gain through a leptin-independent pathway. This study provides novel information on the control of body weight in mice and should improve our understanding of the mechanisms of obesity in humans. Topics: Aging; Animal Feed; Animals; Body Weight; Eating; Intracellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Knockout; Mice, Mutant Strains; Obesity; Proteins | 2011 |
Hyperphagia and central mechanisms for leptin resistance during pregnancy.
The purpose of this work was to study the central mechanisms involved in food intake regulation and leptin resistance during gestation in the rat. Sprague Dawley rats of 7, 13, and 18 d of pregnancy [days of gestation (G) 7, G13, and G18] were used and compared with nonpregnant animals in diestrus-1. Food intake was already increased in G7, before hyperleptinemia and central leptin resistance was established in midpregnancy. Leptin resistance was due to a reduction in leptin transport through the blood-brain barrier (BBB) and to alterations in leptin signaling within the hypothalamus based on an increase in suppressor of cytokine signaling 3 levels and a blockade of signal transducer and activator of transcription-3 phosphorylation (G13), followed by a decrease in LepRb and of Akt phosphorylation (G18). In early gestation (G7), no change in hypothalamic neuropeptide Y (NPY), agouti-related peptide (AgRP), or proopiomelanocortin (POMC) expression was shown. Nevertheless, an increase in NPY and AgRP and a decrease in POMC mRNA were observed in G13 and G18 rats, probably reflecting the leptin resistance. To investigate the effect of maternal vs. placental hormones on these mechanisms, we used a model of pseudogestation. Rats of 9 d of pseudogestation were hyperphagic, showing an increase in body and adipose tissue weight, normoleptinemia, and normal responses to iv/intracerebroventricular leptin on hypothalamic leptin signaling, food intake, and body weight. Leptin transport through the BBB, and hypothalamic NPY, AgRP and POMC expression were unchanged. Finally, the transport of leptin through the BBB was assessed using a double-chamber culture system of choroid plexus epithelial cells or brain microvascular endothelial cells. We found that sustained high levels of prolactin significantly reduced leptin translocation through the barrier, whereas progesterone and β-estradiol did not show any effect. Our data demonstrate a dual mechanism of leptin resistance during mid/late-pregnancy, which is not due to maternal hormones and which allows the maintenance of hyperphagia in the presence of hyperleptinemia driven by an increase in NPY and AgRP and a decrease in POMC mRNA. By contrast, in early pregnancy maternal hormones induce hyperphagia without the regulation of hypothalamic NPY, AgRP, or POMC and in the absence of leptin resistance. Topics: Agouti-Related Protein; Animals; Animals, Newborn; Blood-Brain Barrier; Blotting, Western; Body Weight; Cells, Cultured; Eating; Enzyme-Linked Immunosorbent Assay; Female; Hyperlipidemias; Hyperphagia; Hypothalamus; In Situ Hybridization; Infusions, Intraventricular; Injections, Intravenous; Leptin; Neuropeptide Y; Pregnancy; Pro-Opiomelanocortin; Progesterone; Rats; Rats, Sprague-Dawley | 2011 |
BMI was right all along: taller children really are fatter (implications of making childhood BMI independent of height) EarlyBird 48.
Several studies suggest that taller children may be wrongly labelled as 'overweight' because body mass index (BMI) is not independent of height (Ht) in childhood, and recommend adjustment to render the index Ht independent. We used objective measures of %body fat and hormonal/metabolic markers of fatness to investigate whether BMI and the corresponding fat mass index (FMI) mislead in childhood, or whether taller children really are fatter.. Longitudinal observational study measuring children annually from age 7 to 12 years.. Two hundred and eighty healthy children (56% boys) from the EarlyBird study.. BMI (body mass (BM)/Ht(2)), FMI (fat mass (FM)/Ht(2)), %body fat ((FM/BM) × 100, where FM was measured by dual-energy X-ray absorptiometry), fasting leptin (a hormonal measure of body fatness) and insulin resistance (a metabolic marker derived from the validated homeostasis model assessment program for insulin resistance--HOMA2-IR) were all analysed in relation to Ht. Alternative Ht-independent indices of BM and FM were compared with BMI and FMI as indicators of true fatness and related health risk.. BMI and FMI correlated with Ht at each annual time point (r~0.47 and 0.46, respectively), yet these correlations were similar in strength to those between Ht and %fat (r~0.47), leptin (r~0.41) and insulin resistance (r~0.40). Also, children who grew the most between 7 and 12 years showed greater increases in BMI, FMI, leptin and insulin resistance (tertile 1 vs 3, all p<0.05). BMI and FMI explained ~20% more of the variation in %fat, ~15% more in leptin and ~10% more in insulin resistance than the respective Ht-independent reformulations (BM/Ht(3.5) and FM/Ht(7), both p<0.001).. Taller children really are fatter than their shorter peers, have higher leptin levels and are more insulin resistant. Attempts to render indices of BM or FM independent of Ht in children seem inappropriate if the object of the index is to convey health risk. Topics: Absorptiometry, Photon; Body Composition; Body Height; Body Mass Index; Body Weight; Child; Data Interpretation, Statistical; Fasting; Female; Humans; Insulin Resistance; Leptin; Longitudinal Studies; Male; Obesity | 2011 |
Honey promotes lower weight gain, adiposity, and triglycerides than sucrose in rats.
Various dietary carbohydrates have been linked to obesity and altered adipose metabolism; however, the influences of honey vs common sweeteners have not been fully explored. We hypothesized that in comparison with sucrose, a honey-based diet would promote lower weight gain, adiposity, and related biomarkers (leptin, insulin, and adiponectin) as well as a better blood lipid profile. Thirty-six male Sprague-Dawley rats (228.1 ± 12.5 g) were equally divided by weight into 2 groups (n = 18) and provided free access to 1 of 2 diets of equal energy densities differing only in a portion of the carbohydrate. Diets contained 20% carbohydrate (by weight of total diet) from either clover honey or sucrose. After 33 days, epididymal fat pads were excised and weighed, and blood was collected for analyses of serum concentrations of lipids, glucose, and markers of adiposity and inflammation. Body weight gain was 14.7% lower (P ≤ .05) for rats fed honey, corresponding to a 13.3% lower (P ≤ .05) consumption of food/energy, whereas food efficiency ratios were nearly identical. Epididymal fat weight was 20.1% lower (P ≤ .05) for rats fed honey. Serum concentrations of triglycerides and leptin were lower (P ≤ .05) by 29.6% and 21.6%, respectively, and non-high-density lipoprotein cholesterol was higher (P ≤ .05) by 16.8% for honey-fed rats. No significant differences in serum total cholesterol, high-density lipoprotein cholesterol, adiponectin, C-reactive protein, monocyte chemoattractant protein-1, glucose, or insulin were detected. These results suggest that in comparison with sucrose, honey may reduce weight gain and adiposity, presumably due to lower food intake, and promote lower serum triglycerides but higher non-high-density lipoprotein cholesterol concentrations. Topics: Adiponectin; Adipose Tissue; Adiposity; Animals; Biomarkers; Blood Glucose; Body Weight; C-Reactive Protein; Chemokine CCL2; Diet; Dietary Carbohydrates; Eating; Energy Intake; Honey; Insulin; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Sucrose; Triglycerides; Weight Gain | 2011 |
Chronic blood pressure and appetite responses to central leptin infusion in rats fed a high fat diet.
Obesity has been suggested to induce selective leptin resistance whereby leptin's anorexic effects are attenuated, whereas the effects to increase sympathetic nervous system activity and blood pressure remain intact. Most studies, however, have tested only the acute responses to leptin administration. This study tested whether feeding a high-fat diet causes resistance to the appetite and cardiovascular responses to chronic central leptin infusion.. Sprague-Dawley rats were fed high-fat diet (40% kcal from fat, n=5) or normal-fat diet (13% kcal from fat, n=5) for a year. Radiotelemeters were implanted for continuous monitoring of mean arterial pressure (MAP) and heart rate (HR). A 21G steel cannula was implanted in the lateral cerebral ventricle [intracerebroventricular (ICV)]. After recovery, leptin was infused ICV at 0.02 μg/kg per min for 10 days.. High-fat rats were heavier than normal-fat rats (582±12 vs. 511±19 g) and exhibited significantly higher MAP (114±3 vs. 96±7 mmHg). Although the acute (24 h) effects of leptin were attenuated in high-fat rats, chronic ICV leptin infusion decreased caloric intake in both groups similarly (50±8 vs. 40±10%) by day 5. Despite decreased food intake and weight loss, leptin infusion significantly increased MAP and HR in both high-fat and normal-fat rats (7±2 and 5±1 mmHg; 18±11 and 21±10 b.p.m., respectively).. These results suggest that obesity induced by feeding a high-fat diet blunts the acute anorexic effects of leptin but does not cause significant resistance to the chronic central nervous system effects of leptin on appetite, MAP, or HR. Topics: Animals; Appetite; Blood Pressure; Body Weight; Dietary Fats; Feeding Behavior; Injections, Intraventricular; Leptin; Rats; Rats, Sprague-Dawley | 2011 |
Activation of microglia in specific hypothalamic nuclei and the cerebellum of adult rats exposed to neonatal overnutrition.
Much attention has been drawn to the possible involvement of hypothalamic inflammation in the pathogenesis of metabolic disorders, especially in response to a high-fat diet. Microglia, the macrophages of the central nervous system, can be activated by proinflammatory signals resulting in the local production of specific interleukins and cytokines, which in turn could exacerbate the pathogenic process. Because obesity itself is considered to be a state of chronic inflammation, we evaluated whether being overweight results in microglial activation in the hypothalamus of rats on a normal diet. Accordingly, we used a model of neonatal overnutrition that entailed adjustment of litter size at birth (small litters: four pups/dam versus normal litters: 12 pups/dam) and resulted in a 15% increase in bodyweight and increased circulating leptin levels at postnatal day 60. Rats that were overnourished during neonatal life had an increased number of activated microglia in specific hypothalamic areas such as the ventromedial hypothalamus, which is an important site for metabolic control. However, this effect was not confined to the hypothalamus because significant microglial activation was also observed in the cerebellar white matter. There was no change in circulating tumour necrosis factor (TNF) α levels or TNFα mRNA levels in either the hypothalamus or cerebellum. Interleukin (IL)6 protein levels were higher in both the hypothalamus and cerebellum, with no change in IL6 mRNA levels. Because circulating IL6 levels were elevated, this rise in central IL6 could be a result of increased uptake. Thus, activation of microglia occurs in adult rats exposed to neonatal overnutrition and a moderate increase in weight gain on a normal diet, possibly representing a secondary response to systemic inflammation. Moreover, this activation could result in local changes in specific hypothalamic nuclei that in turn further deregulate metabolic homeostasis. Topics: Animals; Body Weight; Cerebellum; Energy Metabolism; Female; Homeostasis; Hypothalamus; Interleukin-6; Leptin; Major Histocompatibility Complex; Male; Microglia; Overnutrition; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha | 2011 |
Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice.
The hormone leptin modulates a diverse range of biological functions, including energy homeostasis and reproduction. Leptin promotes GnRH function via an indirect action on forebrain neurons. We tested whether leptin deficiency or leptin resistance due to a high-fat diet (HFD) can regulate the potent reproductive neuropeptide kisspeptin. In mice with normalized levels of estradiol, leptin deficiency markedly reduced kisspeptin gene expression, particularly in the arcuate nucleus (ARC), and kisspeptin immunoreactive cell numbers in the rostral periventricular region of the third ventricle (RP3V). The HFD model was used to determine the effects of diet-induced obesity and central leptin resistance on kisspeptin cell number and gene expression. DBA/2J mice, which are prone to HFD-induced infertility, showed a marked decrease in kisspeptin expression in both the RP3V and ARC and cell numbers in the RP3V after HFD. This is the first evidence that kisspeptin can be regulated by HFD and/or increased body weight. Next we demonstrated that leptin does not signal (via signal transducer and activator of transcription 3 or 5, or mammalian target of rapamycin) directly on kisspeptin-expressing neurons in the RP3V. Lastly, in leptin receptor-deficient mice, neither GnRH nor kisspeptin neurons were activated during a preovulatory-like GnRH/LH surge induction regime, indicating that leptin's actions on GnRH may be upstream of kisspeptin neurons. These data provide evidence that leptin's effects on reproductive function are regulated by kisspeptin neurons in both the ARC and RP3V, although in the latter site the effects are likely to be indirect. Topics: Animals; Body Weight; Dietary Fats; Enzyme-Linked Immunosorbent Assay; Estradiol; Female; Gonadotropin-Releasing Hormone; Hypothalamus; Immunohistochemistry; Kisspeptins; Leptin; Male; Mice; Mice, Inbred C57BL; Neurons; Obesity; Proteins; Radioimmunoassay; Reverse Transcriptase Polymerase Chain Reaction; Tumor Suppressor Proteins | 2011 |
Hormonal, hypothalamic and striatal responses to reduced body weight gain are attenuated in anorectic rats bearing small tumors.
Lack of compensatory or even reduced food intake is frequently observed in weight-losing cancer patients and contributes to increased morbidity and mortality. Our previous work has shown increased transcription factor expression in the hypothalamus and ventral striatum of anorectic rats bearing small tumors. mRNA expression of molecules known to be involved in pathways regulating appetite in these structures was therefore assessed in this study. Given that pain, pro-inflammatory cytokines and metabolic hormones can modify food intake, spinal cord cellular activation patterns and plasma concentrations of cytokines and hormones were also studied. Morris hepatoma 7777 cells injected subcutaneously in Buffalo rats provoked a 10% lower body weight and 15% reduction in food intake compared to free-feeding tumor-free animals 4 weeks later when the tumor represented 1-2% of body mass. No differences in spinal cord activation patterns or plasma concentration of pro-inflammatory cytokines were observed between groups. However, the changes in plasma ghrelin and leptin concentrations found in food-restricted weight-matched rats in comparison to ad libitum-fed animals did not occur in anorectic tumor-bearing animals. Real-time PCR showed that tumor-bearing rats did not display the increase in hypothalamic agouti-related peptide mRNA observed in food-restricted weight-matched animals. In addition, microarray analysis and real-time PCR revealed increased ventral striatal prostaglandin D synthase expression in food-restricted animals compared to anorectic tumor-bearing rats. These findings indicate that blunted hypothalamic AgRP mRNA expression, probably as a consequence of relatively high leptin and low ghrelin concentrations, and reduced ventral striatal prostaglandin D synthesis play a role in maintaining cancer-associated anorexia. Topics: Adaptation, Physiological; Agouti-Related Protein; Analysis of Variance; Animals; Appetite Regulation; Basal Ganglia; Body Weight; Cachexia; Carcinoma, Hepatocellular; Cytokines; Disease Models, Animal; Eating; Gene Expression Regulation; Ghrelin; Hypothalamus; Immunohistochemistry; Intramolecular Oxidoreductases; Leptin; Lipocalins; Liver Neoplasms; Male; Matched-Pair Analysis; Neoplasms, Experimental; Pain Perception; Rats; Rats, Inbred BUF; RNA, Messenger; Spinal Cord; Weight Loss | 2011 |
Exercise attenuates matrix metalloproteinase activity in preexisting atherosclerotic plaque.
Few studies have investigated if exercise by itself has anti-atherosclerotic effects, without combining interventions with a low-fat diet. We studied the effects of exercise as a stand-alone intervention on preexisting atheromata by measuring not only plaque size but also the levels of plaque-destabilizing matrix-metalloproteinase (MMP) activity in vivo.. We used near-infrared fluorescent (NIRF) molecular imaging with an MMP-2/9 activatable NIRF probe to visualize the inflammatory protease activity within preexisting atheromata of 17-week-old ApoE(-/-) mice on: (a) normal chow diet (NCD), (b) Western diet (WD), and (c) WD with treadmill exercise for 10 weeks. We also measured tissue levels of aortic lipid peroxidation (LPO) and plasma levels of glucose/lipid/cytokine profiles. Exercise did not attenuate growth of preexisting atheromatous plaques. However, exercise strongly decreased proteolytic activity in plaques for animals on WD, with levels decreasing almost to NCD levels. Exercise was associated with decreased aortic LPO levels and increased blood adiponectin/leptin levels; however, exercise did not affect WD-consumption/weight-gain or improve blood glucose/lipid profiles.. Exercise training reduced aortic MMP activity in mice with preexisting atheromata, even though they remained on a high fat diet and plaque-growth was not attenuated. Topics: Adiponectin; Analysis of Variance; Animals; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Blood Glucose; Body Weight; Cytokines; Disease Models, Animal; Down-Regulation; Exercise Therapy; Immunohistochemistry; Infrared Rays; Leptin; Lipid Peroxidation; Lipids; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Microscopy; Molecular Imaging; Plaque, Atherosclerotic | 2011 |
Proteome changes in rat plasma in response to sibutramine.
Sibutramine is an anti-obesity agent that induces weight loss by selective inhibition of neuronal reuptake of serotonin and norepinephrine; however, it is associated with the risk of cardiovascular diseases (CVD), including heart attack and stroke. Here, we analyzed global protein expression patterns in plasma of control and sibutramine-treated rats using proteomic analysis for a better understanding of the two conflicting functions of this drug, appetite regulation, and cardiovascular risk. The control (n=6) and sibutramine-treated groups (n=6) were injected by vehicle and sibutramine, respectively, and 2-DE combined with MALDI-TOF/MS were performed. Compared to control rats, sibutramine-administered rats gained approximately 18% less body weight and consumed about 13% less food. Plasma leptin and insulin levels also showed a significant decrease in sibutramine-treated rats. As a result of proteomic analysis, 23 differentially regulated proteins were discovered and were reconfirmed by immunoblot analysis. Changed proteins were classified into appetite regulation and cardiovascular risk, according to their regulation pattern. Because the differential levels of proteins that have been well recognized as predictors of CVD risk were not well matched with the results of our proteomic analysis, this study does not conclusively prove that sibutramine has an effect on CVD risk. Topics: Adipose Tissue; Animals; Appetite Depressants; Appetite Regulation; Blood Proteins; Body Weight; Cardiovascular Diseases; Chromatography, Liquid; Cyclobutanes; Electrophoresis, Gel, Two-Dimensional; Insulin; Leptin; Male; Obesity; Proteome; Rats; Rats, Sprague-Dawley; Risk Factors; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Weight Loss | 2011 |
Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge.
Acute exposure to bacterial lipopolysaccharide (LPS) is a potent inducer of immune response as well as hypophagia. Nevertheless, desensitization of responses to LPS occurs during long-term exposure to endotoxin. We induced endotoxin tolerance, injecting repeated (6LPS) LPS doses compared with single (1LPS) treatment. 1LPS, but not 6LPS group, showed decreased food intake and body weight, which was associated with an increased plasma leptin and higher mRNA expression of OB-Rb, MC4R, and SOCS3 in the hypothalamus. Hypophagia induced by 1LPS was associated with lower levels of 2-arachidonoylglycerol (2-AG), increased number of p-STAT3 neurons, and decreased AMP-activated protein kinase (AMPK) activity. Desensitization of hypophagia in the 6LPS group was related to high 2-AG, with no changes in p-STAT3 or increased p-AMPK. Leptin decreased food intake, body weight, 2-AG levels, and AMPK activity and enhanced p-STAT3 in control rats. However, leptin had no effects on 2-AG, p-STAT3, or p-AMPK in the 1LPS and 6LPS groups. Rats treated with HFD to induce leptin resistance showed neither hypophagia nor changes in p-STAT3 after 1LPS, suggesting that leptin and LPS recruit a common signaling pathway in the hypothalamus to modulate food intake reduction. Desensitization of hypophagia in response to repeated exposure to endotoxin is related to an inability of leptin to inhibit AMPK phosphorylation and 2-AG production and activate STAT3. SOCS3 is unlikely to underlie this resistance to leptin signaling in the endotoxin tolerance. The present model of prolonged inflammatory challenge may contribute to further investigations on mechanisms of leptin resistance. Topics: Animals; Arachidonic Acids; Body Weight; Cyclic AMP-Dependent Protein Kinases; Diet; Dietary Fats; Eating; Endocannabinoids; Endotoxins; Gas Chromatography-Mass Spectrometry; Glycerides; Immunohistochemistry; Inflammation; Interleukin-10; Leptin; Lipopolysaccharides; Male; Phosphorylation; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; Receptors, Interleukin-10; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins | 2011 |
The relation between body mass index and speaking fundamental frequency in premenopausal and postmenopausal women.
The purpose of this study was to investigate the association between body mass index (BMI) and speaking fundamental frequency (SFF) in premenopausal and postmenopausal women with and without hormone therapy (HT).. A total of 105 middle-aged women participated and were divided into three groups: premenopausal women (n = 41), postmenopausal women without HT (n = 26), and postmenopausal women with HT (n = 38). The mean SFF (in hertz) of connected speech was measured using the Real-Time Pitch program from Computerized Speech Lab (Kay). Correlation coefficients were calculated using partial correlation between BMI and SFF, controlling for age.. A positive correlation was apparent between BMI and SFF in the group of postmenopausal women without HT (P = 0.021). In the group of premenopausal women and the group of postmenopausal women with HT, no correlation was found between BMI and SFF.. In postmenopausal women without HT, increasing BMI is associated with increasing SFF. This correlation is possibly related to the higher amount of estrogen production in adipose tissue in women with a higher BMI. Topics: Adipose Tissue; Age Factors; Body Mass Index; Body Weight; Estrogen Replacement Therapy; Female; Gonadal Steroid Hormones; Humans; Leptin; Middle Aged; Postmenopause; Premenopause; Research Design; Speech; Voice Quality | 2011 |
Simultaneous POMC gene transfer to hypothalamus and brainstem increases physical activity, lipolysis and reduces adult-onset obesity.
Pro-opiomelanocortin (POMC) neurons are identified in two brain sites, the arcuate nucleus of the hypothalamus and nucleus of the solitary tract (NTS) in brainstem. Earlier pharmacological and POMC gene transfer studies demonstrate that melanocortin activation in either site alone improves insulin sensitivity and reduces obesity. The present study, for the first time, investigated the long-term efficacy of POMC gene transfer concurrently into both sites in the regulation of energy metabolism in aged F344xBN rats bearing adult-onset obesity. Pair feeding was included to reveal food-independent POMC impact on energy expenditure. We introduced adeno-associated virus encoding either POMC or green fluorescence protein to the two brain areas in 22-month-old rats, then recorded food intake and body weight, assessed oxygen consumption, serum leptin, insulin and glucose, tested voluntary wheel running, analysed POMC expression, and examined fat metabolism in brown and white adipose tissues. POMC mRNA was significantly increased in both the hypothalamus and NTS region at termination. Relative to pair feeding, POMC caused sustained weight reduction and additional fat loss, lowered fasting insulin and glucose, and augmented white fat hormone-sensitive lipase activity and brown fat uncoupling protein 1 level. By wheel running assessment, the POMC animals ran twice the distance as the Control or pair-fed rats. Thus, the dual-site POMC treatment ameliorated adult-onset obesity effectively, involving a moderate hypophagia lasting ∼60 days, enhanced lipolysis and thermogenesis, and increased physical activity in the form of voluntary wheel running. The latter finding provides a clue for countering age-related decline in physical activity. Topics: Aging; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Dependovirus; Eating; Energy Metabolism; Gene Transfer Techniques; Humans; Insulin; Leptin; Lipolysis; Male; Motor Activity; Obesity; Pro-Opiomelanocortin; Rats; Rats, Inbred F344; Solitary Nucleus | 2011 |
High-fat diet offsets the long-lasting effects of running-wheel access on food intake and body weight in OLETF rats.
We have previously demonstrated that running-wheel access normalizes the food intake and body weight of Otsuka Long-Evens Tokushima Fatty (OLETF) rats. Following 6 wk of running-wheel access beginning at 8 wk of age, the body weight of OLETF rats remains reduced, demonstrating a lasting effect on their phenotype. In contrast, access to a high-fat diet exacerbates the hyperphagia and obesity of OLETF rats. To determine whether diet modulates the long-term effects of exercise, we examined the effects of high-fat diet on food intake and body weight in OLETF rats that had prior access to running wheels for 4 wk. We found that 4 wk of running exercise significantly decreased food intake and body weight of OLETF rats. Consistent with prior results, 4 wk of exercise also produced long-lasting effects on food intake and body weight in OLETF rats fed a regular chow. When running wheels were relocked, OLETF rats stabilized at lower levels of body weight than sedentary OLETF rats. However, access to a high-fat diet offset these effects. When OLETF rats were switched to a high-fat diet following wheel relocking, they significantly increased food intake and body weight, so that they reached levels similar to those of sedentary OLETF rats fed a high-fat diet. Gene expression determination of hypothalamic neuropeptides revealed changes that appeared to be appropriate responses to the effects of diet and running exercise. Together, these results demonstrate that high-fat diet modulates the long-lasting effects of exercise on food intake and body weight in OLETF rats. Topics: Adipose Tissue; Agouti-Related Protein; Animals; Body Weight; Corticotropin-Releasing Hormone; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Eating; Glucose Intolerance; Hypothalamus; Leptin; Male; Physical Conditioning, Animal; Pro-Opiomelanocortin; Rats; Rats, Inbred OLETF; Time Factors | 2011 |
Effects of leptin supplementation to lactating Brandt's voles (Lasiopodomys brandtii) on the developmental responses of their offspring to a high-fat diet.
Maternal serum leptin concentrations have been suggested as a key factor in programming growth patterns and protecting against adult metabolic disease in human offspring. However, the role of maternal leptin in the development of wild rodent offspring is not clear. We tested the hypothesis that maternal hyperleptinemia in lactating Brandt's voles (Lasiopodomys brandtii) can protect their offspring from the risks of high-fat-diet-induced-obesity and insulin resistance. Lactating voles were supplemented with murine leptin (0.64 μg g(-1 ) day(-1)) or phosphate-buffered saline (control) on days 10-17 of lactation (peak lactation). At 12 weeks of age, the female and male offspring of the two maternal groups were randomly assigned to two groups each and fed either a high-fat diet (41% of gross energy as fat) or a control diet (14% of gross energy as fat) until the age of 23 weeks. Body mass, food intake, glucose tolerance and resting metabolic rate were determined in the four offspring groups. After animals were sacrificed, organ masses and adipose tissue distribution, and serum leptin and insulin concentrations were measured. Offspring of leptin-treated mothers showed no significant differences in body mass, energy intake or energy expenditure, body composition, glucose tolerance or serum leptin and insulin concentrations from offspring of control mothers. The high-fat diet induced increases in body mass (by 23% in female and 17% in male offspring) and reduced glucose tolerance in both female and male offspring, indicative of the emergence of insulin resistance, even though digestible energy intake of the male offspring decreased on the high-fat diet. These results indicate that maternal hyperleptinemia during peak lactation in Brandt's voles did not protect against diet-induced obesity or glucose intolerance in their offspring. Topics: Animals; Arvicolinae; Basal Metabolism; Body Composition; Body Weight; Dietary Fats; Eating; Energy Intake; Female; Glucose Intolerance; Lactation; Leptin; Male; Mice; Obesity | 2011 |
Breastmilk ghrelin, leptin, and fat levels changing foremilk to hindmilk: is that important for self-control of feeding?
The aim of this study was to evaluate the changes in the ghrelin, leptin, and fat levels in the foremilk and hindmilk and the possible relationship between these levels with the age and growth of term healthy infants. Sixty-two babies were subdivided (according to their nutrition) into breastfed (BF), formula-fed (FF), and BF plus FF (BF + FF) groups. The total and active ghrelin and tryglyceride levels and the total cholesterol levels in the foremilk and hindmilk were studied at the first and second visits (mean of the second and fifth months, respectively). At both visits, the total and active ghrelin and the total cholesterol levels were lower in the hindmilk than in the foremilk. However, the triglyceride levels were higher in the hindmilk than in the foremilk (p < 0.001). The leptin levels were also higher in the hindmilk, but this difference was not statistically significant. At the second visit, the mean total foremilk ghrelin (p < 0.01), leptin (p < 0.05), tryglyceride (p < 0.001), and cholesterol (p < 0.01) levels in the BF group were decreased compared with the levels at the first visit, whereas the active ghrelin levels increased (p < 0.001). At the second visit, we observed a 3.5% increase in the body mass index in BF infants, a 14.6% increase in FF infants, and an 11.8% increase in BF + FF infants (p < 0.01). The foremilk leptin levels were lower in the BF + FF group than in the BF group at both visits. In conclusion, at the first and second visits, the decreased ghrelin and increased tryglyceride and leptin levels in the hindmilk might be associated with the important role of self-control when feeding BF infants. The stable content of formulas might be associated with a lack of self-control during feeding and increased nutrition. Changing the breast milk ghrelin, leptin, and fat levels between the foremilk and hindmilk and between the first and second visits might explain the differences in the weight gain patterns of BF and FF infants. Topics: Body Weight; Breast Feeding; Child Development; Colostrum; Fatty Acids; Female; Ghrelin; Humans; Infant; Infant Food; Lactation; Leptin; Milk, Human; Pregnancy | 2011 |
Antiobesity activities of indole-3-carbinol in high-fat-diet-induced obese mice.
This study investigated the effects of indole-3-carbinol (I3C), a cruciferous vegetable derivative, on obesity and its associated factors in high-fat-diet-induced obese (DIO) mice.. Eighteen male C57BL/6 mice were randomly assigned to one of three groups: basal, high fat (HF), and HF + 5 mg/kg of I3C intraperitoneally (HFI). After 12 wk of treatment, obesity-associated factors, including body weight, organ weight, serum concentrations of glucose, triacylglycerol, insulin, and adipokines, and macrophage accumulation and lipid metabolism-associated factors in epididymal adipose tissue were measured.. Body weight and epididymal adipose tissue weight were greater (P < 0.01), and adipocytes were larger in the HF group than in the basal and HFI groups. Compared with the HF group, the HFI group had improved glucose tolerance, a higher serum adiponectin concentration, lower serum glucose, triacylglycerol, insulin, and leptin concentrations, and less F4/80 expression in epididymal adipose tissue (P < 0.001). Furthermore, I3C treatment decreased acetyl coenzyme A carboxylase mRNA expression (P < 0.05) and increased peroxisome proliferator-activated receptor-γ protein expression (P < 0.05) in epididymal adipose tissue of DIO mice.. The I3C treatment decreased body weight and fat accumulation and infiltrated macrophages in epididymal adipose tissue of DIO mice, and these reductions were associated with improved glucose tolerance and with modulated expression of adipokines and lipogenic-associated gene products, including acetyl coenzyme A carboxylase and peroxisome proliferator-activated receptor-γ. Topics: Acetyl-CoA Carboxylase; Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Brassicaceae; Dietary Fats; Glucose Intolerance; Indoles; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Phytotherapy; Plant Extracts; PPAR gamma; RNA, Messenger; Triglycerides | 2011 |
Obesity-dependent cannabinoid modulation of proliferation in adult neurogenic regions.
Endocannabinoid signalling participates in the control of neurogenesis, especially after brain insults. Obesity may explain alterations in physiology affecting neurogenesis, although it is unclear whether cannabinoid signalling may modulate neural proliferation in obese animals. Here we analyse the impact of obesity by using two approaches, a high-fat diet (HFD, 60% fat) and a standard/low-fat diet (STD, 10% fat), and the response to a subchronic treatment with the cannabinoid receptor type 1 (CB1) inverse agonist AM251 (3 mg/kg) on cell proliferation of two relevant neurogenic regions, namely the subventricular zone in the striatal wall of the lateral ventricle (SVZ) and the subgranular zone of the dentate gyrus (SGZ), and also in the hypothalamus given its role in energy metabolism. We found evidence of an interaction between diet-induced obesity and CB1 signalling in the regulation of cell proliferation. AM251 reduced caloric intake and body weight in obese rats, as well as corrected plasma levels of cholesterol and triglycerides. AM251 is shown, for the first time, to modulate cell proliferation in HFD-obese rats only. We observed an increase in the number of 5-bromo-2-deoxyuridine-labelled (BrdU+) cells in the SGZ, but a decrease in the number of BrdU+ cells in the SVZ and the hypothalamus of AM251-treated HFD rats. These BrdU+ cells expressed the neuron-specific βIII-tubulin. These results suggest that obesity may impact cell proliferation in the brain selectively, and provide support for a role of CB1 signalling regulation of neurogenesis in response to obesity. Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Cannabinoid Receptor Modulators; Cell Proliferation; Cholesterol; Dietary Fats; Energy Intake; Female; Insulin; Leptin; Male; Neurogenesis; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Triglycerides | 2011 |
Opposing effects of chronic stress and weight restriction on cardiovascular, neuroendocrine and metabolic function.
Chronic stress is associated with dysregulation of energy homeostasis, but the link between the two is largely unknown. For most rodents, periods of chronic stress reduce weight gain. We hypothesized that these reductions in weight are an additional homeostatic challenge, contributing to the chronic stress syndrome. Experiment #1 examined cardiovascular responsivity following exposure to prolonged intermittent stress. We used radio-telemetry to monitor mean arterial pressure and heart rate in freely moving, conscious rats. Three groups of animals were tested: chronic variable stress (CVS), weight-matched (WM), and controls. Using this design, we can distinguish between effects due to stress and effects due to the changing body weight. WM, but not CVS, markedly reduced basal heart rate. Although an acute stress challenge elicited similar peak heart rate, WM expedited the recovery to baseline heart rate. The data suggest that CVS prevents the weight-induced attenuation of cardiovascular stress reactivity. Experiment #2 investigated hypothalamic-pituitary-adrenal axis and metabolic hormone reactivity to novel psychogenic stress. WM increased corticosterone area under the curve. CVS blunted plasma glucose, leptin, and insulin levels in response to restraint. Experiment #3 tested the effects of WM and CVS on PVN oxytocin and corticotrophin-releasing hormone mRNA expression. CVS increased, while WM reduced PVN CRH mRNA expression, whereas both CVS and WM reduced dorsal parvocellular PVN oxytocin mRNA. Overall, the data suggest that weight loss is unlikely to account for the deleterious effects of chronic stress on the organism, but in fact produces beneficial effects that are effectively absent or indeed, reversed in the face of chronic stress exposure. Topics: Animals; Blood Glucose; Body Weight; Cardiovascular Physiological Phenomena; Corticosterone; Disease Models, Animal; Gene Expression Regulation; Hypothalamo-Hypophyseal System; Insulin; Leptin; Male; Neurosecretory Systems; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric; Stress, Psychological; Telemetry | 2011 |
Adiponectin, AFABP, and leptin in human breast milk during 12 months of lactation.
Adiponectin, adipocyte fatty acid-binding protein (AFABP), and leptin have been shown to be present in human breast milk (BM). We determined intraindividual changes of BM levels of these proteins during 12 months of lactation.. Proteins were measured using a high-sensitivity enzyme-linked immunosorbent assay method in 72 healthy mothers after delivery (day 0, D0) and after 1, 3, 6, and 12 months of lactation.. Adiponectin levels in BM on D0 were 22.8 ± 0.8 (mean ± standard error of the mean), in 1 month (M1) 22.0 ± 0.6, in 3 months (M3) 20.5 ± 0.6, in 6 months (M6) 21.4 ± 0.8, and in 12 months (M12) 25.7 ± 1.4 ng/mL. AFABP levels were 12.3 ± 2.0, 6.2 ± 1.3, 1.3 ± 0.2, 2.5 ± 1.0, and 4.6 ± 1.9 ng/mL, respectively. Leptin levels were 0.3 ± 0.04, 0.2 ± 0.03, 0.1 ± 0.01, 0.1 ± 0.02, and 0.2 ± 0.04 ng/mL, respectively. We found significantly higher levels of adiponectin in M12 in comparison to M3 and M6 (P = 0.0026), higher levels of AFABP in D0 and M1 when compared with M3, M6, and M12 (P < 0.0001), and higher levels of leptin on D0 than in M1, M3, M6, and M12 (P < 0.0001). AFABP levels correlated negatively with infants' body weight in M1, but there was no correlation throughout the lactation period between body weight and other proteins. We found positive correlation between adiponectin, AFABP, and leptin throughout the lactation.. All of the hormones were detectable in BM up to 12 months of lactation, with decreasing trend until M3 and subsequent increase till M12. We speculate that higher levels in M6 and M12 may be caused by longer intervals between breast-feeding due to the introduction of complementary food. Topics: Adiponectin; Adult; Birth Weight; Body Weight; Child Development; Colostrum; Czech Republic; Fatty Acid-Binding Proteins; Female; Humans; Infant; Infant, Newborn; Lactation; Leptin; Male; Milk, Human; Pregnancy; Reproducibility of Results; Time Factors | 2011 |
Assessment of nutritional status and serum leptin in children with inflammatory bowel disease.
Children with inflammatory bowel disease (IBD) commonly have altered nutrition and growth. Measurement of serum leptin may enhance other modalities to assess the nutritional state of children with IBD. The aim of the present study was to define the nutritional status of children with newly diagnosed IBD by measuring anthropometry and serum leptin levels.. Twenty-eight children newly diagnosed with IBD and 56 age- and sex-matched controls were enrolled prospectively. Anthropometry (weight, height, and body mass index [BMI] expressed as z scores) and serum leptin levels were measured.. The children with IBD had lower mean BMI z scores and weight-for-age percentiles than controls (P = 0.05 and P = 0.01, respectively). The mean (standard deviation) serum leptin levels of the children with IBD were 2.4 (± 1.9) pg/mL, compared with 5.2 (± 4.6) pg/mL for controls (P = 0.01). The BMI percentile correlated positively with leptin levels in both groups. Following adjustment for BMI percentiles, serum leptin levels were lower in children with IBD than in controls (P = 0.02). Leptin levels did not correlate with serum markers of inflammation or disease activity scores.. Detailed and focused nutritional assessment should be an integral part of the management of all children with IBD. Children at the time of diagnosis of IBD have significant undernutrition and have lower serum leptin levels than controls. The inflammatory state in IBD appears not to alter leptin metabolism. Further study of the effect of leptin in IBD is required. Topics: Adolescent; Anthropometry; Body Mass Index; Body Weight; Child; Child, Preschool; Female; Humans; Infant; Inflammatory Bowel Diseases; Leptin; Male; Nutrition Assessment; Nutritional Status | 2011 |
Prevention and reversal of diet-induced leptin resistance with a sugar-free diet despite high fat content.
Chronic consumption of a Western-type diet, containing both elevated sugar and fat, results in leptin resistance. We hypothesised that fructose, as part of the sugar component of Western-type diets, is one causative ingredient in the development of leptin resistance and that removal of this component will prevent leptin resistance despite high fat (HF) content. We fed rats a sugar-free (SF), 30 % HF (SF/HF) diet or a 40 % high-fructose (HFr), 30 % HF (HFr/HF) diet for 134 d. The HFr/HF diet resulted in impaired anorexic and body-weight responses to both peripherally (0·6 mg/kg, assessed on day 65 of the diet) and centrally (1·5 μg/d, assessed on days 129-134) administered leptin, whereas SF/HF-fed rats were fully leptin responsive. At day 70, half the HFr/HF-fed animals were switched to the SF/HF diet, reversing the leptin resistance (assessed 18 d after the diet switch). The HFr/HF diet elevated serum leptin and reduced adiponectin, and levels were restored abruptly at day 3 after switching to the SF/HF diet. These data demonstrate that a diet containing both HFr and fat leads to leptin resistance, while an isoenergetic SF/HF diet does not. Moreover, removal of fructose from this diet reverses the leptin resistance and the elevated leptin, suggesting a cause-and-effect relationship. These data suggest that fructose is the bioactive component of a HF/high-sugar diet that is essential for the induction of leptin resistance. Topics: Adiponectin; Animals; Anorexia; Appetite; Body Weight; Dietary Fats; Dietary Sucrose; Fructose; Leptin; Male; Metabolic Diseases; Rats; Rats, Sprague-Dawley | 2011 |
Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons.
Although the central nervous system melanocortin system is an important regulator of energy balance, the role of proopiomelanocortin (POMC) neurons in mediating the chronic effects of leptin on appetite, blood pressure, and glucose regulation is unknown. Using Cre/loxP technology we tested whether leptin receptor deletion in POMC neurons (LepR(flox/flox)/POMC-Cre mice) attenuates the chronic effects of leptin to increase mean arterial pressure (MAP), enhance glucose use and oxygen consumption, and reduce appetite. LepR(flox/flox)/POMC-Cre, wild-type, LepR(flox/flox), and POMC-Cre mice were instrumented for MAP and heart rate measurement by telemetry and venous catheters for infusions. LepR(flox/flox)/POMC-Cre mice were heavier, hyperglycemic, hyperinsulinemic, and hyperleptinemic compared with wild-type, LepR(flox/flox), and POMC-Cre mice. Despite exhibiting features of metabolic syndrome, LepR(flox/flox)/POMC-Cre mice had normal MAP and heart rate compared with LepR(flox/flox) but lower MAP and heart rate compared with wild-type mice. After a 5-day control period, leptin was infused (2 μg/kg per minute, IV) for 7 days. In control mice, leptin increased MAP by ≈5 mm Hg despite decreasing food intake by ≈35%. In contrast, leptin infusion in LepR(flox/flox)/POMC-Cre mice reduced MAP by ≈3 mm Hg and food intake by ≈28%. Leptin significantly decreased insulin and glucose levels in control mice but not in LepR(flox/flox)/POMC-Cre mice. Leptin increased oxygen consumption in LepR(flox/flox)/POMC-Cre and wild-type mice. Activation of POMC neurons is necessary for the chronic effects of leptin to raise MAP and reduce insulin and glucose levels, whereas leptin receptors in other areas of the brain other than POMC neurons appear to play a key role in mediating the chronic effects of leptin on appetite and oxygen consumption. Topics: Analysis of Variance; Animals; Appetite; Blood Glucose; Blood Pressure; Body Weight; Eating; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Immunohistochemistry; Insulin; Leptin; Male; Mice; Mice, Knockout; Motor Activity; Neurons; Oxygen Consumption; Pro-Opiomelanocortin; Receptors, Leptin; Telemetry | 2011 |
Maternal "junk-food" feeding of rat dams alters food choices and development of the mesolimbic reward pathway in the offspring.
Individuals exposed to high-fat, high-sugar diets before birth have an increased risk of obesity in later life. Recent studies have shown that these offspring exhibit increased preference for fat, leading to suggestions that perinatal exposure to high-fat, high-sugar foods results in permanent changes within the central reward system that increase the subsequent drive to overconsume palatable foods. The present study has determined the effect of a maternal "junk-food" diet on the expression of key components of the mesolimbic reward pathway in the offspring of rat dams at 6 wk and 3 mo of age. We show that offspring of junk-food-fed (JF) dams exhibit higher fat intake from weaning until at least 3 mo of age (males: 16 ± 0.6 vs. 11 ± 0.8 g/kg/d; females: 19 ± 1.3 vs. 13 ± 0.4 g/kg/d; P<0.01). mRNA expression of μ-opioid receptor (Mu) was 1.6-fold higher (P<0.01) and dopamine active transporter (DAT) was 2-fold lower (P<0.05) in JF offspring at 6 wk of age. By 3 mo, these differences were reversed, and Mu mRNA expression was 2.8-fold lower (P<0.01) and DAT mRNA expression was 1.9-fold higher (P<0.01) in the JF offspring. These findings suggest that perinatal exposure to high-fat, high-sugar diets results in altered development of the central reward system, resulting in increased fat intake and altered response of the reward system to excessive junk-food intake in postnatal life. Topics: Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Body Weight; Dietary Fats; Dietary Sucrose; Dopamine Plasma Membrane Transport Proteins; Female; Food Preferences; Gene Expression; Lactation; Leptin; Limbic System; Male; Neural Pathways; Nucleus Accumbens; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Receptors, Opioid, mu; Reverse Transcriptase Polymerase Chain Reaction; Reward; Ventral Tegmental Area; Weaning | 2011 |
Caloric restriction in leptin deficiency does not correct myocardial steatosis: failure to normalize PPAR{alpha}/PGC1{alpha} and thermogenic glycerolipid/fatty acid cycling.
Evidence supports an antilipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin-deficient mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction versus leptin repletion in obese leptin-deficient (ob/ob) mice.. Echocardiography was performed on 7 mo old C57BL/6 wild-type mice (WT) and ob/ob mice fed ad libitum, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for 4 wk. Ventricular tissue was examined by electron microscopy (EM), triglyceride (TAG) content, oil red O staining, mitochondrial coupling assay, and microarray expression profiling.. LR and CR-ob/ob mice showed decreased body and heart weight, and LV wall thickness compared with ad libitum ob/ob mice. LV fractional shortening was decreased in ad libitum ob/ob mice, but restored to WT in LR and CR groups. However, myocardial lipid content by EM and TAG analysis revealed persistent cardiac steatosis in the CR-ob/ob group. Although CR restored mitochondrial coupling to WT levels, PPARα was suppressed and genes associated with oxidative stress and cell death were upregulated in CR-ob/ob animals. In contrast, LR eliminated cardiac steatosis, normalized mitochondrial coupling, and restored PGC1α and PPARα expression, while inducing core genes involved in glycerolipid/free fatty acid (GL/FFA) cycling, a thermogenic pathway that can reduce intracellular lipids.. Thus, CR in the absence of leptin fails to normalize cardiac steatosis. GL/FFA cycling may be, at least in part, leptin-dependent and a key pathway that protects the heart from lipid accumulation. Topics: Analysis of Variance; Animals; Apoptosis; Body Weight; Caloric Restriction; Echocardiography; Gene Expression Profiling; Hypertrophy, Left Ventricular; Leptin; Lipids; Mice; Mice, Inbred C57BL; Mice, Obese; Microarray Analysis; Microscopy, Electron; Myocardium; Oxidative Stress; PPAR alpha | 2011 |
Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice.
Myostatin deficiency causes dramatically increased skeletal muscle mass and reduced fat mass. Previously, myostatin-deficient mice were reported to have unexpectedly low total energy expenditure (EE) after normalizing to body mass, and thus, a metabolic cause for low fat mass was discounted. To clarify how myostatin deficiency affects the control of body fat mass and energy balance, we compared rates of oxygen consumption, body composition, and food intake in young myostatin-deficient mice relative to wild-type (WT) and heterozygous (HET) controls. We report that after adjusting for total body mass using regression analysis, young myostatin-deficient mice display significantly increased EE relative to both WT (+0.81 ± 0.28 kcal/day, P = 0.004) and HET controls (+0.92 ± 0.31 kcal/day, P = 0.005). Since food intake was not different between groups, increased EE likely accounts for the reduced body fat mass (KO: 8.8 ± 1.1% vs. WT: 14.5 ± 1.3%, P = 0.003) and circulating leptin levels (KO: 0.7 ± 0.2 ng/ml vs. WT: 1.9 ± 0.3 ng/ml, P = 0.008). Interestingly, the observed increase in adjusted EE in myostatin-deficient mice occurred despite dramatically reduced ambulatory activity levels (-50% vs. WT, P < 0.05). The absence of hyperphagia together with increased EE in myostatin-deficient mice suggests that increased leptin sensitivity may contribute to their lean phenotype. Indeed, leptin-induced anorexia (KO: -17 ± 1.2% vs. WT: -5 ± 0.3%) and weight loss (KO: -2.2 ± 0.2 g vs. WT: -1.6 ± 0.1, P < 0.05) were increased in myostatin-deficient mice compared with WT controls. We conclude that increased EE, together with increased leptin sensitivity, contributes to low fat mass in mice lacking myostatin. Topics: Adipose Tissue; Animals; Blotting, Western; Body Composition; Body Weight; Calorimetry, Indirect; Eating; Energy Metabolism; Female; Glucose Tolerance Test; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Myostatin; Oxygen Consumption; Regression Analysis | 2011 |
Interrelationships among changes in leptin, insulin, cortisol and growth hormone and weight status in youth.
While acute alterations in leptin, insulin, cortisol and growth hormone (GH) levels have been reported in children following weight change interventions, little is known about natural hormonal changes as children grow and how these changes are affected by unprovoked weight status changes. The purpose of this investigation was to compare changes in leptin, insulin, cortisol and GH levels in youth who maintained their weight status vs. those who moved from normal weight to overweight or vice versa.. Data were collected from 120 youth at baseline (9.8±1.0 years) and two years later. Participants were selected from a larger cohort to represent all scenarios of weight status: normal weight [>5(th) and <85(th) body mass index (BMI) percentile] at both time points (NN), overweight (≥85(th) BMI percentile) at both time points (OO), normal weight status who changed to overweight (NO) and overweight status which changed to normal weight (ON). Hormonal concentrations were measured from fasting venous blood.. In youth who changed their weight status, there were significant associations (p<0.05) between changes in BMI percentile and changes in leptin, insulin and cortisol (partial R(2)=0.35, 0.13 and 0.11, respectively), after accounting for race, sex and changes in pubertal status and aerobic power. Our key findings were that youth who became overweight (NO) showed greater changes for leptin (+205% vs. -21%) and cortisol (-33% vs. +13%), p<0.05 than those who reverted from overweight to normal weight (ON).. Natural changes in weight status in youth show a relationship with changes in leptin, insulin and cortisol levels and the hormonal changes appear to be more sensitive to increases, rather than reductions, in weight status. Topics: Body Weight; Child; Female; Human Growth Hormone; Humans; Hydrocortisone; Insulin; Leptin; Male | 2011 |
Downregulation of hypothalamic insulin receptor expression elicits depressive-like behaviors in rats.
Ongoing epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese. There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS) and may result in increased risk for neurological co-morbidities like depressive illness. One potential mechanistic mediator linking obesity and depressive illness is the adipocyte derived hormone leptin. We previously demonstrated that lentivirus-mediated downregulation of hypothalamic insulin receptors increases body weight, adiposity and plasma leptin levels, which is consistent with features of the metabolic syndrome. Using this novel model of obesity, we examined performance in the forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM), approaches that are often used as measures of depressive-like and anxiety-like behaviors, in rats that received third ventricular injections of either an insulin receptor antisense lentivirus (hypo-IRAS) or a control lentivirus (hypo-Con). Hypo-IRAS rats exhibited significant increases in immobility time and corresponding decreases in active behaviors in the FST and exhibited anhedonia as measured by decreased sucrose intake compared to hypo-Con rats. Hypo-IRAS rats also exhibited increases in anxiety-like behaviors in the EPM. Plasma, hippocampal and amygdalar brain-derived neurotrophic factor (BDNF) levels were reduced in hypo-IRAS rats, suggesting that the obesity/hyperleptinemic phenotype may elicit this behavioral phenotype through modulation of neurotrophic factor expression. Collectively, these data support the hypothesis for an increased risk for mood disorders in obesity, which may be related to decreased expression of hippocampal and amygdalar BDNF. Topics: Adiposity; Analysis of Variance; Animals; Body Weight; Depression; Disease Models, Animal; Down-Regulation; Food Preferences; Genetic Vectors; Hypothalamus; Leptin; Male; Maze Learning; Oligodeoxyribonucleotides, Antisense; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Swimming; Triglycerides | 2011 |
Leptin and the regulation of body weigh.
The cloning of the ob gene and its gene product, leptin, has led to the elucidation of a robust physiologic system that maintains fat stores at a relatively constant level. Leptin is a peptide hormone secreted by adipose tissue in proportion to its mass. Recessive mutations in the leptin gene are associated with massive obesity in mice and humans, establishing a genetic basis for obesity. Leptin circulates in blood and acts on the brain to regulate food intake and energy expenditure. When fat mass falls, plasma leptin levels fall, stimulating appetite and suppressing energy expenditure until fat mass is restored. When fat mass increases, leptin levels increase, suppressing appetite until weight is lost. This system maintains homeostatic control of adipose tissue mass. The discovery of leptin has advanced our understanding of metabolic disease in a number of respects. Its identification has revealed a new endocrine system regulating body weight. This system provides a means by which changes in nutritional state regulate other physiologic systems. A number of leptin deficiency syndromes that are treatable with leptin replacement have been identified. The majority of obese subjects are leptin resistant, which establishes that obesity is the result of hormone resistance. Leptin treatment results in weight loss in a subset of obese patients and can also synergize with other anti-obesity agents to reduce weight in the general population. Leptin provides an entry point for studying a complex human behavior. Finally, this research has established that there is a powerful biological basis for obesity, a fact that is (correctly) changing public perception about the pathogenesis of this medical condition. Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Appetite; Body Weight; Energy Metabolism; Feeding Behavior; Female; Homeostasis; Hormone Replacement Therapy; Humans; Leptin; Mice; Mutation; Nutritional Status; Obesity; Rats; Signal Transduction; Weight Loss | 2011 |
Effect of additional boron on tibias of African ostrich chicks.
The aim of the present study was to find out the effects of boron on ostrich chicks fed with 0 mg/l, 100 mg/l, 200 mg/l, and 400 mg/l of additional boron in water. We measured bone mineral density (BMD), perimeter, length, weight, ash content of ostrich tibias, thickness of cortical bone, and diameter of the marrow cavity. We also analyzed the apoptosis status of paraffin sections using a TUNEL kit and examined serum levels of leptin and estradiol (E(2)). The results were dramatic. Compared with the control group, group C had a very high BMD. The serum levels of leptin in groups C and D were significantly higher than control values, and the levels of E(2) fluctuated. The perimeter, length, weight, and ash content of ostrich tibias all increased significantly with increasing dosage of boron. The cross-section analysis revealed that the bone marrow cavity shifted closer to one side in group D, which was observed on a macro-scale. This shift may be related to the toxicity of excessive boron, as indicated by the apoptosis status. According to the present data, additional boron was helpful for ostrich chick bone development, and 200 mg/l supplement boron in the drinking water appeared to be the most beneficial. Topics: Anatomy, Cross-Sectional; Animal Feed; Animals; Apoptosis; Body Weight; Bone Density; Bone Development; Bone Marrow; Boron Compounds; Estradiol; Female; Fractures, Bone; Immunohistochemistry; In Situ Nick-End Labeling; Leptin; Nutritional Status; Struthioniformes; Tibia | 2011 |
Thyroid hormone levels predict the change in body weight: a prospective study.
Different studies, mostly cross-sectional, have found an association between low levels of thyroid hormones, even within the normal range, and a greater body mass index. The aim of this study was to determine the association between thyroid function and the risk for obesity.. In this population-based prospective study, measurements were made of anthropometric parameters, thyroid hormone function and urinary iodine in a cohort of the Pizarra Study (n = 937), and repeated 6 years later (n = 784). At the second point, measurements were also made of leptin and adiponectin.. Among the persons who were not obese at the start of the study, the odds ratio (OR) of becoming obese for those in the fourth quartile (Q(4)) for free triiodothyronine (FT3) (versus those in Q(1)) was 2·94 (1·46-5·90) (P = 0·005). The OR of becoming obese in persons in Q(4) of FT4 (versus those in Q(1)) was 3·06 (1·23-7·43) (P = 0·01). Those persons in Q(4) of weight gain had a higher FT3 at the 6-year follow-up than those whose weight gain was in Q(1) (P < 0·001). Leptin correlated with thyrotropin (β = 0·58, P = 0·001) and the FT4 (β = -1·12, P = 0·005). Adiponectin correlated with FT3 (r = -0·24, P < 0·001). The urinary iodine correlated negatively with both the BMI (β = -0·08, P = 0·01) and the increase in weight (β = -0·08, P = 0·04).. The changes in the thyroid hormones could be the consequence, rather than the cause, of the increase in weight. The same pathophysiological mechanisms that induce obesity might also be modifying the thyroid hormone pattern. Topics: Adiponectin; Adult; Body Weight; Cohort Studies; Female; Follow-Up Studies; Humans; Insulin Resistance; Iodine; Leptin; Male; Middle Aged; Obesity; Prospective Studies; Thyroid Hormones; Thyrotropin; Triiodothyronine; Weight Gain; Weight Loss | 2011 |
Role of baseline leptin and ghrelin levels on body weight and fat mass changes after an energy-restricted diet intervention in obese women: effects on energy metabolism.
Hormones related to energy balance control may play an important role on weight loss resistance after low-caloric diet (LCD) intervention.. To investigate the predictive value of baseline leptin and ghrelin on body fat mass (FM) loss after 12 wk of LCD intervention and to study whether these associations could be related to changes in resting metabolic rate (RMR).. The study comprised a total of 78 obese women (age 36.7 ± 7 yr). We measured, before and after the LCD intervention, FM (dual-energy x-ray absorptiometry) and RMR (kilojoules per kilogram body weight per day, indirect calorimetry). We also analyzed fasting serum leptin and ghrelin, and leptin to ghrelin ratio was calculated.. FM and RMR changes (data at baseline - data after the intervention) were assessed.. Baseline serum leptin (r = -0.301; age- and baseline FM-adjusted P = 0.009) and ghrelin (r = 0.314, adjusted P = 0.014) levels as well as leptin to ghrelin levels (r = -0.331; adjusted P = 0.009) were significantly correlated with FM changes. Leptin to ghrelin ratio was significantly correlated with RMR at baseline and after the LCD (both P < 0.010). Baseline leptin to ghrelin ratio significantly predicted changes in RMR after the LCD (r = 0.298; P = 0.019) regardless of age, baseline RMR, and total body weight (r = 0.307; P = 0.016) or FM loss (r = 0.312; P = 0.015).. Obese women with higher leptin and lower ghrelin levels at baseline seem to be more resistant to FM loss. The leptin to ghrelin ratio could be proposed as a biomarker for predicting metabolic adaptations to energy restriction treatment and, if confirmed in future studies, as a predictor of treatment success/failure. Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Body Composition; Body Weight; Calorimetry, Indirect; Diet, Reducing; Energy Metabolism; Female; Ghrelin; Humans; Leptin; Middle Aged; Obesity | 2011 |
A combination of grape extract, green tea extract and L-carnitine improves high-fat diet-induced obesity, hyperlipidemia and non-alcoholic fatty liver disease in mice.
To develop a therapeutic agent for obesity-related metabolic disorders, a mixture of dietary components was prepared, including grape extract, green tea extract and l-carnitine (RGTC), and its effects on obesity, hyperlipidemia and non-alcoholic fatty liver disease examined. The RGTC dramatically inhibited the high-fat diet (HFD)-induced increase in body weight and fat in C57BL/6 mice, whereas food consumption was not affected by RGTC treatment. The RGTC also concentration-dependently suppressed the HFD-induced increase in plasma lipids, such as low-density lipoprotein cholesterol and triglycerides. In addition, increases in liver weight and liver steatosis were returned to normal by RGTC treatment in HFD-fed C57BL/6 mice. The plasma levels of glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase were also significantly down-regulated by RGTC treatment. These results suggest that RGTC suppressed HFD-induced obesity, hyperlipidemia and non-alcoholic fatty liver disease, suggesting that RGTC supplementation might be a promising adjuvant therapy for the treatment of these metabolic disorders. Topics: Adipose Tissue; Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Carnitine; Diet, High-Fat; Fatty Liver; Hyperlipidemias; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Plant Extracts; Tea; Vitis | 2011 |
Gestational high fat diet programs hepatic phosphoenolpyruvate carboxykinase gene expression and histone modification in neonatal offspring rats.
In insulin resistance and type II diabetes, there is an elevation of hepatic gluconeogenesis, which contributes to hyperglycaemia. Studies in experimental animals have provided evidence that consumption of high fat (HF) diets by female rats programs the progeny for glucose intolerance in adulthood, but the mechanisms behind the in utero programming remain poorly understood. The present study analysed the effect of a maternal HF diet on fetal gluconeogenic gene expression and potential regulation mechanism related to histone modifications. Dams were fed either a Control (C, 16% kcal fat) or a high-fat (HF, 45% kcal fat) diet throughout gestation. Livers of the offspring were collected on gestational day 21 and analysed to determine the consequences of a maternal HF diet on molecular markers of fetal liver gluconeogenesis. We demonstrated that offspring of HF-fed dams were significantly heavier and had significantly higher blood glucose levels at the time of delivery than offspring of dams fed the C diet. While maternal gluconeogenesis and plasma glucose were not affected by the HF diet, offspring of HF-fed dams had significantly higher mRNA contents of gluconeogenic genes in addition to the elevated plasma glucose. In addition to increased transcription rate, a gestational HF diet resulted in modifications of the Pck1 histone code in livers of offspring. Our results demonstrate that in utero exposure to HF diet has the potential to program the gluconeogenic capacity of offspring through epigenetic modifications, which could potentially lead to excessive glucose production and altered insulin sensitivity in adulthood. Topics: Animals; Animals, Newborn; Blood Glucose; Body Weight; CCAAT-Enhancer-Binding Protein-alpha; Chemokine CCL2; Chromatin Immunoprecipitation; Dietary Fats; DNA; Eating; Epigenesis, Genetic; Female; Gene Expression; Gluconeogenesis; Glucose-6-Phosphatase; Histones; Insulin; Leptin; Litter Size; Liver; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphoenolpyruvate Carboxykinase (GTP); Pregnancy; Rats; Rats, Inbred Strains; RNA-Binding Proteins; Sterol Regulatory Element Binding Protein 1; Transcription Factors | 2011 |
Peroxisome proliferator-activated receptor-gamma expression in the lung tissue of obese rats.
Obesity is a risk factor for asthma and type II diabetes. Peroxisome proliferator- activated receptor (PPAR)-γ has been suggested to regulate inflammatory responses in diabetes and asthma. We investigated whether PPAR-α, PPAR-γ, adiponectin receptors (AdipoR1, AdipoR2), leptin, and tumor necrosis factor (TNF)-α are expressed in rat lung tissues and whether the expression differs between obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long Evans Tokushima Otsuka (LETO) rats.. Obese and lean rats were given with a high fat diet or a 30% restricted diet for 32 weeks, and their blood glucose levels and weights were monitored. After 32 weeks, mRNA levels of PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α in lung tissues were measured using real time PCR.. PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α were expressed in both obese and lean rat lung tissues. Increased serum glucose levels on intraperitoneal glucose tolerance testing and a higher weight gain at 32 weeks were observed in OLETF control rats compared to OLETF diet restricted rats. PPAR-γ expression was markedly elevated in obese control and diet restricted rats compared to lean rats, although PPAR-γ expression in obese rats was not affected by diet restriction. Leptin was highly expressed in OLETF rats compared to LETO rats. TNF-α expression was enhanced in OLETF control rats compared LETO diet restricted rats, and decreased by diet restriction. PPAR-α, AdipoR1, and AdipoR2 expression were not significantly different between obese and lean rats.. PPAR-γ was highly expressed in the lung tissues of obese rats and may be a novel treatment target for regulating lung inflammation associated with obesity. Topics: Animals; Body Weight; Glucose Tolerance Test; Leptin; Lung; Male; Obesity; PPAR gamma; Rats; Rats, Long-Evans; Receptors, Adiponectin; RNA, Messenger; Tumor Necrosis Factor-alpha | 2011 |
Sex-dependent influences of obesity on cerebral white matter investigated by diffusion-tensor imaging.
Several studies have shown that obesity is associated with changes in human brain function and structure. Since women are more susceptible to obesity than men, it seems plausible that neural correlates may also be different. However, this has not been demonstrated so far. To address this issue, we systematically investigated the brain's white matter (WM) structure in 23 lean to obese women (mean age 25.5 y, std 5.1 y; mean body mass index (BMI) 29.5 kg/m(2), std 7.3 kg/m(2)) and 26 lean to obese men (mean age 27.1 y, std 5.0 y; mean BMI 28.8 kg/m(2), std 6.8 kg/m(2)) with diffusion-weighted magnetic resonance imaging (MRI). There was no significant age (p>0.2) or BMI (p>0.7) difference between female and male participants. Using tract-based spatial statistics, we correlated several diffusion parameters including the apparent diffusion coefficient, fractional anisotropy (FA), as well as axial (λ(∥)) and radial diffusivity (λ(⊥)) with BMI and serum leptin levels. In female and male subjects, the putative axon marker λ(∥) was consistently reduced throughout the corpus callosum, particularly in the splenium (r = -0.62, p<0.005). This suggests that obesity may be associated with axonal degeneration. Only in women, the putative myelin marker λ(⊥) significantly increased with increasing BMI (r = 0.57, p<0.005) and serum leptin levels (r = 0.62, p<0.005) predominantly in the genu of the corpus callosum, suggesting additional myelin degeneration. Comparable structural changes were reported for the aging brain, which may point to accelerated aging of WM structure in obese subjects. In conclusion, we demonstrate structural WM changes related to an elevated body weight, but with differences between men and women. Future studies on obesity-related functional and structural brain changes should therefore account for sex-related differences. Topics: Adult; Anisotropy; Body Mass Index; Body Weight; Cerebrum; Corpus Callosum; Diffusion Tensor Imaging; Female; Humans; Leptin; Male; Models, Statistical; Obesity; Sex Characteristics | 2011 |
Reciprocal effects of α-lipoic acid on adenosine monophosphate-activated protein kinase activity in obesity induced by ovariectomy in rats.
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays an important role in regulating whole-body energy homeostasis. The aim of this study was to investigate dietary α-lipoic acid (α-LA) supplementation on the activation of AMPK in both central and peripheral tissues in obese rats induced by ovariectomy.. Ovariectomized (Ovx) rats were treated with α-LA (200 mg/kg) 3 to 10 weeks after surgery. Body weight, food intake, fat mass, phosphorylated AMPKα (pAMPKα), and phosphorylated acetyl-CoA carboxylase (ACC) protein expression in both the hypothalamus and white adipose tissue (WAT) as well as plasma leptin and adiponectin levels were measured in rats after either Ovx or sham operations.. Compared with control rats, ovariectomy led to increased body weight, food intake, and WAT mass 2 to 10 weeks after surgery. Furthermore, plasma leptin and adiponectin levels as well as hypothalamic pAMPKα expression were significantly increased after ovariectomy, accompanied by a reduction in pAMPKα expression in WAT after ovariectomy. However, after treatment with α-LA, the elevation of leptin and adiponectin levels and the activation of hypothalamic AMPKα and ACC, as induced by ovariectomy, were significantly suppressed. Meanwhile, decreased fat mass and increased pAMPKα and phosphorylated ACC expression in the WAT were observed in Ovx rats treated with α-LA.. α-LA significantly decreased appetite and fat accumulation, possibly through the regulation of central and peripheral AMPK activities in rats. Therefore, this study provides a rationale for the therapeutic use of α-LA for obesity in postmenopausal women. Topics: Acetyl-CoA Carboxylase; Adiponectin; Adipose Tissue; Animals; Body Weight; Cyclic AMP-Dependent Protein Kinases; Eating; Female; Hypothalamus; Leptin; Obesity; Ovariectomy; Ovary; Rats; Rats, Sprague-Dawley; Thioctic Acid; Vitamin B Complex | 2011 |
Appetizer administration stimulates food consumption, weight gain and leptin levels in male Wistar rats.
Appetizers based on different spices/herbs are highly acceptable but evaluation of their functionality needs more attention. The present study, investigated the effects of appetizers on food consumption, weight gain, and leptin levels in male Wistar rats. Three appetizers, namely ginger beverage, ajowan beverage, and karpurvalli beverage were administered to groups of rats. The fasting leptin levels ranged from 0.75 to 2.5 ng/ml, while weights were in the range of 147-201 g. Decreased (3.4-10.8%) leptin levels following the consumption of appetizers indicated their appetizing effect, with a greater reduction (p<0.05) for ginger beverage and karpurvalli beverage. Weight gain after 10 days was 7.68% in the control group whereas it was 11.20 and 13.26% in rats fed with ginger and karpurvalli beverages, respectively. However, food consumption was higher in all the appetizer groups than in the controls. Topics: Animals; Appetite; Appetite Stimulants; Beverages; Body Weight; Eating; Fasting; Food; Food Technology; Leptin; Male; Rats; Rats, Wistar; Spices; Weight Gain; Zingiber officinale | 2011 |
Effect of food restriction and intense physical training on estrous cyclicity and plasma leptin concentrations in rats.
Intense physical training and dietary energy restriction have been associated with consequences such as nutritional amenorrhea. We investigated the effects of intense physical training, food restriction or the combination of both strategies on estrous cyclicity in female rats, and the relationship between leptin ad these effects. Twenty-seven female Wistar rats were distributed into four groups: SF: sedentary, fed ad libitum; SR: sedentary subjected to 50% food restriction (based on the food intake of their fed counterparts); TF: trained (physical training on a motor treadmill with a gradual increase in speed and time), fed ad libitum; TR: trained with 50% food restriction. We analysed estrous cyclicity, plasma leptin and estradiol as well as chemical composition of the carcass, body weight variation, and weight of ovaries and perirenal adipose tissue. Data demonstrate that physical training alone was not responsible for significant modifications in either carcass chemical composition or reproductive function. Food restriction reduced leptin levels in all animals and interrupted the estrous cyclicity in some animals, but only the combination of food restriction and physical training was capable of interrupting the estrous cyclicity in all animals. Leptin was not directly related to estrous cyclicity. From our findings, it may be concluded that there is an additive or synergistic effect of energy intake restriction and energy expenditure by intense physical training on estrous cyclicity. Leptin appears to be one among others factors related to estrous cycle, but it probably acts indirectly. Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Weight; Caloric Restriction; Eating; Energy Metabolism; Estradiol; Estrous Cycle; Female; Leptin; Physical Exertion; Rats; Rats, Wistar | 2011 |
Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1, and the expression of osteogenic genes in leptin-deficient ob/ob mice.
Both central and peripheral leptin administrations reduce body weight, food intake, and adiposity in ob/ob mice. In this study we compared effects of intracerebroventricular (ICV) and subcutaneous (SC) administration of leptin on bone metabolism in the appendicular and axial skeleton and adipose tissue gene expression and determined the effects of ICV leptin on bone marrow gene expression in ob/ob mice. In experiment 1, leptin (1.5 or 0.38 µg/d) or control was continuously injected ICV for 12 days. Gene expression analysis of femoral bone marrow stromal cells showed that expression of genes associated with osteogenesis was increased after ICV injection, whereas those associated with osteoclastogenesis, adipogenesis, and adipocyte lipid storage were decreased. In experiment 2, leptin was injected continuously ICV (0.0 or 1.5 µg/d) or SC (0.0 or 10 µg/d) for 12 days. In both experiments, regardless of mode of administration, leptin decreased body weight, food intake, and body fat and increased muscle mass, bone mineral density, bone mineral content, bone area, marrow adipocyte number, and mineral apposition rate. Serum insulin was decreased, whereas serum osteocalcin, insulin-like growth factor 1, osteoprotegerin, pyridinoline, and receptor activator of nuclear factor κB ligand concentrations were increased. In experiment 2, expression of genes in adipose tissue associated with apoptosis, lipid mobilization, insulin sensitivity, and thermogenesis was increased, whereas expression of genes associated with cell differentiation and maturation was decreased regardless of mode of administration. Thus ICV injection of leptin promotes expression of pro-osteogenic factors in bone marrow, leading to enhanced bone formation in ob/ob mice. Topics: Adipocytes; Animals; Body Weight; Bone Density; Bone Marrow; Cell Count; Feeding Behavior; Female; Femur; Gene Expression Regulation; Injections, Intraventricular; Insulin-Like Growth Factor I; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Muscles; Organ Size; Osteogenesis; Tibia | 2011 |
Sex-dependent effects of maternal deprivation and adolescent cannabinoid treatment on adult rat behaviour.
Early life experiences such as maternal deprivation (MD) exert long-lasting changes in adult behaviour and reactivity to stressors. Adolescent exposure to cannabinoids is a predisposing factor in developing certain psychiatric disorders. Therefore, the combination of the two factors could exacerbate the negative consequences of each factor when evaluated at adulthood. The objective of this study was to investigate the long-term effects of early MD [24 hours at postnatal day (PND) 9] and/or an adolescent chronic treatment with the cannabinoid agonist CP-55,940 (0.4 mg/kg, PND 28-42) on diverse behavioural and physiological responses of adult male and female Wistar rats. We tested them in the prepulse inhibition (PPI) of the startle response and analysed their exploratory activity (holeboard) and anxiety (elevated plus maze, EPM). In addition, we evaluated their adrenocortical reactivity in response to stress and plasma leptin levels. Maternal behaviour was measured before and after deprivation. MD induced a transient increase of maternal behaviour on reuniting. In adulthood, maternally deprived males showed anxiolytic-like behaviour (or increased risk-taking behaviour) in the EPM. Adolescent exposure to the cannabinoid agonist induced an impairment of the PPI in females and increased adrenocortical responsiveness to the PPI test in males. Both, MD and adolescent cannabinoid exposure also induced sex-dependent changes in plasma leptin levels and body weights. The present results indicate that early MD and adolescent cannabinoid exposure exerted distinct sex-dependent long-term behavioural and physiological modifications that could predispose to the development of certain neuropsychiatric disorders, though no synergistic effects were found. Topics: Adrenocorticotropic Hormone; Analgesics; Animals; Arousal; Attention; Behavior, Animal; Body Weight; Cannabinoids; Cyclohexanols; Exploratory Behavior; Female; Hypothalamo-Hypophyseal System; Inhibition, Psychological; Injections, Intraperitoneal; Leptin; Male; Maternal Deprivation; Maze Learning; Motor Activity; Organ Size; Pituitary-Adrenal System; Rats; Rats, Wistar; Risk-Taking; Sensory Gating; Sex Factors | 2011 |
Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons.
Ingestion of high-fat, high-calorie diets is associated with hyperphagia, increased body fat, and obesity. The mechanisms responsible are currently unclear; however, altered leptin signaling may be an important factor. Vagal afferent neurons (VAN) integrate signals from the gut in response to ingestion of nutrients and express leptin receptors. Therefore, we tested the hypothesis that leptin resistance occurs in VAN in response to a high-fat diet. Sprague-Dawley rats, which exhibit a bimodal distribution of body weight gain, were used after ingestion of a high-fat diet for 8 wk. Body weight, food intake, and plasma leptin levels were measured. Leptin signaling was determined by immunohistochemical localization of phosphorylated STAT3 (pSTAT3) in cultured VAN and by quantifaction of pSTAT3 protein levels by Western blot analysis in nodose ganglia and arcuate nucleus in vivo. To determine the mechanism of leptin resistance in nodose ganglia, cultured VAN were stimulated with leptin alone or with lipopolysaccharide (LPS) and SOCS-3 expression measured. SOCS-3 protein levels in VAN were measured by Western blot following leptin administration in vivo. Leptin resulted in appearance of pSTAT3 in VAN of low-fat-fed rats and rats resistant to diet-induced obesity but not diet-induced obese (DIO) rats. However, leptin signaling was normal in arcuate neurons. SOCS-3 expression was increased in VAN of DIO rats. In cultured VAN, LPS increased SOCS-3 expression and inhibited leptin-induced pSTAT3 in vivo. We conclude that VAN of diet-induced obese rats become leptin resistant; LPS and SOCS-3 may play a role in the development of leptin resistance. Topics: Animals; Body Weight; Diet; Diet, Atherogenic; Dietary Fats; Drug Resistance; Energy Intake; Leptin; Lipopolysaccharides; Neurons, Afferent; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Vagus Nerve; Vagus Nerve Diseases | 2011 |
Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias.
Calorie restriction (CR) has been demonstrated to alter cytokine levels; however, its potential to modify sickness behavior (fever, anorexia, cachexia) has not. The effect of CR on sickness behavior was examined in male C57BL/6J mice fed ad libitum or restricted 25% (CR25%) or restricted 50% (CR50%) in food intake for 28 days and injected with 50 μg/kg of LPS on day 29. Changes in body temperature, locomotor activity, body weight, and food intake were determined. A separate cohort of mice were fed ad libitum or CR50% for 28 days, and hypothalamic mRNA expression of inhibitory factor κB-α (IκB-α), cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)), suppressor of cytokine signaling 3 (SOCS3), IL-10, neuropeptide Y (NPY), leptin, proopiomelanocortin (POMC), and corticotrophin-releasing hormone (CRH) were determined at 0, 2, and 4 h post-LPS. CR50% mice did not develop fevers, whereas the CR25% mice displayed a fever shorter in duration but with the same peak as the controls. Both CR25% and CR50% mice showed no sign of anorexia and reduced cachexia after LPS administration. Hypothalamic mRNA expression of NPY and CRH were both increased by severalfold in CR50% animals preinjection compared with controls. The CR50% mice did not demonstrate the expected rise in hypothalamic mRNA expression of COX-2, microsomal prostaglandin E synthase-1, POMC, or CRH 2 h post-LPS, and leptin expression was decreased at this time point. Increases in SOCS3, IL-10, and IκB-α expression in CR50% animals were enhanced compared with ad libitum-fed controls at 4 h post-LPS. CR results in a suppression of sickness behavior in a dose-dependent manner, which may be due to CR attenuating proinflammatory pathways and enhancing anti-inflammatory pathways. Topics: Animals; Body Temperature; Body Weight; Caloric Restriction; Cyclooxygenase 2; Disease Models, Animal; Eating; Hypothalamus; Illness Behavior; Inflammation; Intramolecular Oxidoreductases; Leptin; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Motor Activity; Pro-Opiomelanocortin; Prostaglandin-E Synthases; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins | 2011 |
Protein tyrosine phosphatase epsilon affects body weight by downregulating leptin signaling in a phosphorylation-dependent manner.
Molecular-level understanding of body weight control is essential for combating obesity. We show that female mice lacking tyrosine phosphatase epsilon (RPTPe) are protected from weight gain induced by high-fat food, ovariectomy, or old age and exhibit increased whole-body energy expenditure and decreased adiposity. RPTPe-deficient mice, in particular males, exhibit improved glucose homeostasis. Female nonobese RPTPe-deficient mice are leptin hypersensitive and exhibit reduced circulating leptin concentrations, suggesting that RPTPe inhibits hypothalamic leptin signaling in vivo. Leptin hypersensitivity persists in aged, ovariectomized, and high-fat-fed RPTPe-deficient mice, indicating that RPTPe helps establish obesity-associated leptin resistance. RPTPe associates with and dephosphorylates JAK2, thereby downregulating leptin receptor signaling. Leptin stimulation induces phosphorylation of hypothalamic RPTPe at its C-terminal Y695, which drives RPTPe to downregulate JAK2. RPTPe is therefore an inhibitor of hypothalamic leptin signaling in vivo, and provides controlled negative-feedback regulation of this pathway following its activation. Topics: Animals; Body Weight; Cells, Cultured; Diet, Atherogenic; Down-Regulation; Female; Glucose; Homeostasis; Humans; Hypothalamus; Immunoblotting; Janus Kinase 2; Leptin; Mice; Mice, Knockout; Obesity; Phosphorylation; Receptor-Like Protein Tyrosine Phosphatases, Class 4; Receptors, Leptin; Signal Transduction | 2011 |
Leptin does not directly affect CNS serotonin neurons to influence appetite.
Serotonin (5-HT) and leptin play important roles in the modulation of energy balance. Here we investigated mechanisms by which leptin might interact with CNS 5-HT pathways to influence appetite. Although some leptin receptor (LepRb) neurons lie close to 5-HT neurons in the dorsal raphe (DR), 5-HT neurons do not express LepRb. Indeed, while leptin hyperpolarizes some non-5-HT DR neurons, leptin does not alter the activity of DR 5-HT neurons. Furthermore, 5-HT depletion does not impair the anorectic effects of leptin. The serotonin transporter-cre allele (Sert(cre)) is expressed in 5-HT (and developmentally in some non-5-HT) neurons. While Sert(cre) promotes LepRb excision in a few LepRb neurons in the hypothalamus, it is not active in DR LepRb neurons, and neuron-specific Sert(cre)-mediated LepRb inactivation in mice does not alter body weight or adiposity. Thus, leptin does not directly influence 5-HT neurons and does not meaningfully modulate important appetite-related determinants via 5-HT neuron function. Topics: Animals; Appetite; Body Weight; Brain; Electrophysiology; Hypothalamus; Immunoenzyme Techniques; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Pathways; Neurons; Obesity; Receptors, Leptin; Serotonin; Serotonin Plasma Membrane Transport Proteins | 2011 |
Biometric evidence of diet-induced obesity in Lew/Crl rats.
Although Lew/Crl rats are central to a classic model of renal transplantation and may provide a valid system for evaluating the effect of obesity on transplantation outcomes, their response to high-fat diet has not been evaluated sufficiently. The objective of this study was to evaluate biometric and basic metabolic data of Lew/Crl rats fed a 60% kcal, lard-based, very high-fat diet (HFD) compared with those fed a 10% kcal fat control diet (CD). Rats were maintained for 17 wk; body parameters and caloric intake were monitored weekly. Biometric data were collected and calculated before and after euthanasia. Serum was evaluated for liver enzyme activity and total bilirubin, glucose, triglyceride, cholesterol, insulin, leptin, and creatinine concentrations, and urine was evaluated for protein, glucose, specific gravity, and ketones. Tissues were harvested, weighed, and evaluated histologically. Compared with CD rats, HFD rats consumed more calories and weighed more after 3 wk. After 17 wk, HFD rats had significantly increased body weight, girth, volume, epididymal fat pad weight, omental weight, and body fat. In addition, HFD rats had mild elevations in some liver enzymes and a lower serum triglyceride concentration than did CD rats. Histologic assessment and other metabolic markers of disease were not different between the 2 groups. Lew/Crl rats fed a 60% kcal HFD become obese, but they lack significant metabolic abnormalities frequently associated with obesity in other rat strains. Topics: Animals; Biometry; Body Weight; Dietary Fats; Energy Metabolism; Insulin; Leptin; Male; Models, Animal; Obesity; Rats; Rats, Inbred Lew | 2011 |
Body composition and hormonal effects following exposure to mycotoxin deoxynivalenol in the high-fat diet-induced obese mouse.
To characterize the effects of ingesting the common foodborne mycotoxin deoxynivalenol (DON) on body weight and composition in the high-fat (HF) diet-induced obese mice, a model of human obesity.. Female B6C3F1 mice were initially fed HF diets containing 45% kcal (HF45) or 60% kcal (HF60) as fat for 94 days to induce obesity. Half of each group was either continued on unamended HF diets or fed HF diets containing 10 mg/kg DON (DON-HF45 or DON-HF60) for another 54 days. Additional control mice were fed a low-fat (LF) diet containing 10% kcal as fat for the entire 148-day period. DON induced rapid decreases in body weights and fat mass, which stabilized to those of the LF control within 11 days. These effects corresponded closely to a robust transient decrease in food consumption. While lean body mass did not decline in DON-fed groups, further increases were suppressed. DON exposure reduced plasma insulin, leptin, insulin-like growth factor 1, and insulin-like growth factor acid labile subunit as well as increased hypothalamic mRNA level of the orexigenic agouti-related protein.. DON-mediated effects on body weight, fat mass, food intake, and hormonal levels in obese mice were consistent with a state of chronic energy restriction. Topics: Adipose Tissue; Agouti-Related Protein; Animals; Body Composition; Body Weight; Carrier Proteins; Dietary Fats; Eating; Energy Intake; Female; Glycoproteins; Hypothalamus; Insulin; Insulin-Like Growth Factor I; Leptin; Mice; Mice, Obese; Obesity; RNA, Messenger; Trichothecenes | 2011 |
Hypocholesterolemic and hypoglycemic effects of enzymatically modified carbohydrates from rice in high-fat-fed C57BL/6J mice.
Enzymatically modified rice starch (ERS) synthesized with 4-α-glucanotransferase has a longer structure than rice starch, which could delay digestion, similar to dietary fiber. We investigated the effects of ERS on glucose and lipid metabolism with mice fed a high-fat diet containing ERS (HFD-ERS).. Four weeks of ERS feeding showed hypoglycemic effects with a significant reduction in fasting glucose (46%), insulin (57%), and leptin (83%) levels; improved glucose tolerance (20% in AUC of oral glucose tolerance test); and increased adiponectin concentrations (+27%) compared to the HFD group. Notably, phosphorylation of AMP kinase (AMPK) was markedly induced in the HFD-ERS livers compared to HFD livers. Additionally, ERS significantly reduced total cholesterol concentrations with induction of fecal bile acid excretion (+21%, P<0.05) in the HFD-ERS group compared to the HFD group. The mRNA and protein expressions of hepatic LDL receptors were significantly induced. However, cholesterol 7 alpha-hydroxylase (CYP7A1) expression was downregulated possibly due to induction of intestinal farnesoid X receptor (FXR; +2.4-fold, p<0.05) and fibroblast growth factor-15 (FGF-15; +2.2-fold, p<0.01).. Our data suggest that ERS feeding may have hypoglycemic and hypocholesterolemic effects via a mechanism similar to that of dietary fiber. Topics: Adenylate Kinase; Adiponectin; Animals; Anticholesteremic Agents; Bile Acids and Salts; Blood Glucose; Body Weight; Carbohydrates; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Diet, High-Fat; Dietary Fiber; Fibroblast Growth Factors; Glucose Tolerance Test; Glycogen Debranching Enzyme System; Hypoglycemic Agents; Insulin; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Oryza; Phosphorylation; Receptors, Cytoplasmic and Nuclear; Receptors, LDL; Starch | 2011 |
Perinatal programming of body weight control by leptin: putative roles of AMP kinase and muscle thermogenesis.
Breastfeeding, compared with infant-formula feeding, confers later protection against obesity. Leptin represents a candidate for the programming of the lean phenotype as suggested by 1) the presence of leptin in breast milk and its absence in infant formula, 2) a human study that showed a negative correlation between leptin concentrations in breast milk and body weights of infants until 2 y of age, and 3) intervention studies in animals. Milk-borne leptin and leptin synthesized in adipose tissue and the stomach may contribute to leptinemia in newborns. Studies in rodents suggested that early leptin treatment may program either a lean or obese phenotype, probably depending on the dose, route of administration, and timing of exposure to high leptin concentrations, whereas these studies also suggested the importance of the physiologic postnatal surge in leptinemia for the programming effect. Leptin oral administration at physiologic doses to neonate rats during the entire lactation period had later positive effects that prevented the animals from overweight and obesity and other metabolic alterations, which were particularly associated with feeding of a high-fat diet. High leptin sensitivity, which is associated with leanness, and leptin resistance in obesity may be programmed by the early life environment. The differential sensitivity to leptin implies a contribution of leptin-inducible energy expenditure to the adult phenotype. Available data have suggested the involvement of nonshivering thermogenesis induced by a leptin-AMP-activated protein kinase axis in oxidative muscles, which is based on lipid metabolism. Additional studies on the programming effects of leptin, mainly in response to the oral intake of leptin, are required. Topics: Adipose Tissue; Administration, Oral; AMP-Activated Protein Kinases; Animals; Body Weight; Breast Feeding; Child, Preschool; Diet, High-Fat; Energy Metabolism; Fetal Development; Humans; Infant Formula; Infant, Newborn; Leptin; Lipid Metabolism; Mice; Milk; Muscle, Skeletal; Obesity; Phenotype; Rats; Thermogenesis; Thinness | 2011 |
Hippocampal leptin signaling reduces food intake and modulates food-related memory processing.
The increase in obesity prevalence highlights the need for a more comprehensive understanding of the neural systems controlling food intake; one that extends beyond food intake driven by metabolic need and considers that driven by higher-order cognitive factors. The hippocampus, a brain structure involved in learning and memory function, has recently been linked with food intake control. Here we examine whether administration of the adiposity hormone leptin to the dorsal and ventral sub-regions of the hippocampus influences food intake and memory for food. Leptin (0.1 μg) delivered bilaterally to the ventral hippocampus suppressed food intake and body weight measured 24 h after administration; a higher dose (0.4 μg) was needed to suppress intake following dorsal hippocampal delivery. Leptin administration to the ventral but not dorsal hippocampus blocked the expression of a conditioned place preference for food and increased the latency to run for food in an operant runway paradigm. Additionally, ventral but not dorsal hippocampal leptin delivery suppressed memory consolidation for the spatial location of food, whereas hippocampal leptin delivery had no effect on memory consolidation in a non-spatial appetitive response paradigm. Collectively these findings indicate that ventral hippocampal leptin signaling contributes to the inhibition of food-related memories elicited by contextual stimuli. To conclude, the results support a role for hippocampal leptin signaling in the control of food intake and food-related memory processing. Topics: Animals; Appetite Regulation; Body Weight; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Conditioning, Psychological; Feeding Behavior; Hippocampus; Leptin; Male; Memory; Rats; Rats, Sprague-Dawley; Signal Transduction | 2011 |
Influence of high-fat feeding, diet-induced obesity, and hyperamylinemia on the sensitivity to acute amylin.
Obesity results in the increased secretion of various hormones controlling food intake and body weight, such as leptin, and insulin; increased circulating levels of pancreatic amylin have also been described in obese humans and rodents. Because leptin-resistance is present in diet-induced obese (DIO) rats, and because hyperleptinemia seems necessary for the full development of leptin resistance, we tested whether amylin sensitivity is inversely correlated with adiposity, such that DIO reduces the anorectic action of acute amylin. We also determined if hyperamylinemia leads to a change in amylin sensitivity. In the first experiment, rats were chronically exposed to a high fat (HF; 60% fat) diet or fed standard chow for control. The anorectic response to amylin was tested on several occasions over a 14 week observation period. HF feeding led to the expected increase in body adiposity; the response to an acute amylin injection (5-50 μg/kg s.c.) was unaltered for 10 weeks of HF feeding. Even after 12 weeks on a HF diet, which clearly caused obesity, acute administration of amylin (5 μg/kg, s.c.) was still able to suppress food intake, although the suppression was not statistically significant. Further experiments using additional doses of amylin will be necessary to demonstrate possible amylin resistance after HF feeding or in DIO rats. In the second experiment, we tested more specifically whether hyperamylinemia that may result from HF feeding and subsequent obesity, reduces the sensitivity of the amylin signaling system. To avoid confounding factors, we chronically infused lean chow fed rats with amylin (5 or 10 μg/kg/day s.c.) to elevate their plasma amylin concentration to levels observed in obese rats (30-40 pM). In the absence of obesity, hyperamylinemia did not lead to a reduced sensitivity to acute amylin (5-20 μg/kg s.c.) injections; acute amylin reduced eating similarly in all groups of rats. Overall, we concluded that direct diet effects by short term exposure to HF appear to be of little importance for amylin sensitivity; further, long-term maintenance on a HF diet and the resulting obesity only slightly attenuated the anorectic response to acute amylin. Because we observed no marked changes in amylin sensitivity in lean, chow fed rats with induced hyperamylinemia, amylin receptor downregulation in chronic hyperamylinemia does not seem to occur. Topics: Animals; Body Composition; Body Weight; Dietary Fats; Eating; Food Deprivation; Infusion Pumps, Implantable; Insulin; Islet Amyloid Polypeptide; Leptin; Obesity; Rats; Rats, Sprague-Dawley | 2011 |
Seipin ablation in mice results in severe generalized lipodystrophy.
Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is an autosomal recessive disorder characterized by an almost complete loss of adipose tissue, insulin resistance and fatty liver. Here, we create the first murine model of BSCL2 by targeted disruption of seipin, the causative gene for BSCL2. Compared with their wild-type littermates, the seipin(-/-) mice are viable and of normal weight but display significantly reduced adipose tissue mass, hepatic steatosis, glucose intolerance and hyperinsulinemia. The levels of leptin and adiponectin were both significantly decreased in seipin(-/-) mice, so were non-esterified fatty acids upon fasting. Surprisingly, however, hypertriglyceridemia which is common in human BSCL, was not observed in seipin(-/-) mice. Our findings suggest a possible tissue-autonomous role of seipin in liver lipid storage. The availability of the seipin(-/-) mice should help elucidate the molecular function of seipin and lead to a better understanding of the many metabolic consequences of human BSCL2. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Genotype; GTP-Binding Protein gamma Subunits; Humans; Leptin; Lipodystrophy, Congenital Generalized; Magnetic Resonance Imaging; Mice; Mice, Knockout; Real-Time Polymerase Chain Reaction | 2011 |
Supraphysiological triiodothyronine doses diminish leptin and adiponectin gene expression, but do not alter resistin expression in calorie restricted obese rats.
Thyroid hormones regulate energy balance and act on adipokines. However, while it is unclear what the effects are of calorie restriction and high doses of triiodothyronine (T(3)) on adipokines in obesity, thyroid hormones are illicitly administered in isolation or in association with a hypocaloric diet as an obesity treatment. The present study determined the effect of T(3) on serum concentrations and gene expression of the adipokines leptin, resistin, and adiponectin in calorie-restricted obese rats. Male Wistar rats received a hypercaloric diet for 20 weeks followed by calorie restriction for 8 weeks. The animals were then randomly divided into 3 groups: calorie restriction (OR), OR with 5 μg of T(3)/100 g BW (RS1), and OR with 25 μg of T(3)/100 g BW (RS2) for 2 weeks. Blood and adipose tissue samples were collected for biochemical, hormonal, and gene expression analyses. Serum concentrations of leptin (OR: 3.7±0.6, RS1: 3.8±1, RS2 0.2±0.07 ng/dl) and resistin (OR: 2.5±0.6, RS1: 2.5±0.5, RS2 1.6±0.3 ng/dl) were diminished at the higher dose, while serum adiponectin (OR: 31±7, RS1: 24±5, RS2 26±7 ng/dl) levels were lower in the low dose group. Administration of T(3) reduced leptin gene expression (OR: 0.91±0.1, RS1: 0.95±0.1, RS2 0.22±0.1) only at the higher dose, resistin expression (OR: 1.06±0.2, RS1: 1.04±0.1, RS2 0.88±0.2) was not influenced by T(3) treatment, and adiponectin expression (OR: 1.55±0.5, RS1: 0.95±0.15, RS2 0.97±0.13) was diminished independent of the T(3) dose. These results indicate that T(3), directly or indirectly, inhibits the expression of leptin and adiponectin in calorie restricted obese animals. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Caloric Restriction; Dose-Response Relationship, Drug; Gene Expression Regulation; Leptin; Male; Obesity; Rats; Rats, Wistar; Resistin; Triiodothyronine | 2011 |
Reduction of body weight, liver steatosis and expression of stearoyl-CoA desaturase 1 by the isoflavone daidzein in diet-induced obesity.
The lack of safe and effective treatments for obesity has increased interest in natural products that may serve as alternative therapies. From this perspective, we have analysed the effects of daidzein, one of the main soy isoflavones, on diet-induced obesity in rats.. Rats made obese after exposure to a very (60%) high fat-content diet were treated with daidzein (50 mg·kg(-1)) for 14 days. The dose was selected on the basis of the acute effects of this isoflavone on a feeding test. After 14 days, animals were killed and plasma, white and brown adipose tissue, muscle and liver studied for the levels and expression of metabolites, proteins and genes relevant to lipid metabolism.. A single treatment (acute) with daidzein dose-dependently reduced food intake. Chronic treatment (daily for 14 days) reduced weight gain and fat content in liver, accompanied by high leptin and low adiponectin levels in plasma. While skeletal muscle was weakly affected by treatment, both adipose tissue and liver displayed marked changes after treatment with daidzein, affecting transcription factors and lipogenic enzymes, particularly stearoyl coenzyme A desaturase 1, a pivotal enzyme in obesity. Expression of uncoupling protein 1, an important enzyme for thermogenesis, was increased in brown adipose tissue after daidzein treatment.. These results support the use of isoflavones in diet-induced obesity, especially when hepatic steatosis is present and open a new field of use for these natural products. Topics: Acetyl-CoA Carboxylase; Acyl-CoA Oxidase; Adiponectin; Adipose Tissue; Adipose Tissue, White; Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Disease Models, Animal; Eating; Fatty Acid Synthases; Fatty Liver; Insulin; Isoflavones; Leptin; Liver; Male; Muscle, Skeletal; Obesity; PPAR alpha; PPAR gamma; Rats; Rats, Wistar; Stearoyl-CoA Desaturase | 2011 |
Food hoarding and associated neuronal activation in brain reward circuitry in Mongolian gerbils.
Mongolian gerbils (Meriones unguiculatus) display food hoarding and thus provide an opportunity to study the neuromechanisms underlying this behavior. In the present study, male gerbils exhibited a bimodal expression of food hoarding behavior-some displayed high levels of food hoarding whereas others virtually lacked this behavior under normal laboratory conditions with free access to food. Food hoarding was found to be associated with an increase in neuronal activation, indicated by Fos immunoreactive (ir) staining, in several brain areas including the nucleus accumbens, ventral tegmental area (VTA), and lateral hypothalamus. Food hoarding was also associated with increases in the number of cells labeled for tyrosine hydroxylase (TH-ir), the rate limiting enzyme for dopamine conversion, and the number of cells co-labeled for TH-ir/Fos-ir in the VTA, suggesting that dopamine in the brain reward circuitry may be involved in food hoarding. Further, we found that 22 h of food deprivation induced food hoarding in some, but not all, males that naturally did not display food hoarding. In these males, however, food hoarding did not increase TH-ir or TH-ir/Fos-ir expression in the VTA. Together, these data indicate that male Mongolian gerbils display diverse phenotypes of food hoarding behavior and that dopamine in the brain reward circuitry may be involved in the control of naturally occurring, but not food deprivation-induced, food hoarding. Topics: Animals; Behavior, Animal; Body Weight; Brain; Eating; Fats; Feeding Behavior; Food Deprivation; Gene Expression Regulation; Gerbillinae; Leptin; Male; Neural Pathways; Proto-Oncogene Proteins c-fos; Reward; Tyrosine 3-Monooxygenase | 2011 |
Perinatal exposure to bisphenol A at reference dose predisposes offspring to metabolic syndrome in adult rats on a high-fat diet.
Bisphenol A (BPA), a widely used environmental endocrine disruptor, has been reported to disrupt glucose homeostasis. BPA exposure may be a risk factor for type 2 diabetes. In this study, we investigated the effects of early-life BPA exposure on metabolic syndrome in rat offspring fed a normal diet and a high-fat diet. Pregnant Wistar rats were exposed to BPA (50, 250, or 1250 μg/kg · d) or corn oil throughout gestation and lactation by oral gavage. Offspring were fed a normal diet or a high-fat diet after weaning. Body weight, parameters of glucose and lipid metabolism, morphology, and function of β-cells were measured in offspring. On a normal diet, perinatal exposure to 50 μg/kg · d BPA resulted in increased body weight, elevated serum insulin, and impaired glucose tolerance in adult offspring. On a high-fat diet, such detrimental effects were accelerated and exacerbated. Furthermore, severe metabolic syndrome, including obesity, dyslipidemia, hyperleptindemia, hyperglycemia, hyperinsulinemia, and glucose intolerance, was observed in high-fat-fed offspring perinatally exposed to 50 μg/kg · d BPA. No adverse effect of perinatal BPA exposure at 250 and 1250 μg/kg · d was observed no matter on a normal diet or a high-fat diet. These results suggest that perinatal exposure to BPA at reference dose, but not at high dose, impairs glucose tolerance in adult rat offspring on a normal diet and predisposes offspring to metabolic syndrome at adult on a high-fat diet. High-fat diet intake is a trigger that initiates adverse metabolic effects of BPA. Topics: Aging; Animals; Benzhydryl Compounds; Body Weight; Dietary Fats; Energy Intake; Female; Fetus; Glucose; Homeostasis; Insulin-Secreting Cells; Leptin; Lipid Metabolism; Male; Metabolic Syndrome; Mitochondria; Phenols; Pregnancy; Rats; Rats, Wistar | 2011 |
Important roles of brain-specific carnitine palmitoyltransferase and ceramide metabolism in leptin hypothalamic control of feeding.
Brain-specific carnitine palmitoyltransferase-1 (CPT-1c) is implicated in CNS control of food intake. In this article, we explore the role of hypothalamic CPT-1c in leptin's anorexigenic actions. We first show that adenoviral overexpression of CPT-1c in hypothalamic arcuate nucleus of rats increases food intake and concomitantly up-regulates orexigenic neuropeptide Y (NPY) and Bsx (a transcription factor of NPY). Then, we demonstrate that this overexpression antagonizes the anorectic actions induced by central leptin or compound cerulenin (an inhibitor of fatty acid synthase). The overexpression of CPT-1c also blocks leptin-induced down-regulations of NPY and Bsx. Furthermore, the anorectic actions of central leptin or cerulenin are impaired in mice with brain CPT-1c deleted. Both anorectic effects require elevated levels of hypothalamic arcuate nucleus (Arc) malonyl-CoA, a fatty acid-metabolism intermediate that has emerged as a mediator in hypothalamic control of food intake. Thus, these data suggest that CPT-1c is implicated in malonyl-CoA action in leptin's hypothalamic anorectic signaling pathways. Moreover, ceramide metabolism appears to play a role in leptin's central control of feeding. Leptin treatment decreases Arc ceramide levels, with the decrease being important in leptin-induced anorectic actions and down-regulations of NPY and Bsx. Of interest, our data indicate that leptin impacts ceramide metabolism through malonyl-CoA and CPT-1c, and ceramide de novo biosynthesis acts downstream of both malonyl-CoA and CPT-1c in mediating their effects on feeding and expressions of NPY and Bsx. In summary, we provide insights into the important roles of malonyl-CoA, CPT-1c, and ceramide metabolism in leptin's hypothalamic signaling pathways. Topics: Animals; Arcuate Nucleus of Hypothalamus; Blotting, Western; Body Weight; Brain; Carnitine O-Palmitoyltransferase; Ceramides; Cerulenin; Eating; Humans; Hypothalamus; Leptin; Male; Malonyl Coenzyme A; Mice; Mice, Knockout; Nerve Tissue Proteins; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors | 2011 |
Effect of hydroxypropyl methylcellulose on obesity and glucose metabolism in a diet-induced obesity mouse model.
To investigate the effect of hydroxypropyl methylcellulose (HPMC) on weight loss and metabolic disorders associated with obesity using a high-fat diet-induced obese mouse model under a high-fat diet regimen.. Obese male C57BL/6J (B6) mice were fed either a high-fat (60% kcal), low-fat (10% kcal), or high-fat diet plus HPMC (4% and 8%) for 5 weeks. Body, mesenteric adipose, and liver weights were determined at the end of the study. In addition, plasma cholesterol, insulin, glucose, adiponectin, and leptin were analyzed to determine the effects of HPMC. Hepatic and fecal lipids were measured to determine the effect of HPMC on lipid absorption and metabolism.. Supplementation of the high-fat diet with 4% and 8% HPMC resulted in significant weight loss in obese B6 mice. Furthermore, significant decreases were seen in adipose (30%-40%), liver weights (15%-26%), and concentrations of plasma cholesterol (13%-20%) and hepatic lipids (13%-36%). Supplementation with 8% HPMC led to significant improvements in glucose homeostasis and leptin concentrations. Reductions in plasma cholesterol, glucose, and insulin levels were strongly correlated with reduced leptin concentrations. Moreover, increases in fecal secretion of total bile acids, sterols, and fats indicated altered fat absorption when HPMC was incorporated in the diet.. The data indicate that HPMC not only reduces body weight, but also normalizes the metabolic abnormalities associated with obesity and suggest that the effects of HPMC on glucose and lipid homeostasis in B6 mice are mediated by improvements in leptin sensitivity resulting from reduced fat absorption. Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Dietary Fats; Hypromellose Derivatives; Insulin; Leptin; Liver; Male; Methylcellulose; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Random Allocation; Regression Analysis; Weight Loss | 2011 |
Taste perception and implicit attitude toward sweet related to body mass index and soft drink supplementation.
These studies examined the differences in sweet taste perception and implicit attitude toward sweet between normal-weight and overweight/obese adults; and tested the effects of soft drink consumption on sweet taste, explicit preference and implicit attitude toward sweet in normal-weight subjects. In study 1, normal-weight (n = 22) and overweight/obese (n = 11) adults were assessed for sweet taste intensity and pleasantness. Implicit attitude toward sweet was assessed by implicit association test (IAT). In study 2, normal-weight, lightly active adults (n = 12) underwent one month soft drink supplementation (≈760 ml/day). This increased their daily carbohydrate intake by 2.1 ± 0.2g/kg body weight. Sweet taste perception, explicit preference and implicit attitudes to sweet were assessed. In both studies salty taste was also assessed as a contrasting perception. Overweight/obese subjects perceived sweet and salty tastes as less intense (-23% and -19%, respectively) and reported higher IAT scores for sweet than normal-weight controls (2.1-fold). The supplementation changed sweet intensity/pleasantness ratings and it increased explicit preference (2.3-fold) for sweet in a subgroup of initial sucrose-dislikers. In conclusion, overweight/obese individuals are more implicitly attracted to sweet. One month of soft drink supplementation changed sweet taste perception of normal-weight subjects. Topics: Adult; Appetite; Attitude; Body Composition; Body Mass Index; Body Weight; Carbonated Beverages; Female; Food Preferences; Humans; Leptin; Male; Mouth; Obesity; Sucrose; Taste Perception; Taste Threshold; Young Adult | 2011 |
Neuroanatomy of body weight control: lessons learned from leptin.
Rather than arising from the passive accumulation of excess calories, obesity is a state in which the biologically defended level of body fat stores increases due to defects in the homeostatic process that matches food intake and energy expenditure over time. By deleting leptin receptors from distinct brain regions and neuronal subsets, researchers are beginning to identify the neuroanatomical substrates responsible for this regulation. In this issue of the JCI, Scott et al. demonstrate that loss of leptin receptors in a subset of hindbrain neurons increases food intake in mice, but, unlike what is observed when leptin receptors are deleted from hypothalamic neurons, these mice compensate by increasing energy expenditure and hence do not become obese. Although many brain areas can regulate energy intake and/or energy expenditure, it is likely that only a small subset of neurons actively matches the two over time. It is vital to clarify how this works if we are to improve our understanding of obesity pathogenesis and options available for its treatment. Topics: Animals; Body Weight; Brain; Decerebrate State; Energy Intake; Energy Metabolism; Feeding Behavior; Homeostasis; Humans; Hyperphagia; Leptin; Mice; Mice, Knockout; Neurons; Obesity; Organ Specificity; Peptide Hormones; Rats; Receptors, Leptin | 2011 |
Comparative assessment of estrogenic responses with relevance to the metabolic syndrome and to menopausal symptoms in wild-type and aromatase-knockout mice.
Knockout of the Cyp-19 gene (aromatase) renders mice to have insufficient endogenous estrogen production and contributes to the development of symptoms related the metabolic syndrome, including excess adiposity and insulin resistance. This study comparatively assessed the estrogen responsiveness in animal models of genetical versus surgical (ovariectomy) origin of estrogen deficiency. Evaluation of physiological parameters and gene expression pattern in response to estrogens revealed differences in estrogen responsiveness between aromatase deficient and castrated or intact wild-type mice. ArKO mice had a significantly higher bodyweight than matched ovariectomized wild-type mice. The weight of the completely regressed uterus following ovariectomy was higher than the uterine weight of ArKO mice. Further, alterations in metabolic parameters like increased serum leptin levels and decreased plasma glucose levels in genetically deficient mice became apparent. Finally, expression pattern of estrogen responsive genes differed in the two experimental models of estrogen deficiency. Both, in uterine and adipose tissues the regulation of expression of some genes either was inversed of regulation or considerably differed in the magnitude of the response in the two models. Our studies demonstrate that the cause of estrogen deficiency significantly impacts on estrogen responsiveness and may be of relevance for investigations on aspects of estrogen deficiency and metabolic and/or menopausal symptoms. Topics: Animals; Aromatase; Base Sequence; Blood Glucose; Body Weight; DNA Primers; Estrogens; Female; Gene Expression Profiling; Leptin; Menopause; Metabolic Syndrome; Mice; Mice, Knockout; Organ Size; Ovariectomy; Real-Time Polymerase Chain Reaction; Uterus | 2011 |
Pre- and post-weaning cold exposure does not lead to an obese phenotype in adult Brandt's voles (Lasiopodomys brandtii).
Evidence has shown that postnatal undernutrition, overnutrition and cold stress are associated with imbalanced metabolic regulation as rodents achieve adulthood. In this study, we used a breeding colony of Brandt's voles (Lasiopodomys brandtii), a wild rodent species from the Inner Mongolia grasslands in China, to examine the effects of pre- and post-weaning cold exposure on the adult body (fat) mass, serum hormones and hypothalamic neuropeptides. Unlike laboratory rodents, vole offspring exposed to pre-weaning cold did not exhibit overweight or obese phenotypes in adulthood compared with unexposed controls. Moreover, adult male voles that remained in colder conditions had less body mass and lower serum leptin levels despite having higher food intake compared to other groups. To understand the mechanism of this unexpected regulation, hypothalamic gene expression was assessed for pre- and post-weaning cold exposure. Voles exposed to cold before weaning increased hypothalamic, orexigenic agouti-related protein (AgRP) and decreased anorexigenic proopiomelanocortin (POMC) mRNA expression at weaning. These expression changes were associated with hyperphagia and catch-up growth after weaning. Interestingly, these changes in hypothalamic neuropeptides were short lasting because in adult voles these differences were no longer apparent, which might explain why the pre-weaning, cold-exposed voles did not become obese in adulthood. These data suggest that some species do not develop an obese phenotype in response to early life cold stress. Topics: Agouti-Related Protein; Animals; Arvicolinae; Body Composition; Body Weight; Cold Temperature; Eating; Female; Gene Expression; Hypothalamus; Leptin; Male; Mitochondrial Proteins; Obesity; Pro-Opiomelanocortin; Thyroxine; Triiodothyronine; Weaning | 2011 |
Serum leptin concentration and its effect on puberty in Naqu Tibetan adolescents.
This study aimed to clarify the regularity of leptin in Naqu Tibetan adolescents. This study investigated the concentration of fasting serum leptin and clarified its relationship between BMI and other indices. Healthy Naqu Tibetan adolescents aged 12-18 were investigated randomly in the study. They were divided into seven groups (each year as one group, 12 boys and 12 girls in each group); serum concentrations of leptin, estradiol, testosterone (T), follicle stimulating hormone (FSH) and luteinizing hormone (LH) were analyzed. The height and body weight of the 168 healthy Naqu Tibetan adolescents were also assessed. The leptin level in boys decreased with age but increased in girls; in boys and girls they both differed between groups (p<0.05). In boys, the leptin level was inversely correlated with body mass index (BMI), FSH, and T (p<0.05), while in girls, it was positively related to BMI, FSH, LH, and E2 (p<0.01).These findings suggested that during puberty the serum leptin concentration increased with age in girls while it decreased in boys; in the same age group, the leptin level in girls was significantly higher than in boys. Leptin may have some relationship with puberty in Tibetan adolescents. Topics: Adolescent; Adult; Body Height; Body Mass Index; Body Weight; Child; Cohort Studies; Estradiol; Female; Follicle Stimulating Hormone; Humans; Leptin; Luteinizing Hormone; Male; Puberty; Testosterone; Tibet; Young Adult | 2011 |
Litter size variation in hypothalamic gene expression determines adult metabolic phenotype in Brandt's voles (Lasiopodomys brandtii).
Early postnatal environments may have long-term and potentially irreversible consequences on hypothalamic neurons involved in energy homeostasis. Litter size is an important life history trait and negatively correlated with milk intake in small mammals, and thus has been regarded as a naturally varying feature of the early developmental environment. Here we investigated the long-term effects of litter size on metabolic phenotype and hypothalamic neuropeptide mRNA expression involved in the regulation of energy homeostasis, using the offspring reared from large (10-12) and small (3-4) litter sizes, of Brandt's voles (Lasiopodomys brandtii), a rodent species from Inner Mongolia grassland in China.. Hypothalamic leptin signaling and neuropeptides were measured by Real-Time PCR. We showed that offspring reared from small litters were heavier at weaning and also in adulthood than offspring from large litters, accompanied by increased food intake during development. There were no significant differences in serum leptin levels or leptin receptor (OB-Rb) mRNA in the hypothalamus at weaning or in adulthood, however, hypothalamic suppressor of cytokine signaling 3 (SOCS3) mRNA in adulthood increased in small litters compared to that in large litters. As a result, the agouti-related peptide (AgRP) mRNA increased in the offspring from small litters.. These findings support our hypothesis that natural litter size has a permanent effect on offspring metabolic phenotype and hypothalamic neuropeptide expression, and suggest central leptin resistance and the resultant increase in AgRP expression may be a fundamental mechanism underlying hyperphagia and the increased risk of overweight in pups of small litters. Thus, we conclude that litter size may be an important and central determinant of metabolic fitness in adulthood. Topics: Adipose Tissue; Aging; Animals; Arvicolinae; Basal Metabolism; Biomarkers; Body Composition; Body Weight; Feeding Behavior; Female; Gene Expression Regulation; Hypothalamus; Leptin; Litter Size; Male; Neuropeptides; Organ Size; Organ Specificity; Phenotype; RNA, Messenger; Signal Transduction; Thermogenesis; Thyroxine; Triiodothyronine; Weaning | 2011 |
High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons.
Steroidogenic factor 1 (SF-1)-expressing neurons of the ventromedial hypothalamus (VMH) control energy homeostasis, but the role of insulin action in these cells remains undefined. We show that insulin activates phosphatidylinositol-3-OH kinase (PI3K) signaling in SF-1 neurons and reduces firing frequency in these cells through activation of K(ATP) channels. These effects were abrogated in mice with insulin receptor deficiency restricted to SF-1 neurons (SF-1(ΔIR) mice). Whereas body weight and glucose homeostasis remained the same in SF-1(ΔIR) mice as in controls under a normal chow diet, they were protected from diet-induced leptin resistance, weight gain, adiposity and impaired glucose tolerance. High-fat feeding activated PI3K signaling in SF-1 neurons of control mice, and this response was attenuated in the VMH of SF-1(ΔIR) mice. Mimicking diet-induced overactivation of PI3K signaling by disruption of the phosphatidylinositol-3,4,5-trisphosphate phosphatase PTEN led to increased body weight and hyperphagia under a normal chow diet. Collectively, our experiments reveal that high-fat diet-induced, insulin-dependent PI3K activation in VMH neurons contributes to obesity development. Topics: Action Potentials; Age Factors; Animals; Animals, Newborn; Blood Glucose; Body Weight; Calorimetry; Dietary Fats; Dose-Response Relationship, Drug; Eating; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Glucose Tolerance Test; Green Fluorescent Proteins; Hypoglycemic Agents; In Vitro Techniques; Injections, Intraventricular; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Obesity; Patch-Clamp Techniques; Phosphatidylinositol 3-Kinases; Receptor, Insulin; RNA, Messenger; Signal Transduction; Steroidogenic Factor 1; Time Factors; Tolbutamide; Ventromedial Hypothalamic Nucleus | 2011 |
Central infusion of ketone bodies modulates body weight and hepatic insulin sensitivity by modifying hypothalamic leptin and insulin signaling pathways in type 2 diabetic rats.
Although the effects of ketogenic diets on energy and glucose homeostasis have been controversial, elevation of serum ketone levels by subcutaneous injection of β-hydroxybutyrate (BHB) can improve glucose homeostasis. Ketones may work through the brain; therefore, we evaluated whether the intracerebroventricular (ICV) infusion of β-hydroxybutyrates would also modulate peripheral energy and glucose homeostasis, and through what mechanisms, in diabetic rats fed a high fat diet in short- and long-term studies. Short-term (3h) central injection of BHB (50 μg/h) improved serum glucose levels and peripheral insulin sensitivity compared to the artificial cerebrospinal fluid (CSF) group among 90% pancreatectomized (Px) diabetic rats, but not in non-diabetic Sham rats. In addition to short-term infusion, long-term (28 days) central infusion of BHB (12 μg/h) elevated serum BHB levels. Long-term infusion of BHB potentiated leptin and insulin signaling in the hypothalamus to slightly decrease body weight in Px rats. Central BHB infusion had a greater effect on peripheral glucose metabolism than overall energy metabolism. Hepatic insulin signaling (tyrosine phosphorylation of IRS2→serine phosphorylation of Akt→reduced expression of PEPCK) was potentiated and hepatic glucose production in the hyperinsulinemic state was suppressed in the diabetic rats. In addition, glucose tolerance was improved by central BHB infusion through enhanced whole body glucose disposal rates, but insulin secretion was not affected in the diabetic rats. In conclusion, mild ketosis by central infusion of ketones improves energy and glucose metabolism through the potentiation of leptin and insulin signaling in the hypothalamus of diabetic rats. Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Infusions, Intraventricular; Insulin; Insulin Resistance; Ketone Bodies; Leptin; Liver; Male; Rats; Rats, Sprague-Dawley; Signal Transduction | 2011 |
Analysis of time-dependent adaptations in whole-body energy balance in obesity induced by high-fat diet in rats.
High-fat (HF) diet has been extensively used as a model to study metabolic disorders of human obesity in rodents. However, the adaptive whole-body metabolic responses that drive the development of obesity with chronically feeding a HF diet are not fully understood. Therefore, this study investigated the physiological mechanisms by which whole-body energy balance and substrate partitioning are adjusted in the course of HF diet-induced obesity.. Male Wistar rats were fed ad libitum either a standard or a HF diet for 8 weeks. Food intake (FI) and body weight were monitored daily, while oxygen consumption, respiratory exchange ratio, physical activity, and energy expenditure (EE) were assessed weekly. At week 8, fat mass and lean body mass (LBM), fatty acid oxidation and uncoupling protein-1 (UCP-1) content in brown adipose tissue (BAT), as well as acetyl-CoA carboxylase (ACC) content in liver and epidydimal fat were measured.. Within 1 week of ad libitum HF diet, rats were able to spontaneously reduce FI to precisely match energy intake of control rats, indicating that alterations in dietary energy density were rapidly detected and FI was self-regulated accordingly. Oxygen consumption was higher in HF than controls throughout the study as whole-body fat oxidation also progressively increased. In HF rats, EE initially increased, but then reduced as dark cycle ambulatory activity reached values ~38% lower than controls. No differences in LBM were detected; however, epidydimal, inguinal, and retroperitoneal fat pads were 1.85-, 1.89-, and 2.54-fold larger in HF-fed than control rats, respectively. Plasma leptin was higher in HF rats than controls throughout the study, indicating the induction of leptin resistance by HF diet. At week 8, UCP-1 content and palmitate oxidation in BAT were 3.1- and 1.5-fold higher in HF rats than controls, respectively, while ACC content in liver and epididymal fat was markedly reduced.. The thermogenic response induced by the HF diet was offset by increased energy efficiency and time-dependent reduction in physical activity, favoring fat accumulation. These adaptations were mainly driven by the nutrient composition of the diet, since control and HF animals spontaneously elicited isoenergetic intake. Topics: Acetyl-CoA Carboxylase; Adaptation, Physiological; Adipose Tissue; Animals; Body Weight; Carbon Dioxide; Diet; Dietary Fats; Energy Metabolism; Feeding Behavior; Humans; Leptin; Liver; Male; Motor Activity; Muscles; Obesity; Organ Size; Oxidation-Reduction; Oxygen Consumption; Palmitates; Photoperiod; Rats; Rats, Wistar; Time Factors | 2011 |
Leptin stimulates hepatic activation of thyroid hormones and promotes early posthatch growth in the chicken.
Hepatic iodothyronine deiodinases (Ds) are involved in the conversion of thyroid hormones (THs) which interacts with growth hormone (GH) to regulate posthatch growth in the chicken. Previous studies suggest that leptin-like immunoreactive substance deposited in the egg may serve as a maternal signal to program posthatch growth. To test the hypothesis that maternal leptin may affect early posthatch growth through modifying hepatic activation of THs, we injected 5.0μg of recombinant murine leptin into the albumen of breeder eggs before incubation. Furthermore, chicken embryo hepatocytes (CEHs) were treated with leptin in vitro to reveal the direct effect of leptin on expression and activity of Ds. In ovo leptin administration markedly accelerated early posthatch growth, elevated serum levels of total and free triiodothyronine (tT3 and fT3), while that of total thyroxin (tT4) remained unchanged. Hepatic mRNA expression and activity of D1 which converts T4 to T3 or rT3 to T2, were significantly increased in leptin-treated chickens, while those of D3 which converts T3 to T2 or T4 to rT3, were significantly decreased. Moreover, hepatic expression of GHR and IGF-I mRNA was all up-regulated in leptin-treated chickens. Males demonstrated more pronounced responses. A direct effect of leptin on Ds was shown in CEHs cultured in vitro. Expression and activity of D1 were increased, whereas those of D3 were decreased, in leptin-treated cells. These data suggest that in ovo leptin administration improves early posthatch growth, in a gender-specific fashion, probably through improving hepatic activation of THs and up-regulating hepatic expression of GHR and IGF-I. Topics: Animals; Avian Proteins; Body Weight; Cells, Cultured; Chick Embryo; Chickens; Female; Gene Expression; Gene Expression Regulation, Developmental; Hepatocytes; Insulin-Like Growth Factor I; Iodide Peroxidase; Leptin; Liver; Male; Receptors, Somatotropin; Thyroid Hormones; Thyroxine; Triiodothyronine | 2011 |
The relation between dietary fructose, dietary fat and leptin responsiveness in rats.
Others reported that rats fed a high-fructose diet for 6 months were leptin resistant. We tested peripheral and/or central leptin responses in rats fed fructose for shorter time periods. Rats fed a diet containing 60% energy (% kcal) fructose and 10% kcal fat diet for 21 days had the same serum triglycerides (TG), gained less weight than controls, decreased their food intake and weight gain in response to central injections of 0.5 or 1.0 ug leptin, but were resistant to an i.p. injection of 2.0 mg leptin/kg. An i.p. injection of 1 mg leptin/kg increased phosphorylation of hypothalamic signal transducer and activator of transcription 3 (PSTAT3) implying resistance was not a failure of leptin to cross the blood brain barrier. The effects of dietary fructose were compared with those of dietary fat. Rats fed a 10%kcal fructose and 30%kcal fat diet for 39 days were leptin resistant whereas rats fed a 40%kcal fructose and 30%kcal fat diet responded to i.p. leptin. Another monosaccharide, glucose, replicated the effects of fructose in the 30% kcal fat diet. Surprisingly, none of the rats showed a reliable response to third ventricle leptin and peripheral leptin failed to stimulate hypothalamic PSTAT3 although it did increase PSTAT3 in the brainstem of rats fed the 40%kcal fructose or glucose diets. Thus a high-fructose, low-fat diet induces peripheral leptin resistance in less than 4 weeks, but high dietary concentrations of fructose or glucose prevent peripheral leptin resistance in rats fed a high-fat diet. Topics: Animals; Behavior, Animal; Body Weight; Dietary Fats; Dose-Response Relationship, Drug; Drug Administration Routes; Eating; Energy Intake; Fructose; Gene Expression Regulation; Hypothalamus; Leptin; Male; Phosphorylation; Rats; Rats, Sprague-Dawley; RNA, Messenger; STAT3 Transcription Factor; Time Factors; Triglycerides | 2011 |
Early metabolic programming of puberty onset: impact of changes in postnatal feeding and rearing conditions on the timing of puberty and development of the hypothalamic kisspeptin system.
Kiss1 neurons have recently emerged as a putative conduit for the metabolic gating of reproduction, with leptin being a regulator of hypothalamic Kiss1 expression. Early perturbations of the nutritional status are known to predispose to different metabolic disorders later in life and to alter the timing of puberty; however, the potential underlying mechanisms remain poorly defined. Here we report how changes in the pattern of postnatal feeding affect the onset of puberty and evaluate key hormonal and neuropeptide [Kiss1/kisspeptin (Kp)] alterations linked to these early nutritional manipulations. Female rats were raised in litters of different sizes: small (four pups per dam: overfeeding), normal (12 pups per dam), and large litters (20 pups per litter: underfeeding). Postnatal overfeeding resulted in persistently increased body weight and earlier age of vaginal opening, as an external sign of puberty, together with higher levels of leptin and hypothalamic Kiss1 mRNA. Conversely, postnatal underfeeding caused a persistent reduction in body weight, lower ovarian and uterus weights, and delayed vaginal opening, changes that were paralleled by a decrease in leptin and Kiss1 mRNA levels. Kisspeptin-52 immunoreactivity (Kp-IR) in the hypothalamus displayed similar patterns, with lower numbers of Kp-IR neurons in the arcuate nucleus of postnatally underfed animals, and a trend for increased Kp-positive fibers in the periventricular area of early overfed rats. Yet, gonadotropin responses to Kp at puberty were similar in all groups, except for enhanced responsiveness to low doses of Kp-10 in postnatally underfed rats. In conclusion, our data document that the timing of puberty is sensitive to both overfeeding and subnutrition during early (postnatal) periods and suggest that alterations in hypothalamic expression of Kiss1/kisspeptin may underlie at least part of such programming phenomenon. Topics: Animals; Animals, Newborn; Body Weight; Female; Hypothalamus; Kisspeptins; Leptin; Luteinizing Hormone; Maternal Behavior; Neurons; Proteins; Rats; Rats, Wistar; Sexual Maturation | 2011 |
Maternal prenatal undernutrition programs adipose tissue gene expression in adult male rat offspring under high-fat diet.
Several studies have shown that maternal undernutrition leading to low birth weight predisposes offspring to the development of metabolic pathologies such as obesity. Using a model of prenatal maternal 70% food restriction diet (FR30) in rat, we evaluated whether postweaning high-fat (HF) diet would amplify the phenotype observed under standard diet. We investigated biological parameters as well as gene expression profile focusing on white adipose tissues (WAT) of adult offspring. FR30 procedure does not worsen the metabolic syndrome features induced by HF diet. However, FR30HF rats displayed catch-up growth to match the body weight of adult control HF animals, suggesting an increase of adiposity while showing hyperleptinemia and a blunted increase of corticosterone. Using quantitative RT-PCR array, we demonstrated that FR30HF rats exhibited leptin and Ob-Rb as well as many peptide precursor and receptor gene expression variations in WAT. We also showed that the expression of genes involved in adipogenesis was modified in FR30HF animals in a depot-specific manner. We observed an opposite variation of STAT3 phosphorylation levels, suggesting that leptin sensitivity is modified in WAT adult FR30 offspring. We demonstrated that 11β-HSD1, 11β-HSD2, GR, and MR genes are coexpressed in WAT and that FR30 procedure modifies gene expression levels, especially under HF diet. In particular, level variation of 11β-HSD2, whose protein expression was detected by Western blotting, may represent a novel mechanism that may affect WAT glucocorticoid sensitivity. Data suggest that maternal undernutrition differently programs the adult offspring WAT gene expression profile that may predispose for altered fat deposition. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; Adipose Tissue; Adiposity; Animals; Body Weight; Dietary Fats; Female; Gene Expression; Leptin; Male; Malnutrition; Maternal Nutritional Physiological Phenomena; Obesity; Phosphorylation; Rats; Rats, Wistar; STAT3 Transcription Factor | 2011 |
Anti-visceral obesity and antioxidant effects of powdered sea buckthorn (Hippophae rhamnoides L.) leaf tea in diet-induced obese mice.
The potential health benefits of tea have long been studied. This study examined the role of powdered sea buckthorn leaf tea (SLT) in high-fat diet-induced obese mice. The mice were fed two different doses of SLT (1% and 5%, wt/wt) for six weeks. SLT suppressed body weight gain in a dose-dependent manner and significantly reduced visceral fat, plasma levels of leptin, triglyceride and total cholesterol and ALT activity compared with the high-fat-fed control mice. SLT also decreased hepatic triglyceride and cholesterol concentrations and lipid accumulation, whereas elevated fecal lipid excretion. High-fat feeding resulted in simultaneously decreasing hepatic FAS and G6PD activities and increasing PAP, β-oxidation and CPT activities. However, SLT supplementation during high-fat feeding led to a significant decrease in PAP, β-oxidation and CPT activities with a simultaneous increase in G6PD activity. The hepatic CYP2E1 activity and hepatic and erythrocyte lipid peroxides were significantly lowered with SLT supplements. Hepatic and erythrocyte SOD and CAT activities were also increased with SLT supplements in a dose-dependent manner, whereas GSH-Px activity was increased in erythrocytes only. These results indicate that SLT has potential anti-visceral obesity and antioxidant effects mediated by the regulation of lipid and antioxidant metabolism in high-fat diet-induced obese mice. Topics: Animals; Antioxidants; Body Weight; Dietary Fats; Hippophae; Leptin; Male; Mice; Mice, Inbred ICR; Obesity, Abdominal; Powders; Tea; Weight Gain | 2011 |
Obesity and downregulated hypothalamic leptin receptors in male metallothionein-3-null mice.
In the present study, we examined whether metallothionein-3 (Mt3), a zinc-binding protein that is specifically enriched in a brain, plays a role in obesity and hypothalamic leptin signaling in mice. Upon aging, male Mt3-null mice gained more body weight than male wild-type mice; however, the daily amount of food intake was little different. Rather, the obesity in male Mt3-null mice was likely the result of decreased metabolic rates, as indicated by lower oxygen consumption and carbon dioxide production. Consistent with this, mRNA levels for the mitochondrial proton carrier UCP1 were reduced in brown adipose tissue of Mt3-null mice. Although Mt3-null mice showed increases in serum leptin levels, probably due to increased fat mass, the level of the leptin receptor (Lepr) in the hypothalamus of these mice was significantly reduced. In addition, levels of phosphorylated extracellular signal-regulated kinase (p-Erk-1/2) were also reduced in the hypothalamus of Mt3-null mice. Because zinc released from Mt3 may activate Erk-1/2, we examined whether zinc is involved in the upregulation of Lepr levels through the activation of Erk-1/2. Consistent with this possibility, exposure of hypothalamic cells to zinc activated Erk-1/2 and induced Lepr expression in an Erk-dependent manner. The present results demonstrate that Mt3 in the brain of male mice, particularly in the hypothalamus, may be involved in central leptin signaling and the consequent increase in peripheral energy expenditure. In addition to providing insight into the role of zinc and metallothioneins in the development of obesity, this new information may help design ways to overcome the pervasive problem of obesity. Topics: Animals; Blotting, Western; Body Weight; Cells, Cultured; Down-Regulation; Eating; Energy Metabolism; Hypothalamus; Leptin; Male; Metallothionein 3; Metals; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Obesity; Oxygen Consumption; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transfection | 2011 |
Mango modulates body fat and plasma glucose and lipids in mice fed a high-fat diet.
Consumption of fruits and vegetables has been investigated for their role in the prevention of many chronic conditions. Among the fruits, mango provides numerous bioactive compounds such as carotenoids, vitamin C and phenolic compounds, which have been shown to have antioxidant and anti-inflammatory properties. The present study examined the effects of dietary supplementation of freeze-dried mango pulp, in comparison with the hypolipidaemic drug, fenofibrate, and the hypoglycaemic drug, rosiglitazone, in reducing adiposity and alterations in glucose metabolism and lipid profile in mice fed a high-fat (HF) diet. Male C57BL/6J mice were randomly divided into six treatment groups (eight to nine/group): control (10 % energy from fat); HF (60 % energy from fat); HF+1 or 10 % freeze-dried mango (w/w); HF+fenofibrate (500 mg/kg diet); HF+rosiglitazone (50 mg/kg diet). After 8 weeks of treatment, mice receiving the HF diet had a higher percentage body fat (P = 0·0205) and epididymal fat mass (P = 0·0037) compared with the other treatment groups. Both doses of freeze-dried mango, similar to fenofibrate and rosiglitazone, prevented the increase in epididymal fat mass and the percentage of body fat. Freeze-dried mango supplementation at the 1 % dose improved glucose tolerance as shown by approximately 35 % lower blood glucose area under the curve compared with the HF group. Moreover, freeze-dried mango lowered insulin resistance, as indicated by the homeostasis model assessment of insulin resistance, to a similar extent as rosiglitazone and modulated NEFA. The present findings demonstrate that incorporation of freeze-dried mango in the diet of mice improved glucose tolerance and lipid profile and reduced adiposity associated with a HF diet. Topics: Adiponectin; Adiposity; Animals; Blood Glucose; Body Composition; Body Weight; Dietary Fats; Gene Expression Profiling; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Lipids; Male; Mangifera; Mice; Mice, Inbred C57BL; Organ Size; Real-Time Polymerase Chain Reaction | 2011 |
Maternal protein restriction in mice causes adverse metabolic and hypothalamic effects in the F1 and F2 generations.
Maternal protein restriction causes metabolic alterations associated with hypothalamic dysfunction. Because the consequences of metabolic programming can be passed transgenerationally, the present study aimed to assess whether maternal protein restriction alters the expression of hypothalamic neuropeptides in offspring and to evaluate hormonal and metabolic changes in male offspring from the F1 and F2 generations. Female Swiss mice (F0) were mated and fed either a normal-protein (NP group; 19 % protein) or a low-protein (LP group; 5 % protein) diet throughout gestation of the F1 generation (NP1 and LP1). At 3 months of age, F1 females were mated to produce the F2 generation (NP2 and LP2). Animals from all groups were evaluated at 16 weeks of age. LP1 offspring had significantly lower weights and shorter lengths than NP1 offspring at birth, but they underwent a phase of rapid catch-up growth. Conversely, the LP2 offspring were not significantly different from the NP2 offspring in either weight or length. At 16 weeks, no differences were found in body mass among any of the groups, although LP1 and LP2 offspring showed hypercholesterolaemia, hypertriacylglycerolaemia, hyperglycaemia, glucose intolerance, insulin resistance, increased levels of insulin, leptin and resistin, decreased endogenous leptin sensitivity, increased adiposity with elevated leptin levels and leptin resistance characterised by altered expression of neuropeptide Y and pro-opiomelanocortin without any changes in the leptin receptor Ob-Rb. We conclude that severe maternal protein restriction promotes metabolic programming in F1 and F2 male offspring due to a dysregulation of the adipoinsular axis and a state of hypothalamic leptin resistance. Topics: Animals; Birth Weight; Body Weight; Diet, Protein-Restricted; Female; Growth; Hypothalamus; Leptin; Male; Maternal Nutritional Physiological Phenomena; Metabolic Diseases; Mice; Mice, Inbred Strains; Neuropeptide Y; Pregnancy; Prenatal Exposure Delayed Effects; Protein Deficiency; Receptors, Leptin | 2011 |
Chronic AMP-kinase activation with AICAR reduces adiposity by remodeling adipocyte metabolism and increasing leptin sensitivity.
This study investigated the effect of chronic AMP-kinase (AMPK) activation with 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) on white adipose tissue (WAT) metabolism and the implications for visceral (VC) and subcutaneous (SC) adiposity, whole body-energy homeostasis, and hypothalamic leptin sensitivity. Male Wistar rats received daily single intraperitoneal injections of either saline or AICAR (0.7g/kg body weight) for 4 and 8 weeks and were pair-fed throughout the study. AICAR-treated rats had reduced adiposity with increased mitochondrial density in VC and SC fat pads, which was accompanied by reduced circulating leptin and time-dependent and depot-specific regulation of AMPK phosphorylation and FA oxidation. Interestingly, the anorectic effect to exogenous leptin was more pronounced in AICAR-treated animals than controls. This corresponded to reductions in hypothalamic AMPK phosphorylation and suppressor of cytokine signaling 3 content, whereas signal transducer and activator of transcription 3 phosphorylation was either unchanged or increased at 4 and 8 weeks in AICAR-treated rats. Ambulatory activity and whole-body energy expenditure (EE) were also increased with AICAR treatment. Altogether, chronic AICAR-induced AMPK activation increased WAT oxidative machinery, whole-body EE, and hypothalamic leptin sensitivity. This led to significant reductions in VC and SC adiposity without inducing energy-sparing mechanisms that oppose long-term fat loss. Topics: Adenylate Kinase; Adipocytes; Adipose Tissue; Adiposity; Aminoimidazole Carboxamide; Animals; Body Weight; Eating; Energy Metabolism; Enzyme Activation; Hypoglycemic Agents; Hypothalamus; Leptin; Male; Mitochondria; Palmitates; Rats; Rats, Wistar; Ribonucleotides | 2011 |
Leptin resistance develops spontaneously in mice during adult life in a tissue-specific manner. Consequences for hepatic steatosis.
Leptin is an adipocyte-derived hormone which stimulates β-oxidation in peripheral tissues and prevents steatosis. Because leptin production naturally increases during adult life, we have hypothesized that leptin receptors might undergo a physiological and gradual desensitization during ageing. Therefore we have characterized in three- five- and ten-month old mice i) the weight of different white adipose pads, heart and liver, ii) lipid content in these tissues/organs, and iii) responsiveness to acute leptin, measured in terms of phosphorylation of signal transducer and activator of transcription 3 (STAT3) and protein kinase B (Akt). In this study we have detected that leptin-mediated STAT3 phosphorylation appears to be preserved in cardiac tissue even in 10-month old animals but not in adipose tissue and liver of five- and ten-month old mice, respectively. Nevertheless, leptin increased pAkt content in the liver of these mice. In a parallel study we have analyzed the functionality of leptin signalling pathways in 10-month old obese mice and we have observed that the STAT3 pathway appears to be only operative in the heart whereas the Akt pathway remains functional both in heart and liver. Nevertheless, hepatic lipids increased almost 300% compared to age-matched lean controls. Our data demonstrate that during adult life there is a lost of leptin receptor functionality which is tissue-dependent and mainly affects the STAT3 pathway. Otherwise we demonstrate that the antisteatotic effect of leptin is independent of the Akt signalling pathway. Topics: Animals; Blotting, Western; Body Weight; Fatty Liver; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Myocardium; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor | 2011 |
The central cannabinoid CB1 receptor is required for diet-induced obesity and rimonabant's antiobesity effects in mice.
Cannabinoid receptor CB1 is expressed abundantly in the brain and presumably in the peripheral tissues responsible for energy metabolism. It is unclear if the antiobesity effects of rimonabant, a CB1 antagonist, are mediated through the central or the peripheral CB1 receptors. To address this question, we generated transgenic mice with central nervous system (CNS)-specific knockdown (KD) of CB1, by expressing an artificial microRNA (AMIR) under the control of the neuronal Thy1.2 promoter. In the mutant mice, CB1 expression was reduced in the brain and spinal cord, whereas no change was observed in the superior cervical ganglia (SCG), sympathetic trunk, enteric nervous system, and pancreatic ganglia. In contrast to the neuronal tissues, CB1 was undetectable in the brown adipose tissue (BAT) or the liver. Consistent with the selective loss of central CB1, agonist-induced hypothermia was attenuated in the mutant mice, but the agonist-induced delay of gastrointestinal transit (GIT), a primarily peripheral nervous system-mediated effect, was not. Compared to wild-type (WT) littermates, the mutant mice displayed reduced body weight (BW), adiposity, and feeding efficiency, and when fed a high-fat diet (HFD), showed decreased plasma insulin, leptin, cholesterol, and triglyceride levels, and elevated adiponectin levels. Furthermore, the therapeutic effects of rimonabant on food intake (FI), BW, and serum parameters were markedly reduced and correlated with the degree of CB1 KD. Thus, KD of CB1 in the CNS recapitulates the metabolic phenotype of CB1 knockout (KO) mice and diminishes rimonabant's efficacy, indicating that blockade of central CB1 is required for rimonabant's antiobesity actions. Topics: Adiponectin; Adiposity; Animals; Anti-Obesity Agents; Biomarkers; Body Weight; Central Nervous System; Cholesterol; Diet, High-Fat; Energy Intake; Gastrointestinal Transit; Hypothermia; Insulin; Leptin; Mice; Mice, Knockout; Mice, Transgenic; MicroRNAs; Mutation; Obesity; Peripheral Nervous System; Phenotype; Piperidines; Promoter Regions, Genetic; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Triglycerides | 2011 |
Therapeutic impact of leptin on diabetes, diabetic complications, and longevity in insulin-deficient diabetic mice.
The aim of the current study was to evaluate the long-term effects of leptin on glucose metabolism, diabetes complications, and life span in an insulin-dependent diabetes model, the Akita mouse.. We cross-mated Akita mice with leptin-expressing transgenic (LepTg) mice to produce Akita mice with physiological hyperleptinemia (LepTg:Akita). Metabolic parameters were monitored for 10 months. Pair-fed studies and glucose and insulin tolerance tests were performed. The pancreata and kidneys were analyzed histologically. The plasma levels and pancreatic contents of insulin and glucagon, the plasma levels of lipids and a marker of oxidative stress, and urinary albumin excretion were measured. Survival rates were calculated.. Akita mice began to exhibit severe hyperglycemia and hyperphagia as early as weaning. LepTg:Akita mice exhibited normoglycemia after an extended fast even at 10 months of age. The 6-h fasting blood glucose levels in LepTg:Akita mice remained about half the level of Akita mice throughout the study. Food intake in LepTg:Akita mice was suppressed to a level comparable to that in WT mice, but pair feeding did not affect blood glucose levels in Akita mice. LepTg:Akita mice maintained insulin hypersensitivity and displayed better glucose tolerance than did Akita mice throughout the follow-up. LepTg:Akita mice had normal levels of plasma glucagon, a marker of oxidative stress, and urinary albumin excretion rates. All of the LepTg:Akita mice survived for >12 months, the median mortality time of Akita mice.. These results indicate that leptin is therapeutically useful in the long-term treatment of insulin-deficient diabetes. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Eating; Glucagon; Hyperglycemia; Insulin; Leptin; Longevity; Mice; Mice, Transgenic; Oxidative Stress; Pancreas | 2011 |
Effect of treatment of high fat fed/low dose streptozotocin-diabetic rats with Ilepatril on vascular and neural complications.
We have previously shown that treating streptozotocin-induced diabetic rats, an animal model of type 1 diabetes, with Ilepatril (an inhibitor of neutral endopeptidase and angiotensin converting enzyme (ACE)) improves vascular and neural functions. In this study we sought to determine the effect of Ilepatril treatment of high fat fed/low dose streptozotocin-diabetic rats, a model for type 2 diabetes, on vascular and neural complications. Following 8 weeks on a high fat diet rats were treated with 30 mg/kg streptozotocin (i.p.) and after 4 additional weeks a group of these rats was treated for 12 weeks with Ilepatril followed by analysis of neural and vascular functions. Included in these studies were age-matched control rats and rats fed a high fat diet and treated with or without Ilepatril. Diabetic and diet induced obese rats have characteristics of insulin resistance, slowing of nerve conduction velocity, thermal hypoalgesia, reduction in intraepidermal nerve fiber density in the hindpaw and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles of the sciatic nerve. Treatment with Ilepatril was efficacious in improving all of these endpoints although improvement of insulin resistance in diabetic rats was minimal. These studies suggest that dual inhibition of angiotensin converting enzyme and neutral endopeptidase activity of type 2 diabetic rats is an effective approach for treatment of diabetic neural and vascular complications. Topics: Adipose Tissue; Animals; Arterioles; Blood Glucose; Blood Vessels; Body Weight; Carbohydrate Metabolism; Diabetes Complications; Diabetes Mellitus, Experimental; Diet, High-Fat; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glucose Tolerance Test; Glutathione; Heterocyclic Compounds, 3-Ring; Insulin; Lens, Crystalline; Leptin; Male; Muscle, Skeletal; Nerve Fibers; Nervous System; Nociception; Organ Size; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Superoxides; Thiobarbiturates; Tyrosine; Vasodilation | 2011 |
Effects of androgen and leptin on behavioral and cellular responses in female rats.
The causes of anxiety and depression in women with polycystic ovary syndrome (PCOS) remain elusive. To identify steps linking androgen signaling to the regulation of affective symptoms in vivo, we compared behavioral responses in female rats continuously exposed to DHT from puberty (a model of DHT-induced PCOS) and in rats exposed to DHT for 1week. Continuous and 1week of DHT exposure resulted in a general decrease in locomotor activity and time spent on the open arms in the elevated plus maze, indicating anxiety-like behavior. Rats with DHT-induced PCOS have increases in adiposity and circulating leptin levels accompanied by leptin resistance. One week of DHT exposure decreased androgen receptor (AR) expression in the hypothalamus and leptin synthesis and function in adipocytes; it also inhibited signal transducer and activator of transcription 3 (STAT3) and attenuated leptin activity by increasing levels of soluble leptin receptor, a leptin-binding protein, in the hypothalamus. This may affect the androgen-induced anxiety-related behavior in female rats. In conclusion, our results highlight the central role of androgens in behavioral function in female rats and suggest that androgens directly regulate the AR by decreasing its hypothalamic expression. Androgens also increase leptin synthesis in adipocytes, which drives central leptin signaling, and may regulate anxiety-related behaviors. Elucidating mechanisms by which androgens modulate female anxiety-like behavior may uncover useful approaches for treating women with PCOS who have symptoms of anxiety. Topics: Androgens; Animals; Behavior, Animal; Body Weight; Brain; Cell Physiological Phenomena; Dihydrotestosterone; Disease Models, Animal; Female; Humans; Leptin; Maze Learning; Organ Size; Polycystic Ovary Syndrome; Rats; Rats, Wistar; Receptors, Androgen | 2011 |
Changes of orexin A plasma levels in girls with anorexia nervosa during eight weeks of realimentation.
Orexin A (OXA) is a hypothalamic neuropeptide involved in regulation of food intake and nutritional status. There are multiple disturbances of neuropeptide signaling described in girls with anorexia nervosa (AN), but OXA levels have not been addressed in this population to date. Therefore, we analyzed OXA levels of AN girls in this study.. OXA (radioimmunoassay/RIA/method), leptin, insulinlike growth factor-1 (IGF-1), and insulinlike growth factor-1 binding protein-3 (IGFBP-3) levels were measured before and after 8 weeks of realimentation in 36 girls with AN and in 14 healthy controls (control group: CG).. Average weight increased significantly in AN during the study (p < .0001), while plasma levels of OXA decreased (before realimentation: 56.2 ± 2.4 pg/ml; after realimentation: 47.5 ± 1.4 pg/ml; p = .0025). OXA levels before realimentation differed from levels in the CG (47.15 ± 2.6 pg/ml, p = .034), but not afterward. We did not find any correlation between OXA and age, height, weight, BMI; or IGF-1, IGFBP-3, and leptin levels.. OXA levels in untreated AN patients differ significantly from healthy subjects and decrease during realimentation. These findings indicate that OXA may be involved in the nutritional regulation of malnourished children and adolescents. Topics: Adolescent; Anorexia Nervosa; Body Weight; Eating; Female; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Leptin; Neuropeptides; Nutritional Status; Orexins | 2011 |
The role of metabolic syndrome components and adipokines in insulin resistance in prepubertal children.
Insulin resistance has a central role in the pathophysiology of cardiovascular atherosclerotic disease. Adipose tissue is of capital importance in view of its production of adipokines. The present study aims to determine the association of metabolic syndrome components, which constitute risk factors for cardiovascular atherosclerotic disease, and leptin and adiponectin with insulin resistance in prepubertal children.. We conducted a cross-sectional study involving 197 children. Of these, 112 children were obese, 36 were overweight and 49 had normal weight. The association of sex, waist circumference, Acanthosis nigricans, age, BMI Z-score, serum lipids, leptin and adipocytokines with insulin resistance [defined as the homeostatic model assessment for insulin resistance (HOMA-IR) index higher than or equal to 2.5] was investigated using logistic regression.. There was positive association of sex (female), age, BMI Z-score, triglycerides and leptin with insulin resistance (p<0.05).. Among the conventional components of metabolic syndrome, the role of BMI Z-score and triglycerides stands out in insulin resistance of prepubertal children. Sex (female), age and leptin also showed to be of major importance. Topics: Acanthosis Nigricans; Adipokines; Adiponectin; Body Weight; Brazil; Cardiovascular Diseases; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Leptin; Lipids; Logistic Models; Male; Metabolic Syndrome; Obesity; Overweight; Risk Factors | 2011 |
Plasma leptin and adiponectin concentrations in healthy, non-obese children.
Alterations in plasma leptin and adiponectin concentrations are associated with an adverse metabolic profile in obese children.. To simultaneously assess multiple factors with possible effects on plasma leptin and adiponectin concentrations in healthy, non-obese children.. We studied 170 healthy non-obese children (86 males, age 10+1.5 years), with available medical records from birth.. Plasma leptin and adiponectin concentrations were assessed by immunoassay. The ratio of current weight/birth weight (WBWR) was used as an index of children growth from birth. Children's intensity of physical activity and parental characteristics were also assessed.. Leptin was positively associated with WBWR (p<0.0001); parental smoking (analysis of variance, ANOVA; p-=0.03) and parental obesity (ANOVA; p<0.001) were negatively associated with breastfeeding (p<0.01) and children's access to exercise (p<0.0001). Adiponectin was negatively associated with WBWR (p<0.0001) and parental smoking (p=0.04), with an additive negative effect of parental smoking status and parental obesity on children's adiponectin levels (ANOVA; p=0.02).. Children's and parental factors are related and could possibly influence leptin and adiponectin concentrations in healthy non-obese children. Early preventive strategies that target both children and parents could improve the profile of adipocytokine in these children. Topics: Adiponectin; Birth Weight; Body Mass Index; Body Weight; Cardiovascular Diseases; Child; Child Development; Female; Greece; Humans; Leptin; Male; Motor Activity; Obesity; Parents; Reference Values; Risk Factors; Tobacco Smoke Pollution; Weight Gain | 2011 |
Dietary fat increases solid tumor growth and metastasis of 4T1 murine mammary carcinoma cells and mortality in obesity-resistant BALB/c mice.
High-fat diets (HFDs) are known to cause obesity and are associated with breast cancer progression and metastasis. Because obesity is associated with breast cancer progression, it is important to determine whether dietary fat per se stimulates breast cancer progression in the absence of obesity. This study investigated whether an HFD increases breast cancer growth and metastasis, as well as mortality, in obesity-resistant BALB/c mice.. The 4-week-old, female BALB/c mice were fed HFD (60% kcal fat) or control diet (CD, 10% kcal fat) for 16 weeks. Subsequently, 4T1 mammary carcinoma cells were injected into the inguinal mammary fat pads of mice fed continuously on their respective diets. Cell-cycle progression, angiogenesis, and immune cells in tumor tissues, proteases and adhesion molecules in the lungs, and serum cytokine levels were analyzed with immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assay (ELISA). In vitro studies were also conducted to evaluate the effects of cytokines on 4T1 cell viability, migration, and adhesion.. Spleen and gonadal fat-pad weights, tumor weight, the number and volume of tumor nodules in the lung and liver, and tumor-associated mortality were increased in the HFD group, with only slight increases in energy intake and body weight. HF feeding increased macrophage infiltration into adipose tissues, the number of lipid vacuoles and the expression of cyclin-dependent kinase (CDK)2, cyclin D1, cyclin A, Ki67, CD31, CD45, and CD68 in the tumor tissues, and elevated serum levels of complement fragment 5a (C5a), interleukin (IL)-16, macrophage colony-stimulating factor (M-CSF), soluble intercellular adhesion molecule (sICAM)-1, tissue inhibitors of metalloproteinase (TIMP)-1, leptin, and triggering receptor expressed on myeloid cells (TREM)-1. Protein levels of the urokinase-type plasminogen activator, ICAM-1, and vascular cell adhesion molecule-1 were increased, but plasminogen activator inhibitor-1 levels were decreased in the lungs of the HFD group. In vitro assays using 4T1 cells showed that sICAM-1 increased viability; TREM-1, TIMP-1, M-CSF, and sICAM-1 increased migration; and C5a, sICAM-1, IL-16, M-CSF, TIMP-1, and TREM-1 increased adhesion.. Dietary fat increases mammary tumor growth and metastasis, thereby increasing mortality in obesity-resistant mice. Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Body Weight; Cell Movement; Cell Proliferation; Complement C5a; Cyclin A; Cyclin D1; Cyclin-Dependent Kinase 2; Cytokines; Dietary Fats; Energy Intake; Female; Interleukin-16; Ki-67 Antigen; Leptin; Leukocyte Common Antigens; Liver Neoplasms; Lung; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Obesity; Platelet Endothelial Cell Adhesion Molecule-1 | 2011 |
Pioglitazone-induced body weight gain is prevented by combined administration with the lipoprotein lipase activator NO-1886.
Pioglitazone improves insulin resistance in diabetics but often causes body weight gain. The lipoprotein lipase activator NO-1886 has been shown to exert both anti-obesity and anti-insulin-resistance effects. In this study, we investigated the effect of the combined administration of pioglitazone with NO-1886 (pioglitazone+NO-1886) in preventing body weight gain in insulin-resistant, high-fat fed rats. The rats were fed a standard or high-fat diet for 16 weeks. The high-fat fed rats were randomized at week 9 into 4 groups (i.e., control, pioglitazone (30 mg/kg/day), NO-1886 (100mg/kg/day), and pioglitazone+NO-1886 (30 and 100mg/kg/day, respectively)). The high-fat fed control rats developed obesity and insulin resistance. After 7 weeks of drug treatment, pioglitazone+NO-1886 was found to prevent the body weight gain caused by pioglitazone alone (pioglitazone+NO-1886: Δ76.0 ± 16.8 g vs. pioglitazone: Δ127.8 ± 39.5 g, P<0.05) and to increase glucose infusion rate during insulin clamp, compared with the results in the high-fat fed control group. No differences in plasma nonesterified fatty acid, leptin, adiponectin, glucose, or insulin levels were observed between the pioglitazone+NO-1886 and the pioglitazone-alone groups. However, plasma total cholesterol and HDL-cholesterol levels were significantly increased and plasma triglyceride levels were slightly decreased in the pioglitazone+NO-1886 group, compared with the values in the pioglitazone-alone group. In summary, the combined administration of pioglitazone and NO-1886 prevented the pioglitazone-induced body weight gains and ameliorated insulin resistance observed in high-fat fed rats. These results indicate that combined therapy with pioglitazone and NO-1886 may be beneficial for the treatment of type 2 diabetes. Topics: Abdominal Fat; Adiponectin; Animals; Benzamides; Blood Glucose; Body Weight; Drug Combinations; Eating; Enzyme Activation; Hypoglycemic Agents; Insulin; Leptin; Lipids; Lipoprotein Lipase; Male; Organophosphorus Compounds; Pioglitazone; Rats; Rats, Sprague-Dawley; Thiazolidinediones | 2011 |
Effects of the physical form of the diet on food intake, growth, and body composition changes in mice.
The present study investigated effects of the physical form of the diet on food intake, growth, and body composition in male C57BL/6 mice. Three-week-old mice were fed isocaloric diets (AIN93G or a modification containing 25% wheat) in powdered or pelleted form. In experiment 1, mice were assigned into 4 groups offered the AIN93G or the wheat-modified diet in powdered or pelleted form. In experiment 2, mice were pair-fed the powdered diets to the ad libitum level of food intake of those fed the pelleted form of the respective diets. Body weight, food intake, and fecal excretion were recorded, and body composition was assessed on mice 1 wk before termination of the experiment. Mice fed the powdered diets showed greater increases in body weight in 2 wk of feeding than did mice fed the pelleted diets. Compared with the pelleted diets, the powdered diets supported an approximately 85% increase in the fat-mass:body-mass ratio and a 2-fold increase in the abdominal-fat-weight:carcass-weight ratio. In addition, mice fed the powdered diet showed significantly greater plasma concentrations of insulin and leptin and significantly lower plasma adiponectin, compared with their pellet-fed counterparts. Food intake of mice fed the powdered diet was 11% greater for the AIN93G and 16% greater for the wheat diet compared with that of the respective pelleted diet. These results demonstrate that C57BL/6 mice responded to the physical form of these diets in terms of food intake, which affected their growth, body composition, and plasma concentrations of insulin and adipocytokines. Topics: Adiponectin; Age Factors; Analysis of Variance; Animal Feed; Animals; Body Composition; Body Weight; Eating; Gastrointestinal Transit; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL | 2011 |
Synthesis of a new [6]-gingerol analogue and its protective effect with respect to the development of metabolic syndrome in mice fed a high-fat diet.
To determine the effects of a [6]-gingerol analogue (6G), a major chemical component of the ginger rhizome, and its stable analogue after digestion in simulated gastric fluid, aza-[6]-gingerol (A6G), on diet-induced body fat accumulation, we synthesized 6G and A6G. Mice were fed either a control regular rodent chow, a high-fat diet (HFD), or a HFD supplemented with 6G and A6G. Magnetic resonance imaging adiposity parameters of the 6G- and A6G-treated mice were compared with those of control mice. Supplementation with 6G and A6G significantly reduced body weight gain, fat accumulation, and circulating levels of insulin and leptin. The mRNA levels of sterol regulatory element-binding protein 1c (SREBP-1c) and acetyl-CoA carboxylase 1 in the liver were significantly lower in mice fed A6G than in HFD control mice. Our findings indicate that A6G, rather than 6G, enhances energy metabolism and reduces the extent of lipogenesis by downregulating SREBP-1c and its related molecules, which leads to the suppression of body fat accumulation. Topics: Acetyl-CoA Carboxylase; Adiponectin; Adipose Tissue; Amides; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Catechols; Dietary Fats; Energy Metabolism; Fatty Alcohols; Glucose Tolerance Test; Guaiacol; Insulin; Leptin; Lipogenesis; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred ICR; RNA, Messenger; Sterol Regulatory Element Binding Protein 1 | 2011 |
Repeated exposure to severely limited sleep results in distinctive and persistent physiological imbalances in rats.
Chronic sleep disruption in laboratory rats leads to increased energy expenditure, connective tissue abnormalities, and increased weights of major organs relative to body weight. Here we report on expanded findings and the extent to which abnormalities become long-lasting, potentially permanent changes to health status after apparent recuperation from chronic sleep disruption. Rats were exposed 6 times to long periods of disrupted sleep or control conditions during 10 weeks to produce adaptations and then were permitted nearly 4 months of undisturbed sleep. Measurements were made in tissues from these groups and in preserved tissue from the experimental and control groups of an antecedent study that lacked a lengthy recuperation period. Cycles of sleep restriction resulted in energy deficiency marked by a progressive course of hyperphagia and major (15%) weight loss. Analyses of tissue composition in chronically sleep-restricted rats indicated that protein and lipid amounts in internal organs were largely spared, while adipose tissue depots appeared depleted. This suggests high metabolic demands may have preserved the size of the vital organs relative to expectations of severe energy deficiency alone. Low plasma corticosterone and leptin concentrations appear to reflect low substrate availability and diminished adiposity. After nearly 4 months of recuperation, sleep-restricted rats were consuming 20% more food and 35% more water than did comparison control rats, despite normalized weight, normalized adipocytes, and elevated plasma leptin concentrations. Plasma cholesterol levels in recuperated sleep-restricted rats were diminished relative to those of controls. The chronically increased intake of nutriments and water, along with altered negative feedback regulation and substrate use, indicate that internal processes are modified long after a severe period of prolonged and insufficient sleep has ended. Topics: Adipocytes; Animals; Body Weight; Connective Tissue; Corticosterone; Drinking; Feeding Behavior; Hormones; Insulin; Intestine, Small; Leptin; Male; Muscles; Rats; Rats, Sprague-Dawley; Sleep Deprivation; Walking | 2011 |
Effect of immune stress on body weight regulation is altered by ovariectomy in female rats.
It has been suggested that obesity and loss of ovarian function alter the inflammatory response to immune stress. Ovariectomized (OVX) rats, which are used as a model of human menopause, exhibit both hyperphagia-induced obesity and gonadal steroid deficiency. To evaluate the effects of ovariectomy on inflammatory responses, we compared the anorectic response to LPS in OVX rats and gonad intact female rats. As leptin and hypothalamic interleukin-1β (IL1β) play pivotal roles in the anorectic response to immune stress, these factors were also measured. It was found that the OVX rats exhibited an increased anorectic response to LPS compared with the sham-operated rats. The OVX rats showed higher serum leptin concentrations and a greater increase in hypothalamic IL1β mRNA expression after LPS injection. In addition, in order to determine whether gonadal steroid deficiency contributes to the changes in the inflammatory responses of OVX rats, we compared responses between OVX rats treated with gonadal steroids and untreated OVX rats. There were no differences in appetite, the serum leptin level, and hypothalamic IL1β mRNA expression between the two groups after LPS injection. These findings suggest that the loss of ovarian function increases the induction of leptin and hypothalamic IL1β synthesis and consequently increases the anorectic response under immune stress conditions. It is possible that these alterations are caused by OVX-induced obesity rather than the direct effects of gonadal steroid deficiency. Topics: Animals; Body Weight; Female; Gene Expression Regulation; Humans; Hypothalamus; Interleukin-1beta; Leptin; Lipopolysaccharides; Menopause; Models, Biological; Ovariectomy; Ovary; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stress, Physiological | 2011 |
A uroguanylin-GUCY2C endocrine axis regulates feeding in mice.
Intestinal enteroendocrine cells are critical to central regulation of caloric consumption, since they activate hypothalamic circuits that decrease appetite and thereby restrict meal size by secreting hormones in response to nutrients in the gut. Although guanylyl cyclase and downstream cGMP are essential regulators of centrally regulated feeding behavior in invertebrates, the role of this primordial signaling mechanism in mammalian appetite regulation has eluded definition. In intestinal epithelial cells, guanylyl cyclase 2C (GUCY2C) is a transmembrane receptor that makes cGMP in response to the paracrine hormones guanylin and uroguanylin, which regulate epithelial cell dynamics along the crypt-villus axis. Here, we show that silencing of GUCY2C in mice disrupts satiation, resulting in hyperphagia and subsequent obesity and metabolic syndrome. This defined an appetite-regulating uroguanylin-GUCY2C endocrine axis, which we confirmed by showing that nutrient intake induces intestinal prouroguanylin secretion into the circulation. The prohormone signal is selectively decoded in the hypothalamus by proteolytic liberation of uroguanylin, inducing GUCY2C signaling and consequent activation of downstream anorexigenic pathways. Thus, evolutionary diversification of primitive guanylyl cyclase signaling pathways allows GUCY2C to coordinate endocrine regulation of central food acquisition pathways with paracrine control of intestinal homeostasis. Moreover, the uroguanylin-GUCY2C endocrine axis may provide a therapeutic target to control appetite, obesity, and metabolic syndrome. Topics: Animals; Behavior, Animal; Body Composition; Body Weight; Cyclic GMP; Eating; Endocrine System; Epithelial Cells; Feeding Behavior; Female; Hypothalamus; Insulin; Intestinal Mucosa; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Natriuretic Peptides; Protein Precursors; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Satiation; Second Messenger Systems | 2011 |
Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats.
Leptin has been shown to reduce hyperglycemia in rodent models of type 1 diabetes. We investigated the effects of leptin administration in University of California, Davis, type 2 diabetes mellitus (UCD-T2DM) rats, which develop adult-onset polygenic obesity and type 2 diabetes. Animals that had been diabetic for 2 mo were treated with s.c. injections of saline (control) or murine leptin (0.5 mg/kg) twice daily for 1 mo. Control rats were pair-fed to leptin-treated animals. Treatment with leptin normalized fasting plasma glucose and was accompanied by lowered HbA1c, plasma glucagon, and triglyceride concentrations and expression of hepatic gluconeogenic enzymes compared with vehicle (P < 0.05), independent of any effects on body weight and food intake. In addition, leptin-treated animals exhibited marked improvement of insulin sensitivity and glucose homeostasis compared with controls, whereas pancreatic insulin content was 50% higher in leptin-treated animals (P < 0.05). These effects coincided with activation of leptin and insulin signaling pathways and down-regulation of the PKR-like endoplasmic reticulum (ER) kinase/eukaryotic translation inhibition factor 2α (PERK-eIF2α) arm of ER stress in liver, skeletal muscle, and adipose tissue as well as increased pro-opiomelanocortin and decreased agouti-related peptide in the hypothalamus. In contrast, several markers of inflammation/immune function were elevated with leptin treatment in the same tissues (P < 0.05), suggesting that the leptin-mediated increase of insulin sensitivity was not attributable to decreased inflammation. Thus, leptin administration improves insulin sensitivity and normalizes fasting plasma glucose in diabetic UCD-T2DM rats, independent of energy intake, via peripheral and possibly centrally mediated actions, in part by decreasing circulating glucagon and ER stress. Topics: Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Type 2; Eating; eIF-2 Kinase; Endoplasmic Reticulum; Eukaryotic Initiation Factor-2; Glucagon; Gluconeogenesis; Glycated Hemoglobin; Injections, Subcutaneous; Insulin; Insulin-Like Growth Factor I; Janus Kinase 2; Leptin; Lipid Metabolism; Male; Rats; Signal Transduction | 2011 |
Glucose supplement reverses the fasting-induced suppression of cellular immunity in Mongolian gerbils (Meriones unguiculatus).
Glucose plays an important role in immunity. Three day fasting will decrease cellular immunity and blood glucose levels in Mongolian gerbils (Meriones unguiculatus). In the present study, we tested the hypothesis that glucose supplement can reverse the fasting-induced suppression in cellular immunity in gerbils. Twenty-eight male gerbils were selected and randomly divided into fed and fasting groups. Half of the gerbils in each group were then provided with either 10% glucose water or pure water. After 66 h, each gerbil was injected with phytohaemagglutinin (PHA) solution to challenge cellular immunity. Results showed that glucose supplement restored blood glucose levels in fasted gerbils to those of the fed controls. It also recovered cellular immunity, body fat mass and serum leptin levels in fasted gerbils to the values of the fed controls. Blood glucose levels were positively correlated with body fat mass, leptin levels and cellular immune responses. Thymus and spleen masses, and white blood cells in fasted gerbils were not affected by glucose supplement. In general, our data demonstrate that glucose supplement could reverse fasting-induced suppression of cellular immunity in Mongolian gerbils. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Fasting; Gerbillinae; Glucose; Immunity, Cellular; Leptin; Leukocyte Count; Male; Sweetening Agents | 2011 |
Chronic central leptin decreases food intake and improves glucose tolerance in diet-induced obese mice independent of hypothalamic malonyl CoA levels and skeletal muscle insulin sensitivity.
Although acute leptin administration in the hypothalamus decreases food intake and increases peripheral energy metabolism, the peripheral actions of central chronic leptin administration are less understood. In this study, we investigated what effects chronic (7 d) intracerebroventricular (ICV) administration of leptin has on energy metabolism and insulin sensitivity in diet-induced obese mice. C57/BL mice were fed a low-fat diet (LFD; 10% total calories) or high-fat diet (HFD; 60% total calories) for 8 wk after which leptin was administered ICV for 7 consecutive days. Mice fed a HFD showed signs of insulin resistance, as evidenced by an impaired glucose tolerance test. Chronic leptin treatment resulted in a decrease in food intake and body weight and normalization of glucose clearance but no improvement in insulin sensitivity. Chronic ICV leptin increased hypothalamic signal transducer and activator of transcription-3 and AMP-activated protein kinase phosphorylation but did not change hypothalamic malonyl CoA levels in HFD fed and LFD-fed mice. In the gastrocnemius muscles, the levels of malonyl CoA in both leptin-treated groups were lower than their respective control groups, suggesting an increase in fatty acid oxidation. However, only in the muscles of ICV leptin-treated LFD mice was there a decrease in lipid metabolites including diacylglycerol, triacylglycerol, and ceramide. Our results suggest that chronic ICV leptin decreases food consumption and body weight via a mechanism different from acute ICV leptin administration. Although chronic ICV leptin treatment in HFD mice improves glucose tolerance, this occurs independent of changes in insulin sensitivity in the muscles of HFD mice. Topics: Adenylate Kinase; Animals; Body Weight; Diet, High-Fat; Eating; Energy Intake; Glucose Intolerance; Hypothalamus; Insulin; Leptin; Malonyl Coenzyme A; Mice; Mice, Obese; Muscle, Skeletal; STAT3 Transcription Factor | 2011 |
Influence of castration-induced sex hormone deficiency on serum lipid levels and the genes expression in male pigs.
It has been known that the changes in gonadal steroids are closely associated with adipose tissue metabolism. Domestic pigs have been a well-recognized experimental animal in biomedical research because of their similarity to humans in body size and other physiological/anatomical features. The aims of this study were to investigate the influence of castration-induced sex hormone deficiency on serum lipid levels and the genes expression of key enzymes associated with lipogenic and lipolytic processes in male pigs. The experimental animals consisted of 2 groups slaughtered on 147th and 210th day, respectively. In each of the group, 7 full-sib pairs of castrated and intact male hybrids from Yorkshire dams sired by Landrace were contained. The results showed that castration of male pigs led to increased total cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, and leptin levels in serum (p<0.05). No differences in levels of the free fatty acid, insulin, and glucose were observed between boars and barrows (p>0.05). Castration caused upregulation of fatty acid synthase and acetyl-CoA carboxylase alpha genes expression at both 147 and 210 days of age (p<0.05). No differences in expression of hormone sensitive lipase and adipose tissue triglyceride lipase genes were observed between boars and barrows at either 147 or 210 days of age (p>0.05). It is speculated that higher body fat deposition in castrated male pigs might have resulted mainly from increased transcription of the lipogenic genes, but not from decreased transcription of the lipolytic genes. Topics: Animals; Body Weight; Castration; Gene Expression Regulation; Gonadal Steroid Hormones; Insulin; Leptin; Lipids; Male; Sus scrofa; Testosterone | 2011 |
Cord blood adiponectin and infant growth at one year.
The aim of this study was to determine the association between cord blood adiponectin and leptin and early infant growth at one year in small for gestational age (SGA) and appropriate for gestational age (AGA) infants.. In this prospective study adiponectin and leptin concentrations were determined in cord blood of (i) AGA newborns (n = 44) and (ii) SGA newborns (n = 24). At one year of age, height and weight were measured. Linear regression analysis was used to determine which factors were associated with anthropometric measurements at the age of one year.. (i) SGA neonates had a significantly lower median cord blood adiponectin and leptin than AGA neonates; (ii) among SGA neonates, cord blood adiponectin concentrations were negatively correlated with body weight at one year, weight gain after one year and with BMI at one year; and (iii) among AGA neonates cord blood adiponectin concentrations were negatively correlated with body weight at one year, weight gain after one year and with BMI at one year.. The disparity in cord blood adiponectin and leptin concentrations between SGA and AGA neonates suggests a role for adipokines in fetal growth. Topics: Adiponectin; Body Height; Body Mass Index; Body Weight; Child Development; Female; Fetal Blood; Humans; Infant; Infant, Newborn; Infant, Small for Gestational Age; Leptin; Male; Prospective Studies; Weight Gain | 2011 |
Effects of acute changes in neonatal leptin levels on food intake and long-term metabolic profiles in rats.
In rodents there is a rise in serum leptin levels between postnatal days (PND) 5 and 14, with this neonatal leptin surge reported to modulate the maturation of hypothalamic circuits involved in appetite regulation. We hypothesized that acute changes in neonatal leptin levels have different long-term metabolic effects depending on how and when this surge is modified. To advance the timing of the normal leptin peak, male Wistar rats were injected with leptin (sc, 3 μg/g) on PND 2. To ablate the leptin peak on PND 10, a pegylated leptin antagonist (sc, 9 μg/g) was injected. Controls received vehicle. All rats were allowed to eat ad libitum until PND 150. Increased leptin on PND 2 reduced food intake (P<0.01) after 3 months of age with no effect on body weight. Levels of total ghrelin were reduced (P<0.001) and acylated ghrelin increased (P<0.05), with no other modifications in metabolic hormones. In contrast, treatment with the leptin antagonist on PND 9 did not affect food intake but reduced body weight beginning around PND 60 (P<0.02). This was associated with a reduction in fat mass, insulin (P<0.01), and leptin (P<0.007) levels and an increase in testosterone levels (P<0.01). Hypothalamic neuropeptide Y (P<0.05) and leptin receptor (P<0.005) mRNA levels were reduced, whereas mRNA levels for uncoupling protein 2 (P<0.005) were increased in visceral fat, which may indicate an increase in energy expenditure. In conclusion, acute changes in neonatal leptin levels induce different metabolic profiles depending on how and when leptin levels are modified. Topics: Adipose Tissue; Animals; Animals, Newborn; Body Weight; Eating; Ghrelin; Glucose Tolerance Test; Leptin; Male; Polyethylene Glycols; Rats; Rats, Wistar; Receptors, Leptin | 2011 |
Rhythmic leptin is required for weight gain from circadian desynchronized feeding in the mouse.
The neuroendocrine and metabolic effects of leptin have been extensively researched since the discovery, and the later identification, of the leptin gene mutated within the ob/ob mouse. Leptin is required for optimal health in a number of physiological systems (e.g. fertility, bone density, body weight regulation). Despite the extensive leptin literature and many observations of leptin's cyclical pattern over the 24-hour day, few studies have specifically examined how the circadian rhythm of leptin may be essential to leptin signaling and health. Here we present data indicating that a rhythmic leptin profile (e.g. 1 peak every 24 hours) leads to excessive weight gain during desynchronized feeding whereas non-rhythmic leptin provided in a continuous manner does not lead to excessive body weight gain under similar feeding conditions. This study suggests that feeding time can interact with leptin's endogenous rhythm to influence metabolic signals, specifically leading to excessive body weight gains during 'wrongly' timed feeding. Topics: Animals; Body Weight; Circadian Rhythm; Feeding Behavior; Leptin; Male; Mice; Mice, Obese; Obesity; Periodicity; Weight Gain | 2011 |
Effects of non-motorized voluntary running on experimental and spontaneous metastasis in mice.
The present study investigated the effects of non-motorized voluntary running on experimental metastasis of B16BL/6 melanoma and spontaneous metastasis of Lewis lung carcinoma (LLC) in male C57BL/6 mice. After 9 weeks of running, mice (n=30 per group) received an intravenous injection of B16BL/6 cells or a subcutaneous injection of LLC cells, and then they were continued with their running activities. Experiments were terminated 2 weeks after the intravenous injection of B16BL/6 cells or 2 weeks after surgical removal of the primary tumor from mice subcutaneously injected with LLC cells. Mice in the running group ran an average of 4-6 km/day for the duration of the experiment. Voluntary running reduced body weight compared with the sedentary controls, but there were no differences in the number and size of lung metastases between groups with either model. Voluntary running significantly reduced plasma insulin and leptin levels and increased adiponectin level in mice with and without LLC compared with the sedentary controls. Having LLC significantly increased plasma concentrations of vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), PDGF-AB and monocyte chemotactic protein-1 (MCP-1) in mice. Voluntary running significantly increased plasma PDGF-BB and PDGFAB, but not VEGF and MCP-1, in mice with LLC compared to their sedentary counterparts. In conclusion, non-motorized voluntary running was favorable to body weight and the expression of related adipokines, but at 4-6 km/day it did not affect either experimental or spontaneous metastasis in mice. Topics: Adiponectin; Animals; Becaplermin; Body Weight; Chemokine CCL2; Insulin; Leptin; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Physical Conditioning, Animal; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Regression Analysis; Vascular Endothelial Growth Factor A | 2011 |
Biomonitoring of bisphenol A concentrations in maternal and umbilical cord blood in regard to birth outcomes and adipokine expression: a birth cohort study in Taiwan.
Bisphenol A (BPA) is a sealant and flux of plastic materials and has been determined to be an endocrine-disrupting chemical. Prenatal exposure to BPA can lead to substantial adverse effects on fetal growth and development. This study was conducted to assess BPA concentration in pregnant women and umbilical cord blood, and to investigate whether maternal BPA exposure affected fetal outcomes including lower birth weight (LBW), smaller size for gestational age (SGA), and high leptin (HLP) and low adiponectin (LAD) secretion.. We measured the BPA levels of maternal blood (n = 97) and umbilical cord blood (n = 97) with a high-performance liquid chromatography/UV detector. The protein secretion of leptin and adiponectin were separately determined using enzyme-linked immunosorbent assay. A logistic regression was performed to estimate the effects of maternal exposure to BPA on LBW, SGA, and adverse action of adipokines in newborns.. The geometric means of BPA concentration in maternal blood and fetal cord blood were 2.5 ng/ml and 0.5 ng/ml, respectively. Elevated risks of LBW (OR 2.42, 95% confidence interval (CI) 1.72-3.36), SGA (OR 2.01, 95% CI 1.39-3.01), and adverse action of leptin (OR 1.67, 95% CI 1.12-2.25) and adiponectin (OR 1.25, 95% CI 1.52-3.97) were observed in male neonates in the highest quartile of maternal BPA exposure.. Elevated prenatal BPA exposure increased the risk of LBW, SGA, and adverse actions of adipokines in neonates, especially in male infants. These results provide further evidence that maternal exposure is correlated with adverse birth outcomes. Topics: Adiponectin; Adult; Benzhydryl Compounds; Body Weight; Chromatography, High Pressure Liquid; Cohort Studies; Endocrine Disruptors; Environmental Exposure; Environmental Pollutants; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Fetal Development; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Small for Gestational Age; Leptin; Logistic Models; Male; Maternal Exposure; Phenols; Pregnancy; Prenatal Exposure Delayed Effects; Taiwan | 2011 |
Decreased accumulation of ultrasound contrast in the liver of nonalcoholic steatohepatitis rat model.
To investigate the diagnosis of nonalcoholic steatohepatitis (NASH) using contrast ultrasonography in the NASH rat model.. The liver in methionine choline-deficient diet (MCDD) rats, a NASH model constructed by feeding an MCDD, was examined by contrast ultrasonography at weeks 2, 4, 8, 12 and 16, with late phase images of contrast ultrasonography (Kupffer imaging) in which contrast enhancement was achieved by incorporation of a contrast agent by Kupffer cells (KCs), and images were compared to those in rats taking a regular chow.. Decrease in contrast enhancement was observed first in MCDD rats at week 2. KCs were counted based on immunohistochemistry, but their numbers were not reduced and it was assumed that attenuation of contrast enhancement was attributable to reduced phagocytic activity of the KCs.. It is suggested that clinical application of contrast ultrasonography may be valuable for non-invasive diagnosis of NASH. Topics: Animals; Body Weight; Choline Deficiency; Contrast Media; Diet; Disease Models, Animal; Fatty Liver; Kupffer Cells; Leptin; Liver; Male; Methionine; Non-alcoholic Fatty Liver Disease; Rats; Rats, Wistar; Ultrasonography | 2011 |
Neonatal overfeeding induced by small litter rearing causes altered glucocorticoid metabolism in rats.
Elevated glucocorticoid (GC) activity may be involved in the development of the metabolic syndrome. Tissue GC exposure is determined by the tissue-specific GC-activating enzyme 11β-hydroxysteriod dehydrogenase type 1 (11β-HSD1) and the GC-inactivating enzyme 5α-reductase type 1 (5αR1), as well as 5β-reductase (5βR). Our aim was to study the effects of neonatal overfeeding induced by small litter rearing on the expression of GC-regulating enzymes in adipose tissue and/or liver and on obesity-related metabolic disturbances during development. Male Sprague-Dawley rat pup litters were adjusted to litter sizes of three (small litters, SL) or ten (normal litters, NL) on postnatal day 3 and then given standard chow from postnatal week 3 onward (W3). Small litter rearing induced obesity, hyperinsulinemia, and higher circulating corticosterone in adults. 11β-HSD1 expression and enzyme activity in retroperitoneal, but not in epididymal, adipose tissue increased with postnatal time and peaked at W5/W6 in both groups before declining. From W8, 11β-HSD1 expression and enzyme activity levels in retroperitoneal fat persisted at significantly higher levels in SL compared to NL rats. Hepatic 11β-HSD1 enzyme activity in SL rats was elevated from W3 to W16 compared to NL rats. Hepatic 5αR1 and 5βR expression was higher in SL compared to NL rats after weaning until W6, whereupon expression decreased in the SL rats and remained similar to that in NL rats. In conclusion, small litter rearing in rats induced peripheral tissue-specific alterations in 11β-HSD1 expression and activity and 5αR1 and 5βR expression during puberty, which could contribute to elevated tissue-specific GC exposure and aggravate the development of metabolic dysregulation in adults. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Adipose Tissue; Animals; Animals, Newborn; Base Sequence; Blotting, Western; Body Weight; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Protein-beta; Corticosterone; DNA Primers; Feeding Behavior; Glucocorticoids; Glucose Tolerance Test; Leptin; Litter Size; Male; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction | 2011 |
Hyperleptinaemia positively correlated with metabolic syndrome in hemodialysis patients.
To evaluate the relationship between metabolic syndrome (MetS) and the fasting serum leptin concentration in hemodialysis (HD) patients.. Fasting blood samples were obtained from 101 HD patients. MetS and its components were defined using the diagnostic criteria of the International Diabetes Federation.. Forty-eight patients (47.5%) had MetS. Serum leptin concentrations were positively correlated with MetS (p<0.001). Serum leptin levels correlated with increasing numbers of MetS criteria in HD patients (p=0.001). Univariate linear regression analysis showed that the pre-HD body weight (p<0.001), waist circumference (p<0.001), body mass index (p=0.001), triglycerides (p=0.003), insulin level (p=0.043), and homeostasis model assessment of insulin resistance (p=0.003) positively correlated with serum leptin levels in HD patients and high-density lipoprotein-cholesterol (p=0.016) negatively correlated with serum leptin levels in HD patients. Multivariate forward stepwise linear regression analysis of the significant variables revealed that pre-HD body weight (R(2)=0.175; p<0.001) was the independent predictor of the fasting serum leptin concentration.. Fasting serum leptin levels positively correlated with MetS and the pre-HD body weight could influence serum leptin in HD patients. Topics: Aged; Body Weight; Fasting; Female; Humans; Hypertension, Renal; Insulin Resistance; Kidney Failure, Chronic; Leptin; Linear Models; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Renal Dialysis; Risk Factors | 2011 |
Maternal cigarette smoke exposure contributes to glucose intolerance and decreased brain insulin action in mice offspring independent of maternal diet.
Maternal smoking leads to intrauterine undernutrition and is associated with low birthweight and higher risk of offspring obesity. Intrauterine smoke exposure (SE) may alter neuroendocrine mediators regulating energy homeostasis as chemicals in cigarette smoke can reach the fetus. Maternal high-fat diet (HFD) consumption causes fetal overnutrition; however, combined effects of HFD and SE are unknown. Thus we investigated the impact of combined maternal HFD and SE on adiposity and energy metabolism in offspring.. Female Balb/c mice had SE (2 cigarettes/day, 5 days/week) or were sham exposed for 5 weeks before mating. Half of each group was fed HFD (33% fat) versus chow as control. The same treatment continued throughout gestation and lactation. Female offspring were fed chow after weaning and sacrificed at 12 weeks.. Birthweights were similar across maternal groups. Faster growth was evident in pups from SE and/or HFD dams before weaning. At 12 weeks, offspring from HFD-fed dams were significantly heavier than those from chow-fed dams (chow-sham 17.6±0.3 g; chow-SE 17.8±0.2 g; HFD-sham 18.7±0.3 g; HFD-SE 18.8±0.4 g, P<0.05 maternal diet effect); fat mass was significantly greater in offspring from chow+SE, HFD+SE and HFD+sham dams. Both maternal HFD and SE affected brain lactate transport. Glucose intolerance and impaired brain response to insulin were observed in SE offspring, and this was aggravated by maternal HFD consumption.. While maternal HFD led to increased body weight in offspring, maternal SE independently programmed adverse health outcomes in offspring. A smoke free environment and healthy diet during pregnancy is desirable to optimize offspring health. Topics: Adiposity; Animals; Blotting, Western; Body Weight; Brain; Carnitine O-Palmitoyltransferase; Diet, High-Fat; Female; Glucose Intolerance; Insulin; Leptin; Lipase; Maternal Exposure; Maternal Nutritional Physiological Phenomena; Mice; Mice, Inbred BALB C; Monocarboxylic Acid Transporters; Muscle Proteins; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Real-Time Polymerase Chain Reaction; RNA, Messenger; Smoking; Tumor Necrosis Factor-alpha | 2011 |
Regulatory functions of limbic Y1 receptors in body weight and anxiety uncovered by conditional knockout and maternal care.
Neuropeptide Y (NPY) plays an important role in stress, anxiety, obesity, and energy homeostasis via activation of NPY-Y1 receptors (Y1Rs) in the brain. However, global knockout of the Npy1r gene has low or no impact on anxiety and body weight. To uncover the role of limbic Y1Rs, we generated conditional knockout mice in which the inactivation of the Npy1r gene was restricted to excitatory neurons of the forebrain, starting from juvenile stages (Npy1r(rfb)). Npy1r(rfb) mice exhibited increased anxiety and reduced body weight, less adipose tissue, and lower serum leptin levels. Npy1r(rfb) mutants also had a hyperactive hypothalamic-pituitary-adrenocortical axis, as indicated by higher peripheral corticosterone and higher density of NPY immunoreactive fibers and corticotropin releasing hormone immunoreactive cell bodies in the paraventricular hypothalamic nucleus. Importantly, through fostering experiments, we determined that differences in phenotype between Npy1r(rfb) and Npy1r(2lox) mice became apparent when both genotypes were raised by FVB/J but not by C57BL/6J dams, suggesting that limbic Y1Rs are key targets of maternal care-induced programming of anxiety and energy homeostasis. Topics: Age Factors; Analysis of Variance; Animals; Anxiety; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Gene Knockout Techniques; In Situ Hybridization; Leptin; Limbic System; Locomotion; Maternal Behavior; Mice; Mice, Inbred Strains; Mice, Transgenic; Prosencephalon; Receptors, Neuropeptide Y | 2011 |
Regulation of energy balance and body weight by the brain: a distributed system prone to disruption.
Maintaining adequate energy supply via regulation of food intake and energy expenditure is crucial for survival and reproduction. The neural control of energy balance is highly complex, occurs across distributed central and peripheral areas, and incorporates multiple domains of control (including homeostatic and hedonic processes). The sheer number of active compounds (such as leptin and GLP-1) involved in the regulation of food intake speaks to the redundancy and complexity of the system. The balance between energy intake and expenditure is under CNS control. Constant bidirectional communication between the brain and the GI tract, as well as between the brain and other relevant tissues (ie, adipose tissue, pancreas, and liver), ensures that the brain constantly perceives and responds accordingly to the energy status/needs of the body. This elegant biological system is subject to disruption by a toxic obesogenic environment, leading to syndromes such as leptin and insulin resistance, and ultimately further exposing obese individuals to further weight gain and T2DM. Recent imaging studies in humans are beginning to examine the influence that higher-order/hedonic brain regions have on homeostatic areas, as well as their responsiveness to homeostatic peripheral signals. With greater understanding of these mechanisms, the field moves closer to understanding and eventually treating the causalities of obesity. Topics: Adipose Tissue; Appetite Regulation; Body Weight; Brain; Energy Intake; Energy Metabolism; Feeding Behavior; Food Preferences; Gastrointestinal Hormones; Ghrelin; Homeostasis; Humans; Leptin; Neural Pathways; Obesity; Satiation | 2011 |
Correlations between high level sport-climbing and the development of adolescents.
Over the last years concerns have been raised about the health effects particularly on young climbers due to the observation of short stature with low body weight and body fat in sports climbers. The aim of this study was to investigate anthropometric and hormonal data for climbers of the German Junior national team. 16 climbers were compared with 14-age matched nonclimbers with respect to several anthropometric variables, leptin level, and climbing characteristics. Height, weight and body mass index (BMI) standard deviation scores (SDS) for boys were not significantly different from the controls, whereas girls had significantly lower SDS-values for weight and BMI. In comparison with the control group boys and girls had a lower skinfold thickness. The leptin values were lower than the calculated leptin levels but only reached significance for the girls. The young athletes of the GJNT were neither of short stature nor thin when compared with a physically active control group. The low body fat in boys and girls was within expected limits. The lower leptin levels might be attributed to a decrease in total body fat. Topics: Adolescent; Adult; Body Height; Body Mass Index; Body Weight; Body Weights and Measures; Diet; Female; Germany; Ghrelin; Humans; Leptin; Male; Mountaineering; Sex Factors; Skinfold Thickness; Statistics, Nonparametric; Surveys and Questionnaires; Young Adult | 2011 |
Transplanted hypothalamic neurons restore leptin signaling and ameliorate obesity in db/db mice.
Evolutionarily old and conserved homeostatic systems in the brain, including the hypothalamus, are organized into nuclear structures of heterogeneous and diverse neuron populations. To investigate whether such circuits can be functionally reconstituted by synaptic integration of similarly diverse populations of neurons, we generated physically chimeric hypothalami by microtransplanting small numbers of embryonic enhanced green fluorescent protein-expressing, leptin-responsive hypothalamic cells into hypothalami of postnatal leptin receptor-deficient (db/db) mice that develop morbid obesity. Donor neurons differentiated and integrated as four distinct hypothalamic neuron subtypes, formed functional excitatory and inhibitory synapses, partially restored leptin responsiveness, and ameliorated hyperglycemia and obesity in db/db mice. These experiments serve as a proof of concept that transplanted neurons can functionally reconstitute complex neuronal circuitry in the mammalian brain. Topics: Animals; Blood Glucose; Body Weight; Cell Shape; Electrophysiological Phenomena; Excitatory Postsynaptic Potentials; Glucose; Hypothalamus; Hypothalamus, Middle; Inhibitory Postsynaptic Potentials; Insulin; Leptin; Membrane Potentials; Mice; Mice, Obese; Neurogenesis; Neurons; Obesity; Receptors, Leptin; Signal Transduction; Synaptic Transmission | 2011 |
Anti-obesity effects of Chang-Chul-Eui-Ee-In-Tang [see text] in female rats with diet-induced obesity.
To investigate the effects of Chang-Chul-Eui-Ee-In-Tang ([see text], CCEET), modififi ed CCEET (MCCEET), and Semen Coicis (SC, a major component of CCEET) on energy and glucose homeostasis. The possible mechanism of action of CCEET was also determined.. A total of 100 Sprague Dawley female rats were randomly assigned to 5 groups, with 20 in each group. Rats in 4 groups were fed with a high fat diet supplementation (2 g/kg body weight), and water extracts of CCEET, MCCEET, SC, and cellulose (negative control), respectively. The last group was fed with a low-fat diet as a positive control.. CCEET and MCCEET decreased body weight and body fat (mesenteric and retroperitoneal fat) more than SC. This decrease was due to decreased energy intake and increased energy expenditure and fat oxidation. The improvement in energy homeostasis was associated with the enhancement of the hypothalamic leptin signalling pathway involving potentiating the phosphorylation of the signal transducer and activator of transcription-3, as well as attenuating the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK). Both CCEET and MCCEET improved glucose tolerance without changing serum insulin levels during an oral glucose tolerance test but MCCEET had a better effect than CCEET.. Both CCEET and MCCEET safely exerted anti-obesity effects by enhancing energy balance in female rats with diet-induced obesity; MCCEET showed a better effect on glucose homeostasis. Topics: Adenylate Kinase; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Calorimetry; Diet; Drugs, Chinese Herbal; Energy Metabolism; Female; Glucose Tolerance Test; Homeostasis; Hypothalamus; Leptin; Motor Activity; Obesity; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor | 2011 |
High fat diet-induced changes in mouse muscle mitochondrial phospholipids do not impair mitochondrial respiration despite insulin resistance.
Type 2 diabetes mellitus and muscle insulin resistance have been associated with reduced capacity of skeletal muscle mitochondria, possibly as a result of increased intake of dietary fat. Here, we examined the hypothesis that a prolonged high-fat diet consumption (HFD) increases the saturation of muscle mitochondrial membrane phospholipids causing impaired mitochondrial oxidative capacity and possibly insulin resistance.. C57BL/6J mice were fed an 8-week or 20-week low fat diet (10 kcal%; LFD) or HFD (45 kcal%). Skeletal muscle mitochondria were isolated and fatty acid (FA) composition of skeletal muscle mitochondrial phospholipids was analyzed by thin-layer chromatography followed by GC. High-resolution respirometry was used to assess oxidation of pyruvate and fatty acids by mitochondria. Insulin sensitivity was estimated by HOMA-IR.. At 8 weeks, mono-unsaturated FA (16∶1n7, 18∶1n7 and 18∶1n9) were decreased (-4.0%, p<0.001), whereas saturated FA (16∶0) were increased (+3.2%, p<0.001) in phospholipids of HFD vs. LFD mitochondria. Interestingly, 20 weeks of HFD descreased mono-unsaturated FA while n-6 poly-unsaturated FA (18∶2n6, 20∶4n6, 22∶5n6) showed a pronounced increase (+4.0%, p<0.001). Despite increased saturation of muscle mitochondrial phospholipids after the 8-week HFD, mitochondrial oxidation of both pyruvate and fatty acids were similar between LFD and HFD mice. After 20 weeks of HFD, the increase in n-6 poly-unsaturated FA was accompanied by enhanced maximal capacity of the electron transport chain (+49%, p = 0.002) and a tendency for increased ADP-stimulated respiration, but only when fuelled by a lipid-derived substrate. Insulin sensitivity in HFD mice was reduced at both 8 and 20 weeks.. Our findings do not support the concept that prolonged HF feeding leads to increased saturation of skeletal muscle mitochondrial phospholipids resulting in a decrease in mitochondrial fat oxidative capacity and (muscle) insulin resistance. Topics: Animals; Blood Glucose; Body Weight; Cell Respiration; Diet, High-Fat; Energy Metabolism; Fatty Acids; Hindlimb; Homeostasis; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mitochondria, Muscle; Muscle, Skeletal; Oxidative Phosphorylation; Phospholipids | 2011 |
[The role of hormones and types of food behavior in the pathogenesis and treatment of abdominal obesity].
Hormones and the types of eating behavior play the leading role in the development and progression of abdominal obesity. Based on the evaluation of the dynamics of hormones EB and modification of EB types on background of the treatment can determined the most effective method for correction of body weight, which allows not only to achieve the desired result in the short-term, but also to keep the result for a long time. Topics: Adult; Body Weight; Feeding Behavior; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Obesity, Abdominal; Serotonin | 2011 |
Improvements in body fat distribution and circulating adiponectin by alternate-day fasting versus calorie restriction.
Calorie restriction (CR) and alternate-day fasting (ADF) beneficially affect several aspects of adipose tissue physiology, but direct comparisons between regimens have yet to be performed. The present study evaluated the effects of ADF versus CR on body fat distribution and circulating adiponectin levels and examined the kinetic mechanisms that underlie changes in fat distribution. Thirty female C57BL/6J mice were randomized to one of five groups for 4 weeks: (a) CR-25% (25% energy restriction daily), (b) ADF-75% (75% restriction on fast day), (c) ADF-85% (85% restriction on fast day), (d) ADF-100% (100% restriction on fast day) and (e) control (ad libitum fed). Body weights of the CR mice were lower than that of the ADF and control groups posttreatment. After 4 weeks of diet, the proportion of visceral fat decreased (P<.001) and the proportion of subcutaneous fat increased (P<.001) similarly in ADF and CR animals. Adiponectin increased (P<.05) by 62-86% in the ADF groups and by 69% in the CR group. Triglyceride (TG) synthesis and de novo lipogenesis were augmented (P<.05) in the subcutaneous fat pad of ADF and CR animals, relative to control. No differences in net lipolysis were observed, resulting in greater TG accumulation in the subcutaneous fat pad, with a shift in the ratio of TG between depots. These findings indicate that ADF (both modified and true) produces similar beneficial modulations in body fat distribution and adiponectin levels as daily CR. Topics: Adiponectin; Animals; Body Fat Distribution; Body Weight; Caloric Restriction; Diet, Reducing; Female; Food Deprivation; Gene Expression Regulation, Enzymologic; Intra-Abdominal Fat; Leptin; Lipogenesis; Lipolysis; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Specificity; RNA, Messenger; Subcutaneous Fat, Abdominal; Time Factors; Triglycerides | 2010 |
Metabolic effects of low dose angiotensin converting enzyme inhibitor in dietary obesity in the rat.
Given the recent observation of a local renin-angiotensin system (RAS) in adipose tissue, and its association with obesity-related hypertension, the metabolic effects of treatment with a low dose angiotensin converting enzyme inhibitor (ACEI) were investigated in a rodent model of diet-induced obesity.. Male Sprague Dawley rats were exposed to either standard laboratory chow (12% calories as fat) or palatable high fat (30% calories as fat) diet for 12 weeks. A subset from both dietary groups was given low dose ACEI in drinking water (perindopril, 0.3 mg/kg/day) throughout the study. The high fat diet increased body weight, adiposity, circulating leptin and insulin and in the liver we observed fat accumulation and increased tissue ACE activity. Treatment with perindopril decreased food intake and circulating insulin in both diet groups, and hepatic ACE activity in high fat fed animals only. Decreased plasma leptin concentration with ACE inhibition was only evident in chow fed animals. These effects were independent of any blood pressure lowering effect of ACE inhibition.. Chronic low dose ACEI treatment reduced circulating insulin and leptin levels with some reduction in food intake in chow fed rats. Fewer beneficial effects were observed in obesity, and further work is required to investigate higher ACEI doses. Our data suggest a reduction in hepatic ACE activity may affect lipid accumulation and other inflammatory responses, as well as improving insulin resistance. Our findings may have implications for maximizing the clinical benefit of ACEI in patients without overt cardiovascular complications. Topics: Adipose Tissue; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Body Weight; Diet; Dietary Fats; Energy Intake; Energy Metabolism; Insulin; Leptin; Lipid Metabolism; Liver; Male; Obesity; Organ Size; Peptidyl-Dipeptidase A; Perindopril; Rats; Rats, Sprague-Dawley; Time Factors | 2010 |
Serotonin transporter deficiency increases abdominal fat in female, but not male rats.
Depression and abdominal obesity often co-occur, predominantly in women, and are associated with an increased risk for the development of glucose intolerance and subsequently type 2 diabetes. The underlying mechanisms are poorly understood. We found that female, but not male, depression-prone serotonin transporter knockout (SERT(-/-)) rats had a strong increase (54%) in abdominal fat, whereas no increases in plasma concentrations of glucose and insulin were observed. Surprisingly, application of a high-fat, high-sucrose (HFHS)-choice diet, which results in increased abdominal fat deposition and increased plasma glucose levels in wild-type rats, did not result in elevated plasma glucose levels in female SERT(-/-) rats. Our results show that serotonin transporter deficiency affects abdominal fat deposition in a sex-dependent way, but protects against rises in glucose levels, and thereby potentially glucose intolerance. The increased abdominal fat formation could result from serotonin-mediated developmental changes and provides heuristic value for understanding the effects of the depression-associated serotonin transporter promoter polymorphism in humans. Topics: Abdominal Fat; Adiponectin; Adipose Tissue, White; Analysis of Variance; Animals; Blood Glucose; Body Weight; Diet; Dietary Carbohydrates; Dietary Fats; Eating; Female; Insulin; Leptin; Male; Rats; Rats, Transgenic; Rats, Wistar; Serotonin Plasma Membrane Transport Proteins; Sex Characteristics | 2010 |
A murine model of obesity with accelerated atherosclerosis.
The epidemic of obesity sweeping developed nations is accompanied by an increase in atherosclerotic cardiovascular diseases. Dyslipidemia, diabetes, hypertension, and obesity are risk factors for cardiovascular disease. However, delineating the mechanism of obesity-accelerated atherosclerosis has been hampered by a paucity of animal models. Similar to humans, apolipoprotein E-deficient (apoE(-/-)) mice spontaneously develop atherosclerosis over their lifetime. To determine whether apoE(-/-) mice would develop obesity with accelerated atherosclerosis, we fed mice diets containing 10 (low fat (LF)) or 60 (high fat (HF)) kcal % from fat for 17 weeks. Mice fed the HF diet had a marked increase in body weight and atherosclerotic lesion formation compared to mice fed the LF diet. There were no significant differences between groups in serum total cholesterol, triglycerides, or leptin concentrations. Plasma concentrations of the acute-phase reactant serum amyloid A (SAA) are elevated in both obesity and cardiovascular disease. Accordingly, plasma SAA concentrations were increased fourfold (P < 0.01) in mice fed the HF diet. SAA was associated with both pro- and antiatherogenic lipoproteins in mice fed the HF diet compared to those fed the LF diet, in which SAA was primarily associated with the antiatherogenic lipoprotein high-density lipoprotein (HDL). Moreover, SAA was localized with apoB-containing lipoproteins and biglycan in the vascular wall. Taken together, these data suggest male apoE-deficient mice are a model of metabolic syndrome and that chronic low level inflammation associated with increased SAA concentrations may mediate atherosclerotic lesion formation. Topics: Adiponectin; Analysis of Variance; Animals; Apolipoproteins E; Atherosclerosis; Blood Glucose; Blotting, Western; Body Weight; Chemokine CCL2; Chromatography, High Pressure Liquid; Diet; Dietary Fats; Disease Progression; Energy Intake; Enzyme-Linked Immunosorbent Assay; Image Processing, Computer-Assisted; Interleukin-6; Leptin; Lipids; Liver; Male; Mice; Mice, Knockout; Obesity; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha | 2010 |
Interaction of leptin and amylin in the long-term maintenance of weight loss in diet-induced obese rats.
We have previously shown that combined amylin + leptin agonism elicits synergistic weight loss in diet-induced obese (DIO) rats. Here, we assessed the comparative efficacy of amylin, leptin, or amylin + leptin in the maintenance of amylin + leptin-mediated weight loss. DIO rats pretreated with the combination of rat amylin (50 microg/kg/day) and murine leptin (125 microg/kg/day) for 4 weeks were subsequently infused with either vehicle, amylin, leptin, or amylin + leptin for an additional 4 weeks. Food intake, body weight, body composition, plasma parameters, and the expression of key metabolic genes in liver and white adipose tissue (WAT) were assessed. Amylin + leptin treatment (weeks 0-4) reduced body weight to 87.5% of baseline. Rats subsequently maintained on vehicle or leptin regained all weight (to 104.2 and 101.2% of baseline, respectively), those maintained on amylin had partial weight regain (97.0%). By contrast, weight loss was largely maintained with continued amylin + leptin treatment (91.4%), associated with a 10% decrease in adiposity. Cumulative food intake (weeks 5-8) was reduced by amylin and amylin + leptin, but not by leptin alone. Amylin + leptin, but not amylin or leptin alone, reduced plasma triglycerides (by 55%), total cholesterol (by 19%), and insulin (by 57%) compared to vehicle. Amylin + leptin also reduced hepatic stearoyl-CoA desaturase-1 (Scd1) mRNA, and increased WAT mRNA levels of adiponectin, fatty acid synthase (Fasn), and lipoprotein lipase (Lpl). We conclude that, in DIO rats, maintenance of amylin + leptin-mediated weight loss requires continued treatment with both agonists, and is accompanied by sustained improvements in body composition, and indices of lipid metabolism and insulin sensitivity. Topics: Adiponectin; Adipose Tissue, White; Amyloid; Analysis of Variance; Animals; Appetite Depressants; Body Composition; Body Weight; Diet; Drug Interactions; Eating; Gene Expression Profiling; Insulin; Islet Amyloid Polypeptide; Leptin; Liver; Male; Obesity; Rats; RNA, Messenger; Weight Loss | 2010 |
Metabolic characterization of a mouse deficient in all known leptin receptor isoforms.
We have characterized a newly generated mouse model of obesity, a mouse strain deficient in all five previously described leptin receptor isoforms. These transgenic mice, named the db (333)/db (333) mice, were identified from an ENU mutagenesis screen and carry a point mutation in the seventh exon of the db gene encoding the leptin receptor, resulting in a premature stop codon (Y(333)Stop) and gene product that lacks STAT signaling domains. db (333)/db (333) mice have a morbidly obese phenotype, with body weights diverging from wild type as early as 4 weeks of age (P < 0.05). To determine the contribution of the short isoforms of the leptin receptor in this metabolic phenotype, we performed an extensive metabolic characterization of the db (333)/db (333) mouse in relation to the well-characterized db/db mouse lacking only the long form of the leptin receptor. db (333)/db (333) mice have similar endocrine and metabolic parameters as previously described in other leptin receptor transgenic mice including db/db mice that lack only the long isoform of the leptin receptor. However, db (333)/db (333) mice show a subtle trend toward higher body weight and insulin levels, lower oxygen, carbon dioxide production, respiratory exchange ratio (RER), and temperature than db/db mice suggesting the short isoforms may play an additional role in energy homeostasis. Topics: Animals; Base Sequence; Body Temperature; Body Weight; Carbon Dioxide; Codon, Nonsense; DNA Mutational Analysis; Endocrine Glands; Glucose Tolerance Test; Hyperphagia; Inflammation; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Sequence Data; Motor Activity; Obesity; Oxygen Consumption; Phenotype; Protein Isoforms; Receptors, Leptin; Respiration | 2010 |
Neonatal exposure to parathion alters lipid metabolism in adulthood: Interactions with dietary fat intake and implications for neurodevelopmental deficits.
Organophosphates are developmental neurotoxicants but recent evidence also points to metabolic dysfunction. We determined whether neonatal parathion exposure in rats has long-term effects on regulation of adipokines and lipid peroxidation. We also assessed the interaction of these effects with increased fat intake. Rats were given parathion on postnatal days 1-4 using doses (0.1 or 0.2mg/kg/day) that straddle the threshold for barely detectable cholinesterase inhibition and the first signs of systemic toxicity. In adulthood, animals were either maintained on standard chow or switched to a high-fat diet for 7 weeks. We assessed serum leptin and adiponectin, tumor necrosis factor-alpha (TNFalpha) in adipose tissues, and thiobarbituric acid reactive species (TBARS) in peripheral tissues and brain regions. Neonatal parathion exposure uncoupled serum leptin levels from their dependence on body weight, suppressed adiponectin and elevated TNFalpha in white adipose tissue. Some of the effects were offset by a high-fat diet. Parathion reduced TBARS in the adipose tissues, skeletal muscle and temporal/occipital cortex but not in heart, liver, kidney or frontal/parietal cortex; it elevated TBARS in the cerebellum; the high-fat diet again reversed many of the effects. Neonatal parathion exposure disrupts the regulation of adipokines that communicate metabolic status between adipose tissues and the brain, while also evoking an inflammatory adipose response. Our results are consistent with impaired fat utilization and prediabetes, as well as exposing a potential relationship between effects on fat metabolism and on synaptic function in the brain. Topics: Adiponectin; Adipose Tissue; Aging; Animals; Animals, Newborn; Body Weight; Brain; Cholinesterase Inhibitors; Diet; Dietary Fats; Eating; Female; Leptin; Lipid Metabolism; Male; Parathion; Random Allocation; Rats; Rats, Sprague-Dawley; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha | 2010 |
Metabolic effects of whole grain wheat and whole grain rye in the C57BL/6J mouse.
A diet rich in whole grain cereals is suggested to protect against type 2 diabetes and facilitate body weight regulation. However, little is known about the impact of different cereals and the underlying mechanisms. The objective of this study was to compare the long-term metabolic effects of diets supplemented with whole grain wheat or whole grain rye in the C57BL/6J mouse.. Mice were fed the whole grain supplements in a low-fat background diet for 22 wk. Oral and intravenous glucose tolerance tests were performed during the study and in vitro insulin secretion assays were performed at the end of the study. Body weight, energy intake, body fat content, and plasma parameters were measured during the study.. A dietary supplement of whole grain rye suppressed body weight gain and resulted in significantly decreased adiposity, plasma leptin, total plasma cholesterol, and triacylglycerols compared with a supplement of whole grain wheat. Also, a slight improvement in insulin sensitivity was observed in the rye group compared with the wheat group. The decreases in body weight and adiposity were observed in the absence of differences in energy intake.. Long-term administration of whole grain rye evokes a different metabolic profile compared with whole grain wheat in the C57BL/6J mouse, the primary difference being that whole grain rye reduces body weight and adiposity compared with whole grain wheat. In addition, whole grain rye slightly improves insulin sensitivity and lowers total plasma cholesterol. Topics: Adiposity; Animals; Body Weight; Cholesterol; Dietary Carbohydrates; Dietary Supplements; Edible Grain; Female; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Obesity; Secale; Triglycerides; Triticum; Weight Gain | 2010 |
Diet-induced obesity in male mice is associated with reduced fertility and potentiation of acrylamide-induced reproductive toxicity.
The prevalence of human obesity and related chronic disorders such as diabetes, cardiovascular diseases, and cancer is rapidly increasing. Human studies have shown a direct relationship between obesity and infertility. The objective of the current work was to examine the effect of diet-induced obesity on male fertility and the effect of obesity on susceptibility to chemical-induced reproductive toxicity. From 5 to 30 wk of age, genetically intact male C57Bl/6J mice were fed a normal diet or one in which 60% of the kilocalories were from lard. Obese mice exhibited significant differences in the mRNA of several genes within the testes in comparison to lean males. Pparg was increased 2.2-fold, whereas Crem, Sh2b1, Dhh, Igf1, and Lepr were decreased 6.7, 1.4, 3.2, 1.6, and 7.2-fold, respectively. The fertility of male mice was compared through mating with control females. Acrylamide (AA)-induced reproductive toxicity was assessed in obese or lean males treated with water or 25 mg AA kg(-1) day(-1) via gavage for 5 days and then mated to control females. Percent body fat and weight were significantly increased in mice fed a high-fat vs. a normal diet. Obesity resulted in significant reduction in plugs and pregnancies of control females partnered with obese vs. lean males. Serum leptin and insulin levels were each approximately 5-fold higher in obese vs. age-matched lean mice. Sperm from obese males exhibited decreased motility and reduced hyperactivated progression vs. lean mice. Treatment with AA exacerbated male infertility of obese and lean mice; however, this effect was more pronounced in obese mice. Further, females partnered with AA-treated obese mice exhibited a further decrease in the percentage of live fetuses, whereas the percentage of resorptions increased. This work demonstrated that diet-induced obesity in mice caused a significant reduction in male fertility and exacerbated AA-induced reproductive toxicity and germ cell mutagenicity. Topics: Acrylamide; Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Copulation; Cytochrome P-450 CYP2E1; Dietary Fats; Female; Germ-Line Mutation; Infertility, Male; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Paternal Exposure; Pregnancy; Pregnancy Rate; Reverse Transcriptase Polymerase Chain Reaction; Sperm Count; Sperm Motility; Testis; Triglycerides | 2010 |
Parametrial adipose tissue and metabolic dysfunctions induced by fructose-rich diet in normal and neonatal-androgenized adult female rats.
Hyperandrogenemia predisposes an organism toward developing impaired insulin sensitivity. The aim of our study was to evaluate endocrine and metabolic effects during early allostasis induced by a fructose-rich diet (FRD) in normal (control; CT) and neonatal-androgenized (testosterone propionate; TP) female adult rats. CT and TP rats were fed either a normal diet (ND) or an FRD for 3 weeks immediately before the day of study, which was at age 100 days. Energy intake, body weight (BW), parametrial (PM) fat characteristics, and endocrine/metabolic biomarkers were then evaluated. Daily energy intake was similar in CT and TP rats regardless of the differences in diet. When compared with CT-ND rats, the TP-ND rats were heavier, had larger PM fat, and were characterized by basal hypoadiponectinemia and enhanced plasma levels of non-esterified fatty acid (NEFA), plasminogen activator inhibitor-1 (PAI-1), and leptin. FRD-fed CT rats, when compared with CT-ND rats, had high plasma levels of NEFA, triglyceride (TG), PAI-1, leptin, and adiponectin. The TP-FRD rats, when compared with TP-ND rats, displayed enhanced leptinemia and triglyceridemia, and were hyperinsulinemic, with glucose intolerance. The PM fat taken from TP rats displayed increase in the size of adipocytes, decrease in adiponectin (protein/gene), and a greater abundance of the leptin gene. PM adipocyte response to insulin was impaired in CT-FRD, TP-ND, and TP-FRD rats. A very short duration of isocaloric FRD intake in TP rats induced severe metabolic dysfunction at the reproductive age. Our study supports the hypothesis that the early-androgenized female rat phenotype is highly susceptible to developing endocrine/metabolic dysfunction. In turn, these abnormalities enhance the risk of metabolic syndrome, obesity, type 2 diabetes, and cardiovascular disease. Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Adiposity; Androgens; Animals; Body Weight; Dietary Sucrose; Disease Models, Animal; Energy Intake; Fatty Acids, Nonesterified; Female; Fructose; Genitalia, Female; Glucose Metabolism Disorders; Hyperandrogenism; Insulin; Leptin; Obesity; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley; Risk Factors; Testosterone Propionate; Triglycerides | 2010 |
Body fat, insulin resistance, energy expenditure and serum concentrations of leptin, adiponectin and resistin before, during and after pregnancy in healthy Swedish women.
Healthy human pregnancy is associated with changes in food intake, body fatness, energy expenditure and insulin resistance. However, available knowledge is limited regarding the physiological basis of these changes. Published evidence suggests that so-called adipokines (i.e. leptin, adiponectin and resistin) have significant roles when such changes are established. We explored, throughout a complete pregnancy, relationships between total body fat (TBF), energy expenditure, insulin resistance (homeostasic model of insulin resistance, HOMA-IR) and serum concentrations of leptin, adiponectin and resistin. Such concentrations were assessed before pregnancy in gestational weeks 8, 14, 20, 32 and 35, and 2 weeks postpartum in twenty-three healthy women. TBF, BMR (n 23) and HOMA-IR (n 17) were assessed before pregnancy in gestational weeks 14 and 32 and 2 weeks postpartum. TBF (%) was correlated with HOMA-IR (r 0.68-0.79, P < 0.01) and with serum leptin (r 0.85-0.88, P < 0.001) before and during pregnancy. Serum leptin was correlated with HOMA-IR (r 0.53-0.70, P < 0.05) before and during pregnancy. Serum adiponectin was inversely correlated with HOMA-IR in gestational week 32 (r - 0.52, P < 0.05). When HOMA-IR was regressed on TBF (%), the slope of the regression line was 0.046 before pregnancy, which was significantly (P < 0.05) different from the corresponding value, 0.111, in gestational week 32. The results indicate that pregnancy has an enhancing effect on the relationship between body fatness and insulin resistance. This effect, possibly mediated by leptin, may represent a mechanism by which offspring size is regulated in response to the nutritional situation of the mother. Topics: Adiponectin; Adipose Tissue; Basal Metabolism; Body Composition; Body Weight; Energy Metabolism; Female; Humans; Insulin Resistance; Leptin; Pregnancy; Reference Values; Resistin; Sweden | 2010 |
Psychobiology of purging disorder: reduction in circulating leptin levels in purging disorder in comparison with controls.
Purging disorder (PD), a recently recognized eating disorder syndrome, is differentiated from bulimia nervosa (BN) based on the absence of objectively large binge episodes. BN has been associated with low serum leptin levels. This study examined whether PD is also characterized by low serum leptin.. Participants included women with PD (n = 20) or BN (n = 37), and non-eating disorder controls (n = 33). Blood samples for measurement of leptin and total ghrelin were obtained after overnight fast.. In comparison with control values, leptin levels were significantly decreased in PD (p < .01), as well as in BN (p < .02). Plasma ghrelin levels did not differ significantly across groups.. These results provide the first evidence that PD is associated with alteration in a neurobiological pathway influencing eating patterns and body weight. Further research is needed to assess whether low leptin levels in PD and BN are associated with restrained eating and weight suppression. Topics: Adult; Body Mass Index; Body Weight; Bulimia; Bulimia Nervosa; Case-Control Studies; Eating; Fasting; Female; Ghrelin; Humans; Leptin; Young Adult | 2010 |
Altered "set-point" of the hypothalamus determines effects of cortisol on food intake, adiposity, and metabolic substrates in sheep.
Chronic elevation of glucocorticoid concentrations is detrimental to health. We investigated effects of chronic increase in plasma cortisol concentrations on energy balance and endocrine function in sheep. Because food intake and reproduction are regulated by photoperiod, we performed experiments in January (JAN) and August (AUG), when appetite drive is either high or low, respectively. Ovariectomized ewes were treated (intramuscularly) daily with 0.5mg Synacthen Depot(R) (synthetic adrenocorticotropin: ACTH) or saline for 4 wk. Blood samples were taken to measure plasma concentrations of cortisol, luteinising hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), leptin, insulin, and glucose. Adrenocorticotropin treatment increased concentrations of cortisol. During JAN, treatment reduced food intake transiently, but increased food intake in AUG. Leptin concentrations were reduced and glucose concentrations were greater in AUG, and insulin concentrations were similar throughout the year. Treatment with ACTH increased leptin concentrations in AUG only, whereas insulin concentrations increased in JAN only. Synacthen treatment increased glucose concentrations, with a greater effect in JAN. Changes in truncal adiposity and ACTH-induced cortisol secretion were positively correlated in JAN and negatively correlated in AUG. Treatment reduced the plasma LH pulse frequency in JAN and AUG, with an effect on pulse amplitude in JAN only. Treatment did not affect plasma GH or FSH concentrations. We conclude that chronically elevated cortisol concentrations can affect food intake, adiposity, and reproductive function. In sheep, effects of chronically elevated cortisol concentrations on energy balance and metabolism depend upon metabolic setpoint, determined by circannual rhythms. Topics: Adiposity; Adrenocorticotropic Hormone; Animals; Appetite; Area Under Curve; Blood Glucose; Body Weight; Eating; Female; Follicle Stimulating Hormone; Growth Hormone; Hydrocortisone; Hypothalamus; Insulin; Leptin; Luteinizing Hormone; Seasons; Sheep | 2010 |
Neonatal LPS injection alters the body weight regulation systems of rats under non-stress and immune stress conditions.
It has been reported that prenatal immune stress induced by lipopolysaccharides or cytokines increases food intake and leads to obesity and other features of metabolic syndrome in adulthood. Using Sprague-Dawley rats, we evaluated whether neonatal LPS injection altered their body weight regulation systems under non-stress and immune stress conditions. On Day 10 after birth, all pups were injected with LPS (100 microg/kg, i.p.) (PND(10)LPS) or saline (PND(10)Saline). After weaning, body weight was significantly elevated in PND(10)LPS compared with PND(10)Saline. Thereafter, the rats were injected with LPS (100 microg/kg, i.p.) or saline (used as a basal condition) from 7 to 8 weeks of age. Under basal conditions, cumulative food intake were significantly higher, serum leptin concentration was significantly increased, and hypothalamic NPY mRNA expression was significantly decreased in PND(10)LPS compared with PND(10)Saline. Under adult LPS injected conditions, body weight gain and cumulative food intake were suppressed in both the PND(10)LPS and PND(10)Saline groups compared with those observed under basal adult saline-injected conditions. The suppressive effects induced by adult LPS injection were less evident in the PND(10)LPS group than in the PND(10)Saline group. Adult LPS injection increased the serum leptin concentration in the PND(10)Saline rats, but not in the PND(10)LPS rats. In addition, adult LPS injection increased the mRNA expression of anorexinergic factors (IL-1beta, and TNF-alpha), and decreased that of the orexinergic factor NPY in both groups. However, the influence of adult LPS injection upon these factors was less evident in the PND(10)LPS group than in the PND(10)Saline group. These results suggest that neonatal LPS injection alters body weight regulation under both non-stress and immune stress conditions in male rats. Changes in the endocrine, neuropeptide, and cytokine regulation systems might be involved in these alterations. Topics: Aging; Animals; Animals, Newborn; Body Weight; Corticosterone; Feeding Behavior; Hypothalamus; Interleukin-1beta; Leptin; Lipopolysaccharides; Male; Neuropeptide Y; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tumor Necrosis Factor-alpha | 2010 |
Changes of peripheral alpha-melanocyte-stimulating hormone in childhood obesity.
Relationships of blood circulating melanocortins to childhood obesity are not well established. We evaluated serum alpha-melanocyte-stimulating hormone (alpha-MSH) in lean children and different study groups of childhood obesity. We examined serum alpha-MSH in 52 otherwise healthy children with childhood obesity (Ob; mean age, 11 years; 32 girls/20 boys), 27 normal-weight children of same age, 7 additional obese patients with reduced melanocortin-4 receptor function (MC4Rmut), and 22 patients with craniopharyngioma (CP). Fasting serum alpha-MSH and leptin were measured by radioimmunoassay. Serum alpha-MSH was also evaluated 1 hour after 500-kcal liquid meal (CP and Ob) and at the end of 1-year lifestyle intervention in 24 Ob patients. The alpha-MSH levels were similar in obese vs lean children but significantly lower in CP (P < .001) and significantly higher (P < .05) in MC4Rmut patients compared with Ob. One hour after liquid meal, alpha-MSH increased in patients with Ob but not with CP. After 1 year, alpha-MSH levels increased significantly in the successful weight reduction Ob subgroup despite unchanged cortisol levels. The alpha-MSH changes correlated to weight status changes (r = 0.67, P = .0003) but not to changes of cortisol, insulin, or homeostasis model assessment of insulin resistance index. Persistently low alpha-MSH levels in CP patients are suspected to be due to pituitary or hypothalamic damage. High peripheral levels in MC4Rmut carriers indicate up-regulation of alpha-MSH. Changes of weight status are associated with changes of peripheral alpha-MSH. Topics: Adolescent; alpha-MSH; Body Mass Index; Body Weight; Child; Craniopharyngioma; Female; Genotype; Humans; Hydrocortisone; Insulin; Insulin Resistance; Leptin; Male; Mutation; Obesity; Pituitary Neoplasms; Receptor, Melanocortin, Type 4 | 2010 |
Anorexic vs. metabolic effects of central leptin infusion in rats of various ages and nutritional states.
Age-related obesity is known to be adjoined by leptin resistance. It has not been clarified whether the resistance is cause or result of obesity. In the present experiments, the anorexic (suppressing food intake and body weight) and hypermetabolic (increasing body temperature (Tc), activity, and heart rate (HR), indicating metabolic rate) responses to 7-day-long intracerebroventricular leptin infusion were compared in 2- and 6-month-old normally fed (NF2 and NF6 groups), 6-month-old high-fat-diet-induced obese (HF6), and 6-month-old calorie-restricted (CR6) rats. The anorexic effects were inversely related to fat content: They were most pronounced in NF2, less in NF6, non-significant in HF6 rats, but also absent in CR6 animals of the lowest fat content. This virtual leptin resistance in CR6 rats was due to their high orexigenic activity (enhanced feeding response to NPY). In contrast, CR6 rats were hypersensitive to the metabolic effects of leptin infusion (rise in Tc and HR; biotelemetric measurements), NF2 were still sensitive, while NF6 and HF6 rats exhibited moderate or low sensitivity. In conclusion, leptin resistance depends on body fat content rather than on age itself, although with age the proportion of fat tissue increases and contributes to self-perpetuating rise in body weight. Topics: Adipose Tissue; Age Factors; Animals; Anorexia; Body Weight; Caloric Restriction; Dietary Fats; Eating; Energy Intake; Energy Metabolism; Injections, Intraventricular; Leptin; Male; Muscle, Skeletal; Nutritional Status; Obesity; Rats; Rats, Wistar | 2010 |
Pregnancy and lactation have anti-obesity and anti-diabetic effects in A(y)/a mice.
Dominant 'yellow' mutation at the mouse agouti locus (A(y)) results in obesity. Pregnancy and lactation are characterized by large energy demand. The aim of this study was to investigate whether obesity would develop in pregnant and suckling A(y) mice.. Body weight and food intake in pregnancy, lactation, and after weaning, plasma leptin, insulin, corticosterone and blood glucose concentrations on days 7, 13 and 18 of pregnancy, days 1, 10, 21 and 80 postpartum, glucose and insulin tolerance on pregnancy days 7 and 18 were measured in C57Bl/6J mice of a/a (normal metabolism) and A(y)/a genotypes. The same parameters were also measured in age-matched virgin females.. Virgin A(y)/a females exhibited hyperphagia, enhanced body weight, glucose intolerance and normal blood parameters at the mating age. With age, they developed obesity, hyperleptinaemia, hyperinsulinaemia and hyperglycaemia. Obesity did not develop in mated A(y)/a mice; during suckling, they had equal food intake and body weight as a/a mice. During pregnancy, glucose tolerance was enhanced in A(y)/a mice and became equal in both genotypes. In both genotypes, concentrations of hormones increased, and glucose decreased from pregnancy day 7 to day 18 and returned to normal values after parturition. A(y)/a mice did not differ from a/a in corticosterone, insulin and glucose levels during pregnancy and lactation, in leptin levels during suckling; however, A(y)/a mice had two times higher leptin levels than a/a during pregnancy. After weaning, A(y)/a mice began to eat and weigh more than a/a exhibiting normal metabolic parameters for 50 days.. Pregnancy and lactation retard obesity and diabetes development in A(y) mice. Topics: Age Factors; Animals; Blood Glucose; Body Weight; Breast Feeding; Corticosterone; Diabetes Mellitus; Female; Glucose Intolerance; Insulin Resistance; Lactation; Leptin; Mice; Mice, Inbred C57BL; Obesity; Pregnancy | 2010 |
Effects of ghrelin on growth and cardiac function in infants with congenital heart disease.
Ghrelin has effects on appetite and growth. Recent reports suggest effects on cardiac function, but no study has evaluated the ghrelin levels of congenital heart disease (CHD) infants with heart failure. The purpose of the present study was therefore to investigate the relationship between ghrelin level and growth and cardiac function in CHD infants.. Twenty-eight infants with CHD were eligible for the study. Blood samples were obtained at the time of insertion of intracardiac catheter and correlation was examined between ghrelin plasma level and anthropometric parameters, including z score of height and weight, body mass index (BMI), and %bodyweight gain rate, severity of heart failure, and the levels of leptin and insulin-like growth factor-1.. In the CHD group, active ghrelin (A-Ghr) had a significant negative correlation with z score of bodyweight, and a significant positive correlation with cardiac function. There were no correlations, however, with height and BMI. A-Ghr levels were significantly higher in the high heart failure index score group. Significant correlation between A-Ghr and desacyl-ghrelin in the CHD group was observed.. A-Ghr is involved in cardiac function and has little effect on their physique in infants with CHD. Topics: Anthropometry; Biomarkers; Body Height; Body Weight; Case-Control Studies; Child Development; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Ghrelin; Growth; Heart Defects, Congenital; Heart Failure; Heart Function Tests; Humans; Infant; Infant, Newborn; Japan; Leptin; Male; Reference Values; Risk Assessment; Somatomedins; Statistics, Nonparametric | 2010 |
Leptin is essential in maintaining normal vascular compliance independent of body weight.
The adipocytokine leptin centrally regulates body weight by enhancing metabolic rate and signaling satiety, but it also has wide-ranging peripheral effects. Leptin receptors are expressed on vascular smooth muscle cells and have a role in maintaining vascular tone. We investigated the vascular effects of leptin repletion or calorie restriction on leptin-deficient mice (ob/ob) and a leptin antagonist on wild-type (WT) mice. Aortic compliance was assessed by the measurement of pulse wave velocity by noninvasive Doppler; blood pressure was measured by left ventricular catheterization. We found that ob/ob mice have much stiffer aortas than WT mice and that reduction in aortic stiffness was greater in ob/ob mice treated with leptin vs calorie restriction, despite similar weight loss. Interestingly, treating WT mice with a leptin antagonist increases aortic stiffness with no change in weight. Thus, we conclude that leptin is essential for maintaining normal aortic compliance independent of body weight. Topics: Animals; Aorta; Blood Pressure; Body Weight; Caloric Restriction; Compliance; Leptin; Mice; Mice, Inbred C57BL; Obesity; Vascular Resistance | 2010 |
Diet-induced obesity in the short-day-lean Brandt's vole.
To test the hypothesis that mammals that show decrease in body mass under short-day condition should be resistant to high-fat induced obesity, we traced the changes of energy balance in a wild rodent, Brandt's voles (Lasiopodomys brandtii), which were acclimated to either long day (16L: 8D, LD) or short day (8L: 16D, SD) and fed either low-fat diet (LFD) or high-fat diet (HFD) in each photoperiodic manipulation. We found that Brandt's vole was not resistant to high-fat diet-induced obesity and SD, not HFD, induced the elevation in basal metabolic rate, the maximal rate of oxygen consumption after norepinephrine injection, and uncoupling protein 1 content in brown adipose tissue. HFD caused the increase in apparent digestibility and body fat mass, and the decrease in energy intake in both LD and SD voles. The enhancement of energy absorption associated with small intestine tissue recruitment can compensate the lower energy intake, which may contribute to the high-fat diet-induced body fat deposition. Thus, a decrease in body-weight gain but has no resistance to high-fat induced obesity implies an evolutionary and adaptive mechanism which is a benefit for their winter survival. Topics: Adipose Tissue, Brown; Adrenergic alpha-Agonists; Animals; Arvicolinae; Basal Metabolism; Body Composition; Body Weight; Dietary Fats; Electron Transport Complex IV; Energy Intake; Intestine, Small; Ion Channels; Leptin; Male; Mitochondrial Proteins; Norepinephrine; Obesity; Oxygen Consumption; Time Factors; Uncoupling Protein 1 | 2010 |
Administration of physiologic levels of triiodothyronine increases leptin expression in calorie-restricted obese rats, but does not influence weight loss.
Obesity has become a major public health problem, most commonly treated via dietary restriction to promote weight loss. Although leptin and thyroid hormones are involved in the regulation of energy balance, the role of these hormones after the stabilization of weight loss remains unclear. This study was designed to analyze the effect of thyroid hormone on sustained weight loss and leptin gene expression in obese animals after a loss of 5% to 10% of body weight. Thirty-day-old male Wistar rats were separated into 4 groups: control, obese, calorie restriction (CR), and calorie restriction with triiodothyronine administration (CRT). The obese group had increased weight and adiposity, leptin and insulin levels, and leptin gene expression. Dietary restriction in the CR group resulted in decreased body weight and adiposity, diminished leptin, and increased thyroid hormone receptor beta expression. The CRT group, submitted to dietary restriction with concomitant administration of a physiologic triiodothyronine dose, had thyroid hormone receptor beta expression at levels comparable with those observed in the control group and simultaneously increased leptin expression as compared with that in the CR group, suggesting that thyroid hormone modulates leptin expression under conditions of calorie restriction. Increased leptin expression in the CRT group did not result in increased circulating leptin or a statistically significant reduction in body weight during the treatment period. These data provide impetus for further study, as a longer treatment period may result in increased circulating leptin and, thus, further reduction in body weight during calorie restriction in an obesity model. Topics: Animals; Body Composition; Body Weight; Caloric Restriction; Energy Intake; Insulin; Leptin; Male; Obesity; Polymerase Chain Reaction; Rats; Rats, Wistar; Triiodothyronine; Weight Loss | 2010 |
Chronic maternal dietary chromium restriction modulates visceral adiposity: probable underlying mechanisms.
We demonstrated previously that chronic maternal micronutrient restriction altered the body composition in rat offspring and may predispose offspring to adult-onset diseases. Chromium (Cr) regulates glucose and fat metabolism. The objective of this study is to determine the long-term effects of maternal Cr restriction on adipose tissue development and function in a rat model.. Female weanling WNIN rats received, ad libitum, a control diet or the same with 65% restriction of Cr (CrR) for 3 months and mated with control males. Some pregnant CrR mothers were rehabilitated from conception or parturition and their pups weaned to control diet. Whereas some CrR offspring were weaned to control diet, others continued on CrR diet. Various parameters were monitored in the offspring at three monthly intervals up to 15-18 months of age.. Maternal Cr restriction significantly increased body weight and fat percentage, especially the central adiposity in both male and female offspring. Further, the expression of leptin and 11 beta-hydroxysteroid dehydrogenase 1 genes were significantly increased in CrR offspring of both the sexes. Adipocytokine levels were altered in plasma and adipose tissue; circulating triglyceride and FFA levels were increased, albeit in female offspring only. Rehabilitation regimes did not correct body adiposity but restored the circulating levels of lipids and adipocytokines.. Chronic maternal Cr restriction increased body adiposity probably due to increased stress and altered lipid metabolism in WNIN rat offspring, which may predispose them to obesity and associated diseases in later life. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Chromium; Disease Models, Animal; Female; Leptin; Lipids; Male; Maternal Deprivation; PPAR gamma; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains; Reverse Transcriptase Polymerase Chain Reaction; RNA, Ribosomal, 18S | 2010 |
Gene structure, recombinant expression and functional characterization of grass carp leptin.
Leptin is an important hormone for the regulation of food intake, energy expenditure and reproduction in mammals, but information regarding its role in teleosts remains scant. In the present study, the gene structures of grass carp (Ctenopharyngodon idellus) and silver carp (Hypophthalmichthys molitrix) leptins were characterized. Recombinant grass carp leptin (rgc-LEP) was expressed in Escherichia coli and purified, and identified by mass spectrometric analysis. A strong anorexic effect on food intake was observed in grass carp on the first day after intraperitoneal (IP) injection of rgc-LEP, but not during the following days. Body weight of the leptin group (LEP group) and the pair-fed group (PF group) showed no difference throughout the experimental period. The acute and chronic effects on the expression of key genes correlating to food intake, energy expenditure, lipid metabolism and digestion were further characterized by real-time PCR. Accordingly, the mRNA levels of neuropeptide Y (NPY), Stearoyl-CoA desaturase 1 (SCD1) and lipoprotein lipase (LPL) were significantly reduced whereas the mRNA levels of uncoupling protein 2 (UCP2), bile salt-activated lipase (BSAL) and fatty acid elongase (ELO) were significantly elevated on the first day after injection. No effect on the expression of these genes (except LPL) was observed on day 13. In contrast to the down-regulation by exogenous leptin in mammals, the mRNA level of grass carp leptin was elevated 5.76-fold on the first day after rgc-LEP treatment. Our results suggest that leptin has an acute effect on the regulation of food intake, energy expenditure and lipid metabolism in grass carp, but the effect can be rapidly counteracted through mechanisms that are currently unknown. Topics: Acetyltransferases; Animals; Body Weight; Carps; Eating; Energy Metabolism; Fatty Acid Elongases; Fish Proteins; Gene Expression Regulation; Ion Channels; Leptin; Lipid Metabolism; Lipoprotein Lipase; Mitochondrial Proteins; Neuropeptide Y; Recombinant Proteins; Stearoyl-CoA Desaturase; Sterol Esterase; Uncoupling Protein 2 | 2010 |
Central leptin versus ghrelin: effects on bone marrow adiposity and gene expression.
This study compared the central effects of ghrelin and leptin on body and bone marrow adiposity and gene expression in adipose tissue and bone marrow. Male Sprague-Dawley rats were injected intracerebroventricular (ICV) twice daily with control, 66 ng ghrelin (G66), 330 ng ghrelin (G330), or 5 μg leptin (L5) for 5 days. Food intake (FI) and body weight (BW) were measured daily. Gene expression in adipose tissue and bone marrow was assessed using RT-PCR. Leptin reduced FI (P < 0.05) and BW (P < 0.05), whereas ghrelin increased BW (P < 0.05) without affecting FI. Leptin decreased fat pad weights, whereas ghrelin (G330) increased fat pad weights (P < 0.05). In epididymal adipose tissue, leptin increased expression of lipolysis marker ADRB2 and thermogenesis marker MFN2 and decreased expression of adipogenic markers, FASN, SLC2A4, and SCD1, whereas ghrelin increased expression of FASN and SCD1. Leptin decreased bone marrow adipocyte size and number; however, ghrelin had no effect on these parameters. In whole bone marrow, leptin decreased expression of FASN and SCD1 and increased expression of DLK1, whereas ghrelin (G330) decreased expression of COL1A1. Thus, leptin induces similar changes in bone marrow and adipose tissue gene expression, reflecting the decreased adiposity in both compartments. Topics: Adipogenesis; Adipose Tissue, White; Adiposity; Animals; Biomarkers; Body Weight; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Diet; Gene Expression Profiling; Gene Expression Regulation; Ghrelin; Injections, Intraventricular; Leptin; Lipolysis; Male; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thermogenesis | 2010 |
Rosiglitazone reduces blood pressure in female Dahl salt-sensitive rats.
Postmenopausal women (PMW) are at greater risk for salt-sensitive hypertension and insulin resistance than premenopausal women. Peroxisome-proliferator-activated receptor-gamma (PPARgamma) agonists reduce blood pressure (BP) and insulin resistance in humans. As in PMW, ovariectomy (OVX) increases salt sensitivity of BP and body weight in Dahl salt-sensitive (DS) rats. This study addressed whether rosiglitazone (ROSI), a PPARgamma agonist, attenuates salt-sensitive hypertension in intact (INT) and OVX DS rats, and if so, whether insulin resistance, nitric oxide (NO), oxidative stress, and/or renal inflammation were contributing mediators. Telemetric BP was similar in OVX and INT on low salt diet (0.3% NaCl), but was higher in OVX than INT on high salt (8% NaCl). ROSI reduced BP in OVX and INT on both low and high salt diet, but only attenuated salt sensitivity of BP in OVX. Nitrate/nitrite excretion (NO(x); index of NO) was similar in INT and OVX on low salt diet, and ROSI increased NO(x) in both groups. High salt diet increased NO(x) in all groups but ROSI only increased NO(x) in OVX rats. OVX females exhibited insulin resistance, increases in body weight, plasma leptin, cholesterol, numbers of renal cortical macrophages, and renal MCP-1 and osteopontin mRNA expression compared to INT. ROSI reduced cholesterol and macrophage infiltration in OVX, but not INT. In summary, PPARgamma activation reduces BP in INT and OVX females, but attenuates the salt sensitivity of BP in OVX only, likely due to increases in NO and in part to reductions in renal resident macrophages and inflammation. Topics: Albuminuria; Animals; Biomarkers; Blood Glucose; Blood Pressure; Body Weight; Chemokine CCL2; Cholesterol; Estradiol; Feeding Behavior; Female; Gene Expression Regulation; Immunohistochemistry; Inflammation; Insulin; Kidney; Leptin; Nitrates; Nitrites; Osteopontin; Ovariectomy; Rats; Rats, Inbred Dahl; RNA, Messenger; Rosiglitazone; Thiazolidinediones | 2010 |
Effects of experimental weight perturbation on skeletal muscle work efficiency, fuel utilization, and biochemistry in human subjects.
Maintenance of a body weight 10% above or below that "customary" for lean or obese individuals results in respective increases or decreases in the energy expended in low levels of physical activity (nonresting energy expenditure, NREE). These changes are greater than can be accounted for by the altered body weight or composition and are due mainly to altered skeletal muscle work efficiency at low levels of power generation. We performed biochemical analysis of vastus lateralis muscle needle biopsy samples to determine whether maintenance of an altered body weight was associated with changes in skeletal muscle histomorphology. We found that the maintenance of a 10% reduced body weight was associated with significant declines in glycolytic (phosphofructokinase, PFK) enzyme activity and, in particular, in the ratio of glycolytic to oxidative (cytochrome c oxidase, COX) enzyme activity without significant changes in the activities of enzymes relevant to mitochondrial density, respiratory chain activity, or fuel transport; or in skeletal muscle fiber type or glycogen stores. The fractional change in the ratio of PFK/COX activity in subjects following weight loss was significantly correlated with changes in the systemic respiratory exchange ratio (RER) and measures of mechanical efficiency of skeletal muscle at low workloads (pedaling a bicycle to generate 10 or 25 W of power). Thus, predictable changes in systemic skeletal muscle biochemistry accompany the maintenance of an altered body weight and account for a significant portion of the variance in skeletal muscle work efficiency and fuel utilization at reduced body weight. Topics: Adiponectin; Adult; Biopsy; Blood Glucose; Body Weight; Case-Control Studies; Energy Metabolism; Exercise Test; Female; Glycolysis; Humans; Insulin; Leptin; Male; Middle Aged; Muscle Contraction; Muscle Strength; Muscle, Skeletal; Obesity; Triiodothyronine; Weight Gain; Weight Loss | 2010 |
Adult consequences of post-weaning high fat feeding on the limbic-HPA axis of female rats.
The peripubertal period is critical for the final maturation of circuits controlling energy homeostasis and stress response. However, the consequence of juvenile fat consumption on adult physiology is not clear. This study analyzed the adult consequences of post-weaning fat feeding on limbic-hypothalamic-pituitary-adrenal (HPA) axis components and on metabolic regulators of female rats. Wistar rats were fed either a high fat (HF) diet or the normal chow from weaning to puberty or to 3 months of age. Additional groups crossed their diets at puberty onset. Plasma leptin, insulin, and corticosterone levels were determined by radioimmunoassay and their brain receptors by western blot analysis. Adult HF-fed animals though not overweight, had higher corticosterone and reduced glucocorticoid receptor levels in the hypothalamus and hippocampus, compared to the controls. The alterations in HPA axis emerged already at puberty onset. Leptin receptor levels in the hypothalamus were reduced only by continuous fat feeding from weaning to adulthood. The pre-pubertal period appeared more vulnerable to diet-induced alterations in adulthood than the post-pubertal one. Switching from fat diet to normal chow at puberty onset restored most of the diet-induced alterations in the HPA axis. The corticosteroid circuit rather than the leptin or insulin system appears as the principal target for the peripubertal fat diet-induced effects in adult female rats. Topics: Animals; Blood Glucose; Body Weight; Corticosterone; Dietary Fats; Eating; Female; Hypothalamo-Hypophyseal System; Insulin; Leptin; Limbic System; Pituitary-Adrenal System; Random Allocation; Rats; Rats, Wistar; Receptors, Glucocorticoid; Receptors, Leptin; Weaning | 2010 |
Estrous cycle in ob/ob and ovariectomized female mice and its relation with estrogen and leptin.
Hormones like leptin and estrogen have been suggested to increase energy expenditure and modulate estrous cycle. The aim of this study was to investigate the stages of estrous cycle in mouse models with contrasting leptin and estrogen levels. Estrous cycle of wild type (WT), WT ovariectomized (OVX), ob/ob and ob/ob OVX was observed by obtaining vaginal smear and staining with Papanicolaou (PAP) procedure. Quantitative analysis showed cellular morphology and predominance of cellular content across the estrous cycle. Microscopical and quantitative counts showed a 4-5 day regular cycle in WT mouse, WTOVX were acyclic, infertile and hardly showed any cells, ob/ob and ob/ob OVX were both acyclic, infertile and were at persistent estrous or persistent metaestrous phase. Enzyme-Immunometric Assay results showed that leptin levels were about 3 fold higher in WTOVX than WT mouse (p<0.0001) with beta-estradiol values being negligible in WTOVX. The beta-estradiol levels for ob/ob and WT were similar. These results suggest that although leptin and estrogen play an important role in the estrous cycle, they are not the sole factor influencing the cycle. It is probable that in the absence of leptin and decrease in sex steroid hormones with increase in acyclicity, the central nervous system probably interprets the circulation as absence of energy stores and shuts down reproduction indicated by the changes in the estrous cycle. Topics: Animals; Body Weight; Cell Count; Enzyme-Linked Immunosorbent Assay; Estrogens; Estrous Cycle; Female; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Ovariectomy; Papanicolaou Test; Vagina; Vaginal Smears | 2010 |
Genetic suppression of ghrelin receptors activates brown adipocyte function and decreases fat storage in rats.
To clarify the role of ghrelin and its receptor (GHS-R) in the regulatory mechanism of energy metabolism, we analyzed transgenic (Tg) rats expressing an antisense GHS-R mRNA under the control of the tyrosine hydroxylase (TH) promoter. Tg rats showed lower visceral fat weight and higher O(2) consumption, CO(2) production, rectal temperature, dark-period locomotor activity, brown adipose tissue (BAT) weight and uncoupling protein 1 expression compared with wild-type (WT) rats on a standard diet. A high-fat diet for 14days significantly increased body weight, visceral fat weight, and the sizes of white and brown adipocytes in WT rats but not in Tg rats compared with the corresponding standard-diet groups. Antisense GHS-R mRNA was expressed and GHS-R expression was reduced in TH-expressing cells of the vagal nodose ganglion in Tg rats. Ghrelin administered intravenously suppressed noradrenaline release in the BAT of WT rats, but not in Tg rats. These results suggest that ghrelin/GHS-R plays an important role in energy storage by modifying BAT function and locomotor activity. As our previous study showed that peripheral ghrelin-induced noradrenaline release suppression in BAT is blocked by vagotomy, the present findings also suggest that vagal afferents transmit the peripheral ghrelin signal to the sympathetic nervous system innervating BAT. Topics: Adipose Tissue, Brown; Animals; Animals, Genetically Modified; Body Temperature; Body Weight; Cell Count; Cell Size; Eating; Gene Expression Regulation; Ghrelin; Insulin-Like Growth Factor I; Ion Channels; Leptin; Male; Mitochondrial Proteins; Motor Activity; Nodose Ganglion; Norepinephrine; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; Uncoupling Protein 1 | 2010 |
Declining beta-cell compensation for insulin resistance in Hispanic women with recent gestational diabetes mellitus: association with changes in weight, adiponectin, and C-reactive protein.
To identify factors associated with declining beta-cell compensation for insulin resistance.. In a cohort of Hispanic women with recent gestational diabetes mellitus, oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and bioelectrical impedance measurements were performed at 15-month intervals for up to 5 years, or until fasting plasma glucose exceeded 140 mg/dl (7.8 mmol/l). Data were analyzed to identify predictors of declining beta-cell compensation for insulin resistance (the disposition index [DI]) and to examine the mechanism of weight gain and changes in circulating levels of selected adipokines and inflammatory markers on beta-cell compensation decline.. A total of 60 nondiabetic women had a median of four sets of OGTT + IVGTT during a median follow-up of 52 months. Fourteen of the women developed diabetes. None of the baseline characteristics were significantly predictive of a decline in DI. There were significant univariate associations between declining DI and weight gain (specifically fat gain), declining adiponectin and rising C-reactive protein. Multivariate analysis showed that the weight gain was the most significant factor associated with declining DI. The amount of association between weight gain and declining DI was explained 31% by changes in adiponectin and C-reactive protein and 40% by changes in insulin resistance.. These results identify weight gain as the strongest factor associated with declining beta-cell compensation for insulin resistance in Hispanic women at high risk for type 2 diabetes. Such effect may be mediated through at least two effects: alterations in adipokine levels and increasing insulin resistance. Topics: Adiponectin; Adipose Tissue; Adult; Body Weight; C-Reactive Protein; Cholesterol, HDL; Cholesterol, LDL; Diabetes, Gestational; Electric Impedance; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Pregnancy; Triglycerides | 2010 |
Effects of excess corticosterone on LKB1 and AMPK signaling in rat skeletal muscle.
Cushing's syndrome is characterized by marked central obesity and insulin insensitivity, effects opposite those seen with chronic AMP-activated protein kinase (AMPK) activation. This study was designed to determine whether chronic exposure to excess glucocorticoids influences LKB1/AMPK signaling in skeletal muscle. Corticosterone pellets were implanted subcutaneously in rats (hypercorticosteronemia, Hypercort) for 2 wk. Controls were sham operated and fed ad libitum or were sham operated and food restricted (pair-weighted group, Pair) to produce body weights similar to Hypercort rats. At the end of the 2-wk treatment period, rats were anesthetized, and the right gastrocnemius-plantaris (gastroc) and soleus muscles were removed. Left muscles were removed after electrical stimulation for 5 min. No significant differences were noted between treatment groups in ATP, creatine phosphate, or LKB1 activity. The alpha- and beta-subunit isoforms were not significantly influenced in gastroc by corticosterone treatment. Expression of the gamma3-subunit decreased, and gamma1- and gamma2-subunit expression increased. Both alpha2-AMPK and alpha1-AMPK activities were increased in the gastroc in response to electrical stimulation, but the magnitude of the increase was less for alpha2 in the Hypercort rats. Despite elevated plasma insulin and elevated plasma leptin in the Hypercort rats, phosphorylation of TBC1D1 was lower in both resting and stimulated muscle compared with controls. Malonyl-CoA content was elevated in gastroc muscles of resting Hypercort rats. These changes in response to excess glucocorticoids could be responsible, in part, for the decrease in insulin sensitivity and adiposity seen in Cushing's syndrome. Topics: Adrenal Glands; AMP-Activated Protein Kinase Kinases; Animals; Atrophy; Blotting, Western; Body Weight; Corticosterone; Cyclic AMP-Dependent Protein Kinases; Electric Stimulation; Immunoprecipitation; Insulin; Insulin Resistance; Isoenzymes; Leptin; Lipid Metabolism; Male; Muscle Contraction; Muscle, Skeletal; Protein Serine-Threonine Kinases; Proteins; Rats; Rats, Sprague-Dawley; Signal Transduction | 2010 |
Increased leptin storage with altered leptin secretion from adipocytes of rats with sucrose-induced dyslipidemia and insulin resistance: effect of dietary fish oil.
This study examined the effect of long-term feeding a high-sucrose diet (SRD) on the modulation of rat adipocyte's leptin secretion and storage. For this purpose, we analyzed (a) basal and insulin-stimulated leptin release and the role of isoproterenol and palmitate on insulin-stimulated leptin secretion, (b) the correlation between leptin and glycerol released, (c) the relationship between leptin contents and adiposity, and (d) the effect of fish oil (FO) administration on the above parameters. Wistar rats were fed an SRD for 6 months. Whereas half the animals continued with SRD up to month 8, the other half was fed an SRD in which FO partially replaced corn oil from months 6 to 8. Total leptin release was reduced both basally and under insulin stimulation in SRD-fed rats. However, the ratio of leptin released after hormone stimulation to basal leptin levels was similar in the 3 dietary groups. Isoproterenol inhibited insulin-stimulated leptin release in the 3 groups, but the percentage was lower in the SRD. Palmitic acid mimicked the effect of isoproterenol. Leptin release from adipocyte of SRD-fed rats negatively correlated with glycerol release. Leptin store increased in fat pads of SRD and positively correlated with adiposity. Fish oil reduced leptin content and fat pad hypertrophy, and normalized basal lipolysis, leptinemia, and glucose homeostasis. This suggests that enhanced lipolysis and altered insulin sensitivity could play a role in the decrease of leptin released in SRD-fed rats. This is consistent with the reversion of all the alterations after FO administration. Topics: Adipocytes; Adipose Tissue, White; Adrenergic beta-Agonists; Animals; Body Weight; Cell Count; Cell Separation; Diet; Dyslipidemias; Energy Intake; Fatty Acids, Omega-3; Fish Oils; Insulin Resistance; Isoproterenol; Leptin; Lipid Metabolism; Lipolysis; Male; Palmitates; Rats; Rats, Wistar; Sucrose | 2010 |
Nutritional programming affects hypothalamic organization and early response to leptin.
Nutritional programming, taking place in utero or early after birth, is closely linked with metabolic and appetite disorders in adulthood. Following the hypothesis that nutritional programming impacts hypothalamic neuronal organization, we report on discrepancies of multiple molecular and cellular early events that take place in the hypothalamus of rats submitted to intrauterine growth restriction (IUGR). Expression screening performed on hypothalami from IUGR rats at birth and at postnatal d 12 identified changes in gene expression of neurodevelopmental process (cell differentiation and cytoskeleton organization). Additionally, a slight reduction of agouti-related protein and a strong reduction of alpha-MSH-immunoreactive efferent fibers were demonstrated in the paraventricular nucleus of IUGR rats. Rapid catch-up growth of IUGR rats, 5 d after birth, had a positive effect on neurodevelopmental factors and on neuronal projections emanating from the arcuate nucleus. The molecular and cellular anomalies detected in IUGR rats can be related to the reduced and delayed plasma leptin surge from d 0-16 when compared with control and IUGR rats with catch-up growth. However, the ability of leptin to activate intracellular signaling in arcuate nucleus neurons was not reduced in IUGR rats. Other mechanism such as epigenetic regulation of the major appetite-regulating neuropeptides genes was analyzed in parallel with their mRNA expression during postnatal development. This study reveals the importance of an early catch-up growth that reduces abnormal organization of hypothalamic pathways involved in energy homeostasis, whereas protein restriction, maintained during postnatal development leads to an important immaturity of the hypothalamus. Topics: Agouti-Related Protein; alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; DNA; DNA Methylation; Energy Intake; Female; Fetal Growth Retardation; Gene Expression Regulation; Hypothalamus; Leptin; Male; Nerve Fibers; Nerve Tissue Proteins; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pro-Opiomelanocortin; Rats; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA; Signal Transduction | 2010 |
Distribution of leptin-sensitive cells in the postnatal and adult mouse brain.
Leptin plays a pivotal role in the regulation of energy homeostasis and neuroendocrine functions, and increasing evidence indicates that leptin acts on the brain to mediate many of these effects. Recent data have also suggested that leptin influences brain development during early postnatal life. Here we examined the distribution of cells that express mRNA encoding the long form of the leptin receptor (LepRb) in postnatal and adult mouse brains by using in situ hybridization. In both adults and neonates, LepRb mRNA was largely restricted to regions known to control energy balance. Labeled cells were found in the arcuate, ventromedial, and dorsomedial nuclei of the hypothalamus as well as in the lateral hypothalamic area. Heavily labeled cells were also found in the median preoptic and ventral premammillary nuclei, two hypothalamic nuclei that are known to control reproduction. Moreover, during postnatal and adult life, clearly labeled cells were found in extrahypothalamic autonomic control sites such as the nucleus of the tractus solitarius. Importantly, this receptor can induce intracellular signaling because peripheral injection of leptin caused STAT3 phosphorylation in most sites in which LepRb mRNA was expressed. LepRb mRNA was also transiently elevated in certain regions of the postnatal mouse brain, such as the cortex, hippocampus, and laterodorsal nucleus of the thalamus. Taken together, these observations are consistent with the proposed roles of leptin in feeding and neuroendocrine regulation. They also identify regions where LepRb mRNA is expressed during early postnatal life and suggest new roles for leptin in the nervous system during development. Topics: Aging; Animals; Animals, Newborn; Appetite; Body Weight; Brain; Brain Mapping; Energy Metabolism; Female; Hypothalamus; In Situ Hybridization; Leptin; Male; Mice; Mice, Inbred C57BL; Neurons; Neurosecretory Systems; Prosencephalon; Receptors, Leptin; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Up-Regulation | 2010 |
A free-choice high-fat high-sugar diet induces changes in arcuate neuropeptide expression that support hyperphagia.
The mechanisms for how saturated fat and sugar-based beverages contribute to human obesity are poorly understood. This paper describes a series of experiments developed to examine the response of hypothalamic neuropeptides to diets rich in sugar and fat, using three different diets: a high-fat high-sugar (HFHS) choice diet with access to chow, saturated fat and a 30% sugar solution; a high-fat (HF) choice diet with access to chow and saturated fat; or to a high-sugar (HS) choice diet with access to chow and a sugar solution.. We first studied caloric intake, body weight gain, hormonal alterations and hypothalamic neuropeptide expression when male Wistar rats were subjected to an HFHS choice, an HF choice or an HS choice diet for 1 week. Next, we studied caloric intake and body weight gain when rats were subjected to the choice diets for 5 weeks. Finally, we measured neuropeptide expression in hepatic vagotomized rats subjected to an HFHS choice, an HF choice or an HS choice diet for 1 week.. In rats on an HF choice diet, plasma leptin concentrations and proopiomelanocortin (POMC) mRNA increased and neuropeptide Y (NPY) mRNA decreased. Rats on an HFHS choice diet showed identical plasma leptin concentrations as rats on an HF choice diet. However, NPY mRNA increased and POMC mRNA decreased. An HS choice diet for 1 week did not alter hypothalamic neuropeptide expression or plasma leptin concentrations. As hormonal changes did not explain the differences in hypothalamic neuropeptide expression between rats on the choice diets, we addressed whether neuronal feedback signals mediated the hypothalamic neuropeptide response. The POMC mRNA response to different diets depended on an intact innervation of liver and upper intestinal tract.. Our data suggest that the specific combination of saturated fat and a 30% sugar solution results in hyperphagia-induced obesity and alters hypothalamic neuropeptide expression, and that the response of the melanocortin system is mediated by the hepatic vagus. Topics: Animals; Body Weight; Dietary Fats; Dietary Sucrose; Energy Intake; Gene Expression; Hyperphagia; Leptin; Liver; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Wistar | 2010 |
Diet-genotype interactions in the early development of obesity and insulin resistance in mice with a genetic deficiency in tumor necrosis factor-alpha.
The onset of insulin resistance, the sites of action, and the mechanisms through which tumor necrosis factor-alpha (TNF-alpha) exacerbates the increase in adiposity and the development of insulin resistance in mice fed high-fat (HF) diet remain unclear. Here we investigated the effect of TNF-alpha deficiency on adiposity and insulin resistance during the initial 1 to 4 weeks of HF feeding. We examined body weight; the distribution of white adipose tissue (WAT); homeostasis model assessment; and levels of leptin, resistin, and adiponectin in the initial 4 weeks of HF feeding in TNF-alpha knockout (KO) mice and wild-type (WT) controls. Through 4 weeks of HF feeding, KO mice, unlike WT mice, maintained normal insulin sensitivity. Although WT-HF and KO-HF mice had similar levels of WAT at this time, KO-HF mice had more subcutaneous and less epididymal fat than WT-HF mice. The KO-HF mice also had less liver fat than the WT-HF mice. Finally, KO-HF mice had lower plasma levels of resistin than WT-HF mice. These data demonstrate that genetic lack of TNF-alpha protects insulin sensitivity during the early phase of HF feeding in the absence of altered total WAT. The data also suggest that the mechanism maintaining insulin sensitivity in the absence of TNF-alpha may involve redirection of the fat deposition to the metabolically more inert subcutaneous depot or decreases in circulating resistin and resultant decrease in liver fat deposition. The efficacy of therapeutic measures designed to counteract the effects of TNF-alpha may be increased during the early stages of obesity and insulin resistance. Topics: Adiponectin; Adiposity; Animals; Blood Glucose; Body Weight; Diet; Fatty Liver; Genotype; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Resistin; Tumor Necrosis Factor-alpha | 2010 |
Estradiol supplementation helps overcome central leptin resistance of ovariectomized mice on a high fat diet.
Ovariectomized mice on a high fat diet represent a model of diet-induced obesity during estrogen deficiency. Here, we tested the hypothesis that sensitivity to centrally administered leptin in ovariectomized mice with diet-induced obesity could be restored by estrogen supplementation. Ovariectomized C57BL/6 female mice were fed either a standard or high fat diet until they were 27 weeks old. Ovariectomized mice on a high fat diet developed extreme obesity and hyperleptinemia and moderate hyperinsulinemia compared to those on a standard diet. For the last 4 weeks, 17beta-estradiol-3-benzoate or its vehicle was administered subcutaneously in a 4-day cyclic regimen. Finally, leptin or saline was injected into the third ventricle, and food intake and body weight were measured for 36 h. In ovariectomized mice fed a standard diet, the decrease in food intake and body weight was significant and was pronounced in 17beta-estradiol-3-benzoate-supplemented mice. The response to centrally injected leptin in ovariectomized mice on a high fat diet was insignificant, whereas in 17beta-estradiol-3-benzoate-supplemented mice, the effect was significant, particularly with respect to body weight. We showed for the first time that central insensitivity to leptin in ovariectomized diet-induced obese mice was restored with 17beta-estradiol-3-benzoate supplementation, which also attenuated most of the parameters of metabolic syndrome. Only circulating adiponectin, a peripheral insulin sensitivity marker, was lowered following 17beta-estradiol-3-benzoate administration in both high fat and standard diet-fed ovariectomized mice, despite of decreased or unchanged glycemia, respectively. Topics: Animals; Body Weight; Diet; Dietary Fats; Dietary Supplements; Estradiol; Feeding Behavior; Female; Leptin; Mice; Mice, Inbred C57BL; Obesity; Ovariectomy; Weight Gain | 2010 |
Diet-induced obesity in two C57BL/6 substrains with intact or mutant nicotinamide nucleotide transhydrogenase (Nnt) gene.
The C57BL/6J (B6/J) male mouse represents a standard for diet-induced obesity (DIO) and is unique in expressing a loss-of-function nicotinamide nucleotide transhydrogenase (Nnt) gene. This mutation was associated with a marked reduction in glucose-stimulated insulin secretion from B6/J islets in vitro and moderately impaired glucose clearance in vivo. To assess the contribution of this Nnt mutation, we compared DIO responsiveness of Nnt-mutant B6/J males to Nnt wild-type C57BL/6NJ (B6/NJ) males over a 14-week period of feeding a high-fat (60% of calories) diet. Initial mean body weights at 6 weeks did not distinguish the substrains and both substrains were DIO-sensitive. However, B6/J males outgained the B6/NJ males, with a significant 3 g higher mean body weight at 20 weeks accompanied by significant increases in both lean and fat mass. Mean nonfasting serum glucose over time was also significantly higher in B6/J males, as was impairment of glucose tolerance assessed at 8 and 20 weeks of age. Serum leptin, but not insulin, was significantly higher in B6/J males over time. Potential contributions of the wild-type Nnt gene were demonstrable on a lower fat diet (10% of calories) where a significantly greater weight gain over time by B6/NJ males was correlated with a significantly higher serum insulin. In conclusion, DIO developed in response to 60% fat feeding regardless of Nnt allele status. Contribution of the B6/J-unique Nnt mutation was most evident in response to 10% fat feeding that resulted in reduced serum insulin and weight gain compared to B6/NJ males. Topics: Adipose Tissue; Animals; Blood Glucose; Body Fluid Compartments; Body Weight; Diet; Dietary Fats; Glucose Intolerance; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; NADP Transhydrogenases; Obesity; Weight Gain | 2010 |
Light responses of the circadian system in leptin deficient mice.
Some evidences postulate a link between obesity and disturbances in circadian behavior. Here, we studied the manifestation of the circadian rhythm of motor activity and its response to light in the leptin deficiency model of obesity ob/ob mice. Motor activity in both ob/ob and wild type mice was first recorded in a small cage by activity meters with crossed infrared beams (IR) and later in a larger cage with a running wheel, where the number of wheel revolutions (WR) was also determined. Animals were maintained under light-dark (LD) or constant-dark (DD) conditions. We studied the free-running period and the rhythm profile, with special emphasis on the amount of activity in the dark and light phases of the LD cycle, and the phase and period responses to a light pulse. The results showed that ob/ob mice have a strong ultradian, rather than a circadian pattern, whose period range between 3 and 4.8h. Also, these animals showed a percentage of activity during light higher than controls. We did not find differences in the endogenous period of the circadian rhythm between mice groups in DD. However, ob/ob mice showed stronger phase delays after a light pulse at ZT15 than controls, and less masking effects in the transition from LD to DD compared with controls. This suggests a weaker circadian pacemaker of the ob/ob mice compared with controls. Topics: Adaptation, Ocular; Analysis of Variance; Animals; Body Weight; Circadian Rhythm; Female; Leptin; Light; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity | 2010 |
Characterization and expression of Ailuropoda melanoleuca leptin (ob gene).
Leptin, an adipocyte-derived hormone, plays important roles in metabolism and reproduction. In this article, we report the cloning, expression, and identification of the giant panda leptin (gLeptin) gene and its variants. The gLeptin cDNA was 504 bp long, encoding a precursor peptide of 167 amino acids including 21 residues of signal peptide. A short variant of gLeptin was 501 bp long, encoding a 166-aa peptide and also including a 21-aa signal peptide. Giant panda leptin was 99.4%, 94.6%, and 92.8% identical to that of black bear, dog, and cat, respectively, but was only 81.4% and 80.8% identical to that of human and rat. The cloned gLeptin gene was expressed in Escherichia coli, with expression confirmed by Western blotting and MALDI-TOF-TOF MS PMF. After purification, renaturation, and condensation, the gLeptin protein was injected into Kunming mice. The recombinant gLeptin significantly inhibited food intake by 41.8% and reduced body weight by 5.1% in the mice. Topics: Amino Acid Sequence; Animals; Base Sequence; Body Weight; Cloning, Molecular; DNA, Complementary; Feeding Behavior; Gene Expression Regulation; Leptin; Mice; Molecular Biology; Phylogeny; Ursidae | 2010 |
Chlorogenic acid exhibits anti-obesity property and improves lipid metabolism in high-fat diet-induced-obese mice.
This study investigated the efficacy of chlorogenic acid on altering body fat in high-fat diet (37% calories from fat) induced-obese mice compared to caffeic acid. Caffeic acid or chlorogenic acid was supplemented with high-fat diet at 0.02% (wt/wt) dose. Both caffeic acid and chlorogenic acid significantly lowered body weight, visceral fat mass and plasma leptin and insulin levels compared to the high-fat control group. They also lowered triglyceride (in plasma, liver and heart) and cholesterol (in plasma, adipose tissue and heart) concentrations. Triglyceride content in adipose tissue was significantly lowered, whereas the plasma adiponectin level was elevated by chlorogenic acid supplementation compared to the high-fat control group. Body weight was significantly correlated with plasma leptin (r=0.894, p<0.01) and insulin (r=0.496, p<0.01) levels, respectively. Caffeic acid and chlorogenic acid significantly inhibited fatty acid synthase, 3-hydroxy-3-methylglutaryl CoA reductase and acyl-CoA:cholesterol acyltransferase activities, while they increased fatty acid beta-oxidation activity and peroxisome proliferator-activated receptors alpha expression in the liver compared to the high-fat group. These results suggest that caffeic acid and chlorogenic acid improve body weight, lipid metabolism and obesity-related hormones levels in high-fat fed mice. Chlorogenic acid seemed to be more potent for body weight reduction and regulation of lipid metabolism than caffeic acid. Topics: Adiponectin; Adiposity; Animals; Anti-Obesity Agents; Antioxidants; Blotting, Western; Body Weight; Caffeic Acids; Chlorogenic Acid; Dietary Fats; Eating; Energy Intake; Insulin; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred ICR; Myocardium; Obesity; PPAR alpha | 2010 |
A new link between skeleton, obesity and insulin resistance: relationships between osteocalcin, leptin and insulin resistance in obese children before and after weight loss.
The skeleton is regarded recently as an endocrine organ that affects energy metabolism. However, there are very limited data available concerning the relationships between the osteoblast-derived hormone osteocalcin, weight status, adiponectin and leptin in obese humans, especially in children.. We analyzed osteocalcin, adiponectin, leptin and insulin resistance (IR) index homeostasis model assessment (HOMA) in 60 obese and 19 age- and gender-matched normal weight children. Furthermore, these parameters were determined in 60 obese children after participating in an outpatient 1-year lifestyle intervention based on exercise, behavior and nutrition therapy.. Sixty obese children had significantly lower osteocalcin levels (26.8+/-0.8 ng ml(-1)) than 19 normal weight controls (32.2+/-2.3 ng ml(-1)). Boys (29.9+/-1.1 ng ml(-1)) showed significantly (P=0.046) higher osteocalcin levels compared with girls (26.4+/-1.2 ng ml(-1)). In stepwise multiple linear regression analysis adjusted for age, gender and pubertal stage, osteocalcin was significantly negatively related to leptin and HOMA, but not to adiponectin. Changes of osteocalcin in the course of 1 year correlated significantly negatively with changes of IR index HOMA (r=-0.25), standard deviation score-body mass index (SDS-BMI) (r=-0.33) and leptin (r=-0.50). Substantial weight loss in 29 obese children led to a significant increase in osteocalcin and a significant decrease in leptin and HOMA. In 31 obese children without substantial weight loss, osteocalcin levels did not change significantly in the course of 1 year.. Osteocalcin levels were lower in obese children and were related to IR and leptin both in cross-sectional and longitudinal analyses. Therefore, osteocalcin might be a new promising link between obesity and IR. Topics: Biomarkers; Body Mass Index; Body Weight; Bone and Bones; Child; Enzyme-Linked Immunosorbent Assay; Female; Germany; Humans; Insulin Resistance; Leptin; Life Style; Male; Obesity; Osteocalcin; Puberty; Regression Analysis; Sex Factors; Weight Loss | 2010 |
Adipocytokines and endothelial function in preeclamptic women.
Visceral fat accumulation stimulates the production of adipocytokines in patients with metabolic syndrome. Excess body weight gain during pregnancy is a risk factor for preeclampsia. To evaluate whether the pathogenesis of preeclampsia is similar to that of metabolic syndrome, we measured plasma adipocytokine concentrations and investigated the association between plasma adiponectin concentrations and body weight gain or endothelial function in preeclamptic women. We investigated 15 preeclamptic and 17 women with uncomplicated pregnancies. Women with preeclampsia had significantly lower plasma concentrations of adiponectin (10.2+/-2.0 vs. 7.3+/-2.2 microg ml(-1), P<0.01), but higher concentrations of leptin, plasminogen activator inhibitor-1, interleukin-6, vascular cell adhesion molecule-1, E-selectin and C-reactive protein. Plasma triglyceride levels were significantly higher in preeclamptic patients, but the levels of other lipids did not differ significantly between the two groups. We found that flow-mediated vasodilation was significantly decreased in preeclamptic women compared with controls (10.6+/-6.4 vs. 3.8+/-2.0%, P<0.001). Plasma adiponectin concentrations correlated negatively with body mass index (r=-0.50, P<0.05) and body weight gain during pregnancy (r=-0.63, P<0.01), and positively with flow-mediated vasodilation (r=0.50, P<0.05) in preeclamptic women, but not in women with uncomplicated pregnancies. Similar to the patients with metabolic syndrome, we found that dysregulation of adipocytokines, such as low adiponectin levels and high levels of other adipocytokines, and excess body weight gain during pregnancy, may decrease plasma adiponectin concentrations that are associated with endothelial dysfunction in preeclamptic women. Topics: Adipokines; Adiponectin; Body Weight; Case-Control Studies; Endothelium, Vascular; Female; Humans; Interleukin-6; Leptin; Metabolic Syndrome; Plasminogen Activator Inhibitor 1; Pre-Eclampsia; Pregnancy; Triglycerides; Vasodilation | 2010 |
The effect of dietary fat content on phospholipid fatty acid profile is muscle fiber type dependent.
A high-saturated-fat diet (HFD) induces obesity and insulin resistance (IR). IR has been linked to alterations and increased saturation in the phospholipid composition of skeletal muscles. We aimed to determine whether HFD feeding affects fatty acid (FA) membrane profile in a muscle fiber type-specific manner. We measured phospholipid FAs and expression of FA synthesis genes in oxidative soleus (SOL) and glycolytic extensor digitorum longus (EDL) muscles from rats fed either standard chow (standard laboratory diet, SLD) or a HFD. The HFD increased fat mass, plasma insulin, and leptin levels. Compared with EDL, SOL muscles preferentially accumulated C18 over C16 FAs and n-6 over n-3 polyunsaturated FAs (PUFAs) on either diet. With the HFD, SOL muscles contained more n-9 monounsaturated FAs (MUFAs) and n-6 PUFAs and less n-7 MUFAs and n-3 PUFAs than EDL muscles and had lower unsaturation index, a pattern known to be associated with IR. Stearoyl-CoA desaturase-1 expression was approximately 13-fold greater in EDL than in SOL muscles but did not change with the HFD in either muscle. The expression of Elongase-5 was higher, and that of Elongase-6 (Elovl6) was lower in EDL compared with SOL muscles with both diets. In EDL muscles, the expression of Elovl6 was lower in the HFD than in the SLD. The pattern of FA uptake, expression, and diet-induced changes in FA desaturating and elongating enzymes maintained higher FA unsaturation in EDL muscles. Accordingly, the fiber type composition of skeletal muscles and their distribution may be important in the development and progression of obesity and IR. Topics: Adipose Tissue; Animals; Body Weight; Diet; Dietary Fats; Fatty Acids; Glycolysis; In Vitro Techniques; Insulin; Leptin; Male; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Oxidation-Reduction; Phospholipids; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA; Triglycerides | 2010 |
Postprandial response of plasma insulin, amylin and acylated ghrelin to various test meals in lean and obese cats.
The propensity of diets of different composition to promote obesity is a current topic in feline medicine. The effects of three meals with different protein:fat ratios on hormones (insulin, acylated ghrelin and amylin) involved in the control of food intake and glucose metabolism were compared. Five lean (two females and three males, 28.6 (sd 3.4) % body fat mass (BFM), mean body weight (BW) 4590 g) and five obese (two females and three males, 37.1 (sd 4.1) % BFM, mean BW 4670 g) adult cats were studied. Only BFM differed significantly between obese and lean cats. The cats were fed a high-protein (HP), a high-fat and a high-carbohydrate diet in a randomised cross-over design. Food intake did not differ between cats fed on the different diets, but obese cats consumed significantly more energy, expressed as per kg fat-free mass, than lean cats. After a 6-week adaptation period, a test meal was given and blood samples were collected before and 0, 30, 60 and 100 min after the meal. Baseline concentrations of glucose, amylin and acylated ghrelin were higher in obese cats than in lean cats, and obese cats showed the highest postprandial responses of glucose and amylin. The HP diet led to higher postprandial amylin concentrations than the other diets, indicating a possible effect of amino acids on beta-cell secretion. Postprandial ghrelin concentrations were unaffected by diet composition. The relationship between insulin, amylin and ghrelin secretion and their relevant roles in food intake and glucose metabolism in cats require further study. Topics: Acylation; Amyloid; Animals; Blood Glucose; Body Weight; Cat Diseases; Cats; Diet; Dietary Carbohydrates; Dietary Fats; Energy Intake; Female; Food; Ghrelin; Insulin; Insulin-Like Growth Factor I; Islet Amyloid Polypeptide; Leptin; Male; Obesity | 2010 |
Peptide designed to elicit apoptosis in adipose tissue endothelium reduces food intake and body weight.
Because adipose tissue is highly vascularized, modifying adipose tissue vasculature may provide a novel method for reducing body fat. A peptide sequence that elicits apoptosis of endothelium in white fat potently reduced body weight. We sought to determine how inhibiting adipose tissue vasculature changes key aspects of energy balance regulation and the neuroendocrine system that maintains energy balance.. Lean and obese mice or rats were treated with proapoptotic peptide for 4 or 27 days. Daily energy intake and expenditure were measured in mice on a low- (LFD) or high-fat diet (HFD) and in rats on a HFD. A conditioned taste aversion test was performed to assess whether proapoptotic peptide produces visceral illness. Hypothalamic neuropeptide Y, agouti-related peptide, and proopiomelanocoritin (POMC) mRNA expression and plasma leptin levels were evaluated.. Proapoptotic peptide completely reversed HFD-induced obesity in mice and reduced body weight in mice and rats on a HFD but not in those on a LFD. Fat loss occurred with no change of energy expenditure but reduced food intake that occurred without signs of illness and despite reduced circulating leptin and reduced hypothalamic POMC gene expression, indicating that the decrease in food intake is independent of the action of leptin.. These experiments provide compelling evidence for a previously unknown relationship between the status of adipose tissue vasculature and the regulation of food intake. Topics: Adipose Tissue; Agouti-Related Protein; Animals; Apoptosis; Body Composition; Body Weight; Diet, Fat-Restricted; Dietary Fats; Eating; Endothelial Cells; Energy Intake; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neovascularization, Physiologic; Neuropeptide Y; Obesity; Peptide Fragments; Peptides; Pro-Opiomelanocortin; Rats; RNA, Messenger | 2010 |
Overfeeding-induced obesity in spontaneously hypertensive rats: an animal model of the human metabolic syndrome.
The metabolic syndrome (MS) has become an epidemiological problem in Western countries. We developed a diet-induced obese rat model that mimics all the symptoms of MS in humans, but whose insulin resistance, hyperphagia and hyperleptinemia are caused by nutrition rather than genetic modifications.. Spontaneously hypertensive rats (SHR) were allowed for 12 weeks to choose between a cafeteria diet (CD, 20.3 kJ/g) and standard rat chow (11.7 kJ/g). Controls received rat chow.. Body weight (BW) exceeded control levels when SHR were fed with CD. The increase in BW was attributed to enhanced energy intake. The abundance of abdominal fat as well as the plasma levels of leptin and triglycerides increased concomitant with glucose, insulin and C-peptide. This prediabetic condition was further confirmed by a markedly increased insulin response following glucose challenge and by impaired glucose utilization after insulin tolerance tests.. Increases in food intake and BW despite hyperleptinemia indicate leptin resistance following CD feeding. CD-fed SHR feature leptin and insulin resistance, hypertension and obesity, thus mimicking the situation of MS patients. As such, our model is more suitable than the genetically modified rat models used to study human MS. Topics: Abdominal Fat; Animals; Biomarkers; Blood Glucose; Blood Pressure; Body Weight; C-Peptide; Diet; Disease Models, Animal; Energy Intake; Heart Rate; Hyperphagia; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Triglycerides | 2010 |
Nutrient specific feeding and endocrine effects of jejunal infusions.
Intestinal nutrient infusions result in variable decreases in food intake and body weight based on the nutrient type and the specific intestinal infusion site. Only intrajejunal infusions of fatty acids decrease food intake beyond the calories infused. To test whether this extra-compensatory decrease in food intake is specific to fatty acids, small volume intrajejunal infusions of glucose (Glu) and casein hydrolysate (Cas), as well as linoleic acid (LA) were administered to male Sprague-Dawley rats. Equal kilocalorie (kcal) loads of these nutrients (11.4) or vehicle were infused into the jejunum over 7 h/day for five consecutive days. Food intake was continuously monitored and body weight was measured daily. After the infusion on the final day, rats were killed and plasma collected. Intrajejunal infusions of LA and Glu, but not Cas, suppressed food intake beyond the caloric load of the infusate with no compensatory increase in food intake after the infusion period. Rats receiving LA and Glu infusions also lost significant body weight across the infusion days. Plasma glucagon-like peptide-1 (GLP-1) was increased in both the LA and Glu rats compared with control animals, with no significant change in the Cas-infused animals. Peptide YY (PYY) levels increased in response to LA and Cas infusions. These results suggest that intrajejunal infusions of LA and Glu may decrease food intake and body weight via alterations in GLP-1 signaling. Thus, particular nutrients are more effective at producing decreases in food intake, body weight, and inducing changes in peptide levels and could lead to a novel therapy for obesity. Topics: Analysis of Variance; Animals; Body Weight; Caseins; Eating; Energy Intake; Enzyme-Linked Immunosorbent Assay; Glucagon-Like Peptide 1; Glucose; Jejunum; Leptin; Linoleic Acid; Male; Peptide YY; Radioimmunoassay; Rats; Rats, Sprague-Dawley | 2010 |
Decreased blood-brain leptin transfer in an ovine model of obesity and weight loss: resolving the cause of leptin resistance.
Hypothalamic resistance to the anorexigenic actions of the peripheral adipostat hormone leptin is characteristic of obesity. Here, we use an obese animal model of similar body weight to that of the human to test in vivo whether leptin resistance is due to decreased blood-brain leptin transport or intra-hypothalamic insensitivity, and whether sensitivity to leptin is restored by weight loss. For 40 weeks, adult sheep surgically prepared with intra-cerebroventricular (ICV) cannulae were given a complete natural diet ad libitum ('Obese' group) or in restricted quantities ('Lean' group), and then the dietary amounts were reversed for 16 weeks until mean group body weights converged ('Slimmers' and 'Fatteners', respectively).. ICV leptin injection (0.5 mg) at 8-week intervals acutely decreased voluntary food intake by approximately 35% in the 'Obese' group on each occasion and in 'Slimmers' and 'Fatteners' at the end, providing no evidence of intra-hypothalamic insensitivity. The ratio between endogenous leptin concentrations in ventricular cerebrospinal fluid (CSF) and peripheral blood decreased with increasing leptinaemia in 'Obese' sheep, indicating decreased efficiency of blood-brain leptin transport, whereas leptin concentrations remained low and the CSF:blood ratio remained high in 'Lean' sheep. Compared with 'Fatteners' of similar body weight, 'Slimmers' were hypoleptinaemic, but their CSF:blood leptin concentration ratio remained low. Thus, the obesity-induced impairment of leptin blood-brain transport was sustained despite an approximately 15% weight loss.. These results support the hypothesis that central resistance to leptin in obesity with associated peripheral hyperleptinaemia is attributable to decreased efficiency of leptin transport into the brain and not to intra-hypothalamic leptin insensitivity. However, leptin transport efficiency is not restored after weight loss by caloric restriction despite the prevailing hypoleptinaemia. Topics: Animals; Biological Transport, Active; Blood-Brain Barrier; Body Weight; Caloric Restriction; Eating; Hypothalamus; Leptin; Male; Obesity; Sheep; Thinness; Weight Loss | 2010 |
Long-term dietary restriction influences plasma ghrelin and GOAT mRNA level in rats.
The objective of this study was to examine the effect of chronic dietary restriction on the physical characteristics of the intestine and gut-derived satiety hormone production. Male Wistar rats (8 weeks) were randomized to ad libitum (AL) or 35% dietary restriction (DR) for 5 months. At the end of the study, physical measurements were made on the intestine and satiety hormone secretion and mRNA expression determined. A comparison group of young, growing AL rats (5 weeks) was also examined. The adult DR rats gained less weight over 5 months and had lower fat mass than adult AL rats (p<0.05). The weight of the small intestine as a percentage of total body weight was greater in adult DR compared to adult AL but lower than young AL rats. Compared to AL, DR down-regulated proglucagon and cholecystokinin mRNA in the duodenum and ghrelin mRNA in the stomach of adult rats but was not different from young AL. Ghrelin-O-acyltransferase (GOAT) mRNA in the stomach was up-regulated 21-fold in adult AL rats compared to young AL and 14-fold compared to adult DR rats. Total and des-acyl ghrelin was approximately 50% higher in adult DR and young AL rats compared to adult AL. Plasma leptin and insulin were lower in adult DR and young AL rats compared to adult AL. Our findings suggest that long-term energy deficits continue to drive up ghrelin levels which may have profound implications for practical implementation of DR as an anti-aging or anti-obesity strategy in humans. Topics: Acyltransferases; Age Factors; Amyloid; Animals; Body Weight; Diet; Enzyme-Linked Immunosorbent Assay; Gastrointestinal Tract; Gene Expression Regulation; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Insulin; Islet Amyloid Polypeptide; Leptin; Rats; Rats, Wistar; RNA, Messenger; Statistics, Nonparametric; Time Factors | 2010 |
Vasoactive intestinal peptide-null mice demonstrate enhanced sweet taste preference, dysglycemia, and reduced taste bud leptin receptor expression.
It is becoming apparent that there is a strong link between taste perception and energy homeostasis. Recent evidence implicates gut-related hormones in taste perception, including glucagon-like peptide 1 and vasoactive intestinal peptide (VIP). We used VIP knockout mice to investigate VIP's specific role in taste perception and connection to energy regulation.. Body weight, food intake, and plasma levels of multiple energy-regulating hormones were measured and pancreatic morphology was determined. In addition, the immunocytochemical profile of taste cells and gustatory behavior were examined in wild-type and VIP knockout mice.. VIP knockout mice demonstrate elevated plasma glucose, insulin, and leptin levels, with no islet beta-cell number/topography alteration. VIP and its receptors (VPAC1, VPAC2) were identified in type II taste cells of the taste bud, and VIP knockout mice exhibit enhanced taste preference to sweet tastants. VIP knockout mouse taste cells show a significant decrease in leptin receptor expression and elevated expression of glucagon-like peptide 1, which may explain sweet taste preference of VIP knockout mice.. This study suggests that the tongue can play a direct role in modulating energy intake to correct peripheral glycemic imbalances. In this way, we could view the tongue as a sensory mechanism that is bidirectionally regulated and thus forms a bridge between available foodstuffs and the intricate hormonal balance in the animal itself. Topics: Animals; Blood Glucose; Blotting, Western; Body Weight; Eating; Glucagon-Like Peptide 1; Immunohistochemistry; Insulin; Leptin; Mice; Mice, Knockout; Receptors, Leptin; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Taste Buds; Vasoactive Intestinal Peptide | 2010 |
Alcohol consumption, obesity, estrogen treatment and breast cancer.
Alcohol consumption increases breast cancer risk in postmenopausal women in a dose-dependent manner. The objective of the present study was to determine if the effect of alcohol on mammary cancer is modified by body weight and exogenous estrogen. Ovariectomized mice of various body weights, receiving estrogen or placebo supplementation, and consuming water or alcohol were injected with mammary cancer cells. Alcohol intake resulted in insulin sensitivity and increased tumor growth in obese mice. Exogenous estrogen alone inhibited tumor growth. The combination of estrogen and alcohol overcame the inhibitory effects of estrogen on tumor growth in obese mice. Alcohol consumption increased the circulating estrogen and leptin levels. In conclusion, alcohol and estrogen treatment can modify mammary tumor growth, possibly through the regulation of estrogen and leptin, especially in obese mice. Topics: Alcohol Drinking; Animals; Body Weight; Cell Line, Tumor; Estradiol; Estrogens; Female; Hormone Replacement Therapy; Insulin; Insulin-Like Growth Factor I; Leptin; Mammary Neoplasms, Experimental; Mice; Obesity | 2010 |
Nutritional status alters saccharin intake and sweet receptor mRNA expression in rat taste buds.
Sweet taste usually signifies the presence of caloric food. It is commonly accepted that a close association exists among sweet taste perception, preference, and nutritional status. However, the mechanisms involved remain unknown. To investigate whether nutritional status affects the preference for palatable solutions and alters sweet taste receptor gene expression in rats, we measured saccharin intake and preference using a two-bottle preference test, and changes in body weight, plasma leptin levels, and gene expression for the sweet taste receptor in taste buds in high-fat diet-induced obese rats and chronically diet-restricted rats. We found that the consumption and preference ratios for 0.01 and 0.04 M saccharin were significantly lower in the high-fat diet-induced obese rats than in the normal diet rats, while the serum leptin levels were markedly increased in obese rats. Consistent with the changes in saccharin intake, the gene expression level of the sweet taste receptor T1R3 was significantly decreased in the high-fat diet-induced obese rats compared with the control rats. By contrast, the chronically diet-restricted rats showed remarkably enhanced consumption and preference for 0.04 M saccharin. The serum leptin concentration was decreased, and the gene expression of the leptin receptor was markedly increased in the taste buds. In conclusion, our results suggest that nutritional status alters saccharin preference and the expression of T1R3 in taste buds. These processes may be involved in the mechanisms underlying the modulation of peripheral sweet taste sensitivity, in which leptin plays a role. Topics: Animals; Body Weight; Diet; Dietary Fats; Feeding Behavior; Food Deprivation; Food Preferences; Gene Expression; Leptin; Male; Obesity; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; RNA, Messenger; Saccharin; Taste Buds | 2010 |
Attenuation of obesity by early-life food restriction in genetically hyperphagic male OLETF rats: peripheral mechanisms.
The alarming increase in childhood, adolescent and adult obesity has exposed the need for understanding early factors affecting obesity and for treatments that may help prevent or moderate its development. In the present study, we used the OLETF rat model of early-onset hyperphagia induced obesity, which become obese as a result of the absence of CCK(1) receptors, to examine the influence of partial food restriction on peripheral adiposity-related parameters during and after chronic and early short-term food restriction. Pair feeding (to the amount of food eaten by control, LETO rats) took place from weaning until postnatal day (PND) 45 (early) or from weaning until PND90 (chronic). We examined fat pad weight (brown, retroperitoneal, inguinal and epididymal); inguinal adipocyte size and number; and plasma leptin, oxytocin and creatinine levels. We also examined body weight, feeding efficiency and spontaneous intake after release from food-restriction. The results showed that chronic food restriction produced significant reductions in adiposity parameters, hormones and body weight, while early food restriction successfully reduced long-term body weight, intake and adiposity, without affecting plasma measurements. Early (and chronic) dieting produced promising long-term effects that may imply the reorganization of both peripheral and central mechanisms that determine energy balance and further support the theory suggesting that early interventions may effectively moderate obesity, even in the presence of a genetic tendency. Topics: Adipocytes; Adipose Tissue; Adiposity; Animals; Body Weight; Caloric Restriction; Cell Count; Cell Size; Creatinine; Eating; Hyperphagia; Leptin; Male; Obesity; Oxytocin; Rats; Rats, Inbred OLETF | 2010 |
Leptin intake during the suckling period improves the metabolic response of adipose tissue to a high-fat diet.
The intake of leptin during the suckling period protects against obesity and improves insulin and central leptin sensitivity in adult rats.. We analyzed whether leptin treatment to neonates may also improve later peripheral leptin sensitivity in adipose tissue under high-fat (HF) diet conditions.. Male rats were supplemented with a daily oral dose of leptin or the vehicle (controls) during the suckling period. After weaning, animals were fed a normal-fat or an HF diet until the age of 6 months. At this age, mRNA and protein levels of the long-form leptin receptor (OB-Rb) and the expression of other genes related with energy metabolism were measured in various adipose depots (inguinal, mesenteric and retroperitoneal).. HF-diet feeding resulted in lower OB-Rb mRNA and protein levels in internal depots in controls but not in leptin-treated animals; these animals maintained OB-Rb mRNA and protein levels under HF-diet conditions in these depots, particularly in the mesenteric one, and this was accompanied by increased expression of genes related with energy uptake (GLUT4, CD36), fatty acid oxidation (peroxisome proliferator activated receptor-alpha (PPARalpha), CPT1, UCP3) and lipogenesis (PPARgamma, GPAT). Leptin-treatment also ameliorated HF-diet-induced hepatic fat accumulation occurring in control animals.. Leptin treatment during the suckling period may improve the lasting effects of HF-diet feeding on leptin receptor abundance in the adipose tissue and increase its oxidative capacity, resulting in a better handling and partitioning of excess fuel. This, together with the described improvement of central leptin sensitivity, may explain why these animals are more protected against diet-induced obesity and its metabolic-related disorders. Topics: Adipose Tissue; Animals; Animals, Suckling; Blotting, Western; Body Weight; CD36 Antigens; Dietary Fats; Energy Metabolism; Fatty Acids; Gene Expression Regulation, Developmental; Glucose Transporter Type 4; Ion Channels; Leptin; Male; Mitochondrial Proteins; PPAR alpha; PPAR gamma; Rats; Rats, Wistar; Receptors, Leptin; RNA, Messenger; Uncoupling Protein 3; Weaning | 2010 |
Maternal dietary fat determines metabolic profile and the magnitude of endocannabinoid inhibition of the stress response in neonatal rat offspring.
Endocannabinoids (eCBs) are products of phospholipid (PL)-derived arachidonic acid (AA) that regulate hypothalamus-pituitary-adrenal axis activity. We hypothesized that differences in the quality and quantity of maternal dietary fat would modulate the PL AA content in the neonatal brain affecting stress responsiveness via differences in eCB production and activity in stress-activated brain areas. Pregnant rats were fed a 5% [control (C)] or 30% fat [high fat (HF)] diet rich in either n-6 (HF-n-6) or n-3 (HF-n-3) fat during the last week of gestation and lactation. Postnatal d 10 offspring were tested for metabolic hormones, AA (n-6) and eCB brain content, and hormonal effects of eCB receptor antagonism (AM251, 1 or 3 mg/kg ip) on stress responses. Like maternal diet, milk from HF-n-3 mothers had a reduced n-6/n-3 fat ratio compared with that of C and HF-n-6 mothers. Hypothalamic and hippocampal levels of PL AA were diet specific, reflecting the maternal milk and dietary n-6/n-3 ratio, with HF-n-3 offspring displaying reduced AA content relative to C and HF-n-6 offspring. Plasma corticosterone and insulin were elevated in HF-fed pups, whereas leptin was increased only in HF-n-6 pups. Basal eCB concentrations were also diet and brain region specific. In C pups, eCB receptor antagonist pretreatment increased stress-induced ACTH secretion, but not in the HF groups. Stress-induced corticosterone secretion was not sensitive to AM251 treatment in HF-n-3 pups. Thus, the nature of preweaning dietary fat differentially influences neonatal metabolic hormones, brain PL AA levels, and eCB, with functional consequences on hypothalamus-pituitary-adrenal axis modulation in developing rat pups. Topics: Adipose Tissue; Adrenocorticotropic Hormone; Analysis of Variance; Animals; Animals, Suckling; Body Weight; Brain; Brain Chemistry; Cannabinoid Receptor Modulators; Corticosterone; Dietary Fats; Endocannabinoids; Fatty Acids; Female; Hypothalamo-Hypophyseal System; Insulin; Lactation; Leptin; Piperidines; Pituitary-Adrenal System; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Pyrazoles; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Regression Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stress, Physiological | 2010 |
The hyperleptinemia and ObRb expression in hyperphagic obese rats.
Leptin resistance associated with hyperleptinemia in high-fat-diet-induced obese rats and aged obese rats is well established, but it is not clear whether hyperphagia-induced obese rats also develop leptin resistance. We investigated whether Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are a strain of hyperphagia-induced obese rats, develop leptin resistance and whether caloric restriction reversed this leptin resistance-induced leptin receptor (ObRb) deficit. Twenty male OLETF rats, 20 male Long-Evans Tokushima Otsuka (LETO) rats, and 10 male Sprague Dawley (SD) rats were used. All rats were initially studied at 10 weeks of age and were freely fed with standard rat chow and water until they were 38 weeks of age. Daily food intake, body weight, and plasma leptin levels of OLETF rats were remarkably increased compared to LETO or SD rats from 10 to 38 weeks of age. When they were 38 weeks of age, all OLETF rats were randomly divided into two groups. One group was freely fed with standard rat chow (FD, or free diet group), and the other group (RD, or restricted diet group) was fed with only 70% of the amount consumed by the FD group. The LETO and SD rats were dismissed from further study. After 4 weeks of caloric restriction, the average body weight (636+/-33 g vs. 752+/-24 g, P<0.05) and abdominal adipose tissue weight (10.6+/-3.2g vs. 15.8+/-1.5 g, P<0.05) of the RD group were decreased compared with those of the FD group. Plasma leptin levels of the RD group were significantly decreased compared with those of the FD group (3.47+/-1.40 ng/mL vs. 11.55+/-1.16 ng/mL, P<0.05). The mRNA expression of ObRb and leptin-related suppressor of cytokine signaling 3 (SOCS3) in the hypothalamus, liver, and skeletal muscles of the RD group were significantly decreased compared with those of the FD group. Caloric restriction did not improve leptin receptor (ObRb) deficit or the downstream signaling of leptin in the liver, skeletal muscles, and hypothalamus. Thus, we demonstrated that OLETF rats, which are a strain of hyperphagia-induced obese rats, did not develop central or peripheral leptin resistance. We suggest that hyperleptinemia in OLETF rats is a compensatory mechanism to overcome obesity induced by hyperphagia. Topics: Abdominal Fat; Animals; Body Weight; Caloric Restriction; Eating; Hyperphagia; Leptin; Male; Obesity; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Receptors, Leptin; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins | 2010 |
Promoter specific DNA methylation and gene expression of POMC in acutely underweight and recovered patients with anorexia nervosa.
Proopiomelanocortin (POMC) and its derived peptides, in particular alpha-MSH, have been shown to play a crucial role in the regulation of hunger, satiety and energy homeostasis. Studies in patients with anorexia nervosa (AN) suggest an abnormal expression of appetite-regulating hormones. Hormone expression levels may be modulated by epigenetic mechanisms, which were recently shown to be implicated in the pathophysiology of eating disorders. We hypothesised that POMC promoter specific DNA methylation and gene expression will be affected by malnutrition and therefore differ in AN patients at distinct stages of the disorder. Promoter specific DNA methylation of the POMC gene and expression of POMC mRNA variants were determined in peripheral blood mononuclear cells (PBMC) of 30 healthy control women (HCW), 31 underweight (acAN) and 30 weight-recovered patients with AN (recAN). Malnutrition was characterized by plasma leptin. Expression of the functionally relevant long POMC mRNA transcript was significantly correlated with leptin levels and higher in acAN compared to recAN and HCW. Expression of the truncated form and mean promoter DNA methylation was similar in all three subgroups. Methylation of single CpG residues in the E2F binding site was inversely related to POMC expression. Our preliminary data on pattern of POMC regulation suggests an association with the underweight state rather than with persisting trait markers of AN. In contrast to POMC expression in the central nervous system, peripheral POMC mRNA expression decreased with malnutrition and hypoleptinemia. This may represent a counterregulatory mechanism as part of the crosstalk between the immune and neuroendocrine systems. Topics: Adolescent; Adult; alpha-MSH; Anorexia Nervosa; Body Mass Index; Body Weight; Disease-Free Survival; DNA Methylation; Female; Gene Expression; Humans; Leptin; Leukocytes, Mononuclear; Malnutrition; Pro-Opiomelanocortin; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thinness; Young Adult | 2010 |
Detection of extracellular glucose by GLUT2 contributes to hypothalamic control of food intake.
The sugar transporter GLUT2, present in several tissues of the gut-brain axis, has been reported to be involved in the control of food intake. GLUT2 is a sugar transporter sustaining energy production in the cell, but it can also function as a receptor for extracellular glucose. A glucose-signaling pathway is indeed triggered, independently of glucose metabolism, through its large cytoplasmic loop domain. However, the contribution of the receptor function over the transporter function of GLUT2 in the control of food intake remains to be determined. Thus, we generated transgenic mice that express a GLUT2-loop domain, blocking the detection of glucose but leaving GLUT2-dependent glucose transport unaffected. Inhibiting GLUT2-mediated glucose detection augmented daily food intake by a mechanism that increased the meal size but not the number of meals. Peripheral hormones (ghrelin, insulin, leptin) were unaffected, leading to a focus on central aspects of feeding behavior. We found defects in c-Fos activation by glucose in the arcuate nucleus and changes in the amounts of TRH and orexin neuropeptide mRNA, which are relevant to poorly controlled meal size. Our data provide evidence that glucose detection by GLUT2 contributes to the control of food intake by the hypothalamus. The sugar transporter receptor, i.e., "transceptor" GLUT2, may constitute a drug target to treat eating disorders and associated metabolic diseases, particularly by modulating its receptor function without affecting vital sugar provision by its transporter function. Topics: Analysis of Variance; Animals; Biological Transport; Body Weight; Cell Count; Eating; Energy Metabolism; Feeding Behavior; Ghrelin; Glucose; Glucose Transporter Type 2; Homeostasis; Hypothalamus; Immunohistochemistry; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Transgenic; Neuropeptides; Orexins; Proto-Oncogene Proteins c-fos; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Statistics, Nonparametric; Thyrotropin-Releasing Hormone | 2010 |
Meal-induced hormone responses in a rat model of Roux-en-Y gastric bypass surgery.
Roux-en-Y gastric bypass (RYGB) surgery is the most effective treatment for morbid obesity and remission of associated type 2 diabetes, but the mechanisms involved are poorly understood. The aim of the present study was to develop and validate a rat model for RYGB surgery that allows repeated measurement of meal-induced changes in gut and pancreatic hormones via chronic venous catheters. Male Sprague Dawley rats made obese on a palatable high-fat diet were subjected to RYGB or sham surgery and compared with chow-fed, lean controls. Hormonal responses to a mixed-liquid test meal were examined by frequent blood sampling through chronically implanted jugular catheters in freely behaving rats, 3-4 months after surgery, when RYGB rats had significantly reduced body weight and fat mass compared with sham-operated rats. Hyperleptinemia, basal hyperinsulinemia, and hyperglycemia as well as postprandial glucose intolerance seen in sham-operated, obese rats were completely reversed by RYGB and no longer different from lean controls. Postprandial increases in glucagon-like peptide-1, peptide YY, and amylin as well as suppression of ghrelin levels were all significantly augmented in RYGB rats compared with both sham-operated obese and lean control rats. Thus, our rat model replicates most of the salient hormonal and glycemic changes reported in obese patients after RYGB, with the addition of amylin to the list of potential candidate hormones involved in hypophagia, weight loss, and remission of diabetes. The model will be useful for elucidating the specific peripheral and central mechanisms involved in the suppression of appetite, loss of body weight, and remission of type 2 diabetes. Topics: Amyloid; Analysis of Variance; Animals; Body Weight; Eating; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Obesity; Peptide YY; Postprandial Period; Rats; Rats, Sprague-Dawley; Time Factors | 2010 |
Increased hypothalamic signal transducer and activator of transcription 3 phosphorylation after hindbrain leptin injection.
Reduction of food intake and body weight by leptin is attributed largely to its action in the hypothalamus. However, the signaling splice variant of the leptin receptor, LRb, also is expressed in the hindbrain, and leptin injections into the fourth cerebral ventricle or dorsal vagal complex are associated with reductions of feeding and body weight comparable to those induced by forebrain leptin administration. Although these observations suggest direct hindbrain action of leptin on feeding and body weight, the possibility that hindbrain leptin administration also activates the Janus kinase/signal transducer and activator of transcription 3 (STAT3) signaling in the hypothalamus has not been investigated. Confirming earlier work, we found that leptin produced comparable reductions of feeding and body weight when injected into the lateral ventricle or the fourth ventricle. We also found that lateral and fourth ventricle leptin injections produced comparable increases of STAT3 phosphorylation in both the hindbrain and the hypothalamus. Moreover, injection of 50 ng of leptin directly into the nucleus of the solitary tract also increased STAT3 phosphorylation in the hypothalamic arcuate and ventromedial nuclei. Increased hypothalamic STAT3 phosphorylation was not due to elevation of blood leptin concentrations and the pattern of STAT3 phosphorylation did not overlap distribution of the retrograde tracer, fluorogold, injected via the same cannula. Our observations indicate that even small leptin doses administered to the hindbrain can trigger leptin-related signaling in the forebrain, and raise the possibility that STAT3 phosphorylation in the hypothalamus may contribute to behavioral and metabolic changes observed after hindbrain leptin injections. Topics: Analysis of Variance; Animals; Blotting, Western; Body Weight; Eating; Hypothalamus; Immunohistochemistry; Injections, Intraventricular; Leptin; Male; Neurons; Phosphorylation; Rats; Rats, Sprague-Dawley; Rhombencephalon; STAT3 Transcription Factor | 2010 |
Oleanolic acid, a natural triterpenoid improves blood glucose tolerance in normal mice and ameliorates visceral obesity in mice fed a high-fat diet.
Excess visceral adiposity may predispose to chronic diseases like hypertension and type 2 diabetes with a high risk for coronary artery disease. Adipose tissue secreted cytokines and oxidative stress play an important role in chronic disease progression. To combat adiposity, plant-derived triterpenes are currently receiving much attention as they possess antioxidant and anti-inflammatory properties and the ability to regulate glucose and lipid metabolism. In the search for potential antiobese compounds from natural sources, this study evaluated the effects of oleanolic acid (OA), a pentacyclic triterpene commonly present in fruits and vegetables, in glucose tolerance test and on high-fat diet (HFD)-induced obesity in mice. Adult male Swiss mice treated or not with OA (10 mg/kg) were fed a HFD during 15 weeks. Sibutramine (SIB) treated group (10 mg/kg) was included for comparison. Weekly body weights, food and water consumption were measured, and at the end of study period, the levels of blood glucose and lipids, plasma hormone levels of insulin, ghrelin and leptin, and the visceral abdominal fat content were analysed. Mice treated with OA and fed a HFD showed significantly (p<0.05) improved glucose tolerance, decreased body weights, visceral adiposity, blood glucose, plasma lipids relative to their respective controls fed no OA. Additionally, OA treatment, while significantly elevating the plasma hormone level of leptin, decreased the level of ghrelin. However, it caused a greater decrease in plasma amylase activity than lipase. Sibutramine-treated group also manifested similar effects like OA except for blood glucose level that was not different from HFD control. These findings suggest that OA ameliorates visceral adiposity and improves glucose tolerance in mice and thus has an antiobese potential through modulation of carbohydrate and fat metabolism. Topics: Amylases; Animals; Blood Glucose; Body Weight; Drinking; Eating; Ghrelin; Glucose Tolerance Test; Intra-Abdominal Fat; Leptin; Lipase; Lipids; Male; Mice; Obesity; Oleanolic Acid; Phytotherapy; Sambucus | 2010 |
Long-term cyclosporine treatment in non-transplanted rats and metabolic risk factors of vascular diseases.
Cyclosporine (CsA) is an immunosuppressive agent frequently used in the clinic for prevention of allograft rejection and for the treatment of autoimmune diseases. Despite its desired action on the immune system, CsA treatment may present serious adverse effects, which are masked by the concomitant use of other drugs. The search for effective immunosuppression protocols which does not affect the quality of life of patients is driving research to investigate the CsA involvement in vascular diseases, frequent in patients under immunosuppression. Thus, 45 non-transplanted Wistar rats were treated for 8 weeks with vehicle or 5 or 15 mg/kg CsA (n=15/group) by gavage administration to evaluate the specific influence of cyclosporine on the levels of risk factors (metabolic and inflammatory) of vascular disease and its mechanism of action. Therefore, serum insulin levels, glucose tolerance test, serum lipids profile, total homocysteine and fibrinogen levels were assessed. The biochemical alterations reported here suggest the development of a framework straight to diabetes. Glucose homeostasis was affected as indicated by decreased insulin levels and altered glucose tolerance test in CsA 15 mg/kg group compared to other groups. Serum insulin and total homocysteine levels presented a significant negative correlation (R=- 0.76, P<0.0001). Fibrinogen and serum lipids profiles were significantly increased in CsA 15 mg/kg group compared to other groups and correlated positively with total homocysteine levels. Considering the well-established correlation among insulin resistance, lipid and total homocysteine levels, hypercoagulability and atherosclerosis, we can assume that this protocol of long-term CsA treatment in non-transplanted rats alter biochemical parameters related to cardiovascular and cerebrovascular risk, mainly in CsA 15 mg/kg group. Insulin and tHcy serum levels appear to be central in this process. Topics: Animals; Blood Coagulation; Body Weight; Cyclosporine; Fibrinogen; Glucose Tolerance Test; Homocysteine; Humans; Immunosuppressive Agents; Insulin; Leptin; Lipids; Male; Rats; Rats, Wistar; Risk Factors; Vascular Diseases | 2010 |
Post-weaning voluntary exercise exerts long-term moderation of adiposity in males but not in females in an animal model of early-onset obesity.
Given the alarming increase in childhood, adolescent and adult obesity there is an imperative need for understanding the early factors affecting obesity and for treatments that may help prevent or at least moderate it. Exercise is frequently considered as an effective treatment for obesity however the empirical literature includes many conflicting findings. In the present study, we used the OLETF rat model of early-onset hyperphagia-induced obesity to examine the influence of early exercise on peripheral adiposity-related parameters in both males and females. Rats were provided voluntary access to running wheels from postnatal day (PND) 22 until PND45. We examined fat pad weight (brown, retroperitoneal, inguinal and epididymal); inguinal adipocyte size and number; and leptin, adiponectin, corticosterone and creatinine levels. We also examined body weight, feeding efficiency and spontaneous intake. Early voluntary exercise reduced intake, adiposity and leptin in the OLETF males following a sharp reduction in adipocyte size despite a significant increase in fat cell number. Exercising males from the lean LETO control strain presented stable intake, but reduced body fat, feeding efficiency and increased plasma creatinine, suggesting an increment in muscle mass. OLETF females showed reduced feeding efficiency and liver fat, and a significant increase in brown fat. Exercising LETO control females increased intake, body weight and creatinine, but no changes in body fat. Overall, OLETF rats presented higher adiponectin levels than controls in both basal and post-exercise conditions. The results suggest an effective early time frame, when OLETF males can be successfully "re-programmed" through voluntary exercise; in OLETF females the effect is much more moderate. Findings expose sex-dependent peripheral mechanisms in coping with energy challenges. Topics: Adiponectin; Adipose Tissue; Adiposity; Animals; Body Weight; Corticosterone; Creatinine; Eating; Estrous Cycle; Female; Hyperphagia; Leptin; Male; Motor Activity; Obesity; Physical Conditioning, Animal; Rats; Rats, Inbred OLETF; Sex Characteristics | 2010 |
Leptin resistance after heart transplantation.
Topics: Absorptiometry, Photon; Adipocytes; Adipokines; Adult; Analysis of Variance; Area Under Curve; Body Composition; Body Weight; Case-Control Studies; Cross-Sectional Studies; Female; Heart Failure; Heart Transplantation; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Obesity, Abdominal; Oxygen Consumption; Statistics as Topic | 2010 |
Exposure to a high-fat diet alters leptin sensitivity and elevates renal sympathetic nerve activity and arterial pressure in rabbits.
The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2- to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively (P<0.05), after 3 weeks of HFD. Renal sympathetic nerve activity was 48% higher (P<0.05) in HFD compared with control diet rabbits and was correlated to plasma leptin (r=0.87; P<0.01). Intracerebroventricular leptin administration (5 to 100 microg) increased mean arterial pressure similarly in both groups, but renal sympathetic nerve activity increased more in HFD-fed rabbits. By contrast, intracerebroventricular leptin produced less neurons expressing c-Fos in HFD compared with control rabbits in regions important for appetite and sympathetic actions of leptin (arcuate: -54%, paraventricular: -69%, and dorsomedial hypothalamus: -65%). These results suggest that visceral fat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked "selective leptin resistance" in these animals. Topics: Analysis of Variance; Animals; Blood Pressure; Body Weight; Catheters, Indwelling; Dietary Fats; Dose-Response Relationship, Drug; Heart Rate; Hypothalamus; Injections, Intraventricular; Intra-Abdominal Fat; Kidney; Leptin; Male; Neurons; Proto-Oncogene Proteins c-fos; Rabbits; Receptors, Leptin; Sympathetic Nervous System | 2010 |
Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet.
Childhood obesity increases the risk of adult obesity and diabetes, suggesting that early overnutrition permanently programs altered energy and glucose homeostasis. In the present studies, we used a mouse model to investigate whether early overnutrition increases susceptibility to obesity and insulin resistance in response to a high-fat diet (HFD). Litters from Swiss Webster dams were culled to three [chronic postnatal overnutrition (CPO)] or 10 (control) pups and then weaned onto standard chow at postnatal day (P) 23. At 6 wk of age, a subset of mice was placed on HFD, and glucose and insulin tolerance were examined at 16-17 wk of age. Leptin sensitivity was determined by hypothalamic phosphorylated signal transducer and activator of transcription-3 immunoreactivity at P16 and adulthood after ip leptin. CPO mice exhibited accelerated body weight gain and hyperleptinemia during the preweaning period but only a slightly heavier body weight and normal glucose tolerance in adulthood on standard chow diet. Importantly, CPO mice exhibited significant leptin resistance in the arcuate nucleus, demonstrated by reduced activation of phospho-signal transducer and activator of transcription-3, as early as P16 and throughout life, despite normalized leptin levels. In response to HFD, CPO but not control mice displayed insulin resistance in response to an insulin tolerance test. In conclusion, CPO mice exhibited early and persistent leptin resistance in the arcuate nucleus and, in response to HFD, rapid development of obesity and insulin resistance. These studies suggest that early overnutrition can permanently alter energy homeostasis and significantly increase susceptibility to obesity and insulin resistance. Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Area Under Curve; Blood Glucose; Body Weight; Dietary Fats; Eating; Energy Metabolism; Glucose Tolerance Test; Immunohistochemistry; Insulin; Insulin Resistance; Leptin; Mice; Motor Activity; Overnutrition; Phosphorylation; Radioimmunoassay; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor | 2010 |
The lipoprivic control of feeding is governed by fat metabolism, not by leptin or adipose depletion.
A lipoprivic control of feeding has been proposed based on the finding that appetite is stimulated by drugs such as beta-mercaptoacetate (MA) that reduce fatty acid oxidation. The adipose-derived hormone, leptin, has effects on feeding and fat oxidation that are opposite those produced by MA. However, effects of this hormone on MA-induced feeding are not known. Here we examined the effects of endogenous leptin levels and of acute central and peripheral leptin administration on MA-induced feeding. We also examined leptin-induced changes in feeding, body weight, and plasma fuels after capsaicin-induced deletion of the lipoprivic control. MA-induced feeding was not altered under any of these conditions, and leptin's effects were not altered by capsaicin. We then examined MA-induced feeding during chronic leptin treatment. Because chronic leptin produces several distinct metabolic states as body adiposity is reduced, we tested MA before, during, and after leptin treatment at times that coincided with these states. MA-induced feeding was unchanged on d 3 of leptin treatment when rats were in a lipolytic state and rapidly metabolizing body fat stores but reduced on d 10 when they were adipose deplete and their level of fat oxidation was reduced. Together results suggest that the lipoprivic control is normally less active in the fat deplete state than during states associated with fat availability. If so, its insensitivity to leptin would enable the lipoprivic control to operate when dietary fat, adiposity, and leptin levels are elevated. The role played by the lipoprivic control under such conditions remains uncertain. Topics: Adipose Tissue; Animals; Body Weight; Capsaicin; Dietary Fats; Eating; Fats; Feeding Behavior; Leptin; Lipid Metabolism; Male; Rats; Rats, Sprague-Dawley; Sensory System Agents; Thioglycolates; Triglycerides | 2010 |
Improved lipid and glucose metabolism in transgenic rats with increased circulating angiotensin-(1-7).
Obesity and diabetes remain among the world's most pervasive health problems. Although the importance of angiotensin II for metabolic regulation is well documented, the role of the angiotensin-(1-7)/Mas axis in this process is poorly understood. The aim of this study was to evaluate the effect of increased angiotensin-(1-7) plasma levels in lipid and glucose metabolism using transgenic rats that express an angiotensin-(1-7)-releasing fusion protein, TGR(A1-7)3292 (TGR).. The increased angiotensin-(1-7) levels in TGR induced enhanced glucose tolerance, insulin sensitivity, and insulin-stimulated glucose uptake. In addition, TGR presented decreased triglycerides and cholesterol levels, as well as a significant decrease in abdominal fat mass, despite normal food intake. These alterations were accompanied by a marked decrease of angiotensinogen expression and increased Akt in adipose tissue. Furthermore, augmented plasma levels and expression in adipose tissue was observed for adiponectin. Accordingly, angiotensin-(1-7) stimulation increased adiponectin production by primary adipocyte culture, which was blocked by the Mas antagonist A779. Circulating insulin and muscle glycogen content were not altered in TGR.. These results show that increased circulating angiotensin-(1-7) levels lead to prominent changes in glucose and lipid metabolism. Topics: Adipocytes; Adiponectin; Adipose Tissue; Adiposity; Angiotensin I; Angiotensin II; Animals; Biomarkers; Blood Glucose; Body Weight; Cells, Cultured; Cholesterol; Insulin; Leptin; Lipid Metabolism; Male; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptors, G-Protein-Coupled; Time Factors; Triglycerides; Up-Regulation | 2010 |
Multi-hormonal weight loss combinations in diet-induced obese rats: therapeutic potential of cholecystokinin?
Cholecystokinin (CCK) acutely synergizes with amylin to suppress food intake in lean mice. To extend on these findings, the present studies sought to identify neural correlates for the interaction of amylin and CCK, as well as further understand the therapeutic potential of CCK-based combinations in obesity. First, c-Fos activation was assessed in various brain nuclei after a single intraperitoneal injection of amylin (5microg/kg) and/or CCK (5microg/kg). Amylin and CCK additively increased c-Fos within the area postrema (AP), predominantly in noradrenergic (e.g., dopamine-beta-hydroxylase-containing) cells. Next, amylin (100 or 300microg/kg/d) and/or CCK (100 or 300microg/kg/d) were subcutaneously infused for 7days in diet-induced obese (DIO) rats. Amylin treatment of DIO rats for 7days induced significant body weight loss. CCK, while ineffective alone, significantly enhanced body weight loss when co-administered with the higher dose of amylin. Finally, the addition of CCK (300microg/kg/d) to leptin (125microg/kg/d), and to the combination of amylin (50microg/kg/d) and leptin (125microg/kg/d), was also explored in DIO rats via sustained subcutaneous infusion for 14days. Infusion of amylin/leptin/CCK for 14days exerted significantly greater body weight loss, inhibition of food intake, and reduction in adiposity compared to amylin/leptin treatment alone in DIO rats. However, co-infusion of CCK and leptin was an ineffective weight loss regimen in this model. Whereas CCK agonism alone is ineffective at eliciting or maintaining weight loss, it durably augmented the food intake and body weight-lowering effects of amylin and amylin/leptin in a relevant disease model, and when combined with amylin, cooperatively activated neurons within the caudal brainstem. Topics: Amyloid; Analysis of Variance; Animals; Appetite Depressants; Area Postrema; Body Weight; Cholecystokinin; Disease Models, Animal; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eating; Islet Amyloid Polypeptide; Leptin; Male; Neurons; Obesity; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Weight Loss | 2010 |
Female mice target deleted for the neuromedin B receptor have partial resistance to diet-induced obesity.
Previous studies have proposed a role for neuromedin B (NB), a bombesin-like peptide, in the control of body weight homeostasis. However, the nature of this role is unclear. The actions of NB are mediated preferentially by NB-preferring receptors (NBRs). Here we examined the consequences of targeted deletion of NBRs in female mice on body weight homeostasis in mice fed a normolipid diet (ND) or a high-fat diet (HFD) for 13 weeks. Body weight and food ingestion of neuromedin B receptor knockout (NBR-KO) mice fed a normolipid diet showed no difference in relation to wild-type (WT). However, the high-fat diet induced an 8.9- and 4.8-fold increase in body weight of WT and NBR-KO, respectively, compared to their controls maintained with a normolipid diet, even though the mice ingested the same amount of calories, regardless of genotype. Comparing mice fed the high-fat diet, NBR-KO mice accumulated approximately 45% less fat depot mass than WT, exhibited a lower percentage of fat in their carcasses (19.2 vs. 31.3%), and their adipocytes were less hypertrophied. Serum leptin and leptin mRNA in inguinal and perigonadal fat were lower in HFD NBR-KO than HFD WT, and serum adiponectin was similar among HFD groups and unaltered in comparison to ND-fed mice. HFD-fed WT mice developed glucose intolerance but not the HFD-fed NBR-KO mice, although they had similar glycaemia and insulinaemia. NBR-KO and WT mice on the normolipid diet showed no differences in any parameters, except for a trend to lower insulin levels. Therefore, disruption of the neuromedin B receptor pathway did not change body weight homeostasis in female mice fed a normolipid diet; however, it did result in partial resistance to diet-induced obesity. Topics: Adipose Tissue, White; Animals; Azo Compounds; Body Composition; Body Weight; Coloring Agents; Diet; Dietary Fats; Energy Intake; Energy Metabolism; Female; Glucose Tolerance Test; Homeostasis; Hormones; Leptin; Lipids; Liver; Mice; Mice, Knockout; Obesity; Receptors, Bombesin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction | 2010 |
Chronic exposure to a high-fat diet affects stress axis function differentially in diet-induced obese and diet-resistant rats.
Consumption of a high-fat (HF) diet is a contributing factor for the development of obesity. HF diet per se acts as a stressor, stimulating hypothalamo-pituitary-adrenal (HPA) axis activity resulting in elevated glucocorticoid levels; however, the mechanism behind this activation is unclear. We hypothesized that consumption of an HF diet activates HPA axis by increasing norepinephrine (NE) in the paraventricular nucleus (PVN) of the hypothalamus, leading to elevation in corticotrophin-releasing hormone (CRH) concentration in the median eminence (ME) resulting in elevated serum corticosterone (CORT).. To test this hypothesis, diet-induced obese (DIO) and diet-resistant (DR) rats were exposed to either chow or HF diet for 6 weeks.. At the end of 6 weeks, NE in the PVN was measured using HPLC, CRH in the ME, and CORT and leptin levels in the serum were measured using RIA and ELISA, respectively. The gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in NE synthesis, and leptin receptor in brainstem noradrenergic nuclei were also measured.. HF diet increased PVN NE in both DIO and DR rats (P<0.05). However, this was accompanied by increases in CRH and CORT secretion only in DR animals, but not in DIO rats. Leptin receptor mRNA levels in the brainstem noradrenergic areas were not affected in both DIO and DR rats. However, HF diet increased TH mRNA levels only in DIO rats.. Significant differences occur in all the arms of HPA axis function between DIO and DR rats. Further studies are needed to determine whether this could be a causative factor or a consequence to obesity. Topics: Adrenocorticotropic Hormone; Animals; Body Weight; Corticotropin-Releasing Hormone; Diet; Hypothalamus; Leptin; Male; Norepinephrine; Obesity; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley | 2010 |
Adipokines in patients with cancer anorexia and cachexia.
Anorexia, cachexia, and insulin resistance are commonly seen in patients with cancer. Adipocyte-derived hormones or adipokines play a role in the regulation of appetite, body weight, and insulin sensitivity. However, their role in cancer-induced cachexia has not been well-established. The objective of this study was to determine the levels of adipokines and their relation to appetite, weight loss, insulin resistance, and other hormones in cancer cachexia.. We measured adiponectin, resistin, and leptin plasma levels in 21 men with cancer cachexia, 24 noncachectic cancer subjects, and 25 noncancer controls matched by age, sex, and pre-illness body weight. Body weight change, appetite scores, insulin resistance assessed by homeostasis model assessment, and other cytokines and hormones were also measured. Differences between groups were measured by analysis of covariance. Relations between variables were examined by linear regression analyses.. Adiponectin levels were similarly elevated in cachectic and noncachectic cancer patients compared with noncancer controls. Leptin levels were significantly decreased in cancer cachexia and were directly associated with appetite and insulin resistance, explaining 37% and 19% of the variance seen in cancer patients, respectively. Resistin levels were not different between groups.. Leptin may play a role in the increased insulin resistance seen in cancer patients. However, these patients are resistant to the orexigenic effects of hypoleptinemia. Other mechanisms besides weight loss are responsible for the increased adiponectin level seen in cancer patients. It is unlikely that resistin plays a major metabolic role in this setting. Topics: Adipokines; Adiponectin; Adolescent; Adult; Aged; Anorexia; Appetite; Body Weight; Cachexia; Humans; Insulin Resistance; Leptin; Linear Models; Male; Multivariate Analysis; Neoplasms; Resistin; Weight Loss | 2010 |
The positive effects of growth hormone-releasing peptide-6 on weight gain and fat mass accrual depend on the insulin/glucose status.
Ghrelin and GH secretagogues, including GH-releasing peptide (GHRP)-6, stimulate food intake and adiposity. Because insulin modulates the hypothalamic response to GH secretagogues and acts synergistically with ghrelin on lipogenesis in vitro, we analyzed whether insulin plays a role in the metabolic effects of GHRP-6 in vivo. Streptozotocin-induced diabetic rats received saline, GHRP-6, insulin, or insulin plus GHRP-6 once daily for 8 wk. Rats receiving saline suffered hyperglycemia, hyperphagia, polydipsia, and weight loss. Insulin, but not GHRP-6, improved these parameters (P < 0.001 for all), as well as the diabetes-induced increase in hypothalamic mRNA levels of neuropeptide Y and agouti-related peptide and decrease in proopiomelanocortin. Cocaine amphetamine-related transcript mRNA levels were also reduced in diabetic rats, with GHRP-6 inducing a further decrease (P < 0.03) and insulin an increase. Diabetic rats receiving insulin plus GHRP-6 gained more weight and had increased epididymal fat mass and serum leptin levels compared with all other groups (P < 0.001). In epididymal adipose tissue, diabetic rats injected with saline had smaller adipocytes (P < 0.001), decreased fatty acid synthase (FAS; P < 0.001), and glucose transporter-4 (P < 0.001) and increased hormone sensitive lipase (P < 0.001) and proliferator-activated receptor-gamma mRNA levels (P < 0.01). Insulin normalized these parameters to control values. GHRP-6 treatment increased FAS and glucose transporter-4 gene expression and potentiated insulin's effect on epididymal fat mass, adipocyte size (P < 0.001), FAS (P < 0.001), and glucose transporter-4 (P < 0.05). In conclusion, GHRP-6 and insulin exert an additive effect on weight gain and visceral fat mass accrual in diabetic rats, indicating that some of GHRP-6's metabolic effects depend on the insulin/glucose status. Topics: Adipocytes; Agouti-Related Protein; Animals; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Epididymis; Fats; Fatty Acid Synthases; Gene Expression; Ghrelin; Glucose Transporter Type 4; Growth Hormone; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Neuropeptide Y; Oligopeptides; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Weight Gain | 2010 |
Association of plasma leptin levels with maternal body weight and body mass index in premature and term newborns.
Leptin plays an important role in the regulation of body weight and energy metabolism in adults; its role in neonates also needs to be explored. The current study aims to determine the correlation between serum leptin concentrations and anthropometric variables in newborns and their mothers, and to examine the effects of sex, gestational age and antenatal steroid use on neonatal leptin levels.. This was a retrospective study. Blood samples were collected from 55 newborns within 24 hours of birth. Plasma leptin levels were measured by immunometric assay. The relationship between neonatal leptin levels and anthropometric parameters was determined using Pearson's correlation and further evaluated by linear regression analysis.. Neonatal leptin was significantly correlated with maternal body weight (p < 0.002) and maternal body mass index (BMI) (p < 0.001). However, it was not correlated with gestational age (p = 0.130), birth weight (p = 0.097), or birth BMI (p = 0.336). The leptin levels in premature newborns (gestational age < 37 weeks; 0.69 +/- 1.82ng/mL) were significantly less than those in term newborns (gestational age > or = 37 weeks; 2.09 +/- 2.30 ng/mL, p = 0.031). There were no significant differences between sexes (p = 0.277) or in relation to antenatal steroid use (p = 0.611).. Neonatal serum leptin concentrations within 24 hours of birth correlated with maternal body weight and BMI, especially in premature newborns. Premature newborns had significantly lower leptin levels than full-term newborns. Topics: Adult; Betamethasone; Body Mass Index; Body Weight; Female; Humans; Infant, Newborn; Infant, Premature; Leptin; Linear Models; Male; Pregnancy; Retrospective Studies; Sex Characteristics | 2010 |
Effects of diet-induced obesity and voluntary wheel running on bone properties in young male C57BL/6J mice.
Both physical activity and body mass affect bone properties. In this study we examined how diet-induced obesity combined with voluntary physical activity affects bone properties. Forty 7-week-old male C57BL/6J mice were assigned to four groups evenly: control diet (C), control diet + running (CR), high-fat diet (HF, 60% energy from fat), and high-fat diet + running (HFR). After 21-week intervention, all mice were killed and the left femur was dissected for pQCT and mechanical measurements. Body mass increased 80% in HF and 62% in HFR, with increased epididymal fat pad weight and impaired insulin sensitivity. Except for total and trabecular volumetric bone mineral density (BMD), bone traits correlated positively with body mass, fat pad, leptin, and osteoprotegerin. Obesity induced by a high-fat diet resulted in increased femoral bone cross-sectional area, mineral content (BMC), polar moment of inertia, and mechanical parameters. Of the mice accessing the running wheel, those fed the control diet had thinner cortex and less total metaphyseal BMC and BMD, with enlarged metaphyseal marrow cavity, whereas mice fed the high-fat diet had significantly higher trabecular BMD and smaller marrow cavity. However, the runners had a weaker femoral neck as indicated by decreased maximum flexure load. These results suggest that voluntary running exercise affects bone properties in a site-specific manner and that there is a complex interaction between physical activity and obesity. Thus, both diet and exercise should be considered when optimizing the effects on body composition and bone, even though the underlying mechanisms remain partly unknown. Topics: Adipose Tissue; Animals; Biomarkers; Body Weight; Bone Density; Dietary Fats; Femur; Glucose Tolerance Test; Insulin; Insulin Secretion; Leptin; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Osteocalcin; Osteoprotegerin; Physical Conditioning, Animal; Stress, Mechanical; Tomography, X-Ray Computed | 2010 |
Role of adiponectin and leptin on body development in infants during the first year of life.
The control of growth and nutritional status in the foetus and neonate is a complex mechanism, in which also hormones produced by adipose tissue, such as adiponectin and leptin are involved. The aim of this study was to evaluate levels of adiponectin, leptin and insulin in appropriate (AGA) and small for gestational age (SGA) children during the 1st year of life and to correlate these with auxological parameters.. In 33 AGA and 29 SGA infants, weight, length, head circumference, glucose, insulin, adiponectin and leptin levels were evaluated at the second day of life, and at one, six and twelve months, during which a portion of SGA could show catch-up growth (rapid growth in infants born small for their gestational age).. Both total and isoform adiponectin levels were comparable between AGA and SGA infants at birth and until age one year. These levels significantly increased from birth to the first month of life and then decreased to lower values at 1 year of age in all subjects. Circulating leptin concentrations were higher in AGA (2.1 +/- 4.1 ng/ml) than in SGA neonates (0.88 +/- 1.03 ng/ml, p < 0.05) at birth, then similar at the 1st and the 6th month of age, but they increased in SGA from six months to one year, when they showed catch-up growth. Circulating insulin levels were not statistically different in AGA and SGA neonates at any study time point. Insulin levels in both AGA and SGA infants increased over the study period, and were significantly lower at birth compared to one, six and 12 months of age.. During the first year of life, in both AGA and SGA infants a progressive decrease in adiponectin levels was observed, while a difference in leptin values was correlated with the nutritional status. Topics: Adiponectin; Adiposity; Body Height; Body Weight; Child Development; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant; Infant, Newborn; Leptin; Male; Nutritional Status | 2010 |
Physical activity and estrogen treatment reduce visceral body fat and serum levels of leptin in an additive manner in a diet induced animal model of obesity.
Estrogen replacement and physical activity have been demonstrated to reduce the risk to develop a metabolic syndrome in postmenopausal women. In this study we investigate the combined effects of endurance training and estrogen substitution in a rat animal model of diet induced obesity. Effects on lipid and glucose metabolism were evaluated. Ovariectomized (OVX) or sham-operated (SHAM) female Wistar rats were fed with a high fat diet (HF) for 9 weeks. After 3 weeks of overnutrition the OVX rats either remained sedentary, performed treadmill training, received 17β-Estradiol (E(2)), or combined treatment. The OVX rats had a greater increase in body weight and serum levels of cholesterol, triglyceride and low-density lipoprotein cholesterol (LDL). These parameters could be reduced by E(2) and more effectively E(2) in combination with exercise. Also the increase of visceral body fat and leptin could be improved by E(2) and exercise. This combination showed synergistic effects. Serum levels of insulin could be reduced by exercise training, E(2) substitution revealed no significant changes. Our results indicate that ovariectomy increases the susceptibility to develop obesity. In addition they show that the combination of hormone replacement therapy (HRT) and physical activity may influence parameters related to lipid metabolism positively in an additive manner. The results of this study provide evidence that the combination of HRT with physical activity could be a very effective strategy to prevent the development of a metabolic syndrome induced by overnutrition. Topics: Animals; Body Weight; Cholesterol; Estradiol; Female; Insulin; Intra-Abdominal Fat; Leptin; Obesity; Organ Size; Ovariectomy; Physical Conditioning, Animal; Random Allocation; Rats; Rats, Wistar; Triglycerides | 2010 |
Effects of body weight and alcohol consumption on insulin sensitivity.
Obesity is a risk factor for the development of insulin resistance, which can eventually lead to type-2 diabetes. Alcohol consumption is a protective factor against insulin resistance, and thus protects against the development of type-2 diabetes. The mechanism by which alcohol protects against the development of type-2 diabetes is not well known. To determine the mechanism by which alcohol improves insulin sensitivity, we fed water or alcohol to lean, control, and obese mice. The aim of this study was to determine whether alcohol consumption and body weights affect overlapping metabolic pathways and to identify specific target genes that are regulated in these pathways.. Adipose tissue dysfunction has been associated with the development of type-2 diabetes. We assessed possible gene expression alterations in epididymal white adipose tissue (WAT). We obtained WAT from mice fed a calorie restricted (CR), low fat (LF Control) or high fat (HF) diets and either water or 20% ethanol in the drinking water. We screened the expression of genes related to the regulation of energy homeostasis and insulin regulation using a gene array composed of 384 genes.. Obesity induced insulin resistance and calorie restriction and alcohol improved insulin sensitivity. The insulin resistance in obese mice was associated with the increased expression of inflammatory markers Cd68, Il-6 and Il-1alpha; in contrast, most of these genes were down-regulated in CR mice. Anti-inflammatory factors such as Il-10 and adrenergic beta receptor kinase 1 (Adrbk1) were decreased in obese mice and increased by CR and alcohol. Also, we report a direct correlation between body weight and the expression of the following genes: Kcnj11 (potassium inwardly-rectifying channel, subfamily J, member 11), Lpin2 (lipin2), and Dusp9 (dual-specificity MAP kinase phosphatase 9).. We show that alcohol consumption increased insulin sensitivity. Additionally, alterations in insulin sensitivity related with obesity were coupled with alterations in inflammatory genes. We provide evidence that alcohol may improve insulin sensitivity by up-regulating anti-inflammatory genes. Moreover, we have indentified potential gene targets in energy metabolic pathways and signal transducers that may contribute to obesity-related insulin resistance as well as calorie restriction and alcohol-induced insulin sensitivity. Topics: Adipose Tissue; Alcohol Drinking; Animals; Body Weight; Cytokines; Diet; Dietary Fats; Energy Intake; Energy Metabolism; Ethanol; Gene Expression Profiling; Gene Expression Regulation; Glucose Tolerance Test; Inflammation; Insulin; Insulin Resistance; Intramolecular Oxidoreductases; Leptin; Lipocalins; Male; Mice; Mice, Inbred C57BL; Obesity; Phosphatidate Phosphatase; Potassium Channels, Inwardly Rectifying; RNA, Messenger; Signal Transduction | 2010 |
Dietary intervention prior to pregnancy reverses metabolic programming in male offspring of obese rats.
Obesity involving women of reproductive years is increasing dramatically in both developing and developed nations. Maternal obesity and accompanying high energy obesogenic dietary (MO) intake prior to and throughout pregnancy and lactation program offspring physiological systems predisposing to altered carbohydrate and lipid metabolism. Whether maternal obesity-induced programming outcomes are reversible by altered dietary intake commencing before conception remains an unanswered question of physiological and clinical importance. We induced pre-pregnancy maternal obesity by feeding female rats with a high fat diet from weaning to breeding 90 days later and through pregnancy and lactation. A dietary intervention group (DINT) of MO females was transferred to normal chow 1 month before mating. Controls received normal chow throughout. Male offspring were studied. Offspring birth weights were similar. At postnatal day 21 fat mass, serum triglycerides, leptin and insulin were elevated in MO offspring and were normalized by DINT. At postnatal day 120 serum glucose, insulin and homeostasis model assessment (HOMA) were increased in MO offspring; glucose was restored, and HOMA partially reversed to normal by DINT. At postnatal day 150 fat mass was increased in MO and partially reversed in DINT. At postnatal day 150, fat cell size was increased by MO. DINT partially reversed these differences in fat cell size. We believe this is the first study showing reversibility of adverse metabolic effects of maternal obesity on offspring metabolic phenotype, and that outcomes and reversibility vary by tissue affected. Topics: Adipocytes; Animals; Birth Weight; Blood Glucose; Body Weight; Cell Size; Cholesterol; Diet; Eating; Female; Fetal Development; Insulin; Insulin Resistance; Lactation; Leptin; Litter Size; Male; Obesity; Phenotype; Pregnancy; Pregnancy, Animal; Rats; Rats, Wistar; Triglycerides | 2010 |
Effect of serum estradiol and leptin levels on thyroid function, food intake and body weight gain in female Wistar rats.
We evaluated the interplay among estrogen, leptin and thyroid function in the regulation of body mass in female rats. Adult female rats were divided into four groups: control (C, sham-operated), ovariectomized (OVX), ovariectomized treated with estradiol benzoate (Eb) 0.7 or 14microg/100gbw per day, during 21 days. OVX led to an increase in body mass, food intake and food efficiency (change in body mass as function of the amount of food ingested) which were normalized by the lower Eb dose, and decreased significantly when the higher dose was given. Serum leptin levels were increased more than two-fold in all ovariectomized groups. Serum T4 levels of the Eb treated OVX were significantly lower than in the controls. Serum T3 and TSH were unaffected by OVX or by Eb treatment. Uterine type 2 iodothyronine deiodinase (D2) activity changed in parallel with serum estradiol: decreased after OVX, returned to control levels after the lower E2 treatment, and increased significantly after the high Eb dosage. The hypothalamic D2 activity was reduced around 30% in all castrated groups, treated or not with estrogen, whereas in the brown adipose tissue the enzyme was not changed. Interestingly, although estrogen-treated OVX rats had lower body weight, serum leptin was high, suggesting that estrogen increases leptin secretion. Our results show that estradiol is necessary for the hypothalamic action of leptin, since the increase in leptin levels observed in all ovariectomized rats was associated with a decrease in food intake and food efficiency only in the rats treated with estrogen. Topics: Animals; Body Weight; Eating; Estradiol; Female; Leptin; Ovariectomy; Rats; Rats, Wistar; Thyroid Function Tests; Thyroid Gland; Thyroxine | 2010 |
Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin-deficient mice.
The heart of leptin-deficient ob/ob mice is characterized by pathologic left ventricular hypertrophy along with elevated triglyceride (TG) content, increased stearoyl-CoA desaturase (SCD) activity, and increased myocyte apoptosis. In the present study, using an ob/ob;SCD1(-/-) mouse model, we tested the hypothesis that lack of SCD1 could improve steatosis and left ventricle (LV) function in leptin deficiency. We show that disruption of the SCD1 gene improves cardiac function in ob/ob mice by correcting systolic and diastolic dysfunction without affecting levels of plasma TG and FFA. The improvement is associated with reduced expression of genes involved in FA transport and lipid synthesis in the heart, as well as reduction in cardiac FFA, diacylglycerol, TG, and ceramide levels. The rate of FA beta-oxidation is also significantly lower in the heart of ob/ob;SCD1(-/-) mice compared with ob/ob controls. Moreover, SCD1 deficiency reduces cardiac apoptosis in ob/ob mice due to increased expression of antiapoptotic factor Bcl-2 and inhibition of inducible nitric oxide synthase and caspase-3 activities. Reduction in myocardial lipid accumulation and inhibition of apoptosis appear to be one of the main mechanisms responsible for improved LV function in ob/ob mice caused by SCD1 deficiency. Topics: Adipose Tissue; Adiposity; Animals; Apoptosis; Blood Pressure; Body Weight; Caspase 3; Ceramides; Epididymis; Fatty Acids; Female; Gene Knockdown Techniques; Gene Knockout Techniques; Heart; Leptin; Male; Mice; Myocardium; Nitric Oxide Synthase Type II; Obesity; Oxidation-Reduction; Stearoyl-CoA Desaturase; Ventricular Function, Left | 2010 |
Central administration of interleukin-4 exacerbates hypothalamic inflammation and weight gain during high-fat feeding.
In peripheral tissues, the link between obesity and insulin resistance involves low-grade inflammation induced by macrophage activation and proinflammatory cytokine signaling. Since proinflammatory cytokines are also induced in the hypothalamus of animals placed on a high-fat (HF) diet and can inhibit neuronal signal transduction pathways required for normal energy homeostasis, hypothalamic inflammation is hypothesized to contribute to the pathogenesis of diet-induced obesity (DIO). We addressed this hypothesis by perturbing the inflammatory milieu of the hypothalamus in adult male Wistar rats using intracerebroventricular (icv) administration of interleukin-4 (IL-4), a Th2 cytokine that promotes alternative activation (M2) of macrophages and microglia. During HF feeding, icv IL-4 administration increased hypothalamic proinflammatory cytokine gene expression and caused excess weight gain. Intracerebroventricular pretreatment with PS1145, an inhibitor of IKKbeta (a key intracellular mediator of inflammatory signaling), blocked both IL-4 effects, suggesting a causal relationship between IL-4-induced weight gain and hypothalamic inflammation. These observations add to growing evidence linking hypothalamic inflammation to obesity pathogenesis. Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Energy Metabolism; Heterocyclic Compounds, 3-Ring; Hypothalamus; I-kappa B Kinase; Inflammation; Insulin; Interleukin-4; Leptin; Macrophage Activation; Male; Obesity; Pyridines; Rats; Rats, Wistar; Specific Pathogen-Free Organisms | 2010 |
The improvement of sweet taste sensitivity with decrease in serum leptin levels during weight loss in obese females.
Leptin may influence sweet taste sensitivity. However, there are no reports on an association between the sweet taste threshold and serum leptin levels during weight loss in humans. We investigated the changes in the sweet taste threshold and the serum leptin levels during a weight-loss program, in connection with a leptin receptor polymorphism (Lys109Arg) that may be related to insulin and glucose metabolism. The study included 20 obese, but otherwise healthy, females (mean age: 55 +/- 7 years, body mass index: 26.1 +/- 1.7 kg/m(2)). Participants completed a 12-week weight-loss program based on energy restriction through diet and exercise, which aimed at achieving their optimal weight. The sweet taste threshold was determined according to the whole-mouth gustatory method. Genetic analyses were performed using the allele-specific DNA assay. Serum leptin levels were decreased from 9.2 +/- 4.5 to 7.9 +/- 4.9 ng/ml (p = 0.014) after body weight loss. The sweet taste threshold also decreased significantly from 0.59 +/- 0.42 to 0.22 +/- 0.20% in a solution of sucrose (p = 0.004). In contrast, there were no differences in changes of the threshold between participants with and without the Lys109 allele. A multiple regression analysis revealed that the changes in serum leptin levels were significantly correlated with those in the sweet taste threshold, independent of the initial threshold levels and the Lys109 allele. In conclusion, the serum leptin levels are decreased significantly during a weight-loss program in obese females, which may be associated with the decrease in the sweet taste threshold. Topics: Body Mass Index; Body Weight; Female; Humans; Leptin; Middle Aged; Obesity; Taste; Taste Threshold; Weight Loss | 2010 |
Repetitive orogastric gavage affects the phenotype of diet-induced obese mice.
Interest in pharmacological intervention to combat metabolic syndrome and its complications is increasing as the prevalence of obesity is reaching epidemic proportions. The potential efficacy of drugs is often tested in animal models; however, the method of drug delivery is frequently overlooked and may act as a confounder due to stress. We hypothesized that long-term orogastric gavage would negatively influence the development of hepatic steatosis and the metabolic syndrome in a murine model of diet-induced obesity. C57BL/6J male mice were fed a high fat diet and were gavaged with a vehicle once or twice daily for 9 weeks. A group without orogastric gavaging served as control. A similar experiment was performed using leptin deficient ob/ob mice that were fed a standard diet for 4 weeks. Food intake was monitored, insulin resistance determined, and steatosis was assessed by histology and quantified via magnetic resonance spectroscopy. After 9 weeks, control C57BL/6J mice exhibited significantly more weight gain, insulin resistance and hepatic steatosis, compared to mice that were gavaged daily, or twice daily. This effect was likely due to decreased food consumption associated with gavage-induced stress. In contrast, the phenotype of leptin deficient ob/ob mice was not affected by orogastric gavage. Therefore, we concluded that orogastric gavage may lead to increased stress, thereby affecting food intake and the development of diet-induced obesity in a murine model. The effects of what may seem to be trivial laboratory routines, such as orogastric gavage, should be taken into account when designing animal studies for drug development. Topics: Adiposity; Alanine Transaminase; Animals; Blood Glucose; Body Weight; Cholesterol; Dietary Fats; Eating; Energy Intake; Enteral Nutrition; Fasting; Fatty Liver; Insulin Resistance; Leptin; Liver; Magnetic Resonance Spectroscopy; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Organ Size; Phenotype; Severity of Illness Index; Stress, Physiological; Time Factors; Triglycerides; Weight Gain | 2010 |
Central infusion of leptin improves insulin resistance and suppresses beta-cell function, but not beta-cell mass, primarily through the sympathetic nervous system in a type 2 diabetic rat model.
We investigated whether hypothalamic leptin alters beta-cell function and mass directly via the sympathetic nervous system (SNS) or indirectly as the result of altered insulin resistant states.. The 90% pancreatectomized male Sprague Dawley rats had sympathectomy into the pancreas by applying phenol into the descending aorta (SNSX) or its sham operation (Sham). Each group was divided into two sections, receiving either leptin at 300ng/kgbw/h or artificial cerebrospinal fluid (aCSF) via intracerebroventricular (ICV) infusion for 3h as a short-term study. After finishing the infusion study, ICV leptin (3mug/kg bw/day) or ICV aCSF (control) was infused in rats fed 30 energy % fat diets by osmotic pump for 4weeks. At the end of the long-term study, glucose-stimulated insulin secretion and islet morphometry were analyzed.. Acute ICV leptin administration in Sham rats, but not in SNSX rats, suppressed the first- and second-phase insulin secretion at hyperglycemic clamp by about 48% compared to the control. Regardless of SNSX, the 4-week administration of ICV leptin improved glucose tolerance during oral glucose tolerance tests and insulin sensitivity at hyperglycemic clamp, compared to the control, while it suppressed second-phase insulin secretion in Sham rats but not in SNSX rats. However, the pancreatic beta-cell area and mass were not affected by leptin and SNSX, though ICV leptin decreased individual beta-cell size and concomitantly increased beta-cell apoptosis in Sham rats.. Leptin directly decreases insulin secretion capacity mainly through the activation of SNS without modulating pancreatic beta-cell mass. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose Clamp Technique; Glucose Tolerance Test; Injections, Intraventricular; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Male; Rats; Rats, Sprague-Dawley; Sympathectomy, Chemical; Sympathetic Nervous System | 2010 |
Generation of leptin receptor bone marrow chimeras: recovery from irradiation, immune cellularity, cytokine expression, and metabolic parameters.
Leptin regulates appetite and metabolism but also immunity and inflammation. Although functional leptin receptors (LepR) are expressed on hematopoietic cells, the role of these receptors in regulating immune function in vivo remains controversial. To clarify this issue, we performed bone marrow (BM) transplantation between obese db/db mice, lacking LepR, and wild-type (WT) mice. Results indicate that expression of LepR on BM-derived cells directly, though partially, regulates spleen and thymus cellularity, although the environment of db mice contributes to maintaining reduced cellularity of these organs. Selective expression of LepR on BM-derived cells also modulates leptin and adiponectin levels, with induction of a more favorable adipokine environment in the WT→db/db group. However, LepR signaling in BM-derived cells is not involved in regulation of body weight (BW) and composition, glycemia, hepatosteatosis or adipose tissue inflammation, although it modulates expression of interleukin (IL)-1β in the brain. Finally, data indicate that db mice have an increased susceptibility to irradiation compared to WT mice in terms of BW loss and recovery of leukocyte counts in peripheral blood. Therefore, interpretation of results obtained using BM chimeras between WT and db mice should take into account the difference in radiation sensitivity between the two types of animals. Topics: Adiponectin; Animals; Body Weight; Bone Marrow; Bone Marrow Transplantation; Brain; Chimerism; Interleukin-1beta; Leptin; Leukocyte Count; Leukocytes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Receptors, Leptin; Signal Transduction; Spleen; Thymus Gland | 2010 |
Leptin-deficient mice retain normal appetitive spatial learning yet exhibit marked increases in anxiety-related behaviours.
The individual's emotional state influences food intake in both humans and rodents. Moreover, specific cognitive processes regulating the salient aspects of food reward are also critical for ingestive behaviour. However, the molecular mechanisms underlying such influence remain unclear. Genetic mouse models thus are important tools in dissecting the molecular and pathophysiological processes which cause complex human diseases. Leptin, encoded by the ob gene, plays an important part in the energy homeostasis and is critical for the development of obesity.. In these studies, we assess the impact of leptin on behaviours relevant to anxiety and appetitive learning.. Anxiety-related behaviour was assessed in the light dark box and two tests of hyponeophagia. Spatial learning and behavioural flexibility by re-learning was assessed in an appetitive Y-maze task.. Leptin-deficient (ob/ob) mice displayed higher levels of anxiety-related behaviour in both anxiety tests. In the appetitive Y-maze task, leptin deficiency caused no deficit in learning or re-learning and acute restrained stress had no influence on the learning process.. These results emphasise that whilst leptin has previously been shown to modulate aversively motivated learning we found no difference between leptin-deficient mice and their controls in an appetitive learning task. Moreover, both groups showed behavioural flexibility under stressful conditions. On the other hand, leptin deficiency resulted in marked alterations in behaviours relevant to anxiety. Topics: Animals; Anxiety; Appetitive Behavior; Body Weight; Choice Behavior; Disease Models, Animal; Feeding Behavior; Leptin; Male; Maze Learning; Mice; Mice, Obese; Obesity | 2010 |
Circulating leptin moderates the effect of stress on snack intake independent of body mass.
Prior studies have demonstrated influences of leptin on hunger and satiety, the processing of food reward, and taste and palatability perception. This pilot study tested whether leptin accounts for variability in stress-induced changes in snack intake, and explored potential mechanisms underlying this effect. Thirty-four normal weight and class I obese women were exposed to a 30-minute mental stressor and a non-stressful control task in counterbalanced order on consecutive days. Higher serum leptin concentrations predicted decreases in snack intake following the stressor relative to the control condition. Leptin was not a significant predictor of overall hunger or stress-induced changes in hunger, but was associated with greater perceived palatability of one of the four snacks. Overall, findings suggest that leptin may moderate the effect of stress on energy intake through non-homeostatic mechanisms. Topics: Adult; Body Mass Index; Body Weight; Eating; Female; Humans; Leptin; Middle Aged; Neuropsychological Tests; Obesity; Pilot Projects; Stress, Psychological | 2010 |
Anti-diabetic effects of Panax notoginseng saponins and its major anti-hyperglycemic components.
Panax notoginseng (Burk) F.H. Chen (Araliaceae) is a well-known and commonly used traditional Chinese herb for treatment of various diseases, such as hemostasis, edema and odynolysis.. Our aim was to investigate the mechanisms of anti-hyperglycemic and anti-obese effects of Panax notoginseng saponins (PNS) in KK-Ay mice, and explore the components in PNS for such effects.. KK-Ay mice received daily intraperitoneal injections of PNS 200mg/kg or vehicle for 30 days while ginsenoside Re 14 mg/kg, Rd 15 mg/kg, Rg1 40 mg/kg, Rb1 60 mg/kg and notoginsenoside R1 6 mg/kg for 12 days. Fasting blood glucose levels (FBGL), glucose tolerance (GT), serum insulin, leptin levels, body weight changes, food intake, adipose tissues and blood fat levels were measured at different time points.. The PNS group had significantly lower FBGL, improved GT and smaller body weight incremental percentage after the 30-day treatment. Additionally, Rb1 exhibited significant reduction of FBGL on day 12, and Re also exhibited a decreasing trend after the 12-day treatment.. PNS possess anti-hyperglycemic and anti-obese activities by improving insulin- and leptin sensitivity, and Rb1 is responsible for the anti-hyperglycemic effect among the five saponins in KK-Ay mice. Topics: Adiposity; Animals; Anti-Obesity Agents; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus; Disease Models, Animal; Eating; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Panax notoginseng; Plant Roots; Saponins; Time Factors | 2010 |
Leptin associations with age, weight, and sex among chimpanzees (Pan troglodytes).
Leptin is a hormone secreted primarily by adipocytes, a lipostatic signal to the hypothalamus, and is often correlated with adiposity. Associations between leptin, age, and development are unknown in human's closest evolutionary relative, the common chimpanzee (Pan troglodytes).. Serum leptin was assessed cross sectionally in association with age, weight, and sex in healthy captive chimpanzee males (n = 47) and females (n = 49) to test hypotheses related to predicted differences in leptin levels with body mass, development, and sexual dimorphism.. Leptin increased with age and weight among females, but not in males. Leptin was overall higher in females compared to males.. Sex differences in leptin were most evident during adolescence and adulthood, despite similar increases in weight in both sexes indicating that sexual maturation is a key divergence point for differential somatic investment in adiposity and leptin levels between male and female chimpanzees. Topics: Aging; Animals; Body Weight; Cross-Sectional Studies; Female; Leptin; Male; Pan troglodytes; Sex Characteristics | 2010 |
Glucose parameters are altered in mouse offspring produced by assisted reproductive technologies and somatic cell nuclear transfer.
Fortunately, the majority of children conceived through assisted reproductive technologies (ARTs) appear healthy; however, metabolic abnormalities, including elevated glucose and increased and altered adipose tissue deposition, have been reported in adolescents. To parse out factors that may be responsible, we investigated the effects of two different ARTs--in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI)--as well as somatic cell nuclear transfer (SCNT) on glucose clearance, body weight, and body composition of young adult mice. Female and male mice generated through ART weighed more than control (naturally conceived [STOCK]) mice at birth. No differences in body weight were observed in males up to 8 wk of age. ART females took longer than control mice to clear a glucose bolus, with glucose clearance most impaired in SCNT females. IVF females secreted more insulin and had a higher insulin peak 15 min after glucose injection compared with all other groups. Male mice exhibited no differences in glucose clearance, but IVF males required more insulin to do so. SCNT females weighed more than IVF, ICSI, and STOCK females, and they had higher fat content than ICSI females and higher leptin levels than all other groups. These results show that glucose parameters are altered in young adult mice conceived through techniques associated with ART before onset of obesity and may be responsible for its development later in life. The present study suggests that more investigation regarding the long-term effects of manipulations associated with ART is warranted. Topics: Adiposity; Animals; Blood Glucose; Body Composition; Body Weight; Female; Fertilization in Vitro; Glucose; Glucose Tolerance Test; Insulin; Leptin; Male; Metabolic Clearance Rate; Mice; Mice, Inbred C57BL; Nuclear Transfer Techniques; Obesity; Pregnancy; Reproductive Techniques, Assisted; Sex Factors; Sperm Injections, Intracytoplasmic | 2010 |
Maternal perinatal undernutrition programs a "brown-like" phenotype of gonadal white fat in male rat at weaning.
Several studies indicate that maternal undernutrition sensitizes the offspring to the development of metabolic disorders, such as obesity. Using a model of perinatal maternal 50% food-restricted diet (FR50), we recently reported that rat neonates from undernourished mothers exhibit decreased leptin plasma levels associated with alterations of hypothalamic proopiomelanocortin system. The present study aimed at examining the consequences of FR50 on the brain-adipose axis in male rat neonates. Using quantitative RT-PCR array containing 84 obesity-related genes, we demonstrated that most of the genes involved in energy metabolism regulation are expressed in rat gonadal white adipose tissue (WAT) and are sensitive to maternal perinatal undernutrition (MPU). In contrast, hypothalamic gene expression was not substantially affected by MPU. Gene expression of uncoupling protein 1 (UCP1), a marker of brown adipocytes, showed an almost 400-fold stimulation in postnatal day 21 (PND21) FR50 animals, suggesting that their gonadal WAT possesses a brown-like phenotype. This was confirmed by histological and immunoshistochemical procedures, which demonstrated that PND21 FR50 gonadal adipocytes are multilocular, resembling those present in interscapular brown adipose tissue, and exhibit an overexpression of UCP1 and neuropeptide Y (NPY) at the protein level. Control animals contained almost exclusively "classical" unilocular white adipocytes that did not show high UCP1 and NPY labeling. After weaning, FR50 animals exhibited a transient hyperphagia that was associated with the disappearance of brown-like fat pads in PND30 WAT. Our results demonstrate that MPU delays the maturation of gonadal WAT during critical developmental time windows, suggesting that it could have long-term consequences on body weight regulation in the offspring. Topics: Adipocytes; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Animals, Newborn; Body Weight; Energy Metabolism; Gene Expression; Hypothalamus; Leptin; Male; Malnutrition; Neuropeptide Y; Obesity; Phenotype; Pro-Opiomelanocortin; Proteins; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Weaning | 2010 |
Hepatic and very low-density lipoprotein fatty acids in obese offspring of overfed dams.
The combined effects of developmental programming and high-fat feeding at weaning on fatty acid metabolism of the offspring are not well known. In the present study, we aim at characterizing the influence of maternal and offspring's own diets on liver and very low-density lipoprotein (VLDL) lipids; fatty acid profiles of VLDL and liver phospholipids, triglycerides, and cholesteryl esters; and hepatic enzyme activities. Twenty obese male rats born to cafeteria diet-fed dams and 20 control rats born to control diet-fed dams were selected. At weaning, 10 rats of each group were fed control or cafeteria diet. Obese rats had a significant increase in serum glucose, insulin, leptin, VLDL apolipoprotein B100 and lipid levels, and hepatic fatty acid synthase and a reduction in acyl-coenzyme A oxidase and dehydrogenase activities compared with control pups at day 21 and day 90. Hepatic steatosis was apparent only at day 90. The proportions of saturated fatty acids and monounsaturated fatty acids and the oleic to stearic acid ratio were significantly increased, whereas polyunsaturated fatty acids and the arachidonic to linoleic acid ratio were decreased, in liver and VLDL lipids of obese pups compared with controls. The cafeteria diet at weaning induced more severe abnormalities in obese rats. In conclusion, maternal cafeteria diet induced a permanent reduction in hepatic β-oxidation and an increase in hepatic lipogenesis that caused liver steatosis and VLDL and fatty acid alterations in adult offspring. These preexisting alterations in offspring were worsened under a high-fat diet from weaning to adulthood. Nutritional recommendations in obesity must then target maternal and postnatal nutrition, especially fatty acid composition. Topics: Animals; Blood Glucose; Body Weight; Energy Intake; Energy Metabolism; Fatty Acids, Nonesterified; Female; Insulin; Leptin; Lipoproteins, VLDL; Liver; Male; Maternal Exposure; Obesity; Organ Size; Pregnancy; Rats; Rats, Wistar | 2010 |
Hypertension induced by omega-3 polyunsaturated fatty acid deficiency is alleviated by alpha-linolenic acid regardless of dietary source.
Omega-3 polyunsaturated fatty acid deficiency, particularly during the prenatal period, can cause hypertension in later life. This study examined the effect of different sources of alpha-linolenic acid (canola oil or flaxseed oil) in the prevention of hypertension and other metabolic symptoms induced by an omega-3 fatty acid-deficient diet. Dams were provided one of three experimental diets from 1 week before mating. Diets were either deficient (10% safflower oil-DEF) or sufficient (7% safflower oil+3% flaxseed oil-SUF-F; or 10% canola oil-SUF-C) in omega-3 fatty acids. The male offspring were continued on the maternal diet from weaning for the duration of the study. Body weight, ingestive behaviors, blood pressure, body composition, metabolic rate, plasma leptin and brain fatty acids were all assessed. The DEF animals were hypertensive at 24 weeks of age compared with SUF-F or SUF-C animals; this was not evident at 12 weeks. These results suggest that different sources of ALA are effective in preventing hypertension related to omega-3 fatty acid deficiency. However, there were other marked differences between the DEF and, in particular, the SUF-C phenotype including lowered body weight, adiposity, leptin and food intake in SUF-C animals. SUF-F animals also had lower, but less marked reductions in adiposity and leptin compared with DEF animals. The differences observed between DEF, SUF-F and SUF-C phenotypes indicate that body fat and leptin may be involved in omega-3 fatty acid deficiency hypertension. Topics: alpha-Linolenic Acid; Animal Feed; Animals; Blood Pressure; Body Composition; Body Weight; Brain; Calorimetry; Deficiency Diseases; Energy Metabolism; Fatty Acids, Monounsaturated; Female; Heart Rate; Hypertension; Leptin; Linseed Oil; Male; Pregnancy; Prenatal Exposure Delayed Effects; Rapeseed Oil; Rats; Rats, Sprague-Dawley; Safflower Oil | 2010 |
Nutritional recovery with rice bran did not modify energy balance and leptin and insulin levels.
To investigate the effect of nutritional recovery with rice bran on energy balance, leptin and insulin levels.. Weaned Wistar rats were fed on a 17% (Control - C) or 0.5% (Aproteic - A) protein diet for 12d. After this, rats were kept on a C diet (C) or recovered with control (Recovered Control - RC) or control plus recovered rice bran diet (Recovered Rice Bran - RRB).. Despite the increased food intake, group A exhibited lower carcass fat associated to low serum leptin. RRB and RC groups showed lower carcass weight and energy intake and expenditure. Energy expenditure was positively associated with food intake and carcass weight. Negative correlations between HOMA-IR and energy expenditure and energy intake were observed.. Nutritional recovery with rice bran did not modify energy balance, leptin and insulin levels. Topics: Animals; Animals, Newborn; Body Weight; Dietary Fiber; Disease Models, Animal; Eating; Energy Intake; Insulin; Leptin; Male; Oryza; Protein-Energy Malnutrition; Random Allocation; Rats; Rats, Wistar | 2010 |
Metformin reduces body weight gain and improves glucose intolerance in high-fat diet-fed C57BL/6J mice.
In an acute treatment experiment, metformin (150, 300 mg/kg, per os (p.o.)) markedly reduced the consumption of a high-fat diet (HFD) (45 kcal% fat-containing diet) for 2 h after the HFD was given to the fasted male C57BL/6J (B6) mice. In addition, metformin at a higher dose increased plasma active glucagon-like peptide-1 (GLP-1) levels at 1 h after the HFD was given. On the other hand, pioglitazone (12 mg/kg, p.o.) slightly increased the food intake but did not affect active GLP-1 levels when given at 6 and 12 mg/kg, p.o. In a long-team experiment for 9 weeks, metformin treatment (0.25, 0.5% in the HFD) resulted in reduction of body weight gain and HFD intake. When wet weights of various body fat pads of each mouse were measured at 9 weeks after treatment, metformin markedly decreased these weights. However, pioglitazone treatment (0.01, 0.02% in the HFD) did not have obvious effects on these parameters. Oral glucose tolerance test was carried out after 20-h fasting at 4 weeks post-treatment. Whereas metformin treatment (0.25, 0.5%) markedly improved glucose intolerance, pioglitazone treatment (0.02%) slightly improved this parameter. At 9 weeks, both metformin and pioglitazone markedly improved hyperglycemia and hyperinsulinemia. Metformin treatment also improved hyperleptinemia, whereas pioglitazone was ineffective. These results indicate that metformin reduces body weight gain and improves glucose intolerance in HFD-induced obese diabetic B6 mice. Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Energy Intake; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Mice; Mice, Inbred C57BL; Obesity; Pioglitazone; Thiazolidinediones; Weight Gain | 2010 |
Investigations of thyroid hormones and antibodies in obesity: leptin levels are associated with thyroid autoimmunity independent of bioanthropometric, hormonal, and weight-related determinants.
Obesity can alter the thyroid hormone status as a result of a dysregulated endocrine loop between the hypothalamo-pituitary unit and adipose tissue. The adipocytokine leptin has been shown to promote autoimmunity; hence, we aimed to clarify whether leptin excess of obesity could increase the susceptibility to develop autoimmune thyroid disease (AITD).. This cross-sectional study was performed in a tertiary care center.. Free thyroid hormones, TSH, thyroglobulin, and antithyroid antibodies levels were tested in 165 obese and 118 lean subjects. Results were plotted against variables related to body composition, leptin levels, glucose homeostasis, energy expenditure, and pattern of weight accrual.. Compared with controls, obese patients had lower free T3 levels and free T4 levels (P<0.01), greater prevalence of hypothyroidism (P<0.05), and higher commonness of antithyroid antibodies (P<0.05). As a marker of AITD, thyroid peroxidase antibodies were more frequent in the obese group (P<0.01). Correlation analysis showed that leptin levels were associated with AITD (P<0.01) independent of bioanthropometric variables. Multiple logistic regression analysis in pooled groups identified female sex and leptin as significant predictors of AITD.. Obesity increases the susceptibility to harbor AITD with an emerging role for leptin as a peripheral determinant, which needs to be confirmed in future investigations. Topics: Adult; Analysis of Variance; Autoantibodies; Autoimmunity; Body Composition; Body Mass Index; Body Weight; Cross-Sectional Studies; Female; Humans; Hypothyroidism; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Patient Selection; Sex Factors; Thyroid Gland; Thyroxine; Triiodothyronine | 2010 |
Short-term re-feeding of previously energy-restricted C57BL/6 male mice restores body weight and body fat and attenuates the decline in natural killer cell function after primary influenza infection.
A hallmark of energy restriction (ER) is a decrease in total body fat, which is thought to increase lifespan and maintain immune function. However, we have shown that during primary influenza infection, ER induces rapid weight loss, impairs natural killer (NK) cell function, and increases mortality in young and aged mice. To determine whether influenza-induced NK cell function could be restored in ER mice, young adult (6 mo) male C57BL/6 mice were fed an ER diet or re-fed (RF) control diet ad libitum for 2 wk before infection with PR8 influenza A. An initial hyperphagic response was observed in RF mice, characterized by increased food intake, rapid weight gain, and restoration of body fat and fat depots by 5-7 d of re-feeding to levels comparable to control ad libitum (AL) mice. Re-feeding improved survival and attenuated the decline in NK cell function during infection, evidenced by increased numbers, percentages, and CD69 expression by d 3 postinfection in RF mice. Interestingly, an altered metabolic phenotype was observed during infection of RF mice, with plasma leptin concentrations greater than in ER mice but less than in AL mice. In contrast, adiponectin concentrations of RF mice were lower than those of both ER and AL mice. These data suggest that re-feeding for a defined period before, and perhaps throughout, influenza season may provide the energy needed to counter the deleterious effects of ER on NK cell function, especially during exposure to newly emerging strains of influenza, for which vaccines are limited or unavailable. Topics: Adipocytes; Adiponectin; Adiposity; Animals; Body Weight; Bone Marrow Cells; Caloric Restriction; Eating; Food; Influenza A virus; Killer Cells, Natural; Leptin; Male; Mice; Mice, Inbred C57BL; Orthomyxoviridae Infections | 2010 |
[Effects of valproate acid on blood lipid, serum leptin and cerebral cortex in juvenile and adult rats].
To study the effects of valproate acid (VPA) on serum lipid and leptin levels and cerebral cortex in juvenile and adult rats.. Twenty healthy juvenile female Sprague-Dawley (SD) rats (21-day-old) and twenty healthy adult female SD rats (2-month-old) were randomly divided into four groups (n=10 each): juvenile control, juvenile VPA, adult control and adult VPA. Juvenile and adult VPA groups were fed with VPA 200 mg/kg daily, while the two control groups were fed with normal saline. The body weights were recorded weekly. Six weeks after feeding, serum and brain samples were obtained. Serum lipid levels including total cholesterol (TC), triglycerides (TG) and lower density lipoprotein cholesterol (LDL-C) were determined. Serum leptin (LEP) levels were measured by radioimmunoassay (RIA). Myelin staining and Nissl staining were used to evaluate the changes of brain tissues.. The weight and serum LEP and lipid levels in both juvenile and adult VPA groups increased significantly compared with those in the control groups (P<0.05). The juvenile VPA group had more increased serum LEP and lipid levels than the adult VPA group (P<0.05). The Myelin staining showed that the average fiber density in the VPA groups was significantly lower than that in the control groups (P<0.05). The Nissl staining showed that the number of toluidine blue staining neurons in the VPA groups was not statistically different from the control groups.. VPA may increase serum LEP and lipid levels in both juvenile and adult rats, and more increased levels may be found in juvenile rats. Long-term VPA treatment may have an adverse effect on brain myelination, but no effect on neurons. Topics: Animals; Anticonvulsants; Body Weight; Cerebral Cortex; Female; Leptin; Lipids; Myelin Sheath; Rats; Rats, Sprague-Dawley; Valproic Acid | 2010 |
Role of sphingolipid mediator ceramide in obesity and renal injury in mice fed a high-fat diet.
The present study tested a hypothesis that excess accumulation of sphingolipid, ceramide, its metabolites, or a combination contributes to the development of obesity and associated kidney damage. Liquid chromatography/mass spectrometry analysis demonstrated that C57BL/6J mice on the high-fat diet (HFD) had significantly increased plasma total ceramide levels compared with animals fed a low-fat diet (LFD). Treatment of mice with the acid sphingomyelinase (ASMase) inhibitor amitriptyline significantly attenuated the HFD-induced plasma ceramide levels. Corresponding to increase in plasma ceramide, the HFD significantly increased the body weight gain, plasma leptin concentration, urinary total protein and albumin excretion, glomerular damage index, and adipose tissue ASMase activity compared with the LFD-fed mice. These HFD-induced changes were also significantly attenuated by treatment of mice with amitriptyline. In addition, the decline of plasma glucose concentration after an intraperitoneal injection of insulin (0.15 U/kg b.wt.) was more sustained in mice on the HFD with amitriptyline than on the HFD alone. Intraperitoneal injection of glucose (3 g/kg b.wt.) resulted in a slow increase followed by a rapid decrease in the plasma glucose concentration in LFD and HFD plus amitriptyline-treated mice, but such blood glucose response was not observed in HFD-fed mice. Immunofluorescence analysis demonstrated a decrease in the podocin and an increase in the desmin in the glomeruli of HFD-fed mice compared with the LFD and HFD plus amitriptyline-treated mice. In conclusion, our results reveal a pivotal role for ceramide biosynthesis in obesity, metabolic syndrome, and associated kidney damage. Topics: Adipose Tissue; Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Blood Pressure; Body Weight; Ceramides; Diet; Dietary Fats; Fluorescent Antibody Technique; Glucose Tolerance Test; Kidney; Kidney Diseases; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Proteinuria; Reverse Transcriptase Polymerase Chain Reaction; Spectrometry, Mass, Electrospray Ionization; Sphingolipids; Sphingomyelin Phosphodiesterase | 2010 |
High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling.
Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. Yet the specific effects of HFD consumption on brain aging are poorly understood. In the present study 20-month old male C57Bl/6 mice were fed either 'western diet' (41% fat), very high fat lard diet (60% fat), or corresponding control diets for 16 weeks and then assessed for changes in metabolism and brain homeostasis. Although both HFDs increased adiposity and fasting blood glucose, only the high fat lard diet increased age-related oxidative damage (protein carbonyls) and impaired retention in the behavioral test. This selective increase in oxidative damage and cognitive decline was also associated with a decline in NF-E2-related factor 2 (Nrf2) levels and Nrf2 activity, suggesting a potential role for decreased antioxidant response. Taken together, these data suggest that while adiposity and insulin resistance following HFD consumption are linked to increased morbidity, the relationship between these factors and brain homeostasis during aging is not a linear relationship. More specifically, these data implicate impaired Nrf2 signaling and increased cerebral oxidative stress as mechanisms underlying HFD-induced declines in cognitive performance in the aged brain. Topics: Adiposity; Aging; Animals; Blood Glucose; Body Weight; Cognition Disorders; Dietary Fats; Hippocampus; Insulin; Leptin; Male; Maze Learning; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Protein Carbonylation; Signal Transduction | 2010 |
Carbohydrate-to-fat ratio affects food intake and body weight in Wistar rats.
The aim of the study was to evaluate the impact of carbohydrate-to-fat ratio on body weight and appetite regulation in Wistar rats. Twenty-four Wistar rats were randomized to three dietary groups (n = 8): normal carbohydrate diet (NC), low-carbohydrate diet (LC) and high-carbohydrate diet (HC) for 12 weeks. Body weight and food intake were recorded. Circulating leptin and insulin levels were measured by radioimmunoassay method. The expression levels of leptin receptor, insulin receptor, orexin, neuropeptide Y (NPY), agouti-related protein (AgRP) and melanocortin-4 receptor (MC-4R) in the hypothalamus were also measured by realtime polymerase chain reaction (PCR). In the LC group, food intake reduced while body weight increased significantly compared with the NC and HC groups. Plasma leptin levels increased in the LC (18.5 +/- 8.2 ng/mL) group compared with the NC (8.6 +/- 3.8 ng/mL, P < 0.001) and HC (6.6 +/- 1.9 ng/mL, P < 0.001) groups. Realtime reverse transcription-PCR revealed a decrease in the hypothalamic expression level of only leptin receptor in the LC (0.764, 0.471-4.648 copy/mL) and HC (0.357, 0.129-0.781 copy/mL) groups compared with the NC (1.323, 0.616-2.392 copy/mL; P = 0.01) group, and that there was no significant change in those of insulin receptor, AgRP, Orexin, NPY and MC-4R. Low-carbohydrate, high-fat diet raised body weight, which led to a rising of circulating leptin levels and a reduced expression of leptin receptor in the hypothalamus. Topics: Agouti-Related Protein; Animals; Appetite Regulation; Body Weight; Dietary Carbohydrates; Dietary Fats; Eating; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Neuropeptides; Orexins; Polymerase Chain Reaction; Rats; Rats, Wistar; Receptor, Insulin; Receptor, Melanocortin, Type 4; Receptors, Leptin | 2010 |
Lactobacillus plantarum strain No. 14 reduces adipocyte size in mice fed high-fat diet.
Because gut microbiota has recently attracted much attention as an environmental factor involved in the development of obesity, probiotics may be useful in preventing and/or improving obesity and its related disorders. The present study aimed to investigate the effects of Lactobacillus plantarum strain No. 14 (LP14), a bacterial strain reported to decrease body fat percentage in healthy volunteers, on adipocyte size in mice. Female C57BL/6 mice were fed either normal- or high-fat diet and administered intragastrically with LP14 (1 x 10(8) colony-forming units/mouse) or vehicle daily for 11 weeks. High dietary fat intake increased body weight gain, white adipose tissue weight, mean adipocyte size and serum total cholesterol and leptin concentrations, and decreased serum adiponectin concentration. In mice fed the high-fat diet, LP14 administration significantly reduced the mean adipocyte size and tended to reduce the white adipose tissue weight and serum total cholesterol and leptin concentrations as compared with the vehicle-administered mice. All mice had undetectable serum levels of conjugated linoleic acids that reportedly exert antiobesity action. In a separate experiment, LP14 ingestion had no influence on serum triacylglycerol accumulation following olive oil administration in Triton WR1339-treated mice, suggesting that dietary fat absorption is unaffected by LP14. In conclusion, we propose that LP14 may exert a beneficial effect on the onset of diet-induced obesity by reducing the cell size of white adipose tissues, and it seems unlikely that previously reported mechanisms for other bacterial strains are involved in the action of LP14. Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Body Weight; Cholesterol; Dietary Fats; Female; Lactobacillus plantarum; Leptin; Mice; Mice, Inbred C57BL; Obesity; Triglycerides; Weight Gain | 2010 |
Effects of castration on insulin levels and glucose tolerance in the mouse differ from those in man.
Plasma insulin concentration is increased in prostate cancer patients during androgen deprivation therapy (ADT) and hyperinsulinemia has been associated with aggressive prostate cancer behavior. To investigate the possible role of castration-induced hyperinsulinemia as a mechanism that may attenuate the beneficial effects of ADT in patients with prostate cancer, a murine model would be useful. We therefore investigated long-term metabolic effects of castration in several mouse models.. We studied the long-term influence of castration on energy intake, body weight, glucose tolerance, plasma-insulin, plasma insulin-like growth factor-1 (IGF-1), plasma adiponectin, and plasma leptin in C57BL/6, Swiss nu/nu, and CB17 scid mice receiving various diets. In each case, mice were randomized to have either bilateral orchiectomy or a sham operation.. Energy intake, body weight, blood glucose levels in glucose tolerance test, plasma insulin, plasma IGF-1, and plasma leptin level in all had a trend to be decreased in castrated as compared to sham operated mice. Plasma adiponectin level was increased in the castrated mice.. The effects of castration on glucose, insulin, and related markers in several mouse models studied does not coincide with clinical observations; further studies in this area will require clinical research and/or the use of alternate models such as the dog. Topics: Adiponectin; Androgens; Animals; Blood Glucose; Body Weight; Disease Models, Animal; Energy Intake; Glucose Tolerance Test; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, SCID; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Random Allocation | 2010 |
[Circulating leptin and the trophological status of patients with chronic obstructive pulmonary disease].
To study the specific features of the nutritional status of patients with persistent chronic obstructive pulmonary disease (COPD) in relation to the hormone-regulating function of energy exchange in terms of leptin and to concurrently evaluate the functional status of fat and protein digestion and absorption and to measure body fat percentage. To assess the influence of these factors on the regulation of the serum concentration of leptin and its potential role in the development of trophological insufficiency in patients.. In 93 patients with COPD (Stages I, II, and III in 22, 36, and 35 patients, respectively, the nutritional status was evaluated by somatometric methods. The concentration of leptin was measured by enzyme immunoassay using a test system (DSL, USA). Absorption was estimated by biochemical studies and by using radionuclides. Body fat content was determined, by measuring bioelectric impedance with an OmRon BF-302 apparatus (Japan).. Protein and fat absorption was decreased in patients with moderate and mainly severe COPD as compared with that in the control group and correlated with body weight deficit and lower body fat percentage. Decreased leptin levels were detected in Stages II-III COPD and correlated with the degree of the disease and reduced protein (r = 0.68 +/- 0.02) and fat (r = 0.64 +/- 0.18) absorption.. Protein and fat absorption impairments correlating with body weight deficit in patients with COPD underline the significant role of this mechanism in the development of trophological insufficiency. In COPD patients with trophological insufficiency, the lower circulating leptin levels that correlate with impaired absorption of fatty acids and protein characterize the pathogenetic role of secondary malabsorption syndrome in leptin-mediated impairments of energy exchange mechanisms. Functional insufficiency of the hormone-regulating mechanism responsible for energy exchange in terms of leptin in patients with Stages II-III COPD gives warning of the insufficient stock of adipose tissue and its reduced energy reserve. Topics: Absorption; Adipose Tissue; Adult; Aged; Body Weight; Dietary Fats; Dietary Proteins; Energy Metabolism; Female; Humans; Intestine, Small; Leptin; Male; Middle Aged; Nutritional Status; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Severity of Illness Index | 2010 |
Macrophage migration inhibitory factor deficiency leads to age-dependent impairment of glucose homeostasis in mice.
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine produced by many cells and tissues including pancreatic beta-cells, liver, skeletal muscle, and adipocytes. This study investigates the potential role of MIF in carbohydrate homeostasis in a physiological setting outside of severe inflammation, utilizing Mif knockout (MIF-/-) mice. Compared with wild-type (WT) mice, MIF-/- mice had a lower body weight, from birth until 4 months of age, but subsequently gained weight faster, resulting in a higher body weight at 12 months of age. The lower weight in young mice was related to a higher energy expenditure, and the higher weight in older mice was related to an increased food intake and a higher fat mass. Fasting blood insulin level was higher in MIF-/- mice compared with WT mice at any age. After i.p. glucose injection, the elevation of blood insulin level was higher in MIF-/- mice compared with WT mice, at 2 months of age, but was lower in 12-month-old MIF-/- mice. As a result, the glucose clearance during intraperitoneal glucose tolerance tests was higher in MIF-/- mice compared with WT mice until 4 months of age, and was lower in 12-month-old MIF-/- mice. Insulin resistance was estimated (euglycemic-hyperinsulinemic clamp tests), and the phosphorylation activity of AKT was similar in MIF-/- mice and WT mice. In conclusion, this mouse model provides evidence for the role of MIF in the control of glucose homeostasis. Topics: Age Factors; Analysis of Variance; Animals; Blood Glucose; Blotting, Western; Body Composition; Body Weight; Energy Metabolism; Glucose Clamp Technique; Glucose Tolerance Test; Homeostasis; Insulin; Insulin Resistance; Leptin; Lipids; Macrophage Migration-Inhibitory Factors; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Reverse Transcriptase Polymerase Chain Reaction; Statistics, Nonparametric | 2010 |
Histamine regulation in glucose and lipid metabolism via histamine receptors: model for nonalcoholic steatohepatitis in mice.
Histamine has been proposed to be an important regulator of energy intake and expenditure. The aim of this study was to evaluate histamine regulation of glucose and lipid metabolism and development of nonalcoholic steatohepatitis (NASH) with a hyperlipidemic diet. Histamine regulation of glucose and lipid metabolism, adipocytokine production, and development of hyperlipidemia-induced hepatic injury were studied in histamine H1 (H1R(-/-)) and H2 (H2R(-/-)) receptor knockout and wild-type mice. H1R(-/-) mice showed mildly increased insulin resistance. In contrast, H2R(-/-) mice manifested profound insulin resistance and glucose intolerance. High-fat/high-cholesterol feeding enhanced insulin resistance and glucose intolerance. Studies with two-deoxy-2-[(18)F]-fluoro-d-glucose and positron emission tomography showed a brain glucose allocation in H1R(-/-) mice. In addition, severe NASH with hypoadiponectinemia as well as hepatic triglyceride and free cholesterol accumulation and increased blood hepatic enzymes were observed in H2R(-/-) mice. H1R(-/-) mice showed an obese phenotype with visceral adiposity, hyperleptinemia, and less severe hepatic steatosis and inflammation with increased hepatic triglyceride. These data suggest that H1R and H2R signaling may regulate glucose and lipid metabolism and development of hyperlipidemia-induced NASH. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Dietary Fats; Fatty Acid Synthases; Fatty Liver; Fluorodeoxyglucose F18; Glucose; Histamine; Hyperlipidemias; Leptin; Lipid Metabolism; Liver; Mice; Mice, Knockout; Radiopharmaceuticals; Receptors, Histamine H1; Receptors, Histamine H2; Sterol Regulatory Element Binding Proteins | 2010 |
A soluble activin receptor type IIb prevents the effects of androgen deprivation on body composition and bone health.
Androgen deprivation, a consequence of hypogonadism, certain cancer treatments, or normal aging in men, leads to loss of muscle mass, increased adiposity, and osteoporosis. In the present study, using a soluble chimeric form of activin receptor type IIB (ActRIIB) we sought to offset the adverse effects of androgen deprivation on muscle, adipose tissue, and bone. Castrated (ORX) or sham-operated (SHAM) mice received either TBS [vehicle-treated (VEH)] or systemic administration of ActRIIB-mFc, a soluble fusion protein comprised of a form of the extracellular domain of ActRIIB fused to a murine IgG2aFc subunit. In vivo body composition imaging demonstrated that ActRIIB-mFc treatment results in increased lean tissue mass of 23% in SHAM mice [19.02 +/- 0.42 g (VEH) versus 23.43 +/- 0.35 g (ActRIIB-mFc), P < 0.00001] and 26% in ORX mice [15.59 +/- 0.26 g (VEH) versus 19.78 +/- 0.26 g (ActRIIB-mFc), P < 0.00001]. Treatment also caused a decrease in adiposity of 30% in SHAM mice [5.03 +/- 0.48 g (VEH) versus 3.53 +/- 0.19 g (ActRIIB-mFc), NS] and 36% in ORX mice [7.12 +/- 0.53 g (VEH) versus 4.57 +/- 0.28 g (ActRIIB-mFc), P < 0.001]. These changes were also accompanied by altered serum levels of leptin, adiponectin, and insulin, as well as by prevention of steatosis (fatty liver) in ActRIIB-mFc-treated ORX mice. Finally, ActRIIB-mFc prevented loss of bone mass in ORX mice as assessed by whole body dual x-ray absorptiometry and micro-computed tomography of proximal tibias. The data demonstrate that treatment with ActRIIB-mFc restored muscle mass, adiposity, and bone quality to normal levels in a mouse model of androgen deprivation, thereby alleviating multiple adverse consequences of such therapy. Topics: Activin Receptors, Type II; Adipose Tissue; Analysis of Variance; Androgen Antagonists; Animals; Body Composition; Body Weight; Bone Density; Cell Line; Humans; Immunoglobulin Fc Fragments; Immunoglobulin G; Leptin; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Orchiectomy; Random Allocation; Recombinant Fusion Proteins; Solubility | 2010 |
Analysis of serum adiponectin, resistin and leptin levels in children and adolescents with autoimmune thyroid disorders.
Leptin, adiponectin and resistin, mainly produced by adipocytes, play a major role in body weight regulation. Disturbances in the maintenance of normal body weight are found to occur also in thyroid diseases. There is a close relationship of the changes in thyroid hormones with the contents of adipose tissue and adipocyte-secreted proteins regulating energetic metabolism in the body. The study objective was to analyze the levels of leptin, adiponectin and resistin in children with untreated Graves' disease, subclinical hypothyroidism in Hashimoto's thyroiditis and in children with simple goiter. The study involved 78 patients with Graves' disease (29 girls and 2 boys, aged 6-21 years, mean 15.2) and with Hashimoto's thyroiditis (30 girls and 2 boys, aged 9-18 years, mean 14.5). The control group consisted of adolescents with simple goiter (13 girls and 2 boys, aged 9-18 years, mean 14.8). The levels of leptin, adiponectin and resistin were determined using the ELISA method (R&D System, USA). Patients with untreated Graves' disease showed higher adiponectin level than the patients with hypothyroidism in Hashimoto's thyroiditis and in simple goiter (14.24 +/- 0.89 vs. 9.18 +/- 2.65, 10.15 +/- 2.5, p < 0.007, p < 0.01), but lower resistin level as compared to simple goiter and Hashimoto's thyroiditis (10.24 +/- 5.2 vs. 13.29 +/- 3.8, 12.2 +/- 2.8, p < 0.01, NS). The analysis of leptin levels revealed no significant differences between children with subclinical hypothyroidism and untreated Graves' disease (4.42 +/- 0.87 vs. 3.1 +/- 0.45 NS). In conclusion, we suggest that disturbances in thyroid hormones in thyroid diseases have an essential effect on the levels of adiponectin and resistin released by adipose tissue. Topics: Adiponectin; Adipose Tissue; Adolescent; Body Weight; Child; Enzyme-Linked Immunosorbent Assay; Female; Goiter; Graves Disease; Hashimoto Disease; Humans; Leptin; Male; Resistin; Statistics, Nonparametric; Thyroid Hormones; Young Adult | 2010 |
Evaluation of leptin in breast milk, lactating mothers and their infants.
Leptin is present in human milk, but it is not clear what the relationship between breast milk (BM) leptin levels and maternal and infant serum leptin concentrations is. The objective of this study was to evaluate the leptin concentration in BM and to investigate its relationship with infants' and mothers' anthropometric parameters and with serum leptin concentration in breast-fed (BF) infants and lactating mothers.. We enrolled 36 adequate for gestational age healthy, exclusively BF, term infants aged <6 months. Leptin concentration in serum and BM was determined by radioimmunoassay (RIA) test (human-leptin-RIA-sensitive, Mediagnost). Infants' and mothers' weights, lengths and body mass indexes (BMI) were measured.. The median leptin concentration was 3.42 ng/ml (interquartile range (IR): 2.65) in BF infants' serum, 3.02 ng/ml (IR: 2.85) in mothers' serum (n=17) and 0.51 ng/ml (IR: 0.34) in BM (n=24). BM leptin concentrations were significantly lower than serum BF infant (P<0.001) and maternal (P<0.001) leptin levels. Infant serum leptin concentration correlated positively with infant weight (r=0.437, P=0.008) and BMI (r=0.561, P=0.004). Mother serum leptin levels correlated positively with weight (r=0.755, P<0.001) and BMI (r=0.661, P=0.007). No correlations were found between BM leptin and serum leptin concentrations in BF infants and mothers.. We confirmed the presence of leptin in BM at a lower concentration than that found in infant and lactating mother serum. We observed a positive correlation between serum leptin levels in BF infants and their growth parameters. Topics: Adult; Body Mass Index; Body Weight; Breast Feeding; Cross-Sectional Studies; Female; Gestational Age; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Lactation; Leptin; Male; Milk, Human; Mothers | 2010 |
Insulin- and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling but not in ob/ob or db/db mice.
Hepatic steatosis results from several processes. To assess their relative roles, hepatocellular long-chain fatty acid (LCFA) uptake was assayed in hepatocytes from C57BL/6J control mice, mice with steatosis from a high-fat diet (HFD) or 10%, 14%, or 18% ethanol (EtOH) in drinking water [functioning leptin-signaling groups (FLSGs)], and ob/ob and db/db mice. V(max) for uptake was increased vs. controls (P < 0.001) and correlated significantly with liver weight and triglycerides (TGs) in all FLSG mice but was minimally or not increased in ob/ob and db/db mice, in which liver weights and TGs greatly exceeded projections from regressions in FLSG animals. Coefficients of determination (R(2)) for these FLSG regressions suggest that increased LCFA uptake accounts for ∼80% of the increase in hepatic TGs within these groups, but increased lipogenic gene expression data suggest that enhanced LCFA synthesis is the major contributor in ob/ob and db/db. Got2, Cd36, Slc27a2, and Slc27a5 gene expression ratios were significantly upregulated in the EtOH groups, correlating with sterol regulatory element binding protein 1c (SREBP1c) and V(max), but only Cd36 expression was increased in HFD, ob/ob, and db/db mice. Comparison of V(max) with serum insulin and leptin suggests that both hormones contribute to upregulation of uptake in the FLSG animals. Thus, increased LCFA uptake, reflecting SREBP1c-mediated upregulation of four distinct transporters, is the dominant cause of steatosis in EtOH-fed mice. In ob/ob and db/db mice, increased LCFA synthesis appears more important. In FLSG animals, insulin upregulates hepatocellular LCFA uptake. Leptin appears to upregulate LCFA uptake or to be essential for full expression of upregulation by insulin. Topics: Aging; Animals; Body Weight; Energy Intake; Ethanol; Fatty Acid Transport Proteins; Fatty Acids; Fatty Liver; Gene Expression Regulation; Insulin; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Oleic Acid; Organ Size; Random Allocation; Receptors, Leptin; Signal Transduction | 2010 |
Anthropometric indexes, insulin resistance, and serum leptin and lipid levels in women with cryptogenic epilepsy receiving topiramate treatment.
We aimed to investigate the effects of topiramate monotherapy on anthropometric indexes, insulin resistance, and serum leptin and lipid levels in 33 premenopausal women (mean age+/-standard deviation: 26.7+/-7.1years) with cryptogenic epilepsy. Body mass index (BMI), waist circumference and serum leptin, insulin and lipid levels were measured at baseline and at 6months after initiation of topiramate. We found reductions in BMI (p<0.001), waist circumference (p<0.001) and serum high-density lipoprotein (HDL) cholesterol levels (p=0.011). We also found significant improvements in insulin resistance (p=0.023), but not in serum leptin levels (p=0.45). Our results suggest that topiramate treatment in women with epilepsy is associated with reduced BMI and waist circumference and improvement in insulin resistance; however, according to our data, topiramate treatment is also associated with lower HDL cholesterol levels, which may substantially increase vascular disease. Topics: Adolescent; Adult; Anthropometry; Anticonvulsants; Body Mass Index; Body Weight; Enzyme-Linked Immunosorbent Assay; Epilepsy; Female; Fructose; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Topiramate; Young Adult | 2010 |
Peripheral leptin and ghrelin receptors are regulated in a tissue-specific manner in activity-based anorexia.
The aim of this research was to investigate the effect of long-term exposure to low leptin and high ghrelin levels, inherent to activity-based anorexia (ABA), on peripheral metabolism-implicated tissues such as muscle and fat depots. For this purpose, rats under ABA were submitted to a global study which included the characterization of body weight and composition change, the evaluation of leptin and ghrelin levels as well as their receptors expression at peripheral level. Our results confirm that feeding restriction to 1 h per day, and particularly the combination of this fasting regime with exercise (ABA), significantly reduces fat mass, decreases leptin circulating levels, increases ghrelin levels strikingly and enhances insulin sensitivity. By direct in vitro assays, we show that visceral and gonadal fat participate more than subcutaneous fat in the hypoleptinemia of these animals. The study of ghrelin (GHS-R1a) and leptin (LEPR) receptors at peripheral level exhibits a tissue-specific expression pattern. Concretely, oxidative-soleus type of muscle appears to be more susceptible to ghrelin and leptin circulating levels than glycolytic-gastrocnemius type under exercise and food restriction situations. In relation to adipose tissue, chronic hyperghrelinemia induces GHS-R1a expression on visceral and subcutaneous fat which might suggest the prevention of lipid loss. On the other hand, only subcutaneous fat express the active long form of LEPR compared to visceral and gonadal fat under low leptin levels in ABA animals. All together, these findings indicate tissue-specific mechanisms for the control of energy homeostasis in response to nutrient and energy availability. Topics: 3T3-L1 Cells; Adipose Tissue; Animals; Anorexia; Body Composition; Body Weight; Energy Intake; Energy Metabolism; Fasting; Female; Ghrelin; Homeostasis; Humans; Insulin; Leptin; Male; Mice; Motor Activity; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; Receptors, Leptin | 2010 |
A selective cannabinoid-1 receptor antagonist, PF-95453, reduces body weight and body fat to a greater extent than pair-fed controls in obese monkeys.
Cannabinoid-1 (CB(1)) receptor antagonists exhibit pharmacological properties favorable to treatment of obesity, caused by both centrally mediated effects on appetite and peripherally mediated effects on energy metabolism. However, the relative contribution of these effects to the weight loss produced by CB(1) receptor antagonists remains unclear. Here, we compare food intake-related and independent effects of the CB(1)-selective antagonist 1-(7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-3-(methylamino) azetidine-3-carboxamide (PF-95453) in obese cynomolgus monkeys. Monkeys were divided into three study groups (n = 10 each) and treated once daily for 8 weeks with either vehicle or PF-95453 as follows: 1, fed ad libitum and dosed orally with vehicle; 2, fed ad libitum and dosed orally with PF-95453 (0.5 mg/kg weeks 1-3, 1.0 mg/kg weeks 4-8); and 3, fed an amount equal to the amount consumed by the drug-treated group and dosed orally with vehicle (pair-fed). PF-95453 treatment significantly reduced food consumption by 23%, body weight by 10%, body fat by 39%, and leptin by 34% while increasing adiponectin by 78% relative to vehicle-treated controls. Pair-fed animals did not exhibit reductions in body weight or leptin but did show significantly reduced body fat (11%) and increased adiponectin (15%) relative to vehicle-treated controls but markedly less than after PF-95453 treatment. Indeed, significant differences were noted between the drug-treated and pair-fed groups with respect to body weight reduction, body fat reduction, increased adiponectin, and leptin reduction. Similar to humans, monkeys treated with the CB(1) receptor antagonist exhibited decreased body weight and body fat, a substantial portion of which seemed to be independent of the effects on food intake. Topics: Adiponectin; Adiposity; Animals; Anti-Obesity Agents; Azetidines; Blood Glucose; Body Composition; Body Weight; Diet; Dogs; Dose-Response Relationship, Drug; Eating; Endpoint Determination; Feeding Behavior; Glucose Tolerance Test; Leptin; Lipids; Macaca fascicularis; Male; Obesity; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Triazines; Weight Loss | 2010 |
Adipokines, endothelial dysfunction and nutritional status in peritoneal dialysis patients.
Adipokines such as leptin and adiponectin are adipocyte-specific secretory proteins that play important roles in the metabolic regulation of body weight, insulin resistance and cardiovascular complications. The relationship between the malnutrition-inflammation complex syndrome and high levels of some adipokines in peritoneal dialysis (PD) patients is still unclear. An association between high body mass index (BMI) and improved survival in PD patients has also been proposed. The purpose of this study was to investigate the levels of plasma adipokines and inflammation and oxidative stress markers in overweight and normal weight PD patients.. Thirty PD patients (12 M, 18 F; mean age 57.3 ± 16.6 years) were examined and 23 healthy volunteers were included as a control group. The levels of high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor-α, interleukin-6, leptin, the leptin receptor, adiponectin, malondialdehyde/4-hydroxynonenal, oxidized low-density lipoprotein, carbonyl groups and asymmetric dimethylarginine (ADMA) were measured in both groups. The nutritional status of each patient was determined by albumin levels, BMI, percentage of body fat (%F), lean body mass (LBM) and the Subjective Global Assessment (SGA) score. The adequacy of dialysis was estimated by weekly Kt/V measurements.. According to the seven-point SGA scores and the albumin levels, the nutrition status of 15 patients was good (6-7 points), while 15 patients were mildly malnourished (3-5 points). The concentrations of hsCRP, leptin and adiponectin were statistically higher in the PD group than in the control group (p < 0.05). Markers of oxidative stress and inflammation were also higher in the PD group. The adiponectin level was inversely correlated with %F and BMI (Spearman's R = -0.3, p ≤ 0.05) and positively correlated with hsCRP level (R = -0.4). The level of leptin was positively correlated with %F, BMI and LBM (R = 0.4, p ≤ 0.05). Patients with normal BMI values had lower leptin concentrations (50.2 vs 242.8 μg/l) and higher adiponectin levels (30.0 vs 20.3 μg/ml) than overweight patients. The statistical analysis indicated that there were no differences in oxidative stress, inflammation and ADMA concentration between the lean and overweight PD patients.. The nutritional status of lean and overweight patients was comparable. Signs of malnutrition were detected in both groups. The severity of chronic inflammation and oxidative stress were not related to BMI in PD patients. Topics: Adiponectin; Adult; Aged; Aldehydes; Arginine; Biomarkers; Body Mass Index; Body Weight; C-Reactive Protein; Cardiovascular Diseases; Endothelium; Female; Humans; Inflammation; Interleukin-6; Leptin; Lipoproteins, LDL; Male; Malnutrition; Malondialdehyde; Middle Aged; Nutritional Status; Oxidative Stress; Peritoneal Dialysis; Risk Factors; Tumor Necrosis Factor-alpha | 2010 |
A twice-a-day feeding regimen optimizes performance in broiler breeder hens.
To evaluate the effects of different methods of feed allocation on performance, plasma hormone concentration, and ovarian morphology, an experiment was conducted using 32 Cobb 500 broiler breeder hens. The experiment was started at 27 wk and lasted to 39 wk of age. Feeding regimens included: i) hens with an ad libitum feeding program, ii) hens that received their restricted feed once a day, iii) hens that received their restricted feed twice a day, and iv) hens that received their restricted feed 3 times a day. Each hen was assumed as an experimental unit and treatments were replicated 8 times. Daily egg production, BW, and egg and yolk weights were measured. Two blood samples were taken 3 and 6 h after the first feed allocation every 2 wk. Plasma samples were assayed for glucose, triacylglycerol (TAG), cholesterol, as well as leptin-like concentration, glucagon, triiodothyronine, thyroxine, progesterone, estradiol, and testosterone. Liver, abdominal fat pad, and ovary were collected at necropsy. Ovaries were weighed and follicles were characterized as large yellow follicles, small yellow follicles, and large white follicles. Results showed inferior egg production in ad libitum-fed birds along with high levels of plasma glucose, TAG, cholesterol, leptin-like concentration, and testosterone. Twice-a-day-fed birds produced more egg in the entire production period than once-a-day-fed birds. Better performance of twice-a-day-fed hens was associated with lower plasma glucose, TAG, and leptin-like concentration, whereas their estradiol and glucagon were higher than once-a-day-fed hens. Results obtained in our study suggest that allocation of restricted feed 2 times a day may alleviate or delay lipotoxicity development and improve reproductive performance in broiler breeder hens. Topics: Animal Feed; Animals; Blood Glucose; Body Weight; Chickens; Cholesterol; Feeding Behavior; Feeding Methods; Female; Leptin; Liver; Oviposition; Reproduction; Triglycerides | 2010 |
Effects of escin mixture from the seeds of Aesculus hippocastanum on obesity in mice fed a high fat diet.
Escins, a triterpene glycoside mixture obtained from the ethanol extract of Aesculus hippocastanum L. (Hippocastanaceae) seed, was evaluated for its in vivo effects on the plasma levels of some hormones (leptin, insulin, FT(3), FT(4)) and biochemical parameters (glucose, triglyceride, total cholesterol, HDL-C, LDL-C concentrations) in mice fed with a high fat diet for 5 weeks. A high fat diet induced a remarkable increment in the plasma leptin (p <0.01), total cholesterol (p <0.01) and LDL-C (p <0.001) concentrations compared to control group animals. Combined administration of a high-fat diet with escins decreased leptin (31.6%) (p<0.05) and FT(4) (36.0%) (p<0.05) levels, increased HDL-C concentration (17.0%), while remained ineffective on LDL-C concentration in mice. Results have shown that escins may have beneficial effects in the understanding of obesity. Topics: Aesculus; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cholesterol; Dietary Fats; Escin; Insulin; Leptin; Lipids; Lipoproteins; Male; Medicine, Traditional; Mice; Obesity; Phytotherapy; Plant Extracts; Seeds; Thyroid Hormones; Time Factors; Turkey | 2010 |
Up-regulation of hepatic lipolysis stimulated lipoprotein receptor by leptin: a potential lever for controlling lipid clearance during the postprandial phase.
As a hepatic receptor for triglyceride-rich lipoproteins, the lipolysis-stimulated lipoprotein receptor (LSR) may be involved in the dynamics of lipid distribution between the liver and peripheral tissues. Here, we explore the potential role of leptin in regulating LSR. At physiological concentrations (1-10 ng/ml), leptin increased LSR protein and mRNA levels in Hepa1-6 cells through an ERK1/2-dependent and α-amanitin-sensitive pathway. In vivo, leptin treatment of C57BL6/Rj mice (1 μg 2×/d, 8 d) led to a significant increase in hepatic LSR mRNA and protein, decreased liver triglycerides and increased VLDL secretion as compared to controls. LSR(+/-) mice with elevated postprandial lipemia placed on a high-fat (60% kcal) diet exhibited accelerated weight gain and increased fat mass as compared to controls. While plasma leptin levels were increased 3-fold, hepatic leptin receptor protein levels and phosphorylation of ERK1/2 were significantly reduced. Therefore, leptin is an important regulator of LSR protein levels providing the means for the control of hepatic uptake of lipids during the postprandial phase. However, this may no longer be functional in LSR(+/-) mice placed under a chronic dietary fat load, suggesting that this animal model could be useful for the study of molecular mechanisms involved in peripheral leptin resistance. Topics: Animals; Blotting, Western; Body Weight; Cell Line; Fluorescent Antibody Technique; Leptin; Lipid Metabolism; Lipolysis; Liver; Mice; Mice, Inbred C57BL; Polymerase Chain Reaction; Postprandial Period; Receptors, Lipoprotein; Up-Regulation | 2010 |
Erythropoietin as a possible mechanism for the effects of intermittent hypoxia on bodyweight, serum glucose and leptin in mice.
The aim of this study was to determine the effects of intermittent hypoxia training (IHT), with and without fatty-diet, on bodyweight, serum glucose, leptin, insulin, and their receptors, and to test whether erythropoietin (EPO) mediates these effects.. Kunming mice were divided into four groups. 1: untreated control; 2: IHT; 3: fatty-diet; 4: fatty-diet and IHT. After 40 days exposure to IHT, the bodyweight, serum glucose, serum leptin, insulin and EPO were measured by ELISA. Liver leptin and insulin receptors were quantified. A separate set of mice were treated with several doses of EPO (0-320 U/kg i.p.) for 5 days. In addition, human hepatic cell lines were treated with EPO for 24h and the expression of genes OB-Ra, OB-Rb and IR were measured using RT-PCR.. IHT reduced bodyweight and serum glucose, with corresponding increases in the serum levels of leptin, insulin, EPO and expression of leptin and insulin receptors in liver. Repeated EPO treatment increased serum leptin concentration, but had no effects on insulin levels. The expression of the genes OB-Ra, OB-Rb and IR were increased after EPO treatment.. We postulate that, in mice, IHT reduces bodyweight and serum glucose by increasing EPO synthesis which secondarily increases leptin and insulin production in liver. Topics: Animals; Blood Glucose; Body Weight; Cell Line; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Hypoxia; Leptin; Liver; Mice; Receptor, Insulin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction | 2010 |
Increased male offspring's risk of metabolic-neuroendocrine dysfunction and overweight after fructose-rich diet intake by the lactating mother.
An adverse endogenous environment during early life predisposes the organism to develop metabolic disorders. We evaluated the impact of intake of an iso-caloric fructose rich diet (FRD) by lactating mothers (LM) on several metabolic functions of their male offspring. On postnatal d 1, ad libitum eating, lactating Sprague-Dawley rats received either 10% F (wt/vol; FRD-LM) or tap water (controls, CTR-LM) to drink throughout lactation. Weaned male offspring were fed ad libitum a normal diet, and body weight (BW) and food intake were registered until experimentation (60 d of age). Basal circulating levels of metabolic markers were evaluated. Both iv glucose tolerance and hypothalamic leptin sensitivity tests were performed. The hypothalamus was dissected for isolation of total RNA and Western blot analysis. Retroperitoneal (RP) adipose tissue was dissected and either kept frozen for gene analysis or digested to isolate adipocytes or for histological studies. FRD rats showed increased BW and decreased hypothalamic sensitivity to exogenous leptin, enhanced food intake (between 49-60 d), and decreased hypothalamic expression of several anorexigenic signals. FRD rats developed increased insulin and leptin peripheral levels and decreased adiponectinemia; although FRD rats normally tolerated glucose excess, it was associated with enhanced insulin secretion. FRD RP adipocytes were enlarged and spontaneously released high leptin, although they were less sensitive to insulin-induced leptin release. Accordingly, RP fat leptin gene expression was high in FRD rats. Excessive fructose consumption by lactating mothers resulted in deep neuroendocrine-metabolic disorders of their male offspring, probably enhancing the susceptibility to develop overweight/obesity during adult life. Topics: Adipokines; Animals; Animals, Newborn; Blotting, Western; Body Weight; Dietary Carbohydrates; Eating; Female; Fructose; Gene Expression; Hypothalamus; Lactation; Leptin; Male; Metabolic Diseases; Neurosecretory Systems; Overweight; Pregnancy; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Sex Factors; STAT3 Transcription Factor; Time Factors | 2010 |
Association of the leptin gene with knee osteoarthritis susceptibility in a Han Chinese population: a case-control study.
Previous studies have suggested that leptin works as a key regulator in the pathogenesis of osteoarthritis (OA), and genetic factors modulate OA. This study assessed the contribution of leptin gene (LEP) polymorphism(s) to knee OA among Han Chinese. Three tag single-nucleotide polymorphisms (SNPs) covering all those LEP SNPs of which the minor allele frequencies were over 10% were selected. Study subjects (697 patients and 699 controls) were divided into four groups (underweight, normal weight, overweight and obese) by body mass index (BMI). Allele and genotype frequencies in the three tag SNPs were significantly different in the normal weight and overweight groups. In the normal weight, overweight and obese groups, BMI (P=4.3 × 10(-5), 0.012 and 0.009, respectively) and gender (P=3.5 × 10(-22), 5.1 × 10(-23) and 2.1 × 10(-8), respectively) were effective factors. Age was an independent effective factor in the overweight group (P=0.009). Haplotypes were associated with OA in the normal weight group (CAT, P=0.015) and the overweight group (AGC, P=0.015). Our results suggest an association between LEP and knee OA in the normal weight and overweight groups among Han Chinese. Topics: Asian People; Body Weight; Case-Control Studies; China; Ethnicity; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Leptin; Male; Obesity; Osteoarthritis, Knee; Overweight; Polymorphism, Genetic | 2010 |
Immune-metabolic balance in stressed rats during Candida albicans infection.
We evaluated the host metabolic response to chronic varied stress during infection with the fungus Candida albicans. We used four groups of female Wistar rats: normal uninfected and unstressed, stressed, C. albicans infected and infected, and stressed. Infected rats reacted with rapid metabolic adjustments, evident as anorexia and body weight loss, partly mediated by glucocorticoids and TNF-alpha. Higher circulating levels of IL-6 and glucose (p < 0.05) revealed the progress and catabolic effect of the inflammatory response. Infected and stressed rats instead showed anorexia associated with infection and weight loss as the result of reduced food intake. This group exhibited a prompt reduction in circulating leptin on day 3 (p < 0.05), reduction in glucose levels and depletion of hepatic glycogen depots. We also evaluated the contribution of TNF-alpha, glucocorticoids, and food deprivation to liver damage. Lipid peroxidation in liver detected in the infected and infected-stressed groups was exacerbated by the glucocorticoid receptor antagonist RU 486, suggesting the modulatory activity of glucocorticoids, while hepatic fat accumulation and glycogen depletion decreased with anti-TNF-alpha treatment. Food deprivation exacerbated liver injury while the response to stress contributed to greater fungal colonization. Our findings emphasize the impact of metabolic alterations on tissue damage when the host immune activity is modulated by stress mediators. Topics: Animals; Blood Glucose; Body Weight; Candidiasis; Eating; Female; Food Deprivation; Glucocorticoids; Hormone Antagonists; Leptin; Liver; Liver Glycogen; Mifepristone; Rats; Rats, Wistar; Stress, Psychological; Tumor Necrosis Factor-alpha | 2010 |
Large litter rearing enhances leptin sensitivity and protects selectively bred diet-induced obese rats from becoming obese.
Because rearing rats in large litters (LLs) protects them from becoming obese, we postulated that LL rearing would protect rats selectively bred to develop diet-induced obesity (DIO) from becoming obese by overcoming their inborn central leptin resistance. Male and female DIO rats were raised in normal litters (NLs; 10 pups/dam) or LLs (16 pups/dam) and assessed for anatomical, biochemical, and functional aspects of leptin sensitivity at various ages when fed low-fat chow or a 31% fat high-energy (HE) diet. LL rearing reduced plasma leptin levels by postnatal day 2 (P2) and body weight gain by P8. At P16, LL DIO neonates had increased arcuate nucleus (ARC) binding of leptin to its extracellular receptors and at P28 an associated increase of their agouti-related peptide and alpha-MSH axonal projections to the paraventricular nucleus. Reduced body weight persisted and was associated with increased ARC leptin receptor binding and sensitivity to the anorectic effects of leptin, reduced adiposity, and enhanced insulin sensitivity in LL DIO rats fed chow until 10 wk of age. The enhanced ARC leptin receptor binding and reduced adiposity of LL DIO rats persisted after an additional 5 wk on the HE diet. Female LL DIO rats had similar reductions in weight gain on both chow and HE diet vs. normal litter DIO rats. We postulate that LL rearing enhances DIO leptin sensitivity by lowering plasma leptin levels and thereby increasing leptin receptor availability and that this both enhances the ARC-paraventricular nucleus pathway development and protects them from becoming obese. Topics: Adiposity; Agouti-Related Protein; alpha-MSH; Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Body Weight; Breeding; Diet; Eating; Female; Gestational Age; Immunohistochemistry; Lactation; Leptin; Litter Size; Male; Obesity; Paraventricular Hypothalamic Nucleus; Protein Binding; Rats; Receptors, Leptin; Time Factors; Weaning; Weight Gain | 2010 |
Basal plasma levels of insulin, leptin, ghrelin, and amylin do not signal adiposity in rats recovering from forced overweight.
This study examined how adiposity signals are related to adiposity during recovery from forced overweight (OW). Rats were rendered OW by chronic intragastric overfeeding (OW). Overfeeding was stopped when OW rats reached 126-129% of saline-infused normal-weight (NW) rats. Adipose tissue (AT) mass was estimated by computed tomography, and blood was drawn from chronic atrial cannulas throughout. Basal levels (i.e. after 2-3 h fasts late in the diurnal phase) of the hypothesized adiposity signals insulin, leptin, ghrelin, and amylin were assayed. OW rats gained approximately 130 g more body weight (BW) and approximately 100 g more AT mass during overfeeding. Plasma levels of insulin and leptin increased, whereas those of ghrelin decreased, linearly with AT mass; amylin did not change reliably. During recovery, OW rats' BW and AT mass decreased but were still elevated vs. NW rats after 39 d. OW rats' insulin returned to NW levels on d 1 of recovery and decreased below NW levels thereafter. Leptin was no longer elevated after d 8 of recovery. Ghrelin and amylin did not change reliably during recovery. Although AT mass decreased in OW rats during each intermeasurement interval between d 0 and d 23 of recovery, insulin and leptin did so during only the first interval (d 0-5). Insulin and leptin levels were exponentially related to AT mass during recovery. These data indicate that basal insulin, leptin, ghrelin, and amylin do not encode AT mass in rats dynamically regulating BW and adiposity during recovery from OW. Topics: Adipose Tissue; Adiposity; Amyloid; Animals; Body Weight; Eating; Ghrelin; Immunoassay; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Overweight; Rats; Rats, Long-Evans; Signal Transduction; Time Factors | 2010 |
Age-associated adaptations in murine adipose tissues.
Ageing is associated with an increase in visceral obesity in men and women. Although wild-type mice with a C57Bl/6 genetic background are extensively used in studies on obesity and metabolism, little information is available on age-associated changes in their adipose tissues. We have evaluated development and composition of subcutaneous (SC) and gonadal (GON) adipose tissue in male C57Bl/6 mice at the ages of 10 weeks, 12 months or 24 months, while kept on normal chow. Total body weight as well as SC and GON fat mass significantly increased between 10 weeks and 12 months, but markedly decreased again up to 24 months of age. Adipocyte size in both fat depots and blood vessel size in GON fat followed this trend. Plasma leptin levels correlated positively with body weight and SC or GON fat mass. Both 12 and 24 months old mice displayed better insulin sensitivity as compared to 10 weeks old counterparts, reflected by significantly decreased plasma levels of insulin and/or glucose. Thus, ageing of C57Bl/6 male mice is associated with a biphasic pattern (increase up to 12 months followed by a decrease up to 24 months) of body weight, SC and GON fat mass, adipocyte and blood vessel size. Topics: Adipose Tissue, White; Adiposity; Aging; Animals; Blood Glucose; Blood Vessels; Body Weight; Cell Count; Cell Size; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Mice; Mice, Inbred C57BL; Models, Animal; Obesity, Abdominal; Subcutaneous Fat, Abdominal | 2010 |
Long-term physiological and behavioral effects of exposure to a highly palatable diet during the perinatal and post-weaning periods.
Environmental conditions promote weight gain in children and adults, with early nutritional states and the availability of energy condensed/high-fat palatable diets appearing to facilitate the development of obesity. Little is known about the extent to which prenatal and postnatal dietary manipulations alter the response of the adult offspring to high-fat, highly palatable diets. Here we exposed rat dams to highly palatable diet (supplemental diet, SD), rich in fat and sugars, during pregnancy and lactation, and assessed the potential interactions with the effects of a similar diet offered post-weaning on a range of physiological and behavioral parameters in the adult male offspring. Post-weaning exposure to SD increased body weight, body fat, and plasma leptin levels, as well as the plasma glucose response to glucose challenge, compared to chow-fed rats. Combining perinatal SD with post-weaning exposure (SD/SD group) elevated fasting plasma glucose levels, and induced leptin resistance in the adult rats. The same treatment also resulted in sensitized locomotor response to an acute injection of amphetamine. The glucocorticoid response to stress was not affected by the dietary treatments. We conclude that exposure of mother and young to a highly palatable diet with high-fat and high sugar content during the critical perinatal period, increases the risk of developing an obesity-like condition in rats exposed to the same palatable diet post-weaning, and this effect may be accompanied by adaptations in the reward-related mesostriatal dopaminergic system. Topics: Adiposity; Age Factors; Amphetamine; Animal Nutritional Physiological Phenomena; Animals; Appetite Regulation; Association Learning; Behavior, Animal; Blood Glucose; Body Weight; Central Nervous System Stimulants; Conditioning, Psychological; Critical Period, Psychological; Dietary Fats; Eating; Female; Food Preferences; Leptin; Male; Motivation; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Reward; Taste | 2010 |
MR molecular imaging of aortic angiogenesis.
The objectives of this study were to use magnetic resonance (MR) molecular imaging to 1) characterize the aortic neovascular development in a rat model of atherosclerosis and 2) monitor the effects of an appetite suppressant on vascular angiogenesis progression.. The James C. Russell:LA corpulent rat strain (JCR:LA-cp) is a model of metabolic syndrome characterized by obesity, insulin resistance, hyperlipidemia, and vasculopathy, although plaque neovascularity has not been reported in this strain. MR molecular imaging with alpha(nu)beta(3)-targeted nanoparticles can serially map angiogenesis in the aortic wall and monitor the progression of atherosclerosis.. Six-week old JCR:LA-cp (+/?; lean, n = 5) and JCR:LA-cp (cp/cp; obese, n = 5) rats received standard chow, and 6 obese rats were fed the appetite suppressant benfluorex over 16 weeks. Body weight and food consumption were recorded at baseline and weeks 4, 8, 12, and 16. MR molecular imaging with alpha(nu)beta(3)-targeted paramagnetic nanoparticles was performed at weeks 0, 8, and 16. Fasted plasma triglyceride, cholesterol, and glucose were measured immediately before MR scans. Plasma insulin and leptin levels were assayed at weeks 8 and 16.. Benfluorex reduced food consumption (p < 0.05) to the same rate as lean animals, but had no effect on serum cholesterol or triglyceride levels. MR (3-T) aortic signal enhancement with alpha(nu)beta(3)-targeted nanoparticles was initially equivalent between groups, but increased (p < 0.05) in the untreated obese animals over 16 weeks. No signal change (p > 0.05) was observed in the benfluorex-treated or lean rat groups. MR differences paralleled adventitial microvessel counts, which increased (p < 0.05) among the obese rats and were equivalently low in the lean and benfluorex-treated animals (p > 0.05). Body weight, insulin, and leptin were decreased (p < 0.05) from the untreated obese animals by benfluorex, but not to the lean control levels (p < 0.05).. Neovascular expansion is a prominent feature of the JCR:LA-cp model. MR imaging with alpha(nu)beta(3)-targeted nanoparticles provided a noninvasive assessment of angiogenesis in untreated obese rats, which was suppressed by benfluorex. Topics: Animals; Aorta; Appetite Depressants; Atherosclerosis; Body Weight; Cholesterol; Disease Models, Animal; Eating; Fenfluramine; Insulin; Integrin alphaVbeta3; Leptin; Magnetic Resonance Angiography; Male; Metabolic Syndrome; Nanoparticles; Neovascularization, Pathologic; Obesity; Rats; Time Factors; Triglycerides | 2010 |
Maternal deprivation has sexually dimorphic long-term effects on hypothalamic cell-turnover, body weight and circulating hormone levels.
Maternal deprivation (MD) has numerous outcomes, including modulation of neuroendocrine functions. We previously reported that circulating leptin levels are reduced and hypothalamic cell-turnover is affected during MD, with some of these effects being sexually dimorphic. As leptin modulates the development of hypothalamic circuits involved in metabolic control, we asked whether MD has long-term consequences on body weight, leptin levels and the expression of neuropeptides involved in metabolism. Rats were separated from their mother for 24h starting on postnatal day (PND) 9 and sacrificed at PNDs 13, 35 and 75. In both sexes MD reduced body weight, but only until puberty, while leptin levels were unchanged at PND 35 and significantly reduced at PND 75. Adiponectin levels were also reduced at PND 75 in females, while testosterone levels were reduced in males. At PND 13, MD modulated cell-turnover markers in the hypothalamus of males, but not females and increased nestin, a marker of immature neurons, in both sexes, with males having higher levels than females and a significantly greater rise in response to MD. There was no effect of MD on hypothalamic mRNA levels of the leptin receptor or metabolic neuropeptides or the mRNA levels of leptin and adiponectin in adipose tissue. Thus, MD has long-term effects on the levels of circulating hormones that are not correlated with changes in body weight. Furthermore, these endocrine outcomes are different between males and females, which could be due to the fact that MD may have sexually dimorphic effects on hypothalamic development. Topics: Adiponectin; Adipose Tissue; Animals; Animals, Newborn; Biomarkers; Body Weight; Cell Proliferation; Female; Hormones; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Male; Maternal Deprivation; Neuropeptides; Rats; Rats, Wistar; Sex Characteristics; Time Factors | 2010 |
An acylic polyisoprenoid derivative, geranylgeranylacetone protects against visceral adiposity and insulin resistance in high-fat-fed mice.
Induction of heat shock protein (HSP)72 improves insulin resistance and obesity in diabetic animal models. Geranylgeranylacetone (GGA), known as an antiulcer drug, induces HSP72 and protects organs against several cellular stresses. This study investigated whether GGA administration would induce HSP72 in liver and render physiological protection against high-fat feeding in mice. A single and 4-wk oral administration of 200 mg/kg GGA was performed in high-fat diet (HFD)-fed mice. Metabolic parameters, cytokines, and gene expressions related to insulin signaling were evaluated. A single administration of GGA induced HSP72 in liver of normal chow-fed and HFD-fed mice. Insulin resistance after HFD was slightly ameliorated. Four weeks of GGA administration also increased HSP72 in liver and significantly improved insulin resistance and glucose homeostasis upon glucose challenge. Activation of c-jun NH₂-terminal kinase (JNK) was attenuated, and insulin signaling was improved in the liver of HFD mice. Visceral adiposity was decreased in GGA-treated mice, accompanied by reduced leptin and increased adiponectin levels. GGA can be a novel therapeutic approach to treat metabolic syndrome as well as type 2 diabetes by improving insulin signaling and reducing adiposity. These beneficial effects of GGA could be mediated through HSP72 induction and JNK inactivation in the liver. Topics: Adiponectin; Animals; Area Under Curve; Blood Glucose; Body Weight; Diterpenes; Eating; Glucose Tolerance Test; HSP72 Heat-Shock Proteins; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Signal Transduction | 2010 |
Growth, metabolic status and ovarian function in buffalo (Bubalus bubalis) heifers fed a low energy or high energy diet.
The aim was to establish the capacity of buffalo heifers to adapt their metabolic requirements to a low energy diet. Murrah buffalo (Bubalus bubalis) heifers undergoing regular estrous cycles were randomly assigned by age, live weight (LW) and body condition score (BCS) to a high energy group (HE, 5.8 milk forage units (MFU)/day, n=6) or low energy group (LE, 3.6 MFU/day, n=6). Circulating concentrations of metabolic substrates, metabolic hormones and reproductive hormones were determined weekly for 19 weeks. Ovarian follicular characteristics and oocyte parameters were also ascertained weekly. Heifers fed the LE diet had a better dry matter conversion than heifers fed the HE diet and the calculated daily energy provision was negative for heifers fed the LE diet (-0.248 MFU) and positive for heifers fed the HE diet (5.4 MFU). Heifers fed the HE diet had an increase in 50 kg LW over the duration of the study whereas LW remained constant for heifers fed the LE diet. The BCS of heifers fed the HE diet (4.2) was greater (P<0.05) than the BCS for heifers fed the LE diet (3.4). Heifers fed the HE diet had greater (P<0.05) circulating concentrations of metabolic substrates (glucose, total cholesterol and HDL cholesterol) and metabolic hormones (insulin, glucagon, leptin and T3) compared with heifers fed the LE diet. There were no significant differences in circulating reproductive hormones between the two groups of heifers. Ovarian follicular characteristics were similar for the two groups of heifers while heifers fed the LE diet tended to have oocytes of reduced quality compared with heifers fed the HE diet. The most notable finding was that heifers fed the LE diet had a negative calculated daily energy provision but were able to maintain LW and reproductive activity. It was concluded that buffalo heifers may potentially have the capacity to undergo metabolic adjustment and reduce their energy requirements when dietary energy is limiting. This adaptive capacity would explain why buffaloes remain productive in environments that are limiting to other ruminants. Topics: Animal Feed; Animals; Blood Glucose; Body Weight; Buffaloes; Cholesterol; Cholesterol, HDL; Diet; Energy Metabolism; Estradiol; Estrous Cycle; Female; Follicle Stimulating Hormone; Glucagon; Growth Hormone; Insulin; Insulin-Like Growth Factor I; Leptin; Luteinizing Hormone; Ovarian Follicle; Ovary; Progesterone; Triiodothyronine | 2010 |
Long-term obesity levels in female OLETF rats following time-specific post-weaning food restriction.
Obesity and the metabolic syndrome represent serious health threats affecting increasing numbers of individuals, with females being more affected than males and with growing incidence among children and adolescents. In the present study, we used the OLETF rat model of early-onset obesity to examine the influence of different timing of food restriction on long-term obesity levels in females. Food restriction took place at different time windows: from weaning until postnatal day (PND) 45 (early); from weaning until PND90 (chronic); or from PND45 until PND70 (late). Follow-up continued until PND90. During and after the termination of the diet-restriction period, we focused on peripheral adiposity-related measures such as fat pad weight (brown, retroperitoneal and inguinal); inguinal adipocyte size and number; and leptin, oxytocin and glucose levels. We also examined body weight, feeding efficiency, spontaneous intake after release from diet-restriction, and plasma creatinine levels and estrous cycle characteristics as a result of the chronic diet. The results suggest that while food restriction produced significant weight and adiposity loss, OLETF females presented poor weight loss retention after the early and late short-term diets. The estrous cycle structure and time of first estrous of the OLETF rats were normalized by chronic food restriction. Females responded to early food restriction in a different manner than males did in previous studies, further emphasizing the importance of sex-appropriate approaches in the investigation and treatment of the pathologies related to obesity and the metabolic syndrome. Topics: Adipocytes; Adiposity; Animals; Body Weight; Caloric Restriction; Cell Count; Cell Size; Eating; Female; Leptin; Male; Obesity; Oxytocin; Rats; Rats, Inbred OLETF; Time Factors; Weaning | 2010 |
Hypothalamic Angptl4/Fiaf is a novel regulator of food intake and body weight.
The angiopoietin-like protein 4 (Angptl4)/fasting-induced adipose factor (Fiaf) is known as a regulator of peripheral lipid and glucose metabolism. In the present study, we investigated the physiological role of Angptl4 in central regulation of body weight homeostasis.. Hypothalamic Angptl4 expression levels were measured using immunoblot assay during feeding manipulation or after administration of leptin, insulin, and nutrients. The effects of Angptl4 on food intake, body weight, and energy expenditure were determined following intracerebroventricular (ICV) administration of Angptl4 in C57BL/6 mice. Food intake, energy metabolism, and feeding responses to leptin, insulin, and nutrients were compared between Angptl4-null mice and their wild littermates. Finally, the relationship of hypothalamic AMP-activated protein kinase (AMPK) and Angptl4 was studied.. Hypothalamic Angptl4 expression levels were increased upon food intake or administration of leptin, insulin, and nutrients. Furthermore, central administration of Angptl4 suppressed food intake and body weight gain but enhanced energy expenditure. These effects were mediated via suppression of hypothalamic AMPK activities. Consistently, Angptl4-null mice displayed increased body weight and hypothalamic AMPK activity but reduced energy expenditure. Food intake following a fast was significantly greater in Angptl4-null mice, which was normalized by centrally administered Angptl4. Moreover, anorectic responses to leptin, insulin, and glucose were diminished in Angptl4-null mice. In contrast, Angptl4-null mice were resistant to diet-induced obesity, indicating obesity-promoting effects of Angptl4 under the condition of fat-enriched diet.. We have demonstrated that hypothalamic Angptl4 is regulated by physiological appetite regulators and mediates their anorexigenic effects via inhibition of hypothalamic AMPK activity. Therefore, Angptl4 appears to have an important role in central regulation of energy metabolism. Topics: Angiopoietin-Like Protein 4; Angiopoietins; Animals; Body Weight; Dietary Fats; Eating; Energy Intake; Energy Metabolism; Homeostasis; Hypothalamus; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Motor Activity; Obesity | 2010 |
Disruption of protein arginine N-methyltransferase 2 regulates leptin signaling and produces leanness in vivo through loss of STAT3 methylation.
Arginine methylation by protein N-arginine methyltransferases (PRMTs) is an important posttranslational modification in the regulation of protein signaling. PRMT2 contains a highly conserved catalytic Ado-Met binding domain, but the enzymatic function of PRMT2 with respect to methylation is unknown. The JAK-STAT pathway is proposed to be regulated through direct arginine methylation of STAT transcription factors, and STAT3 signaling is known to be required for leptin regulation of energy balance.. To identify the potential role of STAT3 arginine methylation by PRMT2 in the regulation of leptin signaling and energy homeostasis.. We identified that PRMT2(-/-) mice are hypophagic, lean, and have significantly reduced serum leptin levels. This lean phenotype is accompanied by resistance to food-dependent obesity and an increased sensitivity to exogenous leptin administration. PRMT2 colocalizes with STAT3 in hypothalamic nuclei, where it binds and methylates STAT3 through its Ado-Met binding domain. In vitro studies further clarified that the Ado-Met binding domain of PRMT2 induces STAT3 methylation at the Arg31 residue. Absence of PRMT2 results in decreased methylation and prolonged tyrosine phosphorylation of hypothalamic STAT3, which was associated with increased expression of hypothalamic proopiomelanocortin following leptin stimulation.. These data elucidate a molecular pathway that directly links arginine methylation of STAT3 by PRMT2 to the regulation of leptin signaling, suggesting a potential role for PRMT2 antagonism in the treatment of obesity and obesity-related syndromes. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Energy Metabolism; Glycogen; Leptin; Liver; Methylation; Methyltransferases; Mice; Mice, Mutant Strains; Obesity; Phosphorylation; Protein Structure, Tertiary; Protein-Arginine N-Methyltransferases; Signal Transduction; STAT3 Transcription Factor | 2010 |
Leptin responsiveness of mice deficient in corticotrophin-releasing hormone receptor type 2.
Leptin acts centrally to inhibit food intake and increase energy expenditure. Corticotrophin-releasing hormone (CRH) is one of the neuropeptides that may contribute to leptin-induced hypophagia and thermogenesis. Acute leptin administration increases CRH mRNA expression in the paraventricular nucleus of the hypothalamus and CRH receptor type 2 (CRHR2) expression in the ventromedial nucleus of the hypothalamus. Studies described here used male and female CRHR2 knockout (KO) mice and wild-type (WT) controls to test the importance of CRHR2 in mediating the effects of leptin on food intake, weight gain and body composition. Peripheral injections of 0.5 mg/kg leptin for 3 days inhibited food intake in female WT and male KO mice, but inhibited weight gain in female KO and male WT mice suggesting an important role for thermogenesis in mediating weight loss. A single third ventricle injection of 1 μg leptin inhibited 12 h food intake of all mice, 36 h cumulative intake of KO mice and weight loss in WT and KO female and WT male mice. A 12-day peripheral infusion of 10 μg leptin/day had no effect on food intake of any group, but significantly reduced carcass fat and protein content of all mice. These results indicate that CRHR2 are not essential for the effects of leptin on food intake, body weight or body composition. Leptin response seems to be determined by a combination of mouse gender and genotype, but CRHR2 KO mice may have an extended response to central leptin injections compared with their WT controls. Topics: Analysis of Variance; Animals; Body Composition; Body Weight; Eating; Female; Hypothalamus; Leptin; Male; Mice; Mice, Knockout; Receptors, Corticotropin-Releasing Hormone | 2010 |
Hepatic gene expression profiling reveals key pathways involved in leptin-mediated weight loss in ob/ob mice.
Leptin, a cytokine-like protein, plays an important role in the regulation of body weight through inhibition of food intake and stimulation of energy expenditure. Leptin circulates in blood and acts on the brain, which sends downstream signals to regulate body weight. Leptin therapy has been successful in treating leptin deficient obese patients. However, high levels of leptin have been observed in more common forms of obesity indicating a state of leptin resistance which limits the application of leptin in the treatment of obesity. If the central effect of leptin could be by-passed and genes which respond to leptin treatment could be regulated directly, new therapeutic targets for the treatment of obesity may be possible. The purpose of this study was to identify genes and subsequent pathways correlated with leptin-mediated weight loss.. WE UTILIZED MICROARRAY TECHNOLOGY TO COMPARE HEPATIC GENE EXPRESSION CHANGES AFTER TWO TYPES OF LEPTIN ADMINISTRATION: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We identified 214 genes that correlate with leptin mediated weight loss. Several biological processes such as mitochondrial metabolic pathways, lipid metabolic and catabolic processes, lipid biosynthetic processes, carboxylic acid metabolic processes, iron ion binding and glutathione S-transferases were downregulated after leptin administration. In contrast, genes involved in the immune system inflammatory response and lysosomal activity were found to be upregulated. Among the cellular compartments mitochondrion (32 genes), endoplasmic reticulum (22 genes) and vacuole (8 genes) were significantly over represented.. In this study we have identified key molecular pathways and downstream genes which respond to leptin treatment and are involved in leptin-mediated weight loss. Many of these genes have previously been shown to be associated with obesity; however, we have also identified a number of other novel target genes. Further investigation will be required to assess the possible use of these genes and their associated protein products as therapeutic targets for the treatment of obesity. Topics: Adipocytes; Animals; Body Weight; Carboxylic Acids; Cell Differentiation; Cell Proliferation; Cluster Analysis; Down-Regulation; Drug Administration Routes; Eating; Female; Gene Expression Profiling; Glutathione Transferase; Hypothalamus; Inflammation; Insulin; Iron; Leptin; Lipid Metabolism; Liver; Lysosomes; Mice; Mitochondria; Obesity; Oligonucleotide Array Sequence Analysis; Weight Loss | 2010 |
Suppressor of cytokine signaling 3 knockdown in the mediobasal hypothalamus: counterintuitive effects on energy balance.
An increase in brain suppressor of cytokine signaling 3 (SOCS3) has been implicated in the development of both leptin and insulin resistance. Socs3 mRNA is localized throughout the brain, and it remains unclear which brain areas are involved in the effect of SOCS3 levels on energy balance. We investigated the role of SOCS3 expressed in the mediobasal hypothalamus (MBH) in the development of diet-induced obesity in adult rats. Socs3 mRNA was down-regulated by local injection of adeno-associated viral vectors expressing a short hairpin directed against Socs3, after which we determined the response to high-fat high-sucrose choice diet. In contrast to neuronal Socs3 knockout mice, rats with SOCS3 knockdown limited to the MBH showed increased body weight gain, larger amounts of white adipose tissue, and higher leptin concentrations at the end of the experiment. These effects were partly due to the decrease in locomotor activity, as 24 h food intake was comparable with controls. In addition, rats with Socs3 knockdown in the MBH showed alterations in their meal patterns: average meal size in the light period was increased and was accompanied by a compensatory decrease in meal frequency in the dark phase. In addition, neuropeptide Y (Npy) mRNA levels were significantly increased in the arcuate nucleus of Socs3 knockdown rats. Since leptin is known to stimulate Npy transcription in the absence of Socs3, these data suggest that knockdown of Socs3 mRNA limited to the MBH increases Npy mRNA levels, which subsequently decreases locomotor activity and alters feeding patterns. Topics: Animals; Body Composition; Body Weight; Brain; Down-Regulation; Energy Metabolism; Feeding Behavior; Gene Knockdown Techniques; HEK293 Cells; Humans; Hypothalamus; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Wistar; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Suppressor of Cytokine Signaling Proteins; Weight Gain | 2010 |
During rapid weight loss in obese children, reductions in TSH predict improvements in insulin sensitivity independent of changes in body weight or fat.
Although serum TSH is often elevated in obesity and may be linked to disorders of lipid and glucose metabolism, the clinical relevance of these relationships remains unclear.. Subjects were obese children and adolescents (n=206; mean age 14 yr) undergoing rapid weight and fat loss in a standardized, multidisciplinary, 2-month, in-patient weight loss program.. This was a prospective study that determined thyroid function, glucose and lipid parameters, leptin, anthropometric measures, and body composition measured by dual-energy x-ray absorption at baseline and at the end of the intervention.. At baseline, 52% of children had TSH concentrations in the high normal range (>2.5 mU/liter), but TSH was not correlated with body weight, body mass index sd scores, lean body mass, or body fat percentage. At baseline, independent of adiposity, TSH significantly correlated with total cholesterol (P=0.008), low-density lipoprotein cholesterol (P=0.013), fasting insulin (P=0.010), homeostatic model assessment (HOMA) (P=0.004), and leptin (P=0.006). During the intervention, mean body fat, TSH, HOMA, and fasting insulin decreased by 21, 11, 53, and 54%, respectively. Change (Δ) in TSH did not correlate with Δbody weight or Δbody composition, but ΔTSH significantly correlated with, Δfasting insulin and ΔHOMA, independent of Δbody weight or Δbody composition (P<0.05).. TSH concentrations are elevated in obese children but are not correlated with the amount of excess body weight or fat. During weight loss, independent of changes in body weight or composition, decreases in elevated serum TSH predict decreases in fasting insulin and HOMA. These findings suggest interventions that target high TSH concentrations during weight loss in obese subjects may improve insulin sensitivity. Topics: Adipose Tissue; Adolescent; Body Composition; Body Mass Index; Body Weight; Fasting; Female; Humans; Insulin; Leptin; Male; Obesity; Patient Selection; Physical Fitness; Reference Values; Regression Analysis; Thyrotropin; Thyroxine; Triglycerides; Triiodothyronine; Weight Loss | 2010 |
Impact of maternal periconceptional overnutrition on fat mass and expression of adipogenic and lipogenic genes in visceral and subcutaneous fat depots in the postnatal lamb.
Women entering pregnancy with a high body weight and fat mass have babies who are at increased risk of becoming overweight or obese in later life. We investigated whether maternal overnutrition in the periconceptional period results in an increased fat mass and expression of adipogenic and lipogenic genes in offspring and whether dietary restriction can reverse these changes. Nonpregnant donor ewes (n = 23) were assigned to one of four groups: control-control fed at 100% maintenance energy requirements (MER) for at least 5 months, control-restricted fed 100% MER for 4 months and 70% MER for 1 month, high-high (HH) fed ad libitum (170-190% MER) for 5 months, or high-restricted (HR) fed ad libitum for 4 months and 70% MER for 1 month. Single embryos were transferred to nonobese recipient ewes, and lamb fat depots were weighed at 4 months. Peroxisome proliferator-activated receptor-γ, glyceraldehyde-3-phosphate dehydrogenase, lipoprotein lipase, leptin, and adiponectin mRNA expression was measured in the lamb fat depots. Total fat mass was higher in female lambs in the HH but not HR group than controls. There was a relationship between donor ewe weight and total fat mass and G3PDH mRNA expression in perirenal fat in female lambs. There was no effect of periconceptional nutritional treatment on peroxisome proliferator-activated receptor-γ, glyceraldehyde-3-phosphate dehydrogenase, lipoprotein lipase, leptin, and adiponectin mRNA expression in any fat depot. Thus, exposure to maternal overnutrition in the periconceptional period alone results in an increased body fat mass in the offspring and that a short period of dietary restriction can reverse this effect. Topics: Adiponectin; Animals; Body Composition; Body Weight; Female; Gene Expression; Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); Intra-Abdominal Fat; Leptin; Maternal Nutritional Physiological Phenomena; Overnutrition; PPAR gamma; Pregnancy; Random Allocation; RNA, Messenger; Sheep; Subcutaneous Fat | 2010 |
Ursolic acid ameliorates thymic atrophy and hyperglycemia in streptozotocin-nicotinamide-induced diabetic mice.
The purpose of this study was to assess the effects of low-dose ursolic acid (UA) on glycemic regulation and immune responses in streptozotocin-nicotinamide (STZ/NA)-induced diabetic mice. Diabetic mice were supplemented with two different doses of UA (0.01 and 0.05%, w/w) or metformin (0.5%, w/w) for 4 weeks. Compared with the untreated diabetic group, UA and metformin significantly improved blood glucose, glycosylated hemoglobin, glucose tolerance, insulin tolerance and plasma leptin levels as well as aminotransferase activity. The plasma and pancreatic insulin concentrations were significantly higher in both UA groups than in the untreated diabetic group. Supplementation with metformin increased the pancreatic insulin level without a change in the plasma insulin level. The relative thymus weights were lower in the untreated diabetic group compared to the non-diabetic group; however, the UA or metformin group had significantly improved thymus weights. Mice receiving UA or metformin supplementation had increased CD4(+)CD8(+) subpopulations in the thymus compared to the untreated diabetic mice. Concanavalin A-stimulated splenic T-lymphocyte proliferation and single-positive (CD4(+) and CD8(+)) subpopulations were significantly higher in the UA-supplemented diabetic groups than in the untreated diabetic group, but lipopolysaccharide-stimulated B-lymphocyte proliferation and the CD19(+) subpopulation were not significantly different among the groups. In the STZ/NA-induced diabetic mice, metformin increased the splenic T-lymphocyte CD4(+) and CD8(+) cell numbers without any change in T-lymphocyte proliferation. Both doses of UA lowered splenic IL-6 levels, whereas metformin increased IFN-γ, IL-6 and TNF-α levels compared to the untreated diabetic mice. These results suggest that low-dose UA may be used as a hypoglycemic agent and immune modulator in non-obese type 2 diabetic mice. Topics: Animals; Atrophy; Blood Glucose; Body Weight; Cell Proliferation; Cytokines; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Glucose Tolerance Test; Glycated Hemoglobin; Hyperglycemia; Insulin; Leptin; Lymphocytes; Male; Mice; Mice, Inbred ICR; Niacinamide; Pancreas; Spleen; Thymus Gland; Transaminases; Triterpenes; Ursolic Acid | 2010 |
[The influence of metabolic parameters on fetal development weight in women with type 1 diabetes and homozygotic variant in -2548 G/A of leptin gene and its 668 A/G receptor polymorphism].
Leptin, as many other hormones and metabolic factors, may play a role in fetal development in pregnancy complicated by type 1 diabetes. Different genetic variants in leptin gene and leptin gene receptor may have influence on leptin synthesis in the course of pregnancy and metabolic state of the mother.. To assess the possible influence of metabolic factors on fetal weight in type 1 diabetic subjects with homozygotic variants in leptin gene (-2548 G/A) and leptin gene receptor (668 G/A).. 30 diabetic and homozygotic subjects (out of 100 diabetic subjects) were qualified to the study Genotyping was performed by PCR-RFLR The following factors were assessed: glycemia, leptin concentration, glycated hemoglobin, lipid profile (total cholesterol, LDL, HDL, triglycerides), maternal body weight. Multiple regression models were developed and ROC curves were used in the analysis.. Mean fetal weight in the analyzed group was 3600 g. The following parameters were found to have influence on fetal weight: I trimester leptin (R2-0.80741288, p < 0.05), I trimester glycemia (R2-0.80741288, p < 0.05), III trimester glycemia (R2-0.80741288, p < 0.05), I trimester HbA1C (R2-0.80741288, p < 0.05), III trimester LDL (R2 = 0.63192254, p < 0.05). Moreover the influence of LDL and maternal BMI (R2-0.81869348, p < 0.05) was found. ROC curve analysis revealed the influence of I trimester leptin--AUC 0.62; sensitivity 0.75; specificity 0.5; cut-off 28.127 ng/ml, III trimester HbA1C AUC 0.66; sensitivity 0.23; specificity 0.91; cut-off 7.9%, III trimester mothers weight AUC 0.63; sensitivity 0.25; specificity 0.93; cut-off 98 kg.. Apart from well-known metabolic factors influencing fetal weight, I trimester leptin concentration was found to have an impact on fetal growth. Topics: Adult; Body Mass Index; Body Weight; Case-Control Studies; Diabetes Mellitus, Type 1; Female; Fetal Weight; Genotype; Humans; Infant, Newborn; Leptin; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; Pregnancy; Pregnancy in Diabetics; Receptors, Leptin | 2010 |
A highly saturated fat-rich diet is more obesogenic than diets with lower saturated fat content.
The present study tested the hypothesis that a saturated fatty acid (SFA)-rich diet is more obesogenic than diets with lower SFA content. In 8 female Sprague-Dawley rats fed a low-SFA canola or a moderate-SFA lard-rich diets at 67% of energy for 26 days, body weight gain, final body weight, obesity index, and food and energy intake were comparable. Twenty-nine rats were fed canola or high-SFA butter-rich diets (67% of energy) or chow for 50 days; then high-fat feeding was followed by ad libitum low-fat feeding (27% of energy) for 28 days and by a food-restricted low-fat diet for 32 days. High-fat feeding resulted in a greater body weight gain (P < .04), final body weight (P < .04), and energy intake (P < .008) in butter-fed rats than in canola- and chow-fed controls, after 26 or 50 days. Ad libitum canola and butter low-fat diets or chow feeding resulted in similar weight change, whereas food-restricted low-fat diets led to comparable weight loss and final weight. Canola-fed animals adjusted their intake based on diet energy density, whereas lard and butter-fed animals failed to do so. Abdominal fat (P = .012) and plasma leptin (P = .005) were higher in chow-fed controls than in canola-fed rats, but comparable with those of butter-fed rats. Prone and resistant phenotypes were detected with high-fat feeding. In conclusion, only feeding the high-SFA butter-rich diet led to obesity development and failure to adjust intake based on the energy density and preserving body fat even after weight loss. The high availability of SFA-rich foods in today's obesogenic environment could contribute to develop and maintain obesity. Topics: Abdominal Fat; Animals; Appetite Regulation; Body Weight; Butter; Diet, Fat-Restricted; Diet, Reducing; Dietary Fats; Energy Intake; Fatty Acids; Fatty Acids, Monounsaturated; Female; Food Deprivation; Leptin; Obesity; Rapeseed Oil; Rats; Rats, Sprague-Dawley; Weight Gain; Weight Loss | 2010 |
Diet-induced obesity, exogenous leptin-, and MADB106 tumor cell challenge affect tissue leukocyte distribution and serum levels of cytokines in F344 rats.
The adipocyte-derived catabolic protein leptin alters cell-mediated immunity and cytokine crosstalk. This may provide new insights into the altered immune response, seen in obese individuals. Therefore, we determined the tissue distribution of immune cells in diet-induced obese (dio) and normal weight F344 rats challenged with MADB106 tumor cells or leptin. Immune cell distribution in blood (by FACS analysis) and tissues (NK cells in spleen and liver, immunohistologically) as well as pro-inflammatory cytokines (IL-6, TNF-α; by flow cytometry) were investigated in 28 normal weight and 28 dio rats (n = 4-6/group). Pro-inflammatory cytokines were increased 3-fold for IL-6 and 7-fold for TNF-α in obese animals. Higher numbers of blood monocytes and NK cells were found in obese as compared to normal weight animals. In dio rats challenged with leptin and MADB106 tumor cells, monocyte numbers were decreased as compared to the obese control animals. Immunohistochemistry revealed an altered NK cell distribution in a compartment-, treatment-, and bodyweight-specific manner. In conclusion, our data reveal a distinct distribution pattern of monocytes and NK cells in dio rats as compared to normal weight littermates and an additional modulatory effect of a leptin- and MADB106 tumor cell challenge. Topics: Adenocarcinoma; Animals; Body Weight; Female; Flow Cytometry; Inflammation; Interleukin-6; Killer Cells, Natural; Leptin; Male; Mammary Neoplasms, Animal; Monocytes; Neoplasm Transplantation; Obesity, Abdominal; Rats; Rats, Inbred F344; Recombinant Proteins; Tumor Microenvironment; Tumor Necrosis Factor-alpha | 2010 |
You deserve what you eat: lessons learned from the study of the melanin-concentrating hormone (MCH)-deficient mice.
Diet plays a crucial role in the development of obesity and insulin resistance via multiple mechanisms. Saturated fatty acids can directly trigger tissue specific proinflammatory pathways via Toll-like receptor-4 (TLR4)-dependent mechanisms. Moreover, diet can change the gut microbiome and increase gut permeability. However, very few studies have addressed the obesity-independent role of diet. Dissecting the effects of diet from those of obesity per se will enhance our understanding of the underlying pathogenesis, and, at the translational level, advance our treatment approaches for obesity and its co-morbidities.. Melanin-concentrating hormone (MCH) is an important regulator of appetite and energy balance. MCH-deficient mice are resistant to diet-induced obesity, primarily due to increased locomotor activity. We took advantage of the unique phenotype of these mice to examine the metabolic and inflammatory consequences of a 15-week consumption of a diet high in saturated fat.. MCH-deficient mice chronically exposed to a high-fat diet gain less weight compared to their wild-type littermates, despite similar food intake, and are protected from hepatosteatosis. They also lack obesity-associated upregulation of serum leptin and insulin levels and have improved total body insulin sensitivity. Nevertheless, we found indistinguishable liver-specific innate immune responses in both genotypes associated with high-fat feeding, which involved activation of TLR4 and its downstream effectors, MyD88, p38 MAP kinase and STAT-3.. Our findings indicate that high-fat feeding is deleterious to the liver, independently of the obesity status. They also suggest that MCH is not necessary for the TLR4-dependent immune response triggered by the high-fat diet. Topics: Adipose Tissue; Adiposity; Animals; Blood Glucose; Body Weight; Dietary Fats; Eating; Gene Expression Regulation; Gluconeogenesis; Glucose Tolerance Test; Hypothalamic Hormones; Immunity, Innate; Insulin; Leptin; Lipid Metabolism; Lipogenesis; Liver; Male; Melanins; Mice; Mice, Knockout; Pituitary Hormones; Signal Transduction; Thinness; Toll-Like Receptor 4 | 2010 |
Altered health outcomes in adult offspring of Sprague Dawley and Wistar rats undernourished during early or late pregnancy.
Birth weight in humans has been inversely associated with adult disease risk. Results of animal studies have varied depending on species, strain, and treatment.. We compared birth weight and adult health in offspring following 50% maternal undernutrition on gestation days (GD) 1-15 (UN1-15) or GD 10-21 (UN10-21) in Sprague Dawley and Wistar rats. Offspring from food-deprived dams were weighed and cross-fostered to control dams. Litters were weighed during lactation and initiating at weaning males were fed either control or a high-fat diet. Young and mature adult offspring were evaluated for obesity, blood pressure (BP), insulin response to oral glucose, and serum lipids. Nephron endowment, renal glucocorticoid receptor, and renin-aldosterone-angiotensin system components were measured.. The UN10-21 groups had birth weights lower than controls and transient catch up growth by weaning. Neither strain demonstrated obesity or dyslipidemia following prenatal undernutrition, but long-term body weight deficits occurred in the UN groups of both strains. High-fat diet fed offspring gained more weight than control offspring without an effect of prenatal nutrition. Sprague Dawley were slightly more susceptible than Wistar rats to altered insulin response and increased BP following gestational undernutrition. Nephron endowment in Sprague Dawley but not Wistar offspring was lower in the UN10-21 groups. Glucocorticoid and renin-aldosterone-angiotensin system pathways were not altered.. The most consistent effect of maternal undernutrition was elevated BP in offspring. Long-term health effects occurred with undernutrition during either window, but the UN10-21 period resulted in lower birth weight and more severe adult health effects. Topics: Animals; Animals, Newborn; Birth Weight; Body Weight; Female; Insulin; Leptin; Lipids; Male; Malnutrition; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Weaning | 2010 |
Traditional medicine Taeeumjowitangkagambang exerts antiobesity and hypolipidemic effects via antioxidant enzyme enhancement.
Taeeumjowitangkagambang (ETJKB) is a traditional Korean medicine that has been clinically used for obesity with little mechanistic understanding. The present study investigated antiobesity and hypolipidemic effects of ETJKB in high fat diet fed rats as well as a 3T3-L1 pre-adipocyte differentiation model. ETJKB significantly inhibited the lipidogenesis in 3T3-L1 adipocytes in a concentration-dependent manner as well as reduced the cellular adipokine leptin level. Daily oral gavage of ETJKB to rats fed a high fat diet significantly attenuated body weight gain and abdominal and epididymal fat weights. ETJKB treatment also reduced the levels of total cholesterol, low density lipoprotein (LDL) and triglyceride as well as increased high density lipoprotein (HDL) in serum compared with the untreated control. Similarly, the ETJKB treatment decreased the levels of total lipid, triglyceride and cholesterol in liver tissue in high fat diet fed rats. Interestingly, ETJKB significantly increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase in liver tissue, while decreasing the hydroxyl radical, thiobarbituric acid reactive substances (TBARS), carbonyl concentration. An improvement of antioxidant enzymes was associated with improved body weight control and healthier lipid profiles and therefore may play an important role in the antiobesity and hypolipidemic effects of ETJKB. Topics: 3T3-L1 Cells; Animals; Anti-Obesity Agents; Antioxidants; Body Weight; Catalase; Cholesterol; Glutathione Peroxidase; Hypolipidemic Agents; Leptin; Lipid Peroxidation; Lipoproteins, LDL; Liver; Male; Medicine, Korean Traditional; Mice; Plant Extracts; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Triglycerides | 2010 |
[Effect of repeated fasting/refeeding on body weight control and energy balance regulation in rats].
To investigate the changes of expression on leptin, a series of neuroendocrine factors and hormones associated with body weight control and energy balance regulation of rats, which were treated with repeated fasting/refeeding and followed by fed with high fat diet.. Designing a repeated fasting/refeeding rats model (RFR) fed with basic stock diet on repeated cycles of 1 d fasting and 1 d refeeding for 6 weeks. The rats in RFR-LF/ HF group were switched to a high fat diet and fed the diet every day for another 6 weeks. The control rats were randomly divided into 3 groups, control group, high-fat diet (HF) group and common fat diet (CF) group. The rats in HF and CF group were killed by the end of the 12th week. The body weight, Lee's index, body fat content and serum lipid, GH, T4, leptin, insulin, and plasma ACTH levels were measured. The expression of NPY and POMC mRNA in hypothalamus were detected by reverse transcription chain reaction (RT-PCR).. The Lee's index, body fat content, serum TC, TG, LDL, leptin and insulin levels of RFR-LF/HF group were lower significantly than those of HF group whereas higher significantly than those of CF group. The expression of NPY mRNA of RFR-LF/HF group were higher significantly than those of HF and CF groups, while the expression of POMC mRNA was lower significantly than that of HF and CF groups.. The feeding pattern of repeated fasting/refeeding can decrease the degree of obesity induced by high fat diet, and also reduce the leptin and insulin resistance, but cause serious disturbance of the expression of neuroendocrine peptides in the central nervous system of rat. Topics: Animals; Body Weight; Diet, High-Fat; Dietary Fats; Energy Metabolism; Fasting; Feeding Methods; Food Deprivation; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley | 2010 |
Maternal environmental contribution to adult sensitivity and resistance to obesity in Long Evans rats.
The OLETF rat is an animal model of early onset hyperphagia induced obesity, presenting multiple pre-obese characteristics during the suckling period. In the present study, we used a cross-fostering strategy to assess whether interactions with obese dams in the postnatal environment contributed to the development of obesity.. On postnatal Day (PND)-1 OLETF and control LETO pups were cross-fostered to same or opposite strain dams. An independent ingestion test was performed on PND11 and a nursing test on PND18. Rats were sacrificed at weaning or on PND90, and plasma leptin, insulin, cholesterol, triglycerides and alanine aminotransferase (ALT) were assayed. Fat pads were collected and weighed and adipocyte size and number were estimated. Body weight and intake, as well as the estrous cycle of the female offspring were monitored.. During the suckling period, the pups' phenotype was almost completely determined by the strain of the mother. However, pups independently ingested food according to their genotype, regardless of their actual phenotype. At adulthood, cross fostered males of both strains and LETO females were affected in regard of their adiposity levels in the direction of the foster dam. On the other hand, OLETF females showed almost no alterations in adiposity but were affected by the strain of the dams in parameters related to the metabolic syndrome. Thus, OLETF females showed reduced liver adiposity and circulating levels of ALT, while LETO females presented a disrupted estrous cycle and increased cholesterol and triglycerides in the long term.. The present study provides further support for the early postnatal environment playing a sex-divergent role in programming later life phenotype. In addition, it plays a more central role in determining the functioning of mechanisms involved in energy balance that may provide protection from or sensitivity to later life obesity and pathologies related to the metabolic syndrome. Topics: Adipose Tissue; Alanine Transaminase; Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Animals, Suckling; Body Weight; Cholesterol; Energy Intake; Feeding Behavior; Female; Hyperphagia; Insulin; Lactation; Leptin; Male; Obesity; Pregnancy; Pregnancy Complications; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Time Factors; Triglycerides; Weaning | 2010 |
Fasting serum leptin level correlates with mid-arm fat area in peritoneal dialysis patients.
Leptin correlates with body fat content and plays a pivotal role in inflammatory response. This study aimed to investigate the relationships of fasting serum leptin levels and the anthropometric fat components among peritoneal dialysis (PD) patients. Fasting blood samples were obtained from 40 PD patients. Leptin levels were measured using a commercial enzyme-linked immunosorbent assay kit. Body weight (r=0.424; P=0.006), waist circumference (r=0.352; P=0.026), body mass index (BMI; r=0.483; P=0.002), body fat mass (r=0.352; P=0.026), high sensitivity C-reactive protein (hs-CRP; r=0.494; P=0.001), triceps skinfold thickness (TSF; r=0.505; P=0.001), mid-arm circumference (MAC; r=0.471; P=0.002), and mid-arm fat area (MAFA; r=0.564; P<0.001) were positively correlated, while high density lipoprotein (HDL)-cholesterol (r=-0.345; P=0.028) was negatively correlated with fasting serum leptin levels among the PD patients. Multivariate forward stepwise linear regression analysis showed that MAFA (R(2)=0.318, P=0.011) was the independent predictor of fasting serum leptin levels among the PD patients. In conclusion, fasting leptin level was positively associated with body fat composition (body weight, waist circumference, BMI, body fat mass, TSF, MAC, and MAFA) and hs-CRP among PD patients, and MAFA was the independent predictor of fasting serum leptin levels among the PD patients. Topics: Adult; Aged; Anthropometry; Arm; Body Fat Distribution; Body Weight; C-Reactive Protein; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Humans; Leptin; Linear Models; Male; Middle Aged; Multivariate Analysis; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Waist Circumference | 2010 |
Diet-induced obesity causes metabolic, endocrine and cardiac alterations in spontaneously hypertensive rats.
Although obesity has been associated with several effects in rodents, few investigations have evaluated the metabolic, endocrine, and cardiac parameters of spontaneously hypertensive rats (SHR) with dietary-induced obesity. The current study analyzed the influence of dietary-induced obesity on metabolic, endocrine, and cardiac characteristics in SHR.. Male SHR were distributed in 2 groups: C-SHR (n=10) and OB-SHR (n=10). While C-SHR received a standard commercial diet (CD; 3.2 kcal/g), OB-SHR were submitted to a hypercaloric diet (HD; 4.6 kcal/g) for 20 weeks. Nutritional, metabolic, and endocrine evaluation involved measurement of calorie intake, dietary efficiency, body weight, adiposity, glycemia, triacylglycerol, insulin, and leptin. Cardiovascular evaluation integrated systolic blood pressure (SBP), echocardiography, gross and ultrastructural morphology, and myosin heavy chain (MHC) analyses of the myocardium.. Animals in OB-SHR had greater values of BW, adiposity, triacylglycerol, and leptin and impaired glycemic tolerance compared with the C-SHR group. In the cardiovascular context, dietary-induced obesity increased interstitial collagen, the cardiomyocyte area, and the relative expression of beta-MHC, and well as beta-/alpha-isoform ratio of MHC. Likewise, OB-SHR showed ultrastructural morphologic alterations, with loss and disorganization of myofilaments, lipid droplets, severe mitochondrial damage, and T-tubule dilation. Concerning the in-vivo cardiovascular profile, although SBP and systolic function were unchanged by dietary-induced obesity, echocardiography results evidenced impaired diastolic function in OB-SHR in relation to their control counterparts.. Diet-induced obesity was associated with endocrine alterations, and it accentuated cardiac remodeling, promoting diastolic dysfunction of restrictive filling pattern in the SHR strain. Topics: Adiposity; Animals; Blood Pressure; Body Weight; Diet; Echocardiography; Energy Intake; Insulin; Leptin; Male; Myocardium; Myosin Heavy Chains; Nutritional Status; Obesity; Rats; Rats, Inbred SHR; Statistics, Nonparametric; Triglycerides | 2010 |
Glucosamine attenuates increases of intraabdominal fat, serum leptin levels, and insulin resistance induced by a high-fat diet in rats.
The levels of circulating nonesterified fatty acids increase during obesity and contribute to insulin resistance by inhibiting insulin-stimulated glucose transport and phosphorylation in human muscles. In cells, glucose-6-phosphate is primarily used in glycogenesis and glycolysis; only 1% to 3% is converted to glucosamine-6-phosphate, which enters the hexosamine-biosynthesis pathway. The major end product of this pathway, uridine-5'-diphosphate-N-acetyl-glucosamine, which is increased by exogenous glucosamine (GlcN) administration, mediates insulin resistance. We hypothesized that the administration of GlcN to rats receiving a high-fat (HF) diet may potentiate the effects of an HF diet on glucose tolerance and other metabolic variables. To evaluate this relationship, 2 groups of rats were fed with a control or HF diet; and another 2 groups received glucosamine hydrochloride at a dose of 500 mg/kg dissolved in drinking water for 21 weeks. Metabolic variables related to insulin resistance were then measured. The levels of blood glucose and serum insulin were higher in a glucose tolerance test in the HF group as compared with the control group. Rats receiving GlcN had reduced liver glycogen and only slightly worsened glucose tolerance as compared with control rats, although this did not induce insulin resistance as evaluated by the homeostasis model assessment. Glucosamine administration was able to partially or completely inhibit some effects of the HF diet by reducing fat depot weight and serum leptin levels, thus resulting in a smaller increase in the insulinemic response to a glucose injection and lower postabsorptive glycemia. Topics: Animals; Blood Glucose; Body Weight; Diet; Dietary Fats; Fatty Acids, Nonesterified; Glucosamine; Glucose Tolerance Test; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Male; Obesity; Rats; Rats, Wistar; Weight Loss | 2010 |
ENU mutagenesis identifies mice with morbid obesity and severe hyperinsulinemia caused by a novel mutation in leptin.
Obesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. Leptin is central to the regulation of energy metabolism and control of body weight in mammals.. To better recapitulate the complexity of human obesity syndrome, we applied N-ethyl-N-nitrosourea (ENU) mutagenesis in combination with a set of metabolic assays in screening mice for obesity. Mapping revealed linkage to the chromosome 6 within a region containing mouse Leptin gene. Sequencing on the candidate genes identified a novel T-to-A mutation in the third exon of Leptin gene, which translates to a V145E amino acid exchange in the leptin propeptide. Homozygous Leptin(145E/145E) mutant mice exhibited morbid obesity, accompanied by adipose hypertrophy, energy imbalance, and liver steatosis. This was further associated with severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyperleptinemia, characteristics of human obesity syndrome. Hypothalamic leptin actions in inhibition of orexigenic peptides NPY and AgRP and induction of SOCS1 and SOCS3 were attenuated in Leptin(145E/145E) mice. Administration of exogenous wild-type leptin attenuated hyperphagia and body weight increase in Leptin(145E/145E) mice. However, mutant V145E leptin coimmunoprecipitated with leptin receptor, suggesting that the V145E mutation does not affect the binding of leptin to its receptor. Molecular modeling predicted that the mutated residue would form hydrogen bond with the adjacent residues, potentially affecting the structure and formation of an active complex with leptin receptor within that region.. Thus, our evolutionary, structural, and in vivo metabolic information suggests the residue 145 as of special function significance. The mouse model harboring leptin V145E mutation will provide new information on the current understanding of leptin biology and novel mouse model for the study of human obesity syndrome. Topics: Animals; Body Weight; Ethylnitrosourea; Evolution, Molecular; Exons; Genetic Predisposition to Disease; Homozygote; Humans; Hyperinsulinism; Leptin; Mice; Mutagenesis; Mutation; Obesity, Morbid; Receptors, Leptin | 2010 |
Peripartal feeding strategy with different n-6: n-3 ratios in sows: effects on sows' performance, inflammatory and periparturient metabolic parameters.
The present study aimed to investigate the effects of two lactation sow feeds, differing in n-6:n-3 ratio, given to sows before parturition on body condition and feed intake, periparturient metabolism (leptin, insulin, triiodothyronine (T3) and thyroxine (T4)), inflammatory parameters (TNFalpha, IL-6, serum amyloid A (SAA)) and on piglet performance (birth weight, survivability). The feed contained either a low (supplemented with fish oil; f groups) or high (supplemented with sunflower-seed oil; s groups) n-6:n-3 ratio and was administered from 8 d (f8, s8) or 3 d (f3, s3) before parturition until weaning. The level of inclusion of the oil sources was 2 %. Seventy-two sows were randomly allocated 8 d before expected farrowing into four groups: f3, f8, s3, s8. Type of feed had a significant influence on the sows' feed intake during the first 2 d of lactation (s < f), leptin on days 4, 3 and 2 before parturition (f < s), insulin on day 1 after parturition (f < s), T4 on the day before parturition (s < f) and rectal temperature on the day after parturition (f < s). Onset of administration of the feed (3 v. 8 d) had significant effects on leptin on day 2 before parturition (8 < 3), insulin on day 4 before parturition (3 < 8), T3 on day 4 before parturition and on the day after parturition (3 < 8), SAA on day 3 after parturition (8 < 3) and piglet weight during the first days postpartum (3 < 8). In conclusion, under the present conditions, a lactation feed low in n-6:n-3 ratio administered from 8 d before farrowing ensures improved feed intake during the first days postpartum and was associated with a better metabolic change and inflammatory profile in sows in the periparturient period. Topics: Animal Feed; Animals; Animals, Newborn; Birth Weight; Body Weight; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Feeding Behavior; Female; Gestational Age; Insulin; Interleukin-6; Lactation; Leptin; Lipoproteins, VLDL; Pregnancy; Pregnancy, Animal; Random Allocation; Serum Amyloid A Protein; Swine; Triglycerides; Tumor Necrosis Factor-alpha | 2009 |
Metabolic effects of different protein intakes after short term undernutrition in artificially reared infant rats.
Early postnatal nutrition is involved in metabolic programming. Small for gestational age and premature babies commonly receive insufficient dietary protein during the neonatal period due to nutrition intolerance, whereas high protein formulas are used to achieve catch up growth. Neither the short term, nor the long term effects of such manipulation of protein intake are known.. We hypothesized that high or low protein intake during infancy would induce metabolic alterations both during early-life and in adulthood.. Gastrostomized neonatal rat pups received either 50% (P50%), 100% (P100%), or 130% (P130%) of the normal protein content in rat milk from the 7th to the 15th day of life (D7 to D15), when they were either sacrificed or placed with mothers for the long term study. Glucose tolerance tests (GTT) were performed at D230. Long term rats were sacrificed at D250.. At D15, weight of P50% pups was lower than P100% and P130% pups. Neither liver and kidney mass, nor islet beta-cell areas were altered. Brain weight (adjusted to body weight) was higher in P50% vs. P130% (p<0.05). Insulin/glucose ratio was lower in P50% vs. P130%. Expression of GLUT4 on adipocyte cell membrane and GLUT2 in liver cytosol was significantly enhanced in P50% vs. P130%. Long term, neither GTT results nor body nor organ weights differed between groups.. In neonatal rats, higher protein intakes via the enteral route led to enhanced short term weight gain, insulin resistance, and modified expression of glucose transporters. However, these differences were not sustained. Topics: Adiponectin; Animals; Animals, Newborn; Base Sequence; Blotting, Western; Body Weight; Dietary Proteins; DNA Primers; Enzyme-Linked Immunosorbent Assay; Female; Glucose Tolerance Test; Immunohistochemistry; Leptin; Malnutrition; Organ Size; Pregnancy; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction | 2009 |
Role of neonatal hyperleptinaemia on serum adiponectin and suppressor of cytokine signalling-3 expression in young rats.
Previously we had shown that neonatal leptin treatment programmes for both hyperleptinaemia and hyperinsulinaemia, which lead to leptin resistance and low expression of the hypothalamic leptin receptor (OB-Rb) of rats aged 150 d. Here we investigated in young post-weaned rats (age 30 d) if leptin treatment during lactation induces leptin and insulin resistance and if those changes are accompanied by changes in the suppressor of cytokine signalling-3 (SOCS-3) expression and serum adiponectin concentration. After delivery, the pups were divided into two groups: (1) a leptin group (Lep) that were injected with leptin daily (8 microg/100 g body weight subcutaneously) for the first 10 d of lactation; (2) a control (C) group, receiving saline. After weaning (day 21), body weight was monitored until the animals were age 30 d. They were tested for food intake in response to either leptin (0.5 mg/kg body weight intraperitoneally) (CL, LepL) or saline (CSal, LepSal) when they were aged 30 d. The CL group showed lower food intake, but no response was observed in the LepL group, suggesting leptin resistance. The Lep group had hyperleptinaemia (five-fold), hyperinsulinaemia (+42.5%) and lower levels of serum adiponectin (-43.2%). The hypothalamic expression of OB-Rb was lower (-22%) and SOCS-3 was higher (+52.8%) in the Lep group. We conclude that neonatal leptin treatment programmes for leptin resistance as soon as 30 d and suggests that SOCS-3 appears to be of particular importance in this event. In the Lep group, the lower serum adiponectin levels were accompanied by higher serum insulin, indicating a probable insulin resistance. Topics: Adiponectin; Animals; Animals, Newborn; Blood Glucose; Blotting, Western; Body Composition; Body Weight; Drug Resistance; Eating; Female; Insulin; Insulin Resistance; Leptin; Male; Rats; Rats, Wistar; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins | 2009 |
Comparison of the antiobesity effects of the protopanaxadiol- and protopanaxatriol-type saponins of red ginseng.
A previous study demonstrated that ginseng crude saponins prevent obesity induced by a high-fat diet in rats. Ginseng crude saponins are known to contain a variety of bioactive saponins. The present study investigated and compared the antiobesity activity of protopanaxadiol (PD) and protopanaxatriol (PT) type saponins, major active compounds isolated from crude saponins. Male 4-week-old Sprague-Dawley rats were fed with normal diet (N) or high-fat diet (HF). After 5 weeks, the HF diet group was subdivided into the control HF diet, HF diet-PD and HF diet-PT group (50 mg/kg/day, 3 weeks, i.p.). Treatment with PD and PT in the HF diet group reduced the body weight, total food intake, fat contents, serum total cholesterol and leptin to levels equal to or below the N diet group. The hypothalamic expression of orexigenic neuropeptide Y was significantly decreased with PD or PT treatment, whereas that of anorexigenic cholecystokinin was increased, compared with the control HF diet group. In addition, PD type saponins had more potent antiobesity properties than PT saponins, indicating that PD-type saponins are the major components contributing to the antiobesity activities of ginseng crude saponins. The results suggest that the antiobesity activity of PD and PT type saponins may result from inhibiting energy gain, normalizing hypothalamic neuropeptides and serum biochemicals related to the control of obesity. Topics: Animals; Anti-Obesity Agents; Body Weight; Cholecystokinin; Cholesterol; Eating; Hypothalamus; Leptin; Male; Neuropeptide Y; Obesity; Panax; Rats; Rats, Sprague-Dawley; Sapogenins; Triglycerides | 2009 |
Sex-associated differences in the leptin and ghrelin systems related with the induction of hyperphagia under high-fat diet exposure in rats.
Leptin and ghrelin are known to be main hormones involved in the control of food intake, with opposing effects. Here we have explored whether changes in the leptin and ghrelin system are involved in the long-term effects of high-fat (HF) diet feeding in rats and whether sex-associated differences exist. Male and female Wistar rats were fed until the age of 6 months with a normal-fat (NF) or an HF-diet. Food intake and body weight were followed. Gastric and serum levels of leptin and ghrelin, and mRNA levels of leptin (in stomach and adipose tissue), ghrelin (in stomach), and NPY, POMC, and leptin and ghrelin receptors (OB-Rb and GHS-R) (in the hypothalamus) were measured. In both males and females, total caloric intake and body weight were greater under the HF-diet feeding. In females, circulating ghrelin levels and leptin mRNA expression in the stomach were higher under HF-diet. HF-diet feeding also resulted in higher hypothalamic NPY/POMC mRNA levels, more marked in females, and in lower OB-Rb mRNA levels, more marked in males. In addition, in females, serum ghrelin levels correlated positively with hypothalamic NPY mRNA levels, and these with caloric intake. In males, hypothalamic OB-Rb mRNA levels correlated positively with POMC mRNA levels and these correlated negatively with caloric intake and with body weight. These data reflect differences between sexes in the effects of HF-diet feeding on food intake control systems, suggesting an impairment of the anorexigenic leptin-POMC system in males and an over-stimulation of the orexigenic ghrelin-NPY system in females. Topics: Adipose Tissue; Animals; Body Weight; Diet; Dietary Fats; Feeding Behavior; Female; Gastric Mucosa; Ghrelin; Hyperphagia; Hypothalamus; Leptin; Male; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Wistar; Receptors, Ghrelin; Receptors, Leptin; RNA, Messenger; Sex Characteristics | 2009 |
Central leptin regulates total ceramide content and sterol regulatory element binding protein-1C proteolytic maturation in rat white adipose tissue.
Obesity and type 2 diabetes are associated with insulin and leptin resistance, and increased ceramide contents in target tissues. Because the adipose tissue has become a central focus in these diseases, and leptin-induced increases in insulin sensitivity may be related to effects of leptin on lipid metabolism, we investigated herein whether central leptin was able to regulate total ceramide levels and the expression of enzymes involved in ceramide metabolism in rat white adipose tissue (WAT). After 7 d central leptin treatment, the total content of ceramides was analyzed by quantitative shotgun lipidomics mass spectrometry. The effects of leptin on the expression of several enzymes of the sphingolipid metabolism, sterol regulatory element binding protein (SREBP)-1c, and insulin-induced gene 1 (INSIG-1) in this tissue were studied. Total ceramide levels were also determined after surgical WAT denervation. Central leptin infusion significantly decreased both total ceramide content and the long-chain fatty acid ceramide species in WAT. Concomitant with these results, leptin decreased the mRNA levels of enzymes involved in de novo ceramide synthesis (SPT-1, LASS2, LASS4) and ceramide production from sphingomyelin (SMPD-1/2). The mRNA levels of enzymes of ceramide degradation (Asah1/2) and utilization (sphingomyelin synthase, ceramide kinase, glycosyl-ceramide synthase, GM3 synthase) were also down-regulated. Ceramide-lowering effects of central leptin were prevented by local autonomic nervous system denervation of WAT. Finally, central leptin treatment markedly increased INSIG-1 mRNA expression and impaired SREBP-1c activation in epididymal WAT. These observations indicate that in vivo central leptin, acting through the autonomic nervous system, regulates total ceramide levels and SREBP-1c proteolytic maturation in WAT, probably contributing to improve the overall insulin sensitivity. Topics: Adipose Tissue; Animals; Body Weight; Ceramides; Cholesterol Esters; Energy Intake; Injections, Intraventricular; Leptin; Lipids; Male; Phosphorylation; Rats; Rats, Wistar; STAT3 Transcription Factor; Sterol Regulatory Element Binding Protein 1 | 2009 |
Leptin concentration indexed to fat mass is increased in untreated anorexia nervosa (AN) patients.
Data regarding serum adipocytokine and ghrelin concentrations in different stages of anorexia nervosa (AN) is conflicting.. Our aim is to determine serum concentrations of adiponectin (ApN), leptin and ghrelin in different stages of AN and to evaluate their relationships with study parameters.. Study group was composed of four subgroups: Group 1: patients with a recent diagnosis of AN (n = 19); group 2: weight recovered (10% increase in body weight compared with baseline) subgroup of group 1 during follow-up (n = 10); group 3: recovered patients with a previous history of AN but normal menstrual cycles and body weight currently (n = 10); group 4: control group (n = 10). Venous blood was obtained for measurements of biochemical/hormonal parameters, ApN, leptin and ghrelin. Body composition was determined by bioimpedance analysis.. Changes in adipocytokine and ghrelin concentrations and relationships with anthropometric/biochemical parameters.. Leptin: fat mass (kg) ratio was significantly higher in group 1 patients compared with group 4 (4.3 +/- 4.6 vs. 1.1 +/- 0.5 microg/l kg, P < 0.01). No significant difference was observed among ghrelin concentrations. Leptin showed significant positive correlation with body fat mass in all groups. ApN showed significant positive association with body mass index in Group 1.. Leptin concentrations indexed to fat mass may indicate a nonphysiological higher set point of leptin per unit fat mass in treatment-naive AN patients. Correlation pattern between ApN and fat mass is modified also. Altered adipocytokine profile in AN may contribute to anorectic behaviour. Topics: Adiponectin; Adipose Tissue; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Female; Ghrelin; Humans; Leptin; Male; Young Adult | 2009 |
Antiobesity effects of wild ginseng (Panax ginseng C.A. Meyer) mediated by PPAR-gamma, GLUT4 and LPL in ob/ob mice.
The antiobesity effect of wild ginseng (WG; Panax ginseng C.A. Meyer) in male obese leptin-deficient (B6.V-Lepob, 'ob/ob') mice was evaluated. WG was administered orally to mice at doses of 100 mg/kg and 200 mg/kg daily for 4 weeks. The WG-treated ob/ob mice showed a loss of body weight and a decrease in blood glucose levels compared with control mice. WG regulated the mRNA expression level especially, it increased peroxisome proliferators-activated receptors-gamma (PPAR-gamma) and lipoprotein lipase (LPL) in adipose tissue, as well as glucose transporter 4 (GLUT4) and insulin receptor (IR) in the skeletal muscle and liver. Taken together, these results suggest that WG may play a vital role in the antiobesity effect in ob/ob mice; this has importance in insulin sensitivity. This may prove to be of clinical importance in improving the management of obesity and related metabolic syndromes. Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Glucose Transporter Type 4; Leptin; Lipoprotein Lipase; Liver; Male; Mice; Muscle, Skeletal; Obesity; Panax; PPAR gamma; Receptor, Insulin | 2009 |
A functional leptin system is essential for sodium tungstate antiobesity action.
Sodium tungstate is a novel agent in the treatment of obesity. In diet-induced obese rats, it is able to reduce body weight gain by increasing energy expenditure. This study evaluated the role of leptin, a key regulator of energy homeostasis, in the tungstate antiobesity effect. Leptin receptor-deficient Zucker fa/fa rats and leptin-deficient ob/ob mice were treated with tungstate. In lean animals, tungstate administration reduced body weight gain and food intake and increased energy expenditure. However, in animals with deficiencies in the leptin system, treatment did not modify these parameters. In ob/ob mice in which leptin deficiency was restored through adipose tissue transplantation, treatment restored the tungstate-induced body weight gain and food intake reduction as well as energy expenditure increase. Furthermore, in animals in which tungstate administration increased energy expenditure, changes in the expression of key genes involved in brown adipose tissue thermogenesis were detected. Finally, the gene expression of the hypothalamic neuropeptides, Npy, Agrp, and Cart, involved in the leptin regulation of energy homeostasis, was also modified by tungstate in a leptin-dependent manner. In summary, the results indicate that the effectiveness of tungstate in reducing body weight gain is completely dependent on a functional leptin system. Topics: Adipose Tissue; Adipose Tissue, Brown; Adiposity; Animals; Anti-Obesity Agents; Body Weight; Energy Metabolism; Gene Expression Profiling; Leptin; Male; Mice; Mice, Obese; Neuropeptides; Obesity; Rats; Rats, Zucker; Thinness; Tungsten Compounds | 2009 |
Critical interplay between neuropeptide Y and sex steroid pathways in bone and adipose tissue homeostasis.
Important and novel roles for neuropeptide Y (NPY) signaling in the control of bone homeostasis have recently been identified, with deletion of either the Y1 or Y2 receptors resulting in a generalized increase in bone formation. Whereas the Y2 receptor-mediated anabolic response is mediated by a hypothalamic relay, the Y1-mediated response is likely mediated by osteoblastic Y1 receptors. The presence of Y1 receptors on osteoblasts and various other peripheral tissues suggests that, in addition to neuronal input, circulating factors may also interact with the Y1-mediated pathways. The skeletal and adipose tissue (peripheral and marrow) responses to Y1 receptor deficiency were examined after (1) leptin deficiency, (2) gonadectomy, and (3) hypothalamic NPY overexpression. Bone formation was consistently increased in intact Y1(-/-) mice. However, the hypogonadism of gonadectomy or leptin deficiency blocked this anabolism in male Y1(-/-) mice, whereas females remained unchanged. The Y1-mediated bone anabolic pathway thus seems to be dependent on the presence of intact androgen signaling. Y1 deficiency also led to increased body weight and/or adiposity in all experimental models, with the exception of male ob/ob, showing a general adipogenic effect of Y1 deficiency that is not dependent on androgens. Interestingly, marrow adipocytes were regulated differently than general adipose depots in these models. Taken together, this interaction represents a novel mechanism for the integration of endocrine and neural signals initiated in the hypothalamus and provides further insight into the coordination of bone and energy homeostasis. Topics: Adipose Tissue; Adiposity; Animals; Blood Glucose; Body Weight; Bone and Bones; Bone Resorption; Female; Gene Deletion; Gonadal Steroid Hormones; Homeostasis; Leptin; Male; Mice; Neuropeptide Y; Obesity; Osteogenesis; Receptors, Neuropeptide Y; Signal Transduction; Thinness; Weight Gain | 2009 |
Genetic relationships of body composition, serum leptin, and age at puberty in gilts.
Leptin produced by adipocytes acts through leptin receptors in the hypothalamus to control appetite and food intake and thus communicates information about degree of fatness. It is thought that a degree of body fat is required for initiation of puberty and maintenance of reproductive function in mammals. The objective of this study was to determine whether polymorphisms in the leptin (LEP), leptin receptor (LEPR), paired box 5 (PAX5), aldo-keto reductase (AKR), and pro-opiomelanocortin (POMC) genes were associated with age, leptin concentration, backfat as an indicator of body condition, or BW at puberty in 3 lines of gilts and to characterize genetic relationships among these traits. The first 2 lines, born in 2001, were formed by crossing maternal White Cross (Yorkshire x Maternal Landrace) gilts to Duroc (n = 210) or (lean) Landrace (n = 207) boars. The remaining line (n = 507), born in 2002, was formed by crossing progeny of the Duroc- and Landrace-sired lines. At first estrus, age, BW (BWP), and backfat (BFP) at puberty were recorded and blood was collected for leptin assays. Nine SNP were detected in candidate genes/regions: 1 in LEP, 3 in LEPR, 1 in PAX5, 2 in AKR, and 2 in POMC. Animals were genotyped for each of the SNP; genotypes were validated using GenoProb. The association model included fixed effects of farrowing group, covariates of SNP genotypic probabilities (from GenoProb), and random additive polygenic effects to account for genetic similarities between animals not explained by SNP. Variance components for polygenic effects and error were estimated using MTDFREML. Leptin concentrations were logarithmically transformed for data analysis. All 4 traits were moderately to highly heritable (0.38 to 0.48). Age and leptin at puberty had a significant (P < 0.01) genetic correlation at -0.63 +/- 0.097, and the genetic correlation between BWP and age at puberty was 0.65 +/- 0.083 (P < 0.01). Significant additive associations (a; P < 0.05) were detected at PAX5 for age at puberty (a = 3.2 d) and for BFP (a = 0.61 mm). One SNP in LEPR was associated with leptin concentration (a = 0.31 log units; P < 0.05). The associations from PAX5 correspond to a QTL peak for age at puberty detected on SSC1. Although not necessarily the causative mutation, this result implies that a QTL that can decrease age at puberty without increasing BFP and BWP at puberty may exist in this region in commercial pigs. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Female; Leptin; Polymorphism, Single Nucleotide; Sexual Maturation; Swine | 2009 |
ICV vs. VMH injection of leptin: comparative effects on hypothalamic gene expression.
Leptin regulates feeding behavior and body weight by binding to its receptors localized in specific areas of the hypothalamus. Leptin injected twice daily for 4 days either into the right ventromedial hypothalamus (VMH) or into the right lateral cerebral ventricle (ICV) and using Real-Time Taqman RT-PCR, mRNA expression levels of selected genes in the arcuate nucleus-median eminence (ARC-ME) complex were quantitatively measured. Expression of selected genes from the ipsi- vs. contralateral VMH areas in rats injected with leptin into the VMH was also compared. VMH injections of leptin increased ARC-ME mRNAs of proopiomelanocortin (POMC), 27.3% (p<0.05); gamma-aminobutyric acid A receptor (GABRD), 89.3% (p<0.01); and thyrotropin-releasing hormone (TRH), 57.7% (p<0.01); and decreased janus kinase 2 (JAK2), 44.4% (p<0.001); suppressor of cytokine signaling 3 (SOCS3), 86.6% (p<0.001); signal transducer and activator of transcription 3 (STAT3), 46.8% (p<0.01); tyrosine hydroxylase (TH), 51.1% (p<0.001); prostaglandin E synthase (PTGES), 96.5% (p<0.001); tumor necrosis factor-alpha (TNF-alpha), 47% (p<0.01); and secretin, 55.4% (p<0.001). Only GABRD, 76.6% (p<0.01) and SCT, 64.9% (p<0.01) were up-regulated in the hypothalamic ARC-ME of rats with ICV leptin injections. VMH injections of leptin induced identical reductions in expression levels of CART, SOCS3, PTGES, and TNF-alpha in both VMH areas; except TH mRNA, whose expression was lowered ipsilaterally. Food intake, body and fat pad weights and serum insulin and leptin were also decreased in rats given leptin through VMH. This study suggests that leptin either unilateral exposure through VMH or bilateral exposure through ICV injections induces divergent ARC-ME gene profiles. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Cachexia; Eating; Gene Expression; Hypothalamus; Inflammation; Injections; Injections, Intraventricular; Leptin; Male; Median Eminence; Organ Size; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Ventromedial Hypothalamic Nucleus | 2009 |
Leptin treatment prevents type I diabetic marrow adiposity but not bone loss in mice.
Leptin is a hormone secreted by adipocytes that is implicated in the regulation of bone density. Serum leptin levels are decreased in rodent models of type 1 (T1-) diabetes and in diabetic patients. Whether leptin mediates diabetic bone changes is unclear. Therefore, we treated control and T1-diabetic mice with chronic (28 days) subcutaneous infusion of leptin or saline to elucidate the therapeutic potential of leptin for diabetic osteoporosis. Leptin prevented the increase of marrow adipocytes and the increased aP2 expression that we observed in vehicle-treated diabetic mice. However, leptin did not prevent T1-diabetic decreases in trabecular bone volume fraction or bone mineral density in tibia or vertebrae. Consistent with this finding, markers of bone formation (osteocalcin RNA and serum levels) in diabetic mice were not restored to normal levels with leptin treatment. Interestingly, markers of bone resorption (TRAP5 RNA and serum levels) were decreased in diabetic mice by leptin treatment. In summary, we have demonstrated a link between low leptin levels in T1-diabetes and marrow adiposity. However, leptin treatment alone was not successful in preventing bone loss. Topics: Adiposity; Animals; Blood Glucose; Body Weight; Bone Marrow; Bone Resorption; Diabetes Mellitus, Type 1; Feeding Behavior; Hyperphagia; Insulin; Leptin; Mice; Mice, Inbred BALB C | 2009 |
Intragastric administration of evodiamine suppresses NPY and AgRP gene expression in the hypothalamus and decreases food intake in rats.
Evodiamine (Evo), an alkaloidal component extracted from the fruit of Evodiae fructus (Evodia rutaecarpa Bentham, Rutaceae), decreases the body weight of rats through a poorly defined mechanism. The hypothalamus is one of the areas in the brain linked to the control of food intake and energy expenditure. We postulate that Evo mediates this activity by modulating feeding-related peptides in the hypothalamus. We investigated the effects of Evo on food intake, body weight, the mRNA expression and peptide level of feeding-related peptides in the hypothalamus, in male rats. The juvenile rats of 5 weeks old were used at the start of the experiment. Evo (40 mg/kg or 4 mg/kg) was administered intragastrically for 25 days, and food intake and body weight of rats were recorded daily. Blood samples were collected for leptin radioimmunoassay (RIA). Real-Time PCR was used to analyze the mRNA expression. Western Blotting and immunohistochemistry were used to analyze the peptide. Our results show that intragastric administration of Evo (40 mg/kg) decreased rate of food intake and body weight increase following rat growth, reduced orexigenic neuropeptide Y (NPY) and agouti-gene related protein (AgRP) mRNA levels and NPY peptide level in the arcuate nucleus (ARC) of the hypothalamus, but it increases the circulating level of leptin. Intragastric administration of a smaller dose of Evo (4 mg/kg) was ineffective. These data suggest that Evo decreases food intake, and therefore body weight, partly by down-regulating NPY and AgRP mRNA expression and peptide expression in the ARC of the hypothalamus. Topics: Agouti-Related Protein; Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Body Weight; Dose-Response Relationship, Drug; Down-Regulation; Feeding Behavior; Gene Expression Regulation; Hypothalamus; Leptin; Male; Neuropeptide Y; Plant Extracts; Quinazolines; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2009 |
Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse.
Exercise is a mechanism for maintenance of body weight in humans. Morbidly obese human patients have been shown to possess single nucleotide polymorphisms in the melanocortin-4 receptor (MC4R). MC4R knockout mice have been well characterized as a genetic model that possesses phenotypic metabolic disorders, including obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia, similar to those observed in humans possessing dysfunctional hMC4Rs. Using this model, we examined the effect of voluntary exercise of MC4R knockout mice that were allowed access to a running wheel for a duration of 8 wk. Physiological parameters that were measured included body weight, body composition of fat and lean mass, food consumption, body length, and blood levels of cholesterol and nonfasted glucose, insulin, and leptin. At the termination of the experiment, hypothalamic mRNA expression levels of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), orexin, brain-derived neurotropic factor (BDNF), phosphatase with tensin homology (Pten), melanocortin-3 receptor (MC3R), and NPY-Y1R were determined. In addition, islet cell distribution and function in the pancreas were examined. In the exercising MC4R knockout mice, the pancreatic islet cell morphology and other physiological parameters resembled those observed in the wild-type littermate controls. Gene expression profiles identified exercise as having a significant effect on hypothalamic POMC, orexin, and MC3R levels. Genotype had a significant effect on AGRP, POMC, CART, and NPY-Y1R, with an exercise and genotype interaction effect on NPY gene expression. These data support the hypothesis that voluntary exercise can prevent the genetic predisposition of melanocortin-4 receptor-associated obesity and diabetes. Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Type 2; Gene Expression Regulation; Insulin; Leptin; Liver; Magnetic Resonance Imaging; Mice; Mice, Knockout; Obesity; Organ Size; Pancreas; Phenotype; Physical Conditioning, Animal; Receptor, Melanocortin, Type 4; RNA, Messenger; Signal Transduction | 2009 |
Effect of high-fat diet during gestation, lactation, or postweaning on physiological and behavioral indexes in borderline hypertensive rats.
Maternal obesity is becoming more prevalent. We used borderline hypertensive rats (BHR) to investigate whether a high-fat diet at different stages of development has adverse programming consequences on metabolic parameters and blood pressure. Wistar dams were fed a high- or low-fat diet for 6 wk before mating with spontaneously hypertensive males and during the ensuing pregnancy. At birth, litters were fostered to a dam from the same diet group as during gestation or to the alternate diet condition. Female offspring were weaned on either control or "junk food" diets until about 6 mo of age. Rats fed the high-fat junk food diet were hyperphagic relative to their chow-fed controls. The junk food-fed rats were significantly heavier and had greater fat pad mass than those rats maintained on chow alone. Importantly, those rats suckled by high-fat dams had heavier fat pads than those suckled by control diet dams. Fasting serum leptin and insulin levels differed as a function of the gestational, lactational, and postweaning diet histories. Rats gestated in, or suckled by high-fat dams, or maintained on the junk food diet were hyperleptinemic compared with their respective controls. Indirect blood pressure did not differ as a function of postweaning diet, but rats gestated in the high-fat dams had lower mean arterial blood pressures than those gestated in the control diet dams. The postweaning dietary history affected food-motivated behavior; junk food-fed rats earned less food pellets on fixed (FR) and progressive (PR) ratio cost schedules than chow-fed controls. In conclusion, the effects of maternal high-fat diet during gestation or lactation were mostly small and transient. The postweaning effects of junk food diet were evident on the majority of the parameters measured, including body weight, fat pad mass, serum leptin and insulin levels, and operant performance. Topics: Adiposity; Age Factors; Aging; Animal Nutritional Physiological Phenomena; Animals; Behavior, Animal; Blood Pressure; Body Weight; Conditioning, Operant; Dietary Fats; Disease Models, Animal; Feeding Behavior; Female; Hybridization, Genetic; Hyperphagia; Hypertension; Insulin; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Metabolic Syndrome; Motivation; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred SHR; Rats, Wistar; Reward; Weaning | 2009 |
Mechanism-based modeling of nutritional and leptin influences on growth in normal and type 2 diabetic rats.
Influences of genetic and nutritional factors on body weight, fat mass, and leptin production and effects of leptin were assessed in normal [Wistar-Kyoto (WKY)] and diabetic [Goto-Kakizaki (GK)] rats by mechanism-based modeling. The study included 60 WKY and 60 GK rats; half received high-fat diet (HF), and the others received normal rat chow (N). Body weights and food consumption were measured twice weekly. Six rats per group were sacrificed at 4, 8, 12, 16, and 20 weeks. Abdominal fat was weighed, and plasma leptin was measured by enzyme-linked immunosorbent assay. All data were comodeled using NONMEM version VI level 1.1 (first-order conditional estimation with interaction) (Beal SL, Boeckmann AJ, Sheiner LB, and NONMEM Project Group, NONMEM Users Guides, University of California, San Francisco, CA, 2007). Weight gain was modeled as differences between energy intake and metabolic rate based on allometrically scaled lean body mass (LBM). The GK had higher metabolic rates (1.15 kcal/day/g LBM(0.75)) than WKY-N (0.92) and WKY-HF (1.02) rats and higher efficiency in transforming energy into body weight. Leptin effect was modeled as inhibition of food consumption. Total body fat was estimated from abdominal fat. Leptin production from fat was 4.7-fold higher for GK (3.03 ng/ml/day/g) than WKY (0.66 ng/ml/day/g). Leptin production rate from LBM was 0.53 ng/ml/day/g for all groups. The IC(50) for inhibition of food intake by leptin was approximately 3-fold higher in GK versus WKY, indicating leptin resistance for the effect on food consumption in GK. The GK had similar intake of kilocalories but lower body weights and fat mass than WKY, possibly because of higher metabolic rates. Our mechanism-based model explains intrinsic reasons for differences in growth, food intake, and leptin concentrations among these two strains of rats. Topics: Animals; Biological Phenomena; Body Weight; Diabetes Mellitus; Disease Models, Animal; Eating; Growth; Leptin; Male; Obesity; Rats; Rats, Inbred WKY | 2009 |
Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors.
We previously reported that the plasma levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), in a cohort of viscerally obese men are directly correlated with visceral adipose tissue (VAT) accumulation and metabolic risk factors including low HDL-cholesterol and high triacylglycerol. It is not known, however, if such correlations persist after vigorous lifestyle interventions that reduce metabolic risk factors. We analysed the changes in endocannabinoid levels in a subsample from the same cohort following a 1 year lifestyle modification programme, and correlated them with changes in VAT and metabolic risk factors.. Forty-nine viscerally obese men (average age 49 years, BMI 30.9 kg/m(2), waist 107.3 cm) underwent a 1 year lifestyle modification programme including healthy eating and physical activity. Plasma levels of 2-AG and the other most studied endocannabinoid, anandamide, were measured by liquid chromatography-mass spectrometry. Anthropometric and metabolic risk factors, including VAT, insulin resistance and glucose intolerance, HDL-cholesterol and triacylglycerol, were measured.. Most risk factors were improved by the intervention, which led to a significant decrease in body weight (-6.4 kg, p < 0.0001), waist circumference (-8.0 cm, p < 0.0001) and VAT (-30%, p < 0.0001), and in plasma 2-AG (-62.3%, p < 0.0001) and anandamide (-7.1%, p = 0.005) levels. The decrease in levels of 2-AG but not those of anandamide correlated with decreases in VAT and triacylglycerol levels, and with the increase in HDL(3)-cholesterol levels. Multivariate analyses suggested that decreases in 2-AG and VAT were both independently associated with decreases in triacylglycerol.. This study shows that a strong correlation exists between 2-AG levels and high plasma triacylglycerol and low HDL(3)-cholesterol in viscerally obese men. Topics: Adiponectin; Adipose Tissue; Apolipoproteins; Arachidonic Acids; Body Mass Index; Body Weight; C-Reactive Protein; Endocannabinoids; Glycerides; Humans; Interleukin-6; Leptin; Life Style; Lipids; Male; Obesity; Risk Factors; Triglycerides; Waist Circumference; Weight Loss | 2009 |
Influence of visceral adiposity on ghrelin secretion and expression in rats during fasting.
Although circulating ghrelin levels correlate inversely with adiposity at baseline, little is known about the effect of percent visceral adipose tissue value (PVATV) on ghrelin expression and secretion in response to fasting. Our study demonstrated that ghrelin increased with 24-h fasting in rats with the lowest PVATV (less than 6%), after 3 days in rats with intermediate PVATV (6-9%) and 5 days in rats with the highest PVATV (greater than 9%). Ghrelin mRNA in the stomach was increased after 3 days in low-PVATV (5.8+/-0.9%) rats but not in high-PVATV (14+/-1.6%) rats. Therefore, both ghrelin secretion and mRNA were delayed in response to fasting in rats with increased visceral fat. In rats matched for PVATV, but with different body weights, the fasting induced similar levels of increased ghrelin while in rats with different PVATV ghrelin secretion was different in response to fasting, even when body weights were matched in two groups. These data suggested that the initial PVATV, not lean mass, was related to the pattern of plasma ghrelin in response to fasting in rats. Topics: Adiposity; Animals; Body Composition; Body Weight; Dietary Fats; Fasting; Ghrelin; Humans; Intra-Abdominal Fat; Leptin; Male; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stomach | 2009 |
Dopamine antagonism inhibits anorectic behavior in an animal model for anorexia nervosa.
Excessive physical activity is commonly described as symptom of Anorexia Nervosa (AN). Activity-based anorexia (ABA) is considered an animal model for AN. The ABA model mimics severe body weight loss and increased physical activity. Suppression of hyperactivity by olanzapine in anorectic patients as well as in ABA rats suggested a role of dopamine and/or serotonin in this trait. Here, we investigated the effect of a non-selective dopamine antagonist in the ABA model. A dose-response curve of chronic treatment with the non-selective dopaminergic antagonist cis-flupenthixol was determined in the ABA model. Treatment reduced activity levels in both ad libitum fed and food-restricted rats. Treated ABA rats reduced body weight loss and increased food intake. These data support a role for dopamine in anorexia associated hyperactivity. Interestingly, in contrast to leptin treatment, food-anticipatory activity still persists in treated ABA rats. Topics: Adipose Tissue; Analysis of Variance; Animals; Anorexia Nervosa; Behavior, Animal; Body Composition; Body Temperature; Body Weight; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Delivery Systems; Eating; Female; Flupenthixol; Food Deprivation; Insulin; Leptin; Motor Activity; Radioimmunoassay; Rats; Rats, Wistar | 2009 |
Effects of treadmill exercise on cell proliferation and differentiation in the subgranular zone of the dentate gyrus in a rat model of type II diabetes.
In the present study, we investigated the effects of a treadmill exercise on serum glucose levels and Ki67 and doublecortin (DCX) immunoreactivity, which is a marker of cell proliferation expressed during cell cycles except G0 and early G1 and a marker of progenitors differentiating into neurons, respectively, in the subgranular zone of the dentate gyrus (SZDG) using a type II diabetic model. At 6 weeks of age, Zucker lean control (ZLC) and Zucker diabetic fatty (ZDF) rats were put on a treadmill with or without running for 1 h/day/5 consecutive days at 22 m/min for 5 weeks. Body weight was significantly increased in the control (without running)-ZDF rats compared to that in the other groups. In the control groups blood glucose levels were increased by 392.7 mg/dl in the control-ZDF rats and by 143.3 mg/dl in the control-ZLC rats. However, in the exercise groups, blood glucose levels were similar between the exercise-ZLC and ZDF rats: The blood glucose levels were 110.0 and 118.2 mg/dl, respectively. Ki67 positive nuclei were detected in the SZDG in control and exercise groups. The number of Ki67 positive nuclei was significantly high in exercise groups compared to that in the control groups. In addition, Ki67 positive cells were abundant in ZLC groups compared to those in ZDF groups. DCX-immunoreactive structures in the control-ZDF rats were lower than that in the control-ZLC rats. In the exercise groups, DCX-immunoreactive structures (somata and processes with tertiary dendrites) and DCX protein levels were markedly increased in both the exercise-ZLC and ZDF rats compared to that in the control groups. These results suggest that a treadmill exercise reduces blood glucose levels in ZDF rats and increases cell proliferation and differentiation in the SZDG in ZLC and ZDF rats compared to those in control groups. Topics: Animals; Biomarkers; Blood Glucose; Body Weight; Cell Differentiation; Cell Division; Cell Proliferation; Dentate Gyrus; Diabetes Mellitus, Type 2; Doublecortin Domain Proteins; Doublecortin Protein; Eating; Exercise Test; Female; Interphase; Ki-67 Antigen; Leptin; Male; Microtubule-Associated Proteins; Neurogenesis; Neurons; Neuropeptides; Physical Conditioning, Animal; Rats; Rats, Zucker; Stem Cells | 2009 |
Effects of short-term corticoid ingestion on food intake and adipokines in healthy recreationally trained men.
In order to test the hypothesis that short-term corticoid intake alters food intake, body composition and adipokines secretion in healthy volunteers with regular sport practice, nutrient intake was assessed in eight male athletes with and without prednisolone (PRED, 60 mg/day for 1 week) ingestion in a random, double blind, crossover design. Body weight, body composition, adipokines (i.e., leptin, adiponectin and TNF-alpha), insulin and blood glucose were determined before and at the end of each treatment. PRED did not induce any significant change in body weight, body composition or food intake. Insulin and TNF-alpha were not significantly altered with PRED compared to placebo but blood glucose, leptin and adiponectin concentrations at rest appear significantly increased after PRED treatment (P < 0.05). Our data show that 1 week glucocorticoid treatment does not promote obesity in recreationally trained men but further studies are necessary to understand its effects on the metabolically active hormones, leptin and adiponectin. Topics: Adiponectin; Blood Glucose; Body Composition; Body Weight; Cross-Over Studies; Double-Blind Method; Eating; Humans; Insulin; Leptin; Male; Prednisolone; Random Allocation; Tumor Necrosis Factor-alpha; Young Adult | 2009 |
Anthropometric and leptin changes in women following different dietary approaches to weight loss.
Leptin may favorably respond to fat mass (FM) losses induced by a low-carbohydrate (LC) diet, although this is unclear. We examined serum leptin concentrations in women in midlife undergoing different dietary approaches to body weight (BW) loss. Women followed either a LC, high-protein (LCHP; n = 13) or high-carbohydrate, low-fat (HCLF; n = 12) diet for 12 weeks. Changes in anthropometric and soft-tissue mass measurements and leptin concentrations were assessed. Women in both diet groups had reductions in BW, BMI, fat-free soft-tissue mass, FM, body fat percentage, and central abdominal fat (CAF) (P < 0.001 for all variables) over the 12-week intervention. These changes were not significantly different between diet groups. Serum leptin concentrations decreased by 41.8% (P < 0.001) in the LCHP group and by 44.3% (P < 0.001) in the HCLF group from baseline to week 12, with no significant difference between groups. The association of CAF (r = 0.73) and FM (r = 0.83) change with leptin change was strong in the HCLF group. Leptin change did not relate to change in any variable in the LCHP group. Both LCHP and HCLF diets favorably lower FM, CAF, and leptin in women, suggesting that beneficial changes in leptin can be similarly achieved through different dietary approaches to BW loss. Topics: Abdomen; Adipose Tissue; Adult; Body Mass Index; Body Weight; Diet, Reducing; Female; Humans; Leptin; Weight Loss | 2009 |
Placental insufficiency: programming of leptin secretion, blood pressure, and postnatal growth in two generations of Sprague-Dawley rats.
Regulatory process may be altered in response to the intrauterine environment, leading to the development of altered growth trajectory and disease later in life. Previously, our lab reported reduced leptin levels in pregnant hypertensive Sprague-Dawley rat dams with placental insufficiency. The purposes of this study were to investigate the relationship between leptin levels, growth and hypertension in two generations of offspring exposed to placental insufficiency. Leptin levels were significantly different only at 12 weeks in female first generation offspring (p < 0.05). Variations in postnatal body and organ weights were evident in first generation females at 3 and 12 weeks of age. There were no significant correlations with plasma leptin levels and systolic blood pressure in offspring groups at any age point. Our findings indicate that fetal exposure to maternal hypertension and hypoleptinemia is associated with altered leptin and growth patterns in mature female offspring and not perpetuated to a second generation. Topics: Animals; Blood Pressure; Body Weight; Female; Growth; Leptin; Placental Insufficiency; Pregnancy; Rats; Rats, Sprague-Dawley | 2009 |
From daily behavior to hormonal and neurotransmitters rhythms: comparison between diurnal and nocturnal rat species.
Mammalian species can be defined as diurnal or nocturnal, depending on the temporal niche during which they are active. Even if general activity occurs during nighttime in nocturnal rodents, there is a patchwork of general activity patterns in diurnal rodents, including frequent bimodality (so-called crepuscular pattern, i.e., dawn and dusk peaks of activity) and a switch to a nocturnal pattern under certain circumstances. This raises the question of whether crepuscular species have a bimodal or diurnal - as opposed to nocturnal - physiology. To this end, we investigated several daily behavioral, hormonal and neurochemical rhythms in the diurnal Sudanian grass rat (Arvicanthis ansorgei) and the nocturnal Long-Evans rat (Rattus norvegicus). Daily rhythms of general activity, wheel-running activity and body temperature, with or without blocked wheel, were diurnal and bimodal for A. ansorgei, and nocturnal and unimodal for Long-Evans rats. Moreover, A. ansorgei and Long-Evans rats exposed to light-dark cycles were respectively more and less active, compared to conditions of constant darkness. In contrast to other diurnal rodents, wheel availability in A. ansorgei did not switch their general activity pattern. Daily, unimodal rhythm of plasma leptin was in phase-opposition between the two rodent species. In the hippocampus, a daily, unimodal rhythm of serotonin in A. ansorgei occurred 7 h earlier than that in Long-Evans rats, whereas a daily, unimodal rhythm of dopamine was unexpectedly concomitant in both species. Multiparameter analysis demonstrates that in spite of bimodal rhythms linked with locomotor activity, A. ansorgei have a diurnally oriented physiology. Topics: Analysis of Variance; Animals; Behavior, Animal; Blood Glucose; Body Temperature; Body Weight; Chromatography, High Pressure Liquid; Circadian Rhythm; Dopamine; Eating; Enzyme-Linked Immunosorbent Assay; Female; Hippocampus; Insulin; Leptin; Motor Activity; Murinae; Norepinephrine; Rats; Rats, Long-Evans; Serotonin | 2009 |
Effects of short-term mild calorie restriction diet and renutrition with ruminant milks on leptin levels and other metabolic parameters in mice.
The adaptation of an organism to a calorie-restricted diet is characterized by metabolic, endocrine, and immunologic changes. The objective of this study was to determine, in a mouse model, the changes in serum leptin levels in response to short-term mild calorie-restricted and renutrition diets using different ruminant milks.. Weaned Swiss albino mice were fed with a mild calorie-restricted diet for 12 d, after which they were renourished with cow, goat, sheep, or buffalo milk for 7 d. Body, thymus, and spleen weights and biochemical, hematologic, and endocrine parameters were evaluated.. The mild calorie restriction did not significantly modify insulin and leptin levels. The renutrition diets increased insulin levels, being significant (P < 0.05) only when buffalo and sheep milks were used. Leptin concentrations increased in the control ad libitum (AD) group during the assayed period. After the administration of cow and goat milks, lower leptin levels were observed compared with the control AD group. All repletion diets significantly increased body, thymus, and spleen weights; however, spleen weight did not reach the values observed in the control AD group. Serum glucose and triacylglycerol levels increased after feeding with the renutrition diets. However, serum cholesterol did not increase after the renutrition period. We observed a significant decrease (P < 0.05) in the leukocyte counts in calorie-restricted mice in comparison with AD mice; after the renutrition period, the leukocyte count did not reach the values for the AD mice.. This study suggests that a short-term change in diet with a relatively low body weight loss does not significantly affect leptin concentrations in our mouse model. However, the assayed milks could be effectively used as alternative milk sources for weight gain and for the improvement of other metabolic parameters. Topics: Animals; Body Weight; Buffaloes; Caloric Restriction; Cattle; Goats; Insulin; Leptin; Leukocyte Count; Male; Mice; Milk; Organ Size; Sheep; Species Specificity; Spleen; Thymus Gland | 2009 |
Toward an animal model of childhood-onset obesity: follow-up of OLETF rats during pregnancy and lactation.
The Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of obesity (a spontaneous CCK1 receptor knockout) has been extensively studied as model of hyperphagia-induced obesity. In previous studies, young OLETF rats presented abnormal eating patterns [compared with Long-Evans Tokushima Otsuka (LETO) controls] in a variety of independent ingestion and nursing tests during the suckling period. The aim of the present study was to characterize the early emergence of abnormal adiposity in the pups. Moreover, because both the dams and the pups present the genetic mutation, a close follow-up of the dams' body weight and intake during pregnancy and lactation was performed to examine the circumstances that contribute to build up the pups' early adiposity. Compared with controls, OLETF pups presented higher fat levels, larger adipocytes, and increased waist circumference as early as postnatal day 7 and this profile persisted to the age of weaning. While LETO dams gained weight throughout pregnancy and lactation, OLETF dams were obese and hyperphagic during pregnancy but lost weight during lactation, probably as a result of rearing hyperphagic pups. Current and previous results suggest a possible influence of the dams' obesity during gestation and a high investment in nursing time during lactation on the pups' obesity levels during childhood. This, combined with the innate hyperphagia repeatedly observed in the pups at these early ages, makes the OLETF strain a useful tool in the research of childhood-onset obesity. Topics: Adipocytes; Adipose Tissue, Brown; Adiposity; Age Factors; Age of Onset; Aging; Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Animals, Suckling; Body Mass Index; Body Weight; Disease Models, Animal; Energy Intake; Feeding Behavior; Female; Hyperphagia; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred OLETF; Receptor, Cholecystokinin A; Weaning | 2009 |
Hyperphagia and obesity in female mice lacking tissue inhibitor of metalloproteinase-1.
Certain matrix metalloproteinases and their regulators, the tissue inhibitors of metalloproteinases (TIMPs), are involved in development and remodeling of adipose tissue. In studying Timp1( Topics: Absorptiometry, Photon; Adipocytes; Aging; Animals; Body Weight; Eating; Energy Metabolism; Female; Gene Expression; Glucose Tolerance Test; Hyperphagia; Leptin; Male; Mice; Mice, Mutant Strains; Obesity; Polymerase Chain Reaction; Tissue Inhibitor of Metalloproteinase-1 | 2009 |
Peroxisome proliferator-activated receptor-alpha modulates insulin gene transcription factors and inflammation in adipose tissues in mice.
We have recently reported that PPAR alpha deficiency leads to hypoglycaemia and hypoinsulinemia in mice (Yessoufou et al. Endocrinology 147:4410-4418, 2006). Besides, these mice exhibited high adiposity with an inflammatory state. We, therefore, assessed, in this study, the effects of PPAR alpha deficiency on the expression of mRNA encoding for the insulin gene transcription factors in pancreatic beta-cells along with those implicated in inflammation in adipose tissues. On fasting, the adult PPAR alpha-null mice were hypoglycemic. Serum insulin concentrations and its pancreatic mRNA transcripts were downregulated in PPAR alpha-null mice, suggesting that PPAR alpha gene deletion contributes to low insulin gene transcription. The PPAR alpha gene deletion downregulates the mRNA expression of insulin gene transcription factors, i.e., Pdx-1, Nkx6.1, and MafA. Besides, the pancreatic function was diminished by PPAR alpha deficiency as PPAR alpha-null mice expressed low pancreatic Glut2 and glucokinase mRNA. PPAR alpha-null mice also expressed high adiponectin and leptin mRNA levels compared to wild type animals. Adipose tissues of PPAR alpha-null mice exhibited upregulation of CD14 and CD68 mRNA, generally expressed by macrophages. PPAR alpha gene deletion downregulates the adipocyte mRNA of certain pro-inflammatory agents, like MCP-1, TNF-alpha, IL-1 beta, IL-6, and RANTES, though pro-inflammatory TLR-2 and TLR-4 mRNAs were upregulated in the adipose tissues. Our results suggest that PPAR alpha deficiency, in mice, is implicated in the modulation of insulin gene transcription and inflammatory status in adipose tissues. Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Fatty Acids; Gene Expression Regulation; Inflammation; Insulin; Insulin-Secreting Cells; Interleukin-6; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; PPAR alpha; RNA, Messenger; Toll-Like Receptor 2; Toll-Like Receptor 4; Transcription Factors; Triglycerides; Tumor Necrosis Factor-alpha | 2009 |
The functional assessment of Alpinia pricei on metabolic syndrome induced by sucrose-containing drinking water in mice.
This study was designed to test whether Alpinia pricei (AP), a member of the ginger family indigenous to Taiwan, reduced metabolic syndrome induced by sucrose-containing drinking water in C57BL/6J mice. Mice given a chow diet were divided into a control group (C) or a test group given 30% sucrose water (SW) to drink ad libitum. After 22 weeks, mice in the SW group were subdivided into SW and SW + AP groups, the latter receiving a chow diet with an ethanol extract of AP (1500 mg/kg dosage). Four weeks later, bio-indexes associated with metabolic syndrome were measured. Compared with the C group, the SW group had significantly higher body weight, visceral fat weights, serum and tissue lipid, serum insulin level and the area under the curve for blood glucose of the insulin tolerance test (p < 0.05). These indicators in the SW + AP group were lower than in the SW group except for serum lipid, although slightly higher than the C group. The SW + AP group also showed significantly lower serum levels of leptin and tumor necrosis factor-alpha and a significantly higher level of adiponectin than the SW group. These results indicated that visceral adiposity and insulin resistance induced by sucrose water drinking might be alleviated by AP supplementation. Topics: Adiponectin; Alpinia; Animals; Blood Glucose; Body Weight; Dietary Sucrose; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lipids; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Plant Extracts; Sucrose; Tumor Necrosis Factor-alpha | 2009 |
Hindbrain leptin stimulation induces anorexia and hyperthermia mediated by hindbrain melanocortin receptors.
Of the central nervous system receptors that could mediate the energy balance effects of leptin, those of the hypothalamic arcuate nucleus receive the greatest attention. Melanocortin receptors (MC-Rs) contribute to the feeding and energetic effects of hypothalamically delivered leptin. Energy balance effects of leptin are also mediated by extrahypothalamic neurons including the hindbrain nucleus tractus solitarius. Hindbrain leptin receptors play a role in leptin's anorectic effects, but their contribution to its energetic effects and their functional interaction with melanocortin systems within the hindbrain remains unexplored. Here rats implanted with telemetric devices for recording energetic/cardiovascular responses were examined to determine whether: 1) hindbrain (fourth ventricular) leptin receptor stimulation triggers energetic and cardiovascular effects, 2) these effects are altered by a 6-wk high-fat diet maintenance, and 3) hindbrain MC-Rs mediate the thermogenic, cardiovascular, and anorexic effects of hindbrain leptin delivery. Results show that hindbrain leptin receptor stimulation produced long-lasting (>6 h) increases in core temperature and heart rate and also decreased food intake and body weight. These responses were not altered by high-fat maintenance, in contrast to what has been reported for forebrain leptin delivery. Fourth ventricular pretreatment with MC-R antagonist SHU 9119 completely abolished the hyperthermia, anorexia, and body weight loss seen with hindbrain-directed leptin but had no effects of its own. These data highlight a role for hindbrain leptin receptors in the initiation of energetic and anorexic responses and show that MCRs are part of the downstream mediation of hindbrain leptin-induced energy balance effects, paralleling effects observed for hypothalamic leptin receptors. Topics: Animals; Anorexia; Body Temperature; Body Weight; Dietary Fats; Eating; Energy Metabolism; Fever; Glucose Tolerance Test; Heart Rate; Injections; Leptin; Male; Melanocyte-Stimulating Hormones; Rats; Rats, Sprague-Dawley; Receptors, Melanocortin; Rhombencephalon | 2009 |
C/EBPbeta regulates body composition, energy balance-related hormones and tumor growth.
The prevalence of obesity, an established epidemiologic risk factor for many chronic diseases including cancer, has been steadily increasing in the US over several decades. The mechanisms used to regulate energy balance and adiposity and the relationship of these factors to cancer are not completely understood. Here we have used knockout mice to examine the roles of the transcription factors CCAAT/enhancer-binding protein (C/EBP) beta and C/EBPdelta in regulating body composition and systemic levels of hormones such as insulin-like growth factor-1 (IGF-1), leptin and insulin that mediate energy balance. Dual-energy X-ray absorptiometry showed that C/EBPbeta, either directly or indirectly, modulated body weight, fat content and bone density in both males and females, while the effect of C/EBPdelta was minor and only affected adiposity and body weight in female animals. Levels of IGF-1, leptin and insulin in the serum were decreased in both male and female C/EBPbeta(-/-) mice, and C/EBPbeta was associated with their promoters in vivo. Moreover, colon adenocarcinoma cells displayed reduced tumorigenic potential when transplanted into C/EBPbeta-deficient animals, especially males. Thus, C/EBPbeta contributes to endocrine expression of IGF-1, leptin and insulin, which modulate energy balance and can contribute to cancer progression by creating a favorable environment for tumor cell proliferation and survival. Topics: Adenocarcinoma; Adipose Tissue; Animals; Body Composition; Body Weight; Bone Density; CCAAT-Enhancer-Binding Protein-beta; CCAAT-Enhancer-Binding Protein-delta; Cell Division; Colonic Neoplasms; Female; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; Obesity | 2009 |
Adiponectin receptor-1 expression is decreased in the pancreas of obese mice.
Obesity is epidemic in the 21st century and has been shown to be a risk factor for developing severe acute pancreatitis. Adipose tissue produces small molecules called adipokines, which are important in modulating metabolism and inflammation. The anti-inflammatory adipokine adiponectin is decreased in obesity and inversely mirrors the severity of pancreatitis in a murine experimental model. Adiponectin acts through two receptors, AdipoR1 and AdipoR2; no data are currently available regarding adiponection receptor expression in the obese murine pancreas.. Immunohistochemical and reverse transcription-polymerase chain reaction analysis were undertaken to determine expression of adiponectin receptors AdipoR1 and AdipoR2 in the pancreas and liver of lean (C57BL/6J) and congenitally obese (Lep(Ob) and Lep(Db)) mice.. Immunohistochemistry confirmed expression of both AdipoR1 and AdipoR2 in the pancreas of all three murine strains. Staining was positive in acinar cells and to a lesser extent in islet cells. Pancreatic gene expression of AdipoR2 was similar among lean and obese mice. AdipoR1 gene expression, however, was significantly (P < 0.001) decreased in the pancreas of both Lep(Ob) and Lep(Db) mice compared to wild-type lean animals. Gene expression of both AdipoR1 and AdipoR2 was significantly less in the liver of obese (Lep(Ob) and Lep(Db)) mice compared to wild-type lean animals (P < 0.001).. These data show for the first time that the adiponectin receptors AdipoR1 and AdipoR2 are expressed in the obese murine pancreas. The paucity of AdipoR1 receptors may be important when considering the role played by adipokines in the genesis of severe pancreatitis in obesity. Topics: Animals; Body Weight; DNA Primers; Female; Immunohistochemistry; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pancreas; Receptors, Adiponectin; Reverse Transcriptase Polymerase Chain Reaction | 2009 |
Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin.
Leptin is an adipocyte hormone that plays a major role in energy balance. Leptin receptors in the hypothalamus are known to signal via distinct mechanisms, including signal transducer and activator of transcription-3 (STAT3) and phosphoinositol-3 kinase (PI 3-kinase). Here, we tested the hypothesis that extracellular signal-regulated kinase (ERK) is mediating leptin action in the hypothalamus.. Biochemical, pharmacological, and physiological approaches were combined to characterize leptin activation of ERK in the hypothalamus in rats.. Leptin activates ERK1/2 in a receptor-mediated manner that involves JAK2. Leptin-induced ERK1/2 activation was restricted to the hypothalamic arcuate nucleus. Pharmacological blockade of hypothalamic ERK1/2 reverses the anorectic and weight-reducing effects of leptin. The pharmacological antagonists of ERK1/2 did not attenuate leptin-induced activation of STAT3 or PI 3-kinase. Blockade of ERK1/2 abolishes leptin-induced increases in sympathetic nerve traffic to thermogenic brown adipose tissue (BAT) but does not alter the stimulatory effects of leptin on sympathetic nerve activity to kidney, hindlimb, or adrenal gland. In contrast, blockade of PI 3-kinase prevents leptin-induced sympathetic activation to kidney but not to BAT, hindlimb, or adrenal gland.. Our findings indicate that hypothalamic ERK plays a key role in the control of food intake, body weight, and thermogenic sympathetic outflow by leptin but does not participate in the cardiovascular and renal sympathetic actions of leptin. Topics: Adipose Tissue, Brown; Animals; Body Weight; Energy Intake; Extracellular Signal-Regulated MAP Kinases; Hypothalamus; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Mice; Neurons; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptors, Leptin; Sympathetic Nervous System | 2009 |
Adiponectin deficiency does not affect development and progression of spontaneous colitis in IL-10 knockout mice.
The goal of this study was to investigate the role of the adipokine adiponectin (APN) in development of spontaneous colitis in IL-10 knockout (KO) mice. To this aim, we generated double IL-10 APN KO mice and compared their disease development to that of single IL-10 KO mice. Both IL-10 KO and double IL-10 APN KO mice spontaneously developed colitis of comparable severity. No significant differences in inflammatory infiltrate or crypt elongation were observed in colonic tissue obtained from IL-10 KO and double IL-10 APN KO mice at either 12 or 20 wk of age. A comparable increase in circulating levels of serum amyloid A and IFN-gamma was observed in IL-10 KO and double IL-10 APN KO mice as disease progressed. In vitro stimulation of lymphocytes from mesenteric lymph nodes with anti-CD3 and anti-CD28 induced a significantly higher production of IL-17 and TNF-alpha in IL-10 KO and double IL-10 APN KO mice compared with their healthy littermates. No significant differences in cytokine production from lymphocytes or colonic mRNA expression of cytokines were observed between IL-10 KO and double IL-10 APN KO mice. Both IL-10 KO and double IL-10 APN KO mice had a similar decrease in body weight and bone mass compared with their respective healthy littermates. Finally, APN deficiency did not lead to development of insulin resistance, either in APN KO or double IL-10 APN KO mice. In conclusion, lack of APN does not play a significant role in the pathogenesis of spontaneous colonic inflammation in the IL-10 KO model. Topics: Adiponectin; Age Factors; Aging; Animals; Blood Glucose; Body Weight; Bone Density; Cells, Cultured; Colitis; Disease Progression; Inflammation Mediators; Insulin; Insulin Resistance; Interferon-gamma; Interleukin-10; Interleukin-17; Leptin; Lymphocyte Activation; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA, Messenger; Serum Amyloid A Protein; Severity of Illness Index; Tumor Necrosis Factor-alpha | 2009 |
Influence of herring (Clupea harengus) and herring fractions on metabolic status in rats fed a high energy diet.
Few dietary studies have looked beyond fish oil to explain the beneficial metabolic effects of a fish-containing diet. Our aim was to study whether addition of herring, or sub-fractions of herring, could counteract negative metabolic effects known to be induced by a high-fat, high-sugar diet.. Rats were given six different diets: standard pellets; high energy diet with chicken mince (HiE control); high energy diet with herring mince (HiE herring); and high energy diet with chicken mince and either herring oil (HiE herring oil), herring press juice, PJ (HiE PJ) or herring low molecular weight PJ (HiE LMW-PJ). Factors associated with the metabolic syndrome were measured.. There were no differences in energy intake or body weight between the groups, but animals fed high energy diets had a higher body fat content compared with the pellet group, although not statistically significant in all groups. Mesenteric adipocyte size was smaller in the HiE herring oil group compared with the HiE control. Glucose clamp studies showed that, compared with the pellet group, the HiE control and HiE herring diets, but not the HiE herring oil diet, induced insulin resistance. Addition of herring or herring oil to the high energy diet decreased total cholesterol levels, triacylglycerols and the atherogenic index compared with the HiE control group.. The results suggest that addition of herring or herring oil counteracts negative effects on blood lipids induced by a high energy diet. The lipid component of herring thus seems to be responsible for these beneficial effects. Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Blood Pressure; Body Composition; Body Weight; Cell Size; Chickens; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; Fatty Acids, Unsaturated; Fish Oils; Fish Products; Fishes; Glucose Clamp Technique; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lipid Metabolism; Lipids; Male; Metabolism; Poultry Products; Rats; Rats, Wistar | 2009 |
Diminished metabolic responses to centrally-administered apelin-13 in diet-induced obese rats fed a high-fat diet.
The central administration of apelin, a recently identified adipokine, has been shown to affect food and water intake. The present study investigated whether body weight could affect an animal's response to apelin. The effects of centrally-administered apelin-13 on food and water intake, activity and metabolic rate were investigated in adult male diet-induced obese (DIO) rats fed either a high fat (32%) or control diet. Rats were administered i.c.v. apelin-13, 15-30 min prior to lights out, and food and water intake, activity and metabolic rate were assessed. Intracerebroventricular administration of apelin-13 decreased food and water intake and respiratory exchange ratio in DIO rats on the control diet, but had no effect in DIO rats on the high-fat diet. In an effort to identify potential central mechanisms explaining the observed physiological responses, the mRNA level of the apelin receptor, APJ, was examined in the hypothalamus. A high-fat diet induced an up-regulation of the expression of the receptor. Apelin induced a down-regulation of the receptor, but only in the DIO animals on the high-fat diet. In conclusion, we have demonstrated a diminished central nervous system response to apelin that is coincident with obesity. Topics: Animals; Apelin Receptors; Body Weight; Cytokines; Diet; Dietary Fats; Drinking; Eating; Energy Metabolism; Hypothalamus; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Obesity; Plasminogen Activator Inhibitor 1; Rats; Receptors, G-Protein-Coupled | 2009 |
Inflammatory markers in a randomised soya intervention among men.
The present analysis investigated the effect of soya foods on serum levels of six inflammatory markers, leptin, adiponectin, monocyte attractant protein 1 (MCP-1), macrophage inflammatory protein-1b (MIP-1b), IL-6 and C-reactive protein (CRP), and their relationship with BMI and lifetime soya intake. We randomised twenty-four men to a high- (two daily servings with 30-35 mg isoflavones per serving) or a low-soya diet for 3 months. After a 1-month washout period, the men crossed over to the other treatment. We used a multiplex bead immunoassay to measure leptin, adiponectin, MCP-1 and MIP-1b and ELISA assays for IL-6 and CRP. The statistical analysis applied mixed models that incorporated the four repeated measurements. The men had a mean age of 58.7 (sd 7.2) years and a mean BMI of 28.4 (sd 4.9) kg/m2. We observed no significant intervention effect of the soya treatment on any of the six markers. After adjustment for age and ethnicity, highly significant associations of BMI and body weight with leptin and MCP-1 emerged. Men with high soya intake early in life also had higher levels of leptin and MCP-1, whereas no association was seen for soya intake during adulthood. MIP-1b, adiponectin, IL-6 and CRP were not related to BMI, body weight or soya intake at any time in life. No intervention effect of soya foods on markers of inflammation was observed in this small study, but adiposity and early-life soya intake were related to higher leptin and MCP-1 levels. Topics: Adiponectin; Adult; Aged; Biomarkers; Body Mass Index; Body Weight; C-Reactive Protein; Chemokine CCL2; Chemokine CCL4; Diet; Glycine max; Humans; Interleukin-6; Isoflavones; Leptin; Male; Middle Aged; Multivariate Analysis; Randomized Controlled Trials as Topic | 2009 |
Pref-1 and adipokine expression in adipose tissues of GK and Zucker rats.
In view of the central role of preadipocyte factor-1, adiponectin and leptin in white adipose tissue function, the aim of the present study was to analyze the mRNA expression of these proteins and of the inflammatory markers interleukin-6 and tumor necrosis factor-alpha in visceral and subcutaneous fat pads of rats with different metabolic disorders. We demonstrated highly divergent expression of preadipocyte factor-1, upregulated expression of adiponectin, interleukin-6 and TNF-alpha mRNA in adipose tissues of the diabetic Goto Kakizaki rat compared to the obese Zucker rat. This was correlated to an increased number of large adipocytes and serum levels of adiponectin. Furthermore, in all four strains studied (as above plus Wistar Furth and Zucker Lean), significant heterogeneity was evident in adipokine expression within specific adipose tissues previously defined as belonging to the visceral or subcutaneous fat depots. These results suggest that significantly increased levels of inflammation and redistribution of adipocyte size are mechanisms contributing to the development of type 2 diabetes in the GK rat. Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Cell Size; Gene Expression Regulation; Insulin; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Membrane Proteins; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha | 2009 |
The prolonged effect of repeated maternal glucocorticoid exposure on the maternal and fetal leptin/insulin-like growth factor axis in Papio species.
Maternal obesity represents a risk factor for pregnancy-related complications. Glucocorticoids are known to promote obesity in adults.. We evaluated maternal and fetal metabolic changes during and after 3 weekly courses of betamethasone administered to pregnant baboons (Papio subspecies) at doses equivalent to those given to pregnant women.. Betamethasone administration during the second half of pregnancy increased maternal weight but neither maternal food intake nor fetal weight, as assessed at the end of gestation. Betamethasone increased maternal serum glucose concentration, the ratio of insulin-like growth factor-I and insulin-like growth factor binding protein-3, and serum leptin during treatment (normalized by 17, 35, and 45 days posttreatment, respectively, for each parameter). Maternal and fetal serum leptin concentrations did not differ between groups at the end of gestation.. Prolonged maternal hyperleptinemia caused by betamethasone administration in the second half of gestation did not change fetal metabolic parameters measured and placental leptin distribution at the end of gestation. Topics: Animals; Betamethasone; Blood Glucose; Body Weight; Cesarean Section; Cholesterol; Drug Administration Schedule; Eating; Female; Fetal Blood; Fetal Weight; Fetus; Gestational Age; Glucocorticoids; Hydrocortisone; Injections, Intramuscular; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Maternal-Fetal Exchange; Papio cynocephalus; Placenta; Pregnancy | 2009 |
Altered leptin secretion in hyperinsulinemic mice under hypoxic conditions.
Hypoxia and insulin are known key players in the activation leptin transcription and translation in vivo and in vitro. These insulin- and hypoxia-dependent effects are leptin transcription are mediated via independent elements on the leptin-promotor, even more coincubation of the two stimuli in vitro results in a supraadditive effect on leptin transcription. The aim of this study was to examine whether hyperinsulinemia is able to interfere with the hypoxia-driven expression of leptin in adipose and extra-adipose tissue in vivo.. We used the KK/HlJ mouse strain as a model for hyperinsulinemia and C57BL/6J mice as control. These two groups were exposed to hypoxia for 12 h. Serum levels of insulin and leptin were analyzed by ELISA, mRNA expression of leptin was measured via real-time PCR.. In the hyperinsulinemic KK/HlJ mice, hypoxia was not able to further increase the amount of leptin in serum. Instead, a significant decrease of insulin levels was detected, while serum leptin and insulin levels increased in C57BL/6J. Analysis of leptin mRNA expression in subcutaneous fat, mesenteric fat and kidney revealed that hypoxia induces leptin transcription in kidneys of C57/BL6 but not in hyperinsulinemic animals. In contrast, leptin expression in adipose tissue was not increased during hypoxia.. We conclude that leptin regulation during hypoxia in vivo depends at least in part on the modulating role of insulin. The hypoxia driven induction of insulin expression in C57/BL6 animals may be responsible for the stimulation of leptin transcription. In contrast, already hyperinsulinemic animals showed no induction - neither of insulin nor leptin after short-term hypoxia. Topics: Animals; Blood Glucose; Body Weight; Hyperinsulinism; Hypoxia; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Transcription, Genetic | 2009 |
Evaluation of new leptin fragments on food intake and body weight of normal rats.
Leptin, a protein hormone originating from adipose tissue, circulates in the plasma and affects the energy balance by interacting with the hypothalamus. Leptin plays an important role in the regulation of a variety of physiological functions, including food intake, body temperature and body weight maintenance. Tertiary structure of the leptin molecule reveals the existence of a four-helix bundle that is characteristic of the short-helix cytokines. To identify regions of the leptin molecule responsible for its bioactivity, we have recently synthesized six peptides based on the protein three-dimensional structure. Our results indicated that the fragments Ac-hLEP(92-115)-NH(2) (IV) and Ac-[Ser(117)]-hLEP(116-140)-NH(2) (V) were recognized by leptin receptor present in hp-75 cells validating that this region of the molecule contain the functional epitope of the leptin molecule. In the present study, a new series of decapeptides encompassing the region of fragments IV and V of leptin were synthesized, and their effects on body weight and food intake were assessed when administered into the lateral cerbroventricle of normal rats. Peptides were synthesized by SPPS, purified by RP-HPLC and characterized by LC/ESI-MS. We also performed a conformational study of the peptides by circular dichroism in order to correlate the biological activity and secondary structure of the leptin fragments. Among the fragments tested, we found that Ac-hLEP(110-119)-NH(2) (VI) induce a significant reduction in both body weight and food intake. The use of synthetic leptin-derivate fragments may offer the basis for the development of compounds with potential application in human obesity or to its related metabolic dysfunctions. Topics: Animals; Body Weight; Eating; Humans; Injections, Intraventricular; Leptin; Male; Peptide Fragments; Rats; Rats, Wistar | 2009 |
Palatable foods, stress, and energy stores sculpt corticotropin-releasing factor, adrenocorticotropin, and corticosterone concentrations after restraint.
Previous studies have shown reduced hypothalamo-pituitary-adrenal responses to both acute and chronic restraint stressors in rats allowed to ingest highly palatable foods (32% sucrose +/- lard) prior to restraint. In this study we tested the effects of prior access (7 d) to chow-only, sucrose/chow, lard/chow, or sucrose/lard/chow diets on central corticotropin-releasing factor (CRF) expression in rats studied in two experiments, 15 and 240 min after onset of restraint. Fat depot, particularly intraabdominal fat, weights were increased by prior access to palatable food, and circulating leptin concentrations were elevated in all groups. Metabolite concentrations were appropriate for values obtained after stressors. For unknown reasons, the 15-min experiment did not replicate previous results. In the 240-min experiment, ACTH and corticosterone responses were inhibited, as previously, and CRF mRNA in the hypothalamus and oval nucleus of the bed nuclei of the stria terminalis were reduced by palatable foods, suggesting strongly that both neuroendocrine and autonomic outflows are decreased by increased caloric deposition and palatable food. In the central nucleus of the amygdala, CRF was increased in the sucrose-drinking group and decreased in the sucrose/lard group, suggesting that the consequence of ingestion of sucrose uses different neural networks from the ingestion of lard. The results suggest strongly that ingestion of highly palatable foods reduces activity in the central stress response network, perhaps reducing the feeling of stressors. Topics: Adipose Tissue; Adrenocorticotropic Hormone; Animals; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Energy Intake; Energy Metabolism; Food; Hypothalamus; Insulin; Leptin; Male; Palate; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stress, Physiological; Taste | 2009 |
Dietary L-arginine supplementation reduces white fat gain and enhances skeletal muscle and brown fat masses in diet-induced obese rats.
Previous studies showed that dietary L-arginine supplementation decreased white fat mass in genetically obese rats. This study tested the effectiveness of L-arginine in diet-induced obesity. Male Sprague-Dawley rats were fed for 15 wk a high-fat (HF) (40% energy) or low-fat (LF) (10% energy) diet beginning at 4 wk of age, resulting in 18% higher body weight gains and 74% higher weights of major white fat pads (retroperitoneal, epididymal, subcutaneous, and mesenteric adipose tissues) in HF than in LF fed rats. Starting at 19 wk of age, rats in each dietary group were supplemented for 12 wk with 1.51% L-arginine-HCl or 2.55% L-alanine (isonitrogenous control) (n = 8 per treatment) in drinking water and arginine groups were individually pair-fed to alanine controls. Despite similar energy intake, absolute weights of white fat pads increased by 98% in control rats over a 12-wk period but only by 35% in arginine-supplemented rats. The arginine treatment reduced the relative weights of white fat pads by 30% and enhanced those of soleus muscle by 13%, extensor digitorum longus muscle by 11%, and brown fat by 34% compared with control rats. Serum concentrations of insulin, adiponectin, growth hormone, corticosterone, triiodothyronine, and thyroxine did not differ between control and arginine-supplemented rats. However, arginine treatment resulted in lower serum concentrations of leptin, glucose, triglycerides, urea, glutamine, and branched-chain amino acids, higher serum concentrations of nitric-oxide metabolites, and improvement in glucose tolerance. Thus, dietary arginine supplementation shifts nutrient partitioning to promote muscle over fat gain and may provide a useful treatment for improving the metabolic profile and reducing body white fat in diet-induced obese rats. Topics: Adipose Tissue; Adipose Tissue, Brown; Amino Acids; Animals; Arginine; Blood Glucose; Body Weight; Diet; Dietary Supplements; Glucose Tolerance Test; Leptin; Male; Muscle, Skeletal; Nitric Oxide; Obesity; Organ Size; Rats; Rats, Sprague-Dawley | 2009 |
Beta-adrenergic blockade and leptin replacement effectively mitigate disuse bone loss.
Our objective was to test effects of beta-adrenergic blockade on hindlimb unloading (HU)-induced bone loss and serum leptin and to compare these responses with those observed with leptin replacement. Adult male rats were randomized into six groups (n = 10 each): HU rats treated with vehicle (VEHHU), leptin analog (LEPHU), or beta-blocker (BBHU) during a 28-day HU and cage activity controls (CC) treated with the same three agents and pair-fed to HU rats. On days 0 and 28, pQCT scans of proximal tibia and serum collections for leptin assays were performed, and histomorphometric measures of proximal tibia cancellous bone were assessed. The 20% decrease in cancellous vBMD observed in the VEHHU group was halved in BBHU rats and LEPHU rats. Bone formation rate (BFR) in BBHU rats, but not in LEPHU rats, was preserved. The 3-fold increase in resorption surface with HU was abolished by BB and LEP treatments. The decrease in serum leptin after a 28-day HU was attenuated in BBHU and LEPHU rats and was predictive of the decrease in BFR with HU. Blocking sympathetic adrenergic signaling by peripheral administration of a beta-blocker during HU mitigates disuse-induced decreases in cancellous bone mass through stimulation of osteoblastic activity and suppression of osteoclastic activity. A direct effect of beta-adrenergic blockade on bone cells during HU may be enhanced by an indirect effect mitigating reductions in circulating leptin, possibly through disinhibition of leptin release from adipocytes. Topics: Adrenergic beta-Antagonists; Animals; Body Weight; Bone Resorption; Epididymis; Feeding Behavior; Hindlimb Suspension; Leptin; Male; Organ Size; Rats; Rats, Sprague-Dawley; Tibia; Tomography, X-Ray Computed | 2009 |
Dorsal hindbrain 5'-adenosine monophosphate-activated protein kinase as an intracellular mediator of energy balance.
The fuel-sensing enzyme AMP-activated protein kinase (AMPK) has been implicated in central nervous system control of energy balance. Hypothalamic AMPK activity is increased by food deprivation, and this elevation is inhibited by refeeding or by leptin treatment. The contribution of extrahypothalamic AMPK activity in energy balance control has not been addressed. Here, we investigate the effects of physiological state on the AMPK activity in hindbrain nucleus tractus solitarius (NTS) neurons because treatments that reduce energy availability in these neurons trigger behavioral, endocrine, and autonomic responses to restore energy balance. Food-deprived rats showed significantly increased AMPK activity in both NTS- and hypothalamus-enriched lysates compared with those that were ad libitum fed. Pharmacological inhibition of AMPK activity in medial NTS neurons, by intraparenchymal injection of compound C, suppressed food intake and body weight gain compared with vehicle. Fourth ventricle (4th i.c.v.) compound C delivery increased heart rate and spontaneous activity in free-moving rats. Suppression of AMPK activity has been implicated in leptin's anorectic action in the hypothalamus. Given the role of leptin signaling in food intake inhibition within the medial NTS, we also examined whether stimulation of hindbrain AMPK by 4th i.c.v. administration of 5-aminoimidazole-4-carboxamide-riboside (AICAR), an AMP-mimicking promoter of AMPK activity, could attenuate the inhibition of food intake by 4th i.c.v. leptin. The intake-suppressive effects of leptin (at 2 and 4 h) were completely reversed by AICAR. We conclude that 1) hindbrain AMPK activity contributes to energy balance control through regulation of food intake and energy expenditure, 2) leptin's intake-reducing effects in the NTS are mediated by AMPK, and 3) central nervous system AMPK controls whole-body homeostasis at anatomically distributed sites across the neuraxis. Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Body Weight; Eating; Energy Metabolism; Homeostasis; Hypoglycemic Agents; Leptin; Male; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Rhombencephalon; Ribonucleotides; Second Messenger Systems; Weight Gain | 2009 |
Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet.
Weight gain induced by an energy-dense diet is hypothesized to arise in part from defects in the neuronal response to circulating adiposity negative feedback signals, such as insulin. Peripheral tissue insulin resistance involves cellular inflammatory responses thought to be invoked by excess lipid. Therefore, we sought to determine whether similar signaling pathways are activated in the brain of rats fed a high-fat (HF) diet. The ability of intracerebroventricular (icv) insulin to reduce food intake and activate hypothalamic signal transduction is attenuated in HF-fed compared with low-fat (LF)-fed rats. This effect was accompanied by both hypothalamic accumulation of palmitoyl- and stearoyl-CoA and activation of a marker of inflammatory signaling, inhibitor of kappaB kinase-beta (IKKbeta). Hypothalamic insulin resistance and inflammation were observed with icv palmitate infusion or HF feeding independent of excess caloric intake. Last, we observed that central IKKbeta inhibition reduced food intake and was associated with increased hypothalamic insulin sensitivity in rats fed a HF but not a LF diet. These data collectively support a model of diet-induced obesity whereby dietary fat, not excess calories, induces hypothalamic insulin resistance by increasing the content of saturated acyl-CoA species and activating local inflammatory signals, which result in a failure to appropriately regulate food intake. Topics: Animals; Body Weight; Dietary Fats; Eating; Food-Drug Interactions; Glucose Tolerance Test; Hypothalamus, Middle; I-kappa B Kinase; Injections, Intraventricular; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Obesity; Rats; Rats, Long-Evans; Satiety Response; Signal Transduction | 2009 |
Models use leptin and calculus to count calories.
Thermostats have "set-points" that engineers design with mathematical rigor. Work in this issue of Cell Metabolism (Tam et al., 2009) applies similar modeling strategies to explore the control of murine energy and body weight homeostasis by leptin. Topics: Algorithms; Animals; Body Weight; Energy Metabolism; Leptin; Mice; Models, Biological; Obesity | 2009 |
A mathematical model of murine metabolic regulation by leptin: energy balance and defense of a stable body weight.
We have developed a physiologically based mathematical model, with parameters derived from published experimental data, to simulate the regulatory effects of the leptin pathway on murine energy homeostasis. Model outcomes are consistent with data reported in the literature and reproduce key characteristics of the energy regulatory system, including compensatory responses that counteract changes in body weight and the failure of this ability when the leptin pathway is disrupted. Our model revealed the possibility of multiple steady states for body weight. It also provided a unified theoretical framework for two historically antagonistic hypotheses regarding body weight regulation ("set-point" versus "settling point"). Finally, our model has identified potential avenues for future investigations. Topics: Algorithms; Animals; Body Weight; Energy Metabolism; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Obesity | 2009 |
Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity.
The hypothalamic orexin neuropeptide acutely promotes appetite, yet orexin deficiency in humans and mice is associated with obesity. Prolonged effects of increased orexin signaling upon energy homeostasis have not been fully characterized. Here, we examine the metabolic effects of orexin gain of function utilizing genetic and pharmacologic techniques in mice. Transgenic orexin overexpression confers resistance to high-fat diet-induced obesity and insulin insensitivity by promoting energy expenditure and reducing consumption. Genetic studies indicate that orexin receptor-2 (OX2R), rather than OX1R signaling, predominantly mediates this phenotype. Likewise, prolonged central administration of an OX2R-selective peptide agonist inhibits diet-induced obesity. While orexin overexpression enhances the anorectic-catabolic effects of central leptin administration, obese leptin-deficient mice are completely resistant to the metabolic effects of orexin overexpression or OX2R agonist infusion. We conclude that enhanced orexin-OX2R signaling confers resistance to diet-induced features of the metabolic syndrome through negative energy homeostasis and improved leptin sensitivity. Topics: Analysis of Variance; Animals; Body Weight; Energy Intake; Energy Metabolism; Hypothalamus; Intracellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neuropeptides; Obesity; Orexin Receptors; Orexins; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Signal Transduction | 2009 |
Endogenous nociceptin modulates diet preference independent of motivation and reward.
Previous studies show that the opioid peptide nociceptin stimulates food intake. Here, we studied nociceptin receptor knockout (NOP KO) mice in various behavioral paradigms designed to differentiate psychological and physiological loci at which endogenous nociceptin might control feeding. When presented a choice under food restriction, NOP KO mice displayed reduced preference for high sucrose diet, but lower intake of high fat diet under no-choice conditions. These responses were absent under ad libitum feeding conditions. Conditioned place preference to high fat diet under food-deprived conditions was unaltered in NOP KO mice, suggesting no difference in reward responses. Furthermore, operant food self-administration under a variety of conditions showed no genotype-dependent differences, suggesting no differences in the motivational properties of food. Taste reactivity to sucrose was unchanged in NOP KO mice, though NOP KO mice had altered aversive reactions to quinine solutions under ad libitum feeding, suggesting minor differences in the affective impact of palatable and unpalatable tastants. Although NOP KO mice re-fed following food-deprivation showed normal increases in plasma glucose and insulin, multidimensional scaling analysis showed that the relationship between these measures, body weight and plasma leptin was substantially disrupted in NOP KO, particularly in fasted mice. Additionally, the typical positive relationship between body weight and plasma leptin was considerably weaker in NOP KO mice. Together, these findings suggest that endogenous nociceptin differentially modulates diet preference depending on macronutrient content and homeostatic state, independently of the motivating, rewarding or orosensory properties of food, but may involve metabolic or postingestive processes. Topics: Animals; Blood Glucose; Body Weight; Conditioning, Operant; Dietary Fats; Dietary Sucrose; Drinking Behavior; Female; Food Deprivation; Food Preferences; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motivation; Nociceptin; Nociceptin Receptor; Opioid Peptides; Receptors, Opioid; Reward; Taste Perception | 2009 |
Prolonged but not short negative energy condition restored corticoadrenal leptin sensitivity in the hypothalamic obese rat.
We have reported that neonatal treatment with monosodium L-glutamate (MSG), which causes damage to the arcuate nucleus, leads to severe hyperleptinemia and reduced adrenal leptin receptor (ob-Rb) expression in adulthood. As a result, rats given MSG neonatally display corticoadrenal leptin-resistance, a defect that is overridden by normalization of corticoadrenal hyperfunction. The aim of the present study was to determine whether negative energy conditions could correct corticoadrenal cell dysfunction in rats given MSG neonatally.. Normal (CTR) and MSG-treated female rats were subjected to food removal for 1-5 days, or prolonged (24-61 days) food restriction (FR). Plasma levels of several biomarkers and in vitro corticoadrenal function were evaluated following starvation or FR.. Fasting for 1-5 days reduced plasma leptin levels in CTR and MSG rats, compared to levels in the respective groups fed ad libitum(p < 0.05), but adrenal leptin-resistance was unchanged. With prolonged FR, isolated adrenal cells from MSG rats became sensitive to leptin, which lowered ACTH-induced glucocorticoid release. This restoration of leptin response was associated with normalization of adrenal ob-Rb gene expression.. Dietary restriction in some leptin-resistant obese phenotypes may normalize adrenocortical function. Topics: Adrenal Cortex; Adrenocorticotropic Hormone; Animals; Animals, Newborn; Blood Proteins; Body Weight; Corticosterone; Energy Intake; Female; Food Deprivation; Hypothalamus; Leptin; Male; Obesity; Organ Size; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Leptin; RNA, Messenger; Sodium Glutamate; Time Factors; Triglycerides | 2009 |
Leptin and insulin resistance: good, bad, or still unclear?
Topics: Adiposity; Body Weight; Hormone Replacement Therapy; Humans; Insulin Resistance; Leptin; Lipodystrophy; Obesity | 2009 |
Leptin: weight management and beyond. Introduction to the symposium.
Topics: Body Weight; Humans; Leptin | 2009 |
Dopamine and serotonin release in the nucleus accumbens during starvation-induced hyperactivity.
Activity-based anorexia (ABA) is considered an animal model for anorexia nervosa (AN). By scheduled feeding and voluntary wheel running, it mimics severe body weight loss and increased physical activity in AN. Pharmacological, genetic and imaging studies implicate dopamine and serotonin in the regulation of feeding behavior, food-anticipatory activity, and food reward. Previous studies propose that the nucleus accumbens (NAc) plays an important role in these food-related processes. Here we determined dopamine and serotonin levels in the NAc upon exposure to the ABA model. Surprisingly, the release of dopamine and serotonin in the NAc were not increased during the initiation of food-anticipatory behavior in ABA rats. Dopamine release in the NAc was increased during feeding behavior in ABA rats. During ABA, levels of serotonin were low and circadian activity is blunted. We conclude that during the early stages of development of food-anticipatory activity, increased dopamine does not trigger hyperactivity. Topics: 3,4-Dihydroxyphenylacetic Acid; Analysis of Variance; Animals; Body Temperature; Body Weight; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine; Eating; Female; Homovanillic Acid; Hydroxyindoleacetic Acid; Hyperkinesis; Insulin; Leptin; Microdialysis; Nucleus Accumbens; Radioimmunoassay; Rats; Rats, Wistar; Serotonin; Starvation | 2009 |
Seasonal changes in plasma leptin concentration related to antler cycle in Iberian red deer stags.
The aim of this study is to describe the leptin cycle in male Iberian red deer (Cervus elaphus hispanicus) and relate it to antler and testosterone cycles. An additional aim is to assess the relationship between the plasma leptin concentration during antlers' growth and their final size. Therefore, blood from 21 Iberian red deer males was sampled monthly to analyse leptin and testosterone. At the same time the deer were weighed and their body condition was assessed. The length of antlers was measured every 2 weeks and, after casting, their final length and perimeters were taken. Leptin showed a seasonal cycle, with a peak in June that decreased as testosterone increased. Low values were observed in autumn, winter and early spring. The relationship observed between leptin and body mass or body condition score was different in spring, when plasma testosterone concentration is low, than in autumn, when testosterone increases. Leptin peak amplitude was positively related to final antler size. In conclusion, the relationship between leptin and body mass and body condition score changes through the year, possibly due to the influence of androgens and photoperiod. There was a positive relationship between plasma concentration of leptin during antler growth and final antler length. Topics: Animals; Antlers; Body Weight; Deer; Leptin; Male; Photoperiod; Seasons; Testosterone | 2009 |
Cold exposure does not decrease serum leptin concentration, but increases energy intake and thermogenic capacity in pregnant Brandt's voles (Lasiopodomys brandtii).
In most mammals, maternal body mass and fat mass increase during pregnancy due to hyperphagia. These physiological changes provide the fetus with energy and nutrients and prepare the mother for the high energetic demands of lactation. In the present study, metabolic changes in response to cold and pregnancy were examined in female Brandt's voles (Lasiopodomys brandtii). At 23+/-1 degrees C, the voles increased body mass and deposited body fat during pregnancy. However, at 5+/-1 degrees C pregnant voles did not deposit body fat even though energy intake increased above the level in the warm. Serum leptin concentration increased during pregnancy and was not influenced by cold exposure. Thermogenic capacity, as indicated by uncoupling protein 1 (UCP1) content in brown adipose tissue (BAT), increased in cold-exposed pregnant voles. The number and mass of fetuses were not affected by cold exposure. Our data may indicate the importance of an increased serum leptin concentration for a successful outcome of the pregnancy and also the independence of leptin secretion from body fat in pregnant voles. It also implies the need to develop central leptin resistance with respect to control of energy balance for pregnant voles. Topics: Adipose Tissue, Brown; Animals; Arvicolinae; Basal Metabolism; Body Composition; Body Temperature Regulation; Body Weight; Cold Temperature; Eating; Energy Intake; Female; Ion Channels; Leptin; Litter Size; Liver; Mitochondria; Mitochondrial Proteins; Pregnancy; Prostaglandin-Endoperoxide Synthases; Uncoupling Protein 1 | 2009 |
Maternal obesity is necessary for programming effect of high-fat diet on offspring.
We tested the hypothesis that maternal consumption of dietary fat, independent from obesity, increases serum leptin in neonatal pups and predisposes them to adult obesity. Female rats either were fed a high-fat (HF) diet or a low-fat (LF) diet or were fed the HF diet but pair fed (PF) to the caloric intake of the LF group for 4 wk before breeding and throughout gestation and lactation. Dams consuming the HF diet had increased adiposity and were hyperphagic. At weaning, pups born to obese dams had significantly higher body fat and serum leptin levels and reduced insulin tolerance compared with offspring of LF-fed dams. Pups were weaned onto a chow diet until 8 wk of age, when they were then fed either HF or LF diet. At 18 wk of age, offspring from obese HF dams weighed more than offspring from nonobese LF or PF dams, and offspring eating HF diet weighed significantly more than those eating LF diet. Consequently, HF-fed offspring of obese HF dams weighed the most and LF-fed offspring from obese HF dams were similar in weight to HF-fed offspring from nonobese LF dams. These data suggest that maternal obesity exerts an independent effect on offspring body weight that is of similar magnitude as the effect of the offspring's adult diet. Furthermore, there was no difference in body weight between the nonobese LF and PF offspring on either diet. Together, these data suggest that maternal adiposity, and not dietary fat per se, induces hyperleptinemia and insulin resistance in offspring, as well as an increased body weight that persists into adulthood. Topics: Adiposity; Animals; Body Composition; Body Weight; Dietary Fats; Disease Models, Animal; Eating; Female; Insulin Resistance; Leptin; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Rats; Rats, Long-Evans | 2009 |
Low sympathetic tone and obese phenotype in oxytocin-deficient mice.
Oxytocin (Oxt) is secreted both peripherally and centrally and is involved in several functions including parturition, milk let-down reflex, social behavior, and food intake. Recently, it has been shown that mice deficient in Oxt receptor develop late-onset obesity. In this study, we characterized a murin model deficient in Oxt peptide (Oxt(-/-)) to evaluate food intake and body weight, glucose tolerance and insulin tolerance, leptin and adrenaline levels. We found that Oxt(-/-) mice develop late-onset obesity and hyperleptinemia without any alterations in food intake in addition to having a decreased insulin sensitivity and glucose intolerance. The lack of Oxt in our murin model also results in lower adrenalin levels which led us to hypothesize that the metabolic changes observed are associated with a decreased sympathetic nervous tone. It has been shown that Oxt neurons in the paraventricular nucleus (PVN) are a component of a leptin-sensitive signaling circuit between the hypothalamus and caudal brain stem for the regulation of food intake and energy homeostasis. Nevertheless, the lack of Oxt in these mice does not have a direct impact on feeding behavior whose regulation is probably dependent on the complex interplay of several factors. The lack of hyperphagia evident in the Oxt(-/-) mice may, in part, be attributed to the developmental compensation of other satiety factors such as cholecystokinin or bombesin-related peptides which merits further investigation. These findings identify Oxt as an important central regulator of energy homeostasis. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Brain Stem; Crosses, Genetic; Energy Intake; Glucose Intolerance; Hypothalamus; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Oxytocin; Signal Transduction; Stomach; Sympathetic Nervous System | 2009 |
COX-2-mediated inflammation in fat is crucial for obesity-linked insulin resistance and fatty liver.
The aim was to examine the role of cyclooxygenase (COX)-2-mediated inflammation in the development of obese linked insulin resistance and fatty liver. The rats were fed separately regular diet (CONT), high-fat diet (HFD) ad libitum, or energy restrictedly for 12 weeks. Rats fed HFD ad libitum were further divided into three subgroups co-treated with vehicle (HFa), or a selective COX-2 inhibitor celecoxib (HFa-Cel) or mesulid (HFa-Mes). Euglycemic hyperinsulinemic clamp (EHC) experiment was performed at the end of study. Another set of rats with similar grouping was further divided into those with a 4, 8, or 12-week intervention period for hepatic sampling. Body weight was increased significantly and similarly in HFa, HFa-Cel, and HFa-Mes. Time-dependent increases in plasma insulin, glucose, 8-isoprostanes, leptin levels, homeostasis model assessment of insulin resistance (HOMA-IR) and hepatic triglyceride contents shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. During EHC period, the reduction in stimulation of whole body glucose uptake, suppression of hepatic glucose production and metabolic clearance rate of insulin shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. The enhanced COX-2 and tumor necrosis factor-alpha (TNF-alpha) but attenuated PPAR-gamma and C/EBP-alpha mRNA expressions in epididymal fat shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. The increases in average cell size of adipocytes and CD68 positive cells shown in HFa were also significantly reversed in HFa-Cel and HFa-Mes. Our findings suggest that COX-2 activation in fat inflammation is important in the development of insulin resistance and fatty liver in high fat induced obese rats. Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Blood Glucose; Body Weight; Celecoxib; Cell Size; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprost; Disease Models, Animal; Fatty Liver; Insulin; Insulin Resistance; Leptin; Liver; Macrophages; Male; Membrane Proteins; Obesity; Panniculitis; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha | 2009 |
The effect of intragastric balloon on plasma ghrelin, leptin, and adiponectin levels in patients with morbid obesity.
Ghrelin and leptin are hormones regulating appetite and metabolic processes. Adiponectin plays an important role in the modulation of glucose and lipid metabolism.. The objective of the study was to evaluate the levels of plasma ghrelin, leptin, and adiponectin in obese subjects treated with bioenterics intragastric balloon (BIB), low-calorie diet (1500 kcal), and physical exercise.. BIB was placed for 6 months in 21 subjects with body mass index 47.3 +/- 5.7. The control group consisted of 15 morbidly obese subjects treated with a low-calorie diet and physical effort. Plasma hormone levels were determined by RIA.. In the BIB group, the insertion of the balloon caused a considerable reduction in body mass over a 6-month period (17.1 +/- 8.0 kg) as compared with the control group (3.2 +/- 6.4 kg). After 1 month, the levels of ghrelin increased from 621.9 +/- 182.4 to 903.9 +/- 237 pg/ml and thereafter gradually decreased, reaching the starting level 3 months after the removal of the balloon. In the same group, the levels of leptin decreased from 61.3 +/- 36.7 to 39.9 +/- 17.5 ng/ml. In the control group, the corresponding levels of ghrelin and leptin remained relatively stable. During the observation period, in the BIB group, the levels of adiponectin remained unchanged as opposed to a transient increase noted in the control group.. In patients with morbid obesity, weight loss induced by BIB is associated with a decrease in plasma leptin and a transient elevation of plasma ghrelin. It is likely that the changes in hormones regulating the energy balance caused by BIB can prevent an increase in adiponectin level. Topics: Adiponectin; Adult; Appetite; Blood Glucose; Body Mass Index; Body Weight; Catheterization; Diet, Reducing; Energy Metabolism; Exercise; Female; Ghrelin; Glucose Tolerance Test; Humans; Leptin; Male; Middle Aged; Obesity, Morbid; Stomach; Waist-Hip Ratio; Young Adult | 2009 |
Awa (Tokushima) lactate-fermented tea as well as green tea enhance the effect of diet restriction on obesity in rats.
Drinking tea is recommended for promoting health due to its bioactive nutrients, such as catechins and caffeine. In Tokushima area, we have a unique traditional tea, named Awa tea, which are fermented with Lactobacillus pentosus and Lactobacillus plantarum. The present study was designed to investigate anti-obesity effects of the Awa tea and compare with those of non-fermented green tea. Obese male Wistar rats (19 weeks of age) were given by low energy diets containing 3% of Awa and green tea extracts, respectively, or without any tea extracts (control), for 4 weeks. Awa tea contained smaller amount of catechins than green tea, although they contained similar amounts of polyphenols. This finding indicates that there are distinct kinds of polyphenols from catechins. The diets containing Awa and green tea extracts further decreased whole body weight, fat tissue mass and plasma leptin level, compared with control diet. In addition, their diets increased the daily amount of lipid excreted to feces and total 24-h-energy consumption, compared with the control group. However, there is no significant difference in these anti-obesity effects between Awa tea and green tea. Our results indicate that Awa lactate-fermented tea as well as green tea similarly enhance the effect of diet restriction on obesity, at least in part, through the increase in fat energy consumption and the decrease in fat absorption in rats. Topics: Adipose Tissue; Animals; Body Weight; Camellia sinensis; Combined Modality Therapy; Diet, Reducing; Disease Models, Animal; Energy Metabolism; Fermentation; Insulin; Lactobacillus plantarum; Leptin; Lipid Metabolism; Male; Obesity; Plant Extracts; Rats; Rats, Wistar; Tea | 2009 |
Prolonged exposure to high dietary lipids is not associated with lipotoxicity in heart failure.
Previous studies have reported that elevated myocardial lipids in a model of mild-to-moderate heart failure increased mitochondrial function, but did not alter left ventricular function. Whether more prolonged exposure to high dietary lipids would promote a lipotoxic phenotype in mitochondrial and myocardial contractile function has not been determined. We tested the hypothesis that prolonged exposure to high dietary lipids, following coronary artery ligation, would preserve myocardial and mitochondrial function in heart failure. Rats underwent ligation or sham surgery and were fed normal (10% kcal fat) (SHAM, HF) or high fat diet (60% kcal saturated fat) (SHAM+FAT, HF+FAT) for sixteen weeks. Although high dietary fat was accompanied by myocardial tissue triglyceride accumulation (SHAM 1.47+/-0.14; SHAM+FAT 2.32+/-0.14; HF 1.34+/-0.14; HF+FAT 2.21+/-0.20 micromol/gww), fractional shortening was increased 16% in SHAM+FAT and 28% in HF+FAT compared to SHAM and HF, respectively. Despite increased medium-chain acyl-CoA dehydrogenase (MCAD) activity in interfibrillar mitochondria (IFM) of both SHAM+FAT and HF+FAT, dietary lipids also were associated with decreased state 3 respiration using palmitoylcarnitine (SHAM 369+/-14; SHAM+FAT 307+/-23; HF 354+/-13; HF+FAT 366+/-18 nAO min(-1) mg(-1)) in SHAM+FAT compared to SHAM and HF+FAT. State 3 respiration in IFM also was decreased in SHAM+FAT relative to SHAM using succinate and DHQ. In conclusion, high dietary lipids promoted myocardial lipid accumulation, but were not accompanied by alterations in myocardial contractile function typically associated with lipotoxicity. In normal animals, high dietary fat decreased mitochondrial respiration, but also increased MCAD activity. These studies support the concept that high fat feeding can modify multiple cellular pathways that differentially affect mitochondrial function under normal and pathological conditions. Topics: Acyl-CoA Dehydrogenase; Acyl-CoA Dehydrogenase, Long-Chain; Adiponectin; Animals; Blood Glucose; Body Weight; Butyryl-CoA Dehydrogenase; Dietary Fats; Echocardiography; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Nonesterified; Hemodynamics; Insulin; Leptin; Male; Mitochondria; Mitochondrial Proteins; Organ Size; Oxidative Phosphorylation; Rats; Rats, Wistar | 2009 |
Provision of a voluntary exercise environment enhances running activity and prevents obesity in Snark-deficient mice.
The present study was performed to investigate the involvement of SNARK in physical activity levels in mice. To examine the acute effect of SNARK deficiency on voluntary running, Snark-deficient mice (Snark(+/-): n = 16) and their wild-type counterparts (Snark(+/+): n = 16) were assigned to sedentary or exercise (1 wk voluntary wheel running) groups. In addition, to clarify the differences in voluntary running activity and its effect between genotypes, mice (Snark(+/+): n = 16; Snark(+/-): n = 16) were also kept in individual cages with/without a running wheel for 5 mo. Unexpectedly, in both voluntary running experiments, running distances were increased in Snark(+/-) mice compared with Snark(+/+) mice. Under sedentary conditions, body and white adipose tissue weights were increased significantly in Snark(+/-) mice. However, no significant differences were observed between the two genotypes under exercise conditions, and the values were significantly less than those under sedentary conditions in the long-term experiment. In the short-term experiment, serum interleukin-6 level in exercised Snark(+/+) mice was the same as that in sedentary Snark(+/+) mice, whereas that in sedentary Snark(+/-) mice was significantly lower than in the other groups. In contrast, serum leptin level was reduced significantly in exercised Snark(+/-) mice compared with sedentary Snark(+/-) mice. The results of this study demonstrated that exposure to an environment that allows voluntary exercise promotes increased running activity and prevents obesity in Snark-deficient mice. Topics: Adenylate Kinase; Animals; Body Temperature; Body Weight; Eating; Female; Glycogen; Histocytochemistry; Interleukin-6; Leptin; Male; Mice; Mice, Knockout; Obesity; Organ Size; Physical Conditioning, Animal; Protein Serine-Threonine Kinases; Running | 2009 |
Disengaging insulin from corticosterone: roles of each on energy intake and disposition.
Corticosterone and insulin play complex roles in the amount and composition of calories ingested, and the utilization and deposition of this energy. Understanding the interplay of these two hormones is complicated because increasing concentrations of corticosterone dose-dependently increase circulating insulin levels. We addressed individual contributions of each hormone by controlling, at steady-state levels, corticosterone (by adrenalectomy and exogenous replacement) and insulin (by streptozotocin-induced destruction of pancreatic beta-cells and exogenous replacement) across a spectrum of concentrations in rats, creating 8 hormonal combinations. For 5 days after surgery, all rats received chow. At day 5, they were subdivided into those that continued to receive chow and those that had a choice between chow, lard, and 32% sucrose for a further 5 days. During the choice/chow period, total calories ingested were stimulated by corticosterone and choice diet, and subject to a corticosterone-insulin interaction. Sucrose, but not lard, intake was stimulated by insulin. Body weight was increased by insulin, decreased by high corticosterone, and unaffected by diet. White adipose tissue depot weights were stimulated by insulin, corticosterone, and diet. Plasma triglycerides, free fatty acids, total ketone bodies, glucose, and glycerol were all significantly increased by corticosterone and the choice diet but inhibited by insulin. In contrast, plasma leptin was only increased by insulin and diet, plasma glucagon and liver glycogen was only affected by insulin and liver triglycerides, and arcuate nucleus proopiomelanocortin mRNA was only influenced by diet. Collectively, these data show that corticosterone and insulin determine the intake, form, and compartmentalization of energy both independently and interactively. Topics: Adrenalectomy; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Corticosterone; Diabetes Mellitus, Experimental; Disease Models, Animal; Energy Intake; Energy Metabolism; Glycogen; Insulin; Leptin; Liver; Male; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Streptozocin; Triglycerides | 2009 |
High-fat diet decreases tyrosine hydroxylase mRNA expression irrespective of obesity susceptibility in mice.
Tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of dopamine, a key neurotransmitter in the regulation of food intake. This study examined tyrosine hydroxylase mRNA expression in obese mice fed a high-fat diet. After 8 week feeding of high-fat diet mice were classified as diet-induced obese and obese-resistant according to body weight gain. They were then placed on different dietary interventions including a high-fat diet, a low-fat diet and an energy-restricted high-fat diet for six weeks. The control group was fed a low-fat diet. The results revealed that tyrosine hydroxylase mRNA expression was significantly decreased in the ventral tegmental area (VTA), ventromedial hypothalamic nucleus (VMH), and substantia nigra (SN) of the high-fat diet-induced obese (-29%, -26% and -26%) and obese-resistant mice (-21%, -24% and -18%) compared to controls. After switching the diet from high to low-fat diet tyrosine hydroxylase mRNA was increased in the VTA, VMH, and SN of the diet-induced obese mice and in the VMH, and SN of the obese-resistant mice. Energy restriction, even with high-fat feeding, reduced tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN compared to controls. In addition, tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN showed a significant negative correlation with plasma leptin levels. This study suggests that the up- or down-regulation of tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN is mainly due to the intake of macronutrient type rather than body weight. Topics: Adipocytes, White; Animals; Body Composition; Body Weight; Brain; Diet; Dietary Fats; Down-Regulation; Energy Intake; Genetic Predisposition to Disease; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; RNA, Messenger; Substantia Nigra; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Ventromedial Hypothalamic Nucleus | 2009 |
The STEDMAN project: biophysical, biochemical and metabolic effects of a behavioral weight loss intervention during weight loss, maintenance, and regain.
The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body composition, metabolic rate, hormones, and 80 intermediary metabolites measured by mass spectrometry. In 27 obese adults in a behavioral weight loss intervention, median weight decreased 13.9 lb over the first 6 months, then reverted towards baseline by 12 months. Insulin resistance (HOMA) was partially ameliorated in the first 6 months and showed sustained improvement at 12 months despite weight regain. Ghrelin increased with weight loss and reverted to baseline, whereas leptin and PYY fell at 6 months and remained persistently low. NPY levels did not change. Factors possibly contributing to sustained improvement in insulin sensitivity despite weight regain include adiponectin (increased by 12 months), IGF-1 (increased during weight loss and continued to increase during weight regain), and visceral fat (fell at 6 months but did not change thereafter). We observed a persistent reduction in free fatty acids, branched chain amino acids, and related metabolites that may contribute to improved insulin action. These findings provide evidence for sustained benefits of weight loss in obese humans and insights into mechanisms. Topics: Adiponectin; Adult; Behavior Therapy; Biomarkers; Body Weight; Diet; Energy Metabolism; Female; Ghrelin; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Middle Aged; Neuropeptide Y; Obesity; Peptide YY; Weight Gain; Weight Loss | 2009 |
The passive coping Roman Low Avoidance rat, a non-obese rat model for insulin resistance.
The aim of the study was develop to an animal model that links coping style to insulin resistance. We hypothesized that the psychogenetically selected Roman Low Avoidance (RLA) rats may serve as such a model. To test this hypothesis, we submitted both RLA and Roman High avoidance (RHA) rats to a series of intravenous glucose tolerance tests (IVGTT). These IVGTT were followed by post mortem metabolic characterization of the selection lines. It was found that plasma insulin levels are markedly elevated in the passively coping RLA rat, both in baseline conditions and during the intravenous glucose tolerance tests. The elevation in plasma insulin was accompanied with increased levels of plasma corticosterone, FFA, leptin and triglycerides but not by changes in body weight. We conclude that the passive, highly emotional RLA rat is metabolically different from both the RHA rat and the standard control Wistar rat and may serve as a non-obese animal model for insulin resistance. Topics: Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Blood Glucose; Body Weight; Disease Models, Animal; Drinking; Eating; Exploratory Behavior; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Male; Rats; Rats, Inbred Strains | 2009 |
The role of leptin and cortisol in hyperactivity in patients with acute and weight-recovered anorexia nervosa.
In food-restricted rats, leptin as well as corticotropin releasing factor attenuate semistarvation-induced hyperactivity (SIH). Results from studies in patients with anorexia nervosa (AN) showed an association between excessive physical activity (PA) and leptin. One recent report suggests a role for cortisol in PA. In this study, we assessed the relationships between PA and both, cortisol and leptin levels at the same time in patients with acute anorexia nervosa (acAN) in comparison to recovered patients (recAN).. Plasma leptin, plasma cortisol, body mass index (BMI), and expert-ratings of qualities of PA were assessed in 36 acAN patients, 27 recAN patients and 44 healthy control woman (HCW). Regression analyses were used to predict PA using BMI, leptin and cortisol levels as predictor variables.. Leptin levels but not cortisol significantly contributed to the prediction of PA in acAN. In recAN PA was not elevated and not related to endocrine parameters but correlated positively with core eating disorder symptoms.. Our work lends support to the proposed inverse association between peripheral leptin levels and excessive physical activity in AN. This relationship is specific to the state of semistarvation. The role of additional mediators remains to be clarified. Topics: Adolescent; Adult; Anorexia Nervosa; Body Weight; Electrochemistry; Female; Humans; Hydrocortisone; Hyperkinesis; Leptin; Regression Analysis; Young Adult | 2009 |
Effects of trans-10,cis-12 conjugated linoleic acid on body composition in genetically obese mice.
Conjugated linoleic acid (CLA) has shown a number of biologically beneficial effects, including prevention of obesity. The purpose of this study was to test effects of dietary supplementation of 0.5% trans-10,cis-12 CLA in a high fat diet in neuronal basic helix-loop-helix 2 knock-out animals (N2KO), which is a unique animal model representing adult-onset inactivity-related obesity. Eight wild-type (WT) and eight N2KO female mice were fed either 0.5% trans-10,cis-12 CLA-containing diet or control diet (with 20% soybean oil diet) for 12 weeks. Body weights, food intake, adipose tissue weights, body compositions, and blood parameters were analyzed. Overall, N2KO animals had greater body weights, food intake, adipose tissue weights, and body fat compared to WT animals. CLA supplementation decreased overall body weights and total fat, and the effect of dietary CLA on adipose tissue reduction was greater in N2KO than in WT mice. Serum leptin and triglyceride levels were reduced by CLA in both N2KO and WT animals compared to control animals, while there was no effect by CLA on serum cholesterol. The effect of CLA to lower fat mass, increase lean body mass, and lower serum leptin and triglycerides in sedentary mice supports the possibility of using CLA to prevent or alleviate ailments associated with obesity. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Dietary Supplements; Energy Intake; Female; Leptin; Linoleic Acids, Conjugated; Mice; Mice, Knockout; Mice, Obese; Obesity; Triglycerides | 2009 |
Thin healthy women have a similar low bone mass to women with anorexia nervosa.
An association between anorexia nerviosa (AN) and low bone mass has been demonstrated. Bone loss associated with AN involves hormonal and nutritional impairments, though their exact contribution is not clearly established. We compared bone mass in AN patients with women of similar weight with no criteria for AN, and a third group of healthy, normal-weight, age-matched women. The study included forty-eight patients with AN, twenty-two healthy eumenorrhoeic women with low weight (LW group; BMI < 18.5 kg/m2) and twenty healthy women with BMI >18.5 kg/m2 (control group), all of similar age. We measured lean body mass, percentage fat mass, total bone mineral content (BMC) and bone mineral density in lumbar spine (BMD LS) and in total (tBMD). We measured anthropometric parameters, leptin and growth hormone. The control group had greater tBMD and BMD LS than the other groups, with no differences between the AN and LW groups. No differences were found in tBMD, BMD LS and total BMC between the restrictive (n 25) and binge-purge type (n 23) in AN patients. In AN, minimum weight (P = 0.002) and percentage fat mass (P = 0.02) explained BMD LS variation (r2 0.48) and minimum weight (r2 0.42; P = 0.002) for tBMD in stepwise regression analyses. In the LW group, BMI explained BMD LS (r2 0.72; P = 0.01) and tBMD (r2 0.57; P = 0.04). We concluded that patients with AN had similar BMD to healthy thin women. Anthropometric parameters could contribute more significantly than oestrogen deficiency in the achievement of peak bone mass in AN patients. Topics: Adolescent; Adult; Age of Onset; Anorexia Nervosa; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Diagnostic and Statistical Manual of Mental Disorders; Estrogens; Female; Human Growth Hormone; Humans; Leptin; Organ Size; Reference Values; Thinness; Young Adult | 2009 |
Effects of dietary energy and protein density on plasma concentrations of leptin and metabolic hormones in dairy heifers.
The hormonal and metabolic signals that communicate the level of body energy reserves to the reproductive-mammary axis remain undefined in dairy cattle; consequently, our hypothesis was that leptin may fulfill this role. Our objectives were to determine the effects of diets differing in energy and protein density on dry matter intake (DMI), growth traits [body weight (BW), body condition score (BCS), back-fat (BF) thickness], and temporal changes in plasma concentrations of leptin, insulin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), glucose, and nonesterified fatty acids (NEFA) in dairy heifers during the pre- and postpubertal periods. In period 1, heifers were randomly allotted (n = 10/diet) at 103 kg of BW to diets for a predicted average daily gain of 1.10 (high, H), 0.80 (medium, M), or 0.50 kg/d (low, L). Five heifers in each of the H and L groups were further studied during period 2, either at 12 mo of age (HA, LA) or at 330 kg of BW (HW, LW). The data provide evidence that 1) DMI (18%), BW (17%), and BF (5%) together explained 40% of the variation in plasma leptin concentrations (r(2) = 0.396); 2) unlike the acute postprandial increase in plasma insulin as a result of increased nutrient density (H 1.42 +/- 0.09, M 1.02 +/- 0.09, L 0.68 +/- 0.11 ng/mL), plasma leptin concentrations did not respond acutely with a distinct postprandial profile; 3) although plasma leptin concentrations increased with age, leptin at puberty did not differ among treatment groups (H 5.63 +/- 2.48, M 4.28 +/- 0.55, L 4.12 +/- 0.72 ng/mL) and there was no evidence of an abrupt transition in prepubertal plasma leptin concentrations; 4) plasma leptin concentrations may not be a critical trigger for puberty in rapidly growing heifers, but are apparently essential for puberty in heifers with normal or restricted growth rates; and 5) plasma concentrations of insulin (H 0.59 +/- 0.07, M 0.43 +/- 0.09, L 0.30 +/- 0.09 ng/mL), IGF-1 (H 151.08 +/- 16.47, L 82.51 +/- 17.47 ng/mL), and glucose (H 81.35 +/- 3.39, M 73.59 +/- 2.34, L 68.25 +/- 3.39 mg/dL) reflected nutrient density, whereas GH (H 1.82 +/- 0.23, L 5.87 +/- 0.45 ng/mL) and NEFA (H 209.54 +/- 50.83, L 234.93 +/- 48.97 microM) were inversely related to the plane of nutrition. Collectively, these data suggest that plasma concentrations of leptin may play a role in long-term regulation of energy reserves and puberty in growing Holstein heifers. Topics: Adipose Tissue; Animals; Body Weight; Cattle; Dairying; Diet; Dietary Proteins; Eating; Energy Intake; Female; Hormones; Leptin; Random Allocation; Sexual Maturation; Time Factors | 2009 |
Performance and metabolic and endocrine changes with emphasis on glucose metabolism in high-yielding dairy cows with high and low fat content in liver after calving.
Elevated liver fat content occurs in high-yielding dairy cows during the transition from pregnancy to lactation after fat mobilization and may affect hepatic glucose metabolism, but the degree of liver fat storage is highly variable. Therefore, we studied metabolic and endocrine changes and hepatic glucose metabolism in cows that markedly differ in liver fat content. Multiparous cows from the same herd with high (HFL; n = 10) and low (LFL; n = 10) liver fat contents (mean of d 1, 10, and 21 after calving for each cow, respectively) were studied from 60 d before expected calving to 56 d in milk. Cows were fed ad libitum and all cows received the same diets. Liver samples were taken on d 1, 10, and 21 after calving; mean fat content (+/-SEM) in liver of HFL cows was 174 +/- 9.6 mg/g, whereas mean liver fat content in LFL cows was 77 +/- 3.3 mg/g. Blood samples were taken 20 and 7 d before expected calving and 0, 7, 14, 28, and 56 d after calving to measure plasma concentrations of nonesterified fatty acids, beta-hydroxybutyrate, glucose, insulin, glucagon, insulin-like growth factor-I, and leptin. In liver, glycogen content as well as mRNA levels of phosphoenolpyruvate carboxykinase, pyruvate carboxylase, glucose-6-phosphatase, and glucose transporter were measured by quantitative real-time PCR. Back fat thickness decreased and dry matter intake increased with onset of lactation, and back fat thickness was higher but dry matter intake was lower in HFL than in LFL. Energy-corrected milk yield did not differ between groups, but milk fat content was higher and lactose content was lower in HFL than LFL at the beginning of lactation. Energy balance was more negative in HFL than in LFL. Plasma nonesterified fatty acids and beta-hydroxybutyrate concentrations increased and plasma glucose concentration tended to decrease more in HFL than LFL with onset of lactation. Glucagon to insulin ratios increased more in HFL than LFL with onset of lactation. Hepatic glycogen content was higher in LFL than HFL, whereas mRNA levels of glucose-6-phosphatase and pyruvate carboxylase were higher in HFL than in LFL, and cytosolic phosphoenolpyruvate carboxykinase mRNA level increased similarly after parturition in both groups. In conclusion, an elevated liver fat content was related to greater fat mobilization and reduced feed intake and was associated with effects on hepatic glucose metabolism. As environment and feeding management were the same, individual cow factors were respon Topics: Adipose Tissue; Animals; Body Weight; Cattle; Dairying; Diet; Eating; Enzymes; Female; Gene Expression Regulation, Enzymologic; Glucose; Glucose Transporter Type 2; Insulin-Like Growth Factor I; Lactation; Leptin; Liver; Milk; Postpartum Period; Pregnancy | 2009 |
A reappraisal on the ability of leptin to induce fever.
Leptin is often regarded as a mediator of fever, even though an in-depth analysis of the dose-dependent effects of leptin on body temperature (T(b)), pro-inflammatory cytokines, and circulating leptin has never been performed. In the present study, such an analysis was performed in rats that were food deprived (lower baseline levels of leptin) or free feeding (higher baseline levels of leptin). In a relatively cool environment (22 degrees C), rats deprived of food for 24 h exhibited mild (approximately 0.5 degrees C) hypothermia. Leptin infusion (250 microg/kg iv) elevated the T(b) of the food-deprived rats to a normothermic level, an effect that peaked (120 min post-infusion) when plasma leptin was at a level (approximately 8 ng/mL) often found in leptin-responsive subjects. Increasing the leptin dose to 1000 microg/kg did not produce any further (febrile) elevation in the T(b) of food-deprived rats. The anti-hypothermic effect of leptin in food-deprived rats was not associated with any rise in the plasma levels of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. In free-feeding rats kept in a cooler (22 degrees C) or warmer (28 degrees C) environment, leptin infusion failed to alter T(b) or to produce any surge in plasma TNF-alpha or IL-6, even when the dose infused (3500 microg/kg iv) resulted in excessive, non-physiological rises in plasma leptin (approximately 542 ng/mL at 30 min; approximately 75 ng/mL at 120 min post-infusion). In contrast, free-feeding rats in the same experimental set-up were able to respond to a low dose (2 microg/kg iv) of IL-1beta with a typical biphasic fever, which was associated with surges in plasma TNF-alpha and IL-6. Collectively, our data show that an acute rise in plasma leptin to a level within or fairly above the physiological range does not induce fever. These results challenge the idea that leptin may be a mediator of fever. Topics: Analysis of Variance; Animals; Body Temperature; Body Weight; Dose-Response Relationship, Drug; Feeding Behavior; Fever; Food Deprivation; Interleukin-1beta; Interleukin-6; Leptin; Male; Rats; Rats, Wistar; Time Factors; Tumor Necrosis Factor-alpha | 2009 |
Fenofibrate inhibits adipocyte hypertrophy and insulin resistance by activating adipose PPARalpha in high fat diet-induced obese mice.
Peroxisome proliferator-activated receptor alpha (PPARalpha) activation in rodents is thought to improve insulin sensitivity by decreasing ectopic lipids in non-adipose tissues. Fenofibrate, a lipid-modifying agent that acts as a PPARalpha agonist, may prevent adipocyte hypertrophy and insulin resistance by increasing intracellular lipolysis from adipose tissue. Consistent with this hypothesis, fenofibrate decreased visceral fat mass and adipocyte size in high fat diet-fed obese mice, and concomitantly increased the expression of PPARalpha target genes involved in fatty acid beta-oxidation in both epididymal adipose tissue and differentiated 3T3-L1 adipocytes. However, mRNA levels of adipose marker genes, such as leptin and TNFalpha, were decreased in epididymal adipose tissue by fenofibrate treatment. Fenofibrate not only reduced circulating levels of free fatty acids and triglycerides, but also normalized hyperinsulinemia and hyperglycemia in obese mice. Blood glucose levels of fenofibrate-treated mice were significantly reduced during intraperitoneal glucose tolerance test compared with obese controls. These results suggest that fenofibrate-induced fatty acid beta-oxidation in visceral adipose tissue may be one of the major factors leading to decreased adipocyte size and improved insulin sensitivity. Topics: 3T3 Cells; Adipocytes; Animals; Blood Glucose; Body Weight; Cell Enlargement; Dietary Fats; Fenofibrate; Gene Expression Regulation; Glucose Tolerance Test; Hypolipidemic Agents; Insulin; Insulin Resistance; Leptin; Lipids; Mice; Mice, Inbred C57BL; Mice, Obese; PPAR alpha; Tumor Necrosis Factor-alpha | 2009 |
Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions.
Treatment of diabetes type 2 using chronic pharmacological inhibition of dipeptidyl peptidase 4 (DP4) still requires an in-depth analysis of models for chronic DP4 deficiency, because adverse reactions induced by some DP4 inhibitors have been described.. In the present study, a novel congenic rat model of DP4 deficiency on a "DP4-high" DA rat genetic background was generated (DA.F344-Dpp4(m)/ SvH rats) and comprehensively phenotyped.. Similar to chronic pharmacological inhibition of DP4, DP4 deficient rats exhibited a phenotype involving reduced diet-induced body weight gain and improved glucose tolerance associated with increased levels of glucagon-like peptide-1 (GLP-1) and bound leptin as well as decreased aminotransferases and triglycerides. Additionally, DA.F344-Dpp4(m)/SvH rats showed anxiolytic-like and reduced stress-like responses, a phenomenon presently not targeted by DP4 inhibitors. However, several immune alterations, such as differential leukocyte subset composition at baseline, blunted natural killer cell and T-cell functions, and altered cytokine levels were observed.. While this animal model confirms a critical role of DP4 in GLP-1-dependent glucose regulation, genetically induced chronic DP4 deficiency apparently also affects stress-regulatory and immuneregulatory systems, indicating that the use of chronic DP4 inhibitors might have the potential to interfere with central nervous system and immune functions in vivo. Topics: Animals; Animals, Congenic; Body Weight; Cytokines; Dipeptidyl Peptidase 4; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Killer Cells, Natural; Leptin; Phenotype; Rats; Rats, Inbred F344; T-Lymphocytes; Transaminases; Triglycerides | 2009 |
Osteoarthitis of leptin-deficient ob/ob mice in response to biomechanical loading in micro-CT.
Mechanotransduction is the mechanism that due to reacting chondrocytes on biomechanical loading of body mass. Higher biomechanical loading lead to increased degeneration of chondrocytes, whereas moderate loading is protecting. This suggests that body fat regulates bone metabolism first by means of hormonal factors and second that the effects of muscle and loading are signaling factors in mechanotransduction. Leptin, a peptide hormone produced predominantly by white fat cells, is one of these hormonal factors. The aim of this study was to investigate and measure the different effects of weight-bearing on trabecular bone formation in mice without the stimulation of leptin and with or without osteoarthritis.. 40 C57BL/ 6J ob/ob-mice in the age of 20 weeks have been devided into two groups with an ad-libitum-diet and with reduced diet. The hip- and knee-joints have been examinated in micro-CT-scan and histomorphologically.. Animals with an ad-libitum-diet were found to increase body weight significantly at the age of six weeks in comparison with lean mice. At the age of twenty weeks the obese mice were almost twice as heavy as the lean mice. Significant statistical differences are shown between the two groups for body weight and bone mineral density. Examination of trabecular bone in micro-CT revealed that the only statistically significant difference between the two groups was the trabecular number for the proximal femur. High weight-bearing insignificantly improved all trabecular bone parameters in the obese mice. Correlation was found between trabecular number and bone mineral density on the one hand and body weight on the other hand. The correlation between body weight and osteoarthritis shows a significant increase in grade of osteoarthritis as body weight increases in hip-joint and knee-joint but not in osteoarthritis-positive (OP) versus osteoarthritis-negative (ON) mices. The correlation of the hip-joint between micro-CT data and body weight shows an increase in these data as body weight increases in OP mices. The correlation of the hip-joint between micro-CT data and osteoarthritis shows a decrease in these data as osteoarthritis increases in OP mices. The correlation of the knee-joint between micro-CT data and body weight shows differencies between ON and OP mices. The correlation of the knee-joint between micro-CT data and osteoarthritis shows an increase in these data as osteoarthritis increases in OP mices.. biomechanical loading led to decreased bone mineral density by a decrease in the number of trabeculae. Trabecular thickness was not increased by biomechanical loading in growing mice. Decreased body weight in leptin-deficient mice protects against bone loss. This finding is consistent with the principle of light-weight construction of bone. Differences in osteoarthritis-positive and osteoarthritis-negative mices show the eventual importance of diet in leptin-deficience. It is not possible to conclude that these results also apply to human beings. Topics: Animals; Biomechanical Phenomena; Body Weight; Bone Density; Femur; Hindlimb; Hip Joint; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Osteoarthritis; Stress, Mechanical; Tibia; Tomography, X-Ray Computed; Weight-Bearing | 2009 |
Photoperiodic regulation of satiety mediating neuropeptides in the brainstem of the seasonal Siberian hamster (Phodopus sungorus).
Central regulation of energy balance in seasonal mammals such as the Siberian hamster is dependent on the precise integration of short-term satiety information arising from the gastrointestinal tract with long-term signals on the status of available energy reserves (e.g. leptin) and prevailing photoperiod. Within the central nervous system, the brainstem nucleus of the solitary tract (NTS) and the parabrachial nucleus (PBN) are major relay nuclei that transmit information from the gastrointestinal tract to higher forebrain centres. We extended studies on the seasonal programming of the hypothalamus to examine the effect of the photoperiod on neuropeptidergic circuitries of this gut-brain axis. In the NTS and PBN we performed gene expression and immunoreactivity (-ir) studies on selected satiety-related neuropeptides and receptors: alpha-melanocyte stimulating hormone, melanocortin-3 receptor, melanocortin-4 receptor (MC4-R), growth hormone secretagogue-receptor, cocaine- and amphetamine-regulated transcript, preproglucagon (PPG), glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), peptide YY, galanin, neurotensin, and corticotrophin releasing hormone (CRH). Gene expression of PPG and MC4-R, and -ir of CCK and GLP-1, in the NTS were up-regulated after 14 weeks in long-day photoperiod (16 h light:8 h dark) compared to short-days (8 h light:16 h dark), whereas CRH-ir and NT-ir were increased in short-days within the PBN. We suggest that brainstem neuroendocrine mechanisms contribute to the long-term regulation of body mass in the Siberian hamster by a photoperiod-related modulation of satiety signalling. Topics: Animals; Area Postrema; Body Weight; Brain Stem; Cricetinae; Energy Metabolism; Feeding Behavior; Gene Expression Regulation; Leptin; Male; Melatonin; Neuropeptides; Phodopus; Photoperiod; Receptors, Neuropeptide; Satiety Response; Seasons; Solitary Nucleus | 2009 |
A homologous salmonid leptin radioimmunoassay indicates elevated plasma leptin levels during fasting of rainbow trout.
The present study was conducted to establish a homologous radioimmunoassay (RIA) for quantifying plasma leptin (Lep) levels in salmonid species, and to study Lep levels in relation to nutritional status. A part of the Lep peptide, a 14 amino acid long sequence, identical between a Salmo and an Oncorhynchus species was synthesised. Polyclonal antibodies were raised in rabbit against this antigen and both were subsequently used in the development of a RIA protocol for assessing plasma Lep levels. The limit of detection of the assay was 0.3 nM, and intra- and interassay coefficient of variation (CV) were 8.4% and 13%, respectively. Apart from Atlantic salmon and rainbow trout, the assay exhibits measuring parallelism for a range of fish species, including arctic char, Atlantic cod and turbot, suggesting that the established RIA is useful for quantifying Lep levels in several fish species. The RIA indicates that Lep is found in salmonid plasma at levels of 0.5-5 nM, which is comparable with other peptide hormones, and well within the measuring range of the RIA. A study of fed and fasted rainbow trout showed elevated plasma Lep levels during fasting. In addition there was no correlation between Lep levels and condition factor. These data suggest that the relation between circulating Lep levels and energy status differs from that in mammals. While Lep is linked to energy balance, it may not act as an adiposity signal in salmonids, possibly pointing to functional divergence among ectothermic and endothermic vertebrates. Topics: Animals; Antibody Specificity; Body Weight; Body Weights and Measures; Fasting; Flatfishes; Gadiformes; Growth Hormone; Leptin; Oncorhynchus mykiss; Radioimmunoassay; Salmo salar | 2009 |
Rapamycin protects against high fat diet-induced obesity in C57BL/6J mice.
Rapamycin (RAPA), an immunosuprpressive drug used extensively to prevent graft rejection in transplant patients, has been reported to inhibit adipogenesis in vitro. In this study, we investigated the anti-obesity effects of RAPA in C57BL/6J mice on a high-fat diet (HFD). Mice treated with RAPA (2 mg/kg per week for 16 weeks) had reduced body weight and epididymal fat pads/body weight, reduced daily food efficiency, and lower serum leptin and insulin levels compared with the HFD control mice. However, RAPA-treated mice were hyperphagic, demonstrating an increase in food intake. Dissection of RAPA-treated mice revealed a marked reduction in fatty liver scores, average fat cell size, and percentage of large adipocytes of retroperitoneal and epididymal white adipose tissue (RWAT and EWAT), compared to the HFD control mice. These results suggest that RAPA prevented the effect of the high-fat diet on the rate of accretion in body weight via reducing lipid accumulation, despite greater food intake. It is likely that RAPA may serve as a potential strategy for body weight control and/or anti-obesity therapy. Topics: Adipocytes; Animals; Blood Glucose; Body Weight; Cell Size; Diet; Dietary Fats; Eating; Immunosuppressive Agents; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Sirolimus | 2009 |
Body weight, insulin resistance, and serum adipokine levels 2 years after 2 types of bariatric surgery.
Bariatric surgery reverses obesity-related comorbidities, including type 2 diabetes mellitus. Several studies have already described differences in anthropometrics and body composition in patients undergoing Roux-en-Y gastric bypass compared with laparoscopic adjustable gastric banding, but the role of adipokines in the outcomes after the different types of surgery is not known. Differences in weight loss and reversal of insulin resistance exist between the 2 groups and correlate with changes in adipokines.. Fifteen severely obese women (mean body mass index [BMI]: 46.7 kg/m(2)) underwent 2 types of laparoscopic weight loss surgery (Roux-en-Y gastric bypass=10, adjustable gastric banding=5). Weight, waist and hip circumference, body composition, plasma metabolic markers, and lipids were measured at set intervals during a 24-month period after surgery.. At 24 months, patients who underwent Roux-en-Y were overweight (BMI 29.7 kg/m(2)), whereas patients who underwent gastric banding remained obese (BMI 36.3 kg/m(2)). Patients who underwent Roux-en-Y lost significantly more fat mass than patients who underwent gastric banding (mean difference 16.8 kg, P<.05). Likewise, leptin levels were lower in the patients who underwent Roux-en-Y (P=.003), and levels correlated with weight loss, loss of fat mass, insulin levels, and Homeostasis Model of Assessment 2. Adiponectin correlated with insulin levels and Homeostasis Model of Assessment 2 (r=-0.653, P=.04 and r=-0.674, P=.032, respectively) in the patients who underwent Roux-en-Y at 24 months.. After 2 years, weight loss and normalization of metabolic parameters were less pronounced in patients who underwent gastric banding compared with patients who underwent Roux-en-Y gastric bypass. Our findings require confirmation in a prospective randomized trial. Topics: Adipokines; Adiponectin; Bariatric Surgery; Biomarkers; Body Weight; Female; Follow-Up Studies; Humans; Insulin; Insulin Resistance; Laparoscopy; Leptin; Middle Aged; Obesity, Morbid; Postoperative Period; Recovery of Function; Time Factors; Treatment Outcome; Weight Loss | 2009 |
Plasma adiponectin and insulin sensitivity in overweight and normal-weight middle-aged premenopausal women.
Adiponectin has been reported to regulate systemic insulin sensitivity as a part of a broader control mechanism in energy balance. However, it is not clear whether adiponectin exerts its positive effects on insulin sensitivity equally in a wide range of obesity. We investigated the association of plasma adiponectin concentration with insulin resistance (IR) in a cross-sectional sample of 98 middle-aged premenopausal women with a wide range of obesity. In addition, we studied the relationship between adiponectin, body composition, and blood biochemical and cardiorespiratory fitness variables. Body composition and fat distribution were measured via dual-energy x-ray absorptiometry in normal-weight (NW) (n = 41, body mass index [BMI] < 25 kg/m(2)) and overweight (OW) (n = 57, BMI > or = 25 kg/m(2)) women. Fasting blood samples were obtained; adiponectin, leptin, insulin, glucose, and insulin-like growth factor-I were measured; and IR index was calculated. The IR index from fasting plasma insulin and plasma glucose levels was estimated using the homeostasis model assessment (HOMA), as follows: fasting plasma insulin (in microliter units per milliliter) x fasting plasma glucose (in millimoles per liter)/22.5. Adiponectin was significantly higher (P = .0001) in NW (14.7 +/- 4.7 microg/mL) compared with OW (9.9 +/- 3.1 microg/mL) women. Significant differences (P < .003) in body mass, BMI, percentage of fat mass, fat mass, trunk fat, trunk fat-leg fat ratio, leptin, insulin, and HOMA were also observed between NW and OW groups. Leptin was independently related to plasma adiponectin (beta = -.259, P = .001) in the overall study group. Plasma adiponectin was only related to trunk fat-leg fat ratio (beta = -.242, P = .002) among NW subjects, whereas plasma adiponectin was related to fat-free mass (beta = .182, P = .0001) and HOMA (beta = -.576, P = .002) among OW women. The inverse relationship between adiponectin and leptin concentrations suggests that leptin may be involved in the regulation of adiponectin in middle-aged premenopausal women. Our data also demonstrate that adiponectin may play an important role in sustaining insulin sensitivity only in OW middle-aged premenopausal women. Topics: Absorptiometry, Photon; Adiponectin; Adult; Blood Glucose; Body Composition; Body Weight; Cross-Sectional Studies; Female; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Middle Aged; Overweight; Premenopause | 2009 |
Dietary modulation of ghrelin and leptin and gorging behavior after weight loss in the obese Zucker rat.
In this study, we measured ghrelin and leptin in obese Zucker rats after weight loss induced by calorie restriction using either a low-fat (LF) or high-energy palatable (HEPa) diet. After weight loss, the animals were refed lab chow and offered one hour-palatable test meals on the second and fifteenth days of refeeding. Both LF and HEPa rats lost 10% of their initial body weight (P<0.0001). Plasma ghrelin increased with calorie restriction in both groups (P<0.002) with a tendency to a higher increase in the HEPa group while plasma leptin decreased only in the LF group (P<0.01). Both groups ate the same quantity of chow during refeeding and both groups gorged on palatable diet during test meals at a very high constant intensity in HEPa rats. After one week of refeeding, ghrelin levels remained elevated in HEPa rats (+33.2%; P<0.001) while returning to baseline in LF rats. Plasma leptin remained low in LF rats. We conclude that weight loss on a palatable diet is possible if total energy intake is controlled. After stopping restriction, when a palatable diet is available, observed gorging might be dependent on specific ghrelin and leptin changes. Topics: Adiposity; Animals; Body Weight; Caloric Restriction; Diet; Energy Intake; Feeding Behavior; Ghrelin; Hyperphagia; Leptin; Male; Obesity; Rats; Rats, Zucker; Weight Loss | 2009 |
Relationship between perilipin gene polymorphisms and body weight and body composition during weight loss and weight maintenance.
Genetic variation in the perilipin (PLIN) gene may play a role in the etiology and treatment of obesity.. To examine different polymorphisms in the PLIN gene in relation to body-weight regulation.. 118 subjects followed a 6 wk VLCD, followed by 1 year weight maintenance. Body-weight (BW), body composition, leptin concentration, and polymorphisms of the PLIN gene: PLIN1:rs2289487, PLIN4:rs894160, PLIN6:rs1052700, PLIN5:rs2304795 and PLIN7:rs 2304796 were determined.. BW loss during VLCD was 7.0+/-3.1 kg (p<0.05), and BW regain was 3.7+/-1.4 kg (p<0.05), including changes in body mass index (BMI), waist-circumference, body-composition and leptin concentrations (p<0.05). Linkage disequilibria were observed between PLIN1 and PLIN4: D' >0.9, r2=0.72; PLIN5 and PLIN7: D' >0.9, r2=0.85. In men, body weight, BMI, waist circumference, body fat, leptin concentrations were significantly lower for the haplotype of PLIN1 (C-alleles) and PLIN4 (A-alleles). In women weight loss and loss of fat mass were larger for the haplotype of PLIN1 (C-alleles) and PLIN4 (A-alleles). For PLIN6 genotypes body weight and body fat were lower for homozygotes of the minor allele (T/T) in the men; in the women leptin concentrations were lower. The haplotype of PLIN5 and PLIN7 consisting of A/G and G/G of PLIN5 and A/A of PLIN7 showed a reduction in FM: 5.9+/-0.6 kg vs 3.1+/-0.4 kg, % body fat: 5.5+/-0.6% vs 2.2+/-0.2%, and leptin: 20.5+/-10.8 ng/ml vs 12.9+/-6.7 ng/ml over time in the women (p<0.05).. Since the haplotype of the minor alleles PLIN1-4, PLIN5-7 and PLIN6, was related to body-weight regulation at a lower level of body-weight in the men as well in the women we conclude that the PLIN1-4, 6, and 5-7 locus appears as a genetic influencer of obesity risk in humans. Topics: Adult; Body Composition; Body Weight; Carrier Proteins; Female; Follow-Up Studies; Genetic Predisposition to Disease; Humans; Leptin; Male; Middle Aged; Obesity; Perilipin-1; Phosphoproteins; Risk Factors; Weight Loss | 2009 |
Prenatal stress programming of offspring feeding behavior and energy balance begins early in pregnancy.
To examine the long-term effects of stress experienced early in gestation on the programming of offspring feeding behaviors and energy balance, pregnant mice were exposed to stress during early pregnancy (days 1-7) and adult offspring examined on chow and high fat diets for long-term outcomes. Placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) and insulin-like growth factor 2 (IGF-2) expression was measured to determine the possible sex-specific contribution of prenatal stress (PNS) on fetal programming of embryo growth and development during early pregnancy. PNS mice showed a basal hyperphagia when on chow diet. Prenatal treatment differences were ameliorated when adult mice were on a high fat diet. Interestingly, PNS male mice also had significantly reduced body weights compared to control males on both chow and high fat diets. Body composition analyses revealed reduced body fat and increased lean mass in PNS mice on the high fat diet, but no differences were detected in plasma leptin or insulin-like growth factor 1 (IGF-1) levels. Mechanistic examination of gene expression in embryonic day 12 placentas found that early PNS was associated with increased IGF-2 expression and sex-dependent effects of stress on 11 beta-HSD2, supporting specific aspects of early pregnancy. These studies suggest that the long-term effects of stress during pregnancy on programming of feeding behavior and energy homeostasis begin much earlier in development than previously thought. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Adipose Tissue, Brown; Animals; Blood Glucose; Body Weight; Dietary Fats; Eating; Energy Metabolism; Feeding Behavior; Female; Fetal Development; Homeostasis; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Placenta; Pregnancy; Prenatal Exposure Delayed Effects; Stress, Psychological | 2009 |
Impairment of mitochondrial beta-oxidation in rats under cold-hypoxic environment.
Mitochondrial beta-oxidation of fatty acid provides a major source of energy in mammals. High altitude (HA), characterized by hypobaric hypoxia and low ambient temperatures, causes alteration in metabolic homeostasis. Several studies have depicted that hypoxic exposure in small mammals causes hypothermia due to hypometabolic state. Moreover, cold exposure along with hypoxia reduces hypoxia tolerance in animals. The present study investigated the rate of beta-oxidation and key enzymes, carnitine palmitoyl transferase-I (CPT-I) and hydroxyacyl CoA dehydrogenase (HAD), in rats exposed to cold-hypobaric hypoxic environment. Male Sprague Dawley rats (190-220 g) were randomly divided into eight groups (n = 6 rats in each group): 1 day hypoxia (H1); 7 days hypoxia (H7); 1 day cold (C1); 7 days cold (C7); 1 day cold-hypoxia (CH1); 7 days cold-hypoxia (CH7) exposed; and unexposed control for 1 and 7 days (UC1 and UC7). After exposure, animals were anaesthetized with ketamine (50 mg/kg body weight) and xylazine (10 mg/kg body weight) intraperitonialy and sacrificed. Mitochondrial CPT-I, HAD, (14)C-palmitate oxidation in gastrocnemius muscle and liver, and plasma leptin were measured. Mitochondrial CPT-I was significantly reduced in muscle and liver in CH1 and CH7 as compared to respective controls. HAD activity was significantly reduced in H1 and CH7, and in H1, H7, CH1, and CH7 as compared to unexposed controls in muscle and liver, respectively. A concomitant decrease in (14)C-palmitate oxidation was found. Significant reduction in plasma leptin in hypoxia and cold-hypoxia suggested hypometabolic state. It can be concluded that ss-oxidation of fatty acids is reduced in rats exposed to cold-hypoxic environment due to the persisting hypometabolic state in cold-hypoxia exposure. Topics: 3-Hydroxyacyl CoA Dehydrogenases; Animals; Body Weight; Carbon Isotopes; Carnitine O-Palmitoyltransferase; Cold Temperature; Hypoxia; Leptin; Male; Mitochondria; Muscle, Skeletal; Oxidation-Reduction; Palmitates; Rats; Rats, Sprague-Dawley; Time Factors | 2009 |
Persistent diet-induced obesity in male C57BL/6 mice resulting from temporary obesigenic diets.
Does diet-induced obesity persist after an obesigenic diet is removed? We investigated this question by providing male C57BL/6 mice with free access to two different obesigenic diets followed by a switch to chow to determine if obesity was reversible.. Male C57BL/6 mice were randomly assigned to five weight-matched groups: 1) C group that continuously received a chow diet; 2) HF group on a 60% high fat diet; 3) EN group on the high fat diet plus liquid Ensure; 4) HF-C group switched from high fat to chow after 7 weeks; 5) EN-C group switched from high fat plus Ensure to chow after 7 weeks. All food intake was ad libitum. Body weight was increased after 7 weeks on both obesigenic diets (44.6+/-0.65, 39.8+/-0.63, and 28.6+/-0.63 g for EN, HF, and C groups, respectively) and resulted in elevated concentrations of serum insulin, glucose, and leptin and lower serum triglycerides. Development of obesity in HF and EN mice was caused by increased energy intake and a relative decrease of average energy output along with decreased ambulatory activity. After the switch to chow, the HF-C and EN-C groups lost weight but subsequently maintained a state of persistent obesity in comparison to the C group (34.8+/-1.2, 34.1+/-1.2 vs. 30.8+/-0.8 g respectively; P<0.05) with a 40-50% increase of body fat. All serum hormones and metabolites returned to control levels with the exception of a trend for increased leptin. The HF-C and EN-C groups had an average energy output in line with the C group and the persistent obesity was maintained despite a non-significant increase of energy intake of less than 1 kcal/d at the end of the study.. Our results illustrate the importance of considering the history of energy imbalance in determining body weight and that a persistent elevation of body weight after removal of obesigenic diets can result from very small increases of energy intake. Topics: Adipose Tissue; Animals; Blood Glucose; Body Fat Distribution; Body Weight; Diet; Disease Models, Animal; Energy Intake; Energy Metabolism; Glycerol; Leptin; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Time Factors | 2009 |
Postnatal early overnutrition changes the leptin signalling pathway in the hypothalamic-pituitary-thyroid axis of young and adult rats.
Postnatal early overnutrition (EO) is a risk factor for obesity in adult life. Rats raised in a small litter can develop hyperinsulinaemia, hyperphagia, hyperleptinaemia and hypertension as adults. Since leptin regulates the hypothalamic-pituitary-thyroid axis and the metabolism of thyroid hormones, we studied the leptin signalling pathway in pituitary and thyroid glands of the postnatal EO model. To induce EO, at the third day of lactation the litter size was reduced to three pups per litter (SL group). In control litters (NL group), the litter size was adjusted to 10 pups per litter. Body weight and food intake were monitored. Rat offspring were killed at 21 (weaning) and 180 days old (adulthood). Plasma thyroid hormones, thyroid-stimulating hormone (TSH) and leptin were measured by radioimmunoassay. Proteins of the leptin signalling pathway were analysed by Western blotting. Body weight of offspring in the SL group was higher from the seventh day of lactation (+33%, P < 0.05) until 180 days old (+18%, P < 0.05). Offspring in the SL group showed higher visceral fat mass at 21 and 180 days old (+176 and +52%, respectively, P < 0.05), but plasma leptin was higher only at 21 days (+88%, P < 0.05). The SL offspring showed higher plasma TSH, 3,5,3'-triiodothronine (T(3)) and thyroxine (T(4)) at 21 days (+60, +91 and +68%, respectively, P < 0.05), while the opposite was observed at 180 days regarding thyroid hormones (T(3), -10%; and T(4), -30%, P < 0.05), with no difference in TSH levels. In hypothalamus, no change was observed in the leptin signalling pathway at 21 days. However, lower janus thyrosine kinase 2 (JAK2) and phosphorilated-signal transducer and activator of transcription-3 (p-STAT3) content were detected in adulthood. In pituitary, the SL group presented higher leptin receptors (Ob-R), JAK2 and p-STAT3 content at 21 days and lower JAK2 and STAT3 content at 180 days old. In contrast, in thyroid, the Ob-R expression was lower in young SL rats, while the adult SL group presented higher Ob-R and JAK2 content. We showed that postnatal EO induces short- and long-term effects upon the hypothalamic-pituitary-thyroid axis. These changes may help to explain future development of metabolic and endocrine dysfunctions, such as metabolic syndrome and hypothyroidism. Topics: Age Factors; Aging; Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Blotting, Western; Body Weight; Eating; Female; Hyperphagia; Hypothalamo-Hypophyseal System; Intra-Abdominal Fat; Janus Kinase 2; Lactation; Leptin; Litter Size; Male; Obesity; Overnutrition; Phosphorylation; Radioimmunoassay; Rats; Rats, Wistar; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine | 2009 |
Fat and water 1H MRI to investigate effects of leptin in obese mice.
Leptin is known to be associated with regulation of body weight and fat content. The effects of exogenous leptin on abdominal visceral (VS) and subcutaneous (SC) fat volume and hepatic fat-to-water ratio in leptin-deficient obese mice were investigated by (1)H magnetic resonance imaging (MRI). Chemical shift-selected fat and water (1)H MRI of control and leptin-treated mice were obtained 1 day before treatment and after 7 days of treatment (0.3 mg/kg/day). Hepatic fat-to-water ratio and VS fat volume decreased significantly with treatment, whereas SC fat volume did not change. Noninvasive measurement of fat and water content in different body regions using MRI should prove useful for evaluating new drugs for the treatment of obesity and other metabolic disorders. Topics: Adipose Tissue; Animals; Body Water; Body Weight; Drug Evaluation, Preclinical; Infusions, Subcutaneous; Intra-Abdominal Fat; Leptin; Liver; Magnetic Resonance Imaging; Mice; Mice, Obese; Subcutaneous Fat, Abdominal | 2009 |
[Effect of konjac polysaccharide on levels of leptin and Na+ -K+-ATPase of mice treated with high fat].
To investigate the effect of konjac polysaccharide on serum leptin and intestinal mucosa Na+ -K+-ATPase activity of mice treated with high fat.. Mice were divided into normal control, high-fat control, and high, middle, low dose of konjac polysaccharide combining high fat groups. The mice were feed for twenty days. The levels of serum leptin were determined by ELISA method, and intestinal mucosa Na+ -K+-ATPase activities were determined by spectrophotometry. The body weight, adipose tissue and blood glucose were also examined.. At the 10th day, body weight and postprandial blood glucose of high-fat control group were (31.3 +/- 2.11) g and (7.5 +/- 1.15) mmol/L, those of high dose konjac polysaccharide combining high fat group were(28.0 +/- 2.06) g and (4.8 +/- 0.73) mmol/L. At the 20th day, concentrations of serum leptin and Na+ -K-ATPase activities of high-fat control group were (1078.5 +/- 61.69) pg/ml and (16.2 +/- 1.48) micromol Pi/(mg pro x h), those of high dose konjac polysaccharide combining high fat group were (820.5 +/- 58.52) pg/ml and (11.2 +/- 1.10) micromol Pi/(mg pro x h). All differences between two groups were significant (P < 0.05).. Konjac polysaccharide could decrease level of body weight, postprandial blood glucose, serum leptin and intestinal mucosa Na -K+-ATPase activity of mice treated with high fat. Topics: Amorphophallus; Animals; Blood Glucose; Body Weight; Dietary Fats; Female; Intestinal Mucosa; Leptin; Mice; Polysaccharides; Random Allocation; Sodium-Potassium-Exchanging ATPase | 2009 |
Body weight reduction in rats by oral treatment with zinc plus cyclo-(His-Pro).
We have previously shown that treatment with zinc plus cyclo-(His-Pro) (CHP) significantly stimulated synthesis of the insulin degrading enzyme and lowered plasma insulin and blood glucose levels, alongside improving oral glucose tolerance in genetically type 2 diabetic Goto-Kakizaki (G-K) rats and in aged obese Sprague-Dawley (S-D) rats. Thus, we postulated that zinc plus CHP (ZC) treatment might also improve body weight control in these rats. We therefore determined the effects of ZC treatment on body weights in both genetically diabetic, mature G-K rats and non-diabetic, obese S-D rats.. G-K rats aged 1.5-10 months and non-diabetic overweight or obese S-D rats aged 6-18 months were treated with 0-6 mg CHP plus 0-10 mg zinc L(-1) drinking water for 2-4 weeks, and changes in weight, serum leptin and adiponectin levels, food and water intakes were measured.. The optimal dose of CHP (in combination with zinc) to reduce weight and plasma leptin levels and to increase plasma adiponectin levels was close to 0.1 mg kg(-1) day(-1), in either mature G-K rats and aged overweight or obese S-D rats. Food and water intake significantly decreased in ZC treated rats in both aged S-D rats and mature G-K rats, but not in young S-D and G-K rats.. ZC treatment improved weight control and may be a possible treatment for overweight and obesity. Topics: Adiponectin; Administration, Oral; Age Factors; Animals; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Leptin; Male; Obesity; Peptides, Cyclic; Piperazines; Rats; Rats, Sprague-Dawley; Zinc | 2009 |
The soluble leptin receptor neutralizes leptin-mediated STAT3 signalling and anorexic responses in vivo.
The soluble leptin receptor (SLR) is the major, circulating, leptin-binding protein and, in vitro, the SLR inhibits leptin-binding to cell surface receptors. Here we assessed the effects of the SLR on physiological responses to leptin, in vivo.. SLR and leptin were given as a single injection (intracerebroventricularly, i.c.v.) or by central (i.c.v.) and peripheral (s.c.) infusion to normal adult F344XBN rats. Phosphorylation of hypothalamic STAT3 (Western blot), food intake and body weight, and the thermogenic response in brown adipose tissue (BAT) were measured.. Acute central co-administration of SLR (13.5 microg) and leptin (90 ng) blocked the threefold increase in hypothalamic STAT3 phosphorylation induced by leptin alone, 1 h after the injections. Peripheral leptin infusion (0.1 mg day(-1) for 7 days; s.c.) induced a significant reduction in food intake and body weight, which were partially blocked with a simultaneous central infusion of SLR (4.3 microg day(-1); i.c.v.). In a second experiment, SLR central infusion alone (5.5 microg day(-1)) increased food intake and body weight, suggesting that the SLR was able to neutralize endogenous leptin in the brain. This dose of SLR, infused together with a lower dose of peripheral leptin (0.05 mg day(-1)), abolished the thermogenic response in BAT, but the anorexic responses and weight reduction were only partially attenuated.. These results provide direct evidence that the SLR neutralizes leptin, endogenous or exogenous, in vivo. By neutralizing leptin, the SLR may play a regulatory role in energy homeostasis. Topics: Adipose Tissue, Brown; Animals; Blotting, Western; Body Weight; Dose-Response Relationship, Drug; Eating; Hypothalamus; Leptin; Male; Phosphorylation; Rats; Rats, Inbred BN; Rats, Inbred F344; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor | 2009 |
Gastric carcinogenesis by N-Methyl-N-nitrosourea is enhanced in db/db diabetic mice.
In 2005, a Japanese epidemiological study showed that increase in plasma glucose levels is a risk factor for gastric cancer. However, no animal model has hitherto shown any association between diabetes mellitus and neoplasia in the stomach. Diabetic (db/db) mice have obese and diabetic phenotypes, including hyperglycemia, because of disruption of the leptin receptor. In the present study, effects of hyperglycemia and/or hyperinsulinemia on the development of proliferative lesions were therefore examined in db/db mice given N-methyl-N-nitrosourea (MNU). A total of 120 mice were assigned to four groups: Group A, 40 db/db mice with MNU; Group B, 40 + /db mice with MNU; Group C, 30 misty (wild-type) mice with MNU; Group D, 10 db/db mice without MNU. MNU was given at 60 ppm in drinking water for 20 weeks. Subgroups of animals were sacrificed at weeks 21 and 30 and blood samples were collected to measure glucose, insulin, leptin, and adiponectin concentrations. The removed stomachs were fixed in formalin, and embedded in paraffin for histological examination and immunohistochemistry. At week 30 in Groups A, B, C and D, hyperplasia was observed in 100, 79, 57, and 0%, and dysplasia in 91, 43, 71, and 0%, respectively. Adenocarcinomas and pepsinogen-altered pyloric glands (PAPG), putative preneoplastic lesions, were observed only in Group A, at an incidence of 45%. The serum levels of insulin and leptin were also elevated in Group A. Gastric carcinogenesis by MNU was enhanced in db/db mice, possibly in association with hyperinsulinemia and hyperleptinemia. Topics: Adenocarcinoma; Animals; Body Weight; Carcinogens; Diabetes Complications; Disease Models, Animal; Gastric Mucosa; Insulin; Leptin; Male; Methylnitrosourea; Mice; Mice, Inbred Strains; Precancerous Conditions; Stomach Neoplasms | 2009 |
Phenotypic dichotomy following developmental exposure to perfluorooctanoic acid (PFOA) in female CD-1 mice: Low doses induce elevated serum leptin and insulin, and overweight in mid-life.
The synthetic surfactant, perfluorooctanoic acid (PFOA) is a proven developmental toxicant in mice, causing pregnancy loss, increased neonatal mortality, delayed eye opening, and abnormal mammary gland growth in animals exposed during fetal life. PFOA is found in the sera and tissues of wildlife and humans throughout the world, but is especially high in the sera of children compared to adults. These studies in CD-1 mice aim to determine the latent health effects of PFOA following: (1) an in utero exposure, (2) an in utero exposure followed by ovariectomy (ovx), or (3) exposure as an adult. Mice were exposed to 0, 0.01, 0.1, 0.3, 1, 3, or 5mg PFOA/kg BW for 17 days of pregnancy or as young adults. Body weight was reduced in the highest doses on postnatal day (PND) 1 and at weaning. However, the lowest exposures (0.01-0.3mg/kg) significantly increased body weight, and serum insulin and leptin (0.01-0.1mg/kg) in mid-life after developmental exposure. PFOA exposure combined with ovx caused no additional increase in mid-life body weight. At 18 months of age, the effects of in utero PFOA exposure on body weight were no longer detected. White adipose tissue and spleen weights were decreased at high doses of PFOA in intact developmentally exposed mice, and spleen weight was reduced in PFOA-exposed ovx mice. Brown adipose tissue weight was significantly increased in both ovx and intact mice at high PFOA doses. Liver weight was unaffected in late life by these exposure paradigms. Finally, there was no effect of adult exposure to PFOA on body weight. These studies demonstrate an important window of exposure for low-dose effects of PFOA on body weight gain, as well as leptin and insulin concentrations in mid-life, at a lowest observed effect level of 0.01mg PFOA/kg BW. The mode of action of these effects and its relevance to human health remain to be explored. Topics: Animals; Body Weight; Caprylates; Female; Fluorocarbons; Humans; Insulin; Leptin; Maternal Exposure; Mice; Organ Size; Ovariectomy; Overweight; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Random Allocation | 2009 |
Similar metabolic responses to calorie restriction in lean and obese Zucker rats.
Calorie restriction (CR), which is thought to be largely dependent on the neuroendocrine system modulated by insulin/insulin-like growth factor-I (IGF-I) and leptin signaling, decreases morbidity and increases lifespan in many organisms. To elucidate whether insulin and leptin sensitivities are indispensable in the metabolic adaptation to CR, we investigated the effects of CR on obese Zucker (fa/fa) rats and lean control (+/+) rats. CR did not fully improve insulin resistance in (fa/fa) rats. Nonetheless, CR induced neuropeptide Y (NPY) expression in the hypothalamic arcuate nucleus and metabolism related gene expression changes in the liver in (fa/fa) rats and (+/+) rats. Up-regulation of NPY augmented plasma corticosterone levels and suppressed pituitary growth hormone (GH) expression, thereby modulating adipocytokine production to induce tissue-specific insulin sensitivity. Thus, central NPY activation via peripheral signaling might play a crucial role in the effects of CR, even in insulin resistant and leptin receptor deficient conditions. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Caloric Restriction; Gene Expression Regulation; Ghrelin; Gluconeogenesis; Growth Hormone; Hepatocyte Nuclear Factor 4; Insulin; Leptin; Liver; Mitochondria; Nerve Degeneration; Neuropeptide Y; Obesity; Oxidation-Reduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pituitary Gland; Protein Binding; Rats; Rats, Zucker; Receptors, Leptin; RNA-Binding Proteins; Thinness; Transcription Factors | 2009 |
Forced catch-up growth after fetal protein restriction alters the adipose tissue gene expression program leading to obesity in adult mice.
A mismatch between fetal and postnatal environment can permanently alter the body structure and physiology and therefore contribute later to obesity and related disorders, as revealed by epidemiological studies. Early programming of adipose tissue might be central in this observation. Moreover, adipose tissue secretes adipokines that provide a molecular link between obesity and its related disorders. Therefore, our aim was to investigate whether a protein restriction during fetal life, followed by catch-up growth could lead to obesity in 9-mo-old male mice and could alter the adipose tissue gene expression profile. Dams were fed a low-protein (LP) or an isocaloric control (C) diet during gestation. Postnatal catch-up growth was induced in LP offspring by feeding dams with control diet and by culling LP litters to four pups instead of eight in the C group. At weaning, male mice were fed by lab chow alone (C) or supplemented with a hypercaloric diet (HC), to induce obesity (C-C, C-HC, LP-C, and LP-HC groups). At 9 mo, LP offspring featured increased relative fat mass, hyperglycemia, hypercholesterolemia, and hyperleptinemia. Using a microarray designed to study the expression of 89 genes involved in adipose tissue differentiation/function, we demonstrated that the expression profile of several genes were dependent upon the maternal diet. Among the diverse genes showing altered expression, we could identify genes encoding several enzymes involved in lipid metabolism. These results indicated that offspring submitted to early mismatched nutrition exhibited alterations in adipose tissue gene expression that probably increases their susceptibility to overweight when challenged after weaning with a HC diet. Topics: Adipocytes, White; Adipose Tissue, White; Animals; Blood Glucose; Body Composition; Body Weight; Carbohydrate Metabolism; Diet; Diet, Protein-Restricted; Down-Regulation; Eating; Female; Fetal Development; Fetal Growth Retardation; Gene Expression; Gene Expression Profiling; Leptin; Lipid Metabolism; Lipids; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Up-Regulation | 2009 |
Obesity: Causes and control of excess body fat.
Topics: Adiposity; Amyloid; Asian People; Body Mass Index; Body Weight; Brain-Derived Neurotrophic Factor; Energy Metabolism; Feedback, Physiological; Feeding Behavior; Humans; Islet Amyloid Polypeptide; Leptin; Neural Pathways; Obesity; Receptors, Leptin; United States | 2009 |
Antiobesity activity of aqueous extracts of Rhizoma Dioscoreae Tokoronis on high-fat diet-induced obesity in mice.
We examined the effects of Rhizoma Dioscoreae Tokoronis extracts (RDTEs) on plasma lipids, body weight, and lipogenic enzymes. Mice were administered a standard chow diet, a 60% high-fat diet, or a high-fat diet with RDTE. Mice that were fed a high-fat diet containing RDTE were found to have lower increases in body and epididymal adipose tissue weights and a lessened occurrence of hepatic steatosis than mice that were fed a high-fat diet. The decreased adiposity that was induced by RDTE accounted for lower plasma levels of tumor necrosis factor-alpha, leptin, and glucose and a higher level of adiponectin. RDTE administration also resulted in a significant decrease in triglyceride, total plasma cholesterol, and low-density lipoprotein-cholesterol when compared to the high-fat group. To identify the mechanism by which RDTE induced its antiobesity effect, we investigated the sterol response element binding protein (SREBP) transcription system, which was induced in mice that were fed the high-fat diet. RDTE was found to suppress the expression of SREBP-1 as well as that of fatty acid synthase in adipose and liver tissues in mice provided the high-fat diet. These findings suggest that the antiobesity action of RDTE in mice that are fed a high-fat diet may occur in response to suppression of the SREBP-1-dependent lipogenic pathway. Topics: Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cholesterol; Dietary Fats; Dioscorea; Epididymis; Fatty Acid Synthases; Fatty Liver; Gene Expression; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Phytotherapy; Plant Extracts; Rhizome; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Triglycerides; Tumor Necrosis Factor-alpha | 2009 |
Genetic associations of residual feed intake with serum insulin-like growth factor-I and leptin concentrations, meat quality, and carcass cross sectional fat area ratios in Duroc pigs.
Genetic relationships of measures of residual feed intake and daily feed intake with serum IGF-I concentrations at 8 wk of age and at 105 kg of BW, serum leptin concentration at 105 kg of BW, meat quality, and different fat accumulation traits on 834 Duroc pigs in 7 generations were estimated. Two measures of residual feed intake were estimated from the differences between actual and predicted feed intake: phenotypic residual feed intake (RFI(phe)) and nutritional residual feed intake (RFI(nut)). Meat quality traits included drip loss, cooking loss, pork color score, pork lightness (L*), and pH, whereas fat accumulation traits were subcutaneous fat, intermuscular fat, and total fat percent at 5-6th thoracic vertebra; subcutaneous fat, intermuscular fat, abdominal fat, and total fat percent at one-half body length and at last thoracic vertebra, and seam fat score. The IGF-I concentrations at 8 wk of age and 105 kg of BW had weak genetic correlations with measures of residual feed intake and daily feed intake (absolute values ranging from 0.14 to 0.24). The genetic correlations between measures of residual feed intake and serum leptin concentration were strong and positive (r(g) with RFI(phe) and RFI(nut) were 0.74 and 0.80, respectively). Residual feed intake was moderately but negatively correlated with cooking loss (r(g) with RFI(phe) and RFI(nut) were -0.42 and -0.49, respectively), whereas daily feed intake was moderately and positively correlated with drip loss and pH (0.33 and 0.36, respectively). Daily feed intake was also moderately correlated with subcutaneous fat accumulations at the 5-6th thoracic vertebra (0.31) and one-half body length (0.31) regions and was strongly correlated with accumulations at the last thoracic vertebra region (0.57). The genetic correlations between daily feed intake and intermuscular fat accumulations at all of the carcass sites were strong (0.60, 0.76, and 0.56 for intermuscular fat at 5-6th thoracic vertebra, one-half body length, and last thoracic vertebra, respectively). Residual feed intake was strongly and positively correlated with all of the fat accumulation traits (ranging from 0.53 to 0.88). The results indicate that reducing residual feed intake (increased efficiency) would lead to increased cooking loss and darkness, and decreased serum leptin concentration, fat accumulations at the different sites, and seam fat at the 6th rib interface of pork carcasses. Topics: Animals; Body Weight; Eating; Female; Insulin-Like Growth Factor I; Leptin; Male; Meat; Swine | 2009 |
Relationship between bone mineral density, leptin and insulin concentration in Brazilian obese adolescents.
Despite the epidemic of adolescent obesity, the effect of obesity and hormones on bone mineral accrual during growth is poorly understood. Studies using dual-energy X-ray to examine the effect of obesity on bone mass in children and adolescents have yielded conflicting results. The aim of this study was to explore the combined and independent contributions of body mass index, body composition, leptin, insulin, glucose levels and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) to bone mineral density (BMD) and bone mineral content in a group of Brazilian obese adolescents. This study included 109 post-pubescent obese adolescents. A whole-body dual-energy X-ray absorptiometry scan was performed,using a HOLOGIC QDR4200, to determine whole-body BMD and body composition. Blood samples were collected in the outpatient clinic after an overnight fast, and evaluated for fasting blood glucose and immunoreactive insulin. Leptin levels were assessed with a radioimmunoassay kit. Insulin resistance was assessed by HOMA-IR and the quantitative insulin sensitivity check index. Our results showed that insulin levels and HOMA-IR correlated negatively with BMD and a linear regression analysis showed that serum leptin is inversely associated to BMD adjusted for body mass. In conclusion, our data support the hypothesis that leptin, insulin and HOMA-IR are inversely associated with BMD and play a significant direct role in bone metabolism. Topics: Adiposity; Adolescent; American Indian or Alaska Native; Anthropometry; Biomarkers; Body Weight; Bone Density; Brazil; Female; Humans; Insulin; Leptin; Male; Obesity; Regression Analysis | 2009 |
Up-regulation of apolipoprotein E by leptin in the hypothalamus of mice and rats.
Apolipoprotein E (apoE) is a satiation factor, playing an important role in the regulation of food intake and body weight. We previously reported that apoE was present in the hypothalamus, but it is unclear which type of the cells in this brain area expressing apoE. In addition, hypothalamic apoE mRNA levels were significantly reduced in both genetically obese ob/ob (leptin deficient) mice and high-fat diet-induced obese (leptin resistant) rats, raising the possibility that deficient leptin signaling might be related to the change in apoE gene expression. In the present studies, using double-staining immunohistochemistry, we demonstrated that apoE is mainly present in astrocytes. To characterize the effect of leptin on apoE gene expression, ob/ob and db/db mice were treated with recombinant mouse leptin (3 microg/g daily, i.p.) or vehicle for 5 days. We found that the increased hypothalamic apoE mRNA levels occurred only in leptin-treated ob/ob, but not in pair-fed ob/ob, or db/db, mice, indicating that leptin up-regulated hypothalamic apoE gene expression depends upon an intact leptin receptor, and this effect is not related to the changes in food intake and body weight. The reduced apoE gene expression caused by fasting, which also results in relatively lower leptin level, is restored by intracerebroventricular administration of leptin. In addition, leptin was significantly less efficacious in apoE KO mice because these animals consumed more food and lost less weight following leptin treatment, compared with wild-type controls. These observations imply that apoE signaling, at least partially, mediates the inhibitory effects of leptin on feeding. Topics: Animals; Apolipoproteins E; Astrocytes; Body Weight; Eating; Hypothalamus; Immunohistochemistry; Injections, Intraventricular; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Rats; Rats, Long-Evans; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation | 2009 |
Alterations of behavioral and endocrinological reactivity induced by 3 brief social defeats in rats: relevance to human psychopathology.
In the realm of animal models of psychopathology, social stress based procedures rely on robust theoretical prerequisites to meet construct validity criteria for the target syndromes. In order to further assess the relevance for human psychopathology of a social defeat based model in rats, known to elicit consistent behavioral and hormonal changes, we expanded its characterization on the basis of both behavioral parameters and peripheral biomarkers thought to be pertinent for clinical symptoms. Rats were subjected to 3 daily social defeat experiences that shortly thereafter led to the insurgence of defensive behaviors, anhedonia, and body weight loss. HPA axis showed an activated response when rats were sampled as early as after the first social defeat experience, while none of the peripheral immune, metabolic, and neurotrophic factors examined were concurrently affected. With the aim of determining the long-term bio-behavioral sequelae of the social defeat experience, rats were assessed also 3 weeks after the social defeats. At this time, behavioral changes were still observed, including decreased general activity and sociality in a social avoidance test, increased immobility and decreased escape responses in a forced swim test. These alterations were not paralleled by alterations in anhedonia nor HPA axis responses from controls, nor where evident changes in the humoral component of the immune response nor in brain derived neurotrophic factor levels, whereas a substantial increase in leptin levels was observed in previously socially defeated rats compared to control. Overall these data depict a very complex set of alterations induced both acutely and long-term by social stress in endocrinological and behavioral reactivity of rats. Topics: Adrenocorticotropic Hormone; Animals; Behavior, Animal; Biomarkers; Body Weight; Brain-Derived Neurotrophic Factor; Choice Behavior; Corticosterone; Dominance-Subordination; Endocrine System; Humans; Immunologic Factors; Leptin; Male; Psychopathology; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Social Behavior; Stress, Physiological; Stress, Psychological | 2009 |
Neonatal overfeeding leads to developmental programming of adult obesity: you are what you ate.
Topics: Age Factors; Aging; Animals; Animals, Newborn; Body Weight; Eating; Humans; Hyperphagia; Hypothalamo-Hypophyseal System; Infant Nutritional Physiological Phenomena; Infant, Newborn; Leptin; Obesity; Overnutrition; Signal Transduction; Thyroid Gland; Thyroid Hormones; Thyrotropin | 2009 |
Differential effects of restricted versus unlimited high-fat feeding in rats on fat mass, plasma hormones and brain appetite regulators.
The rapid rise in obesity has been linked to altered food consumption patterns. There is increasing evidence that, in addition to total energy intake, the macronutrient composition of the diet may influence the development of obesity. The present study aimed to examine the impact of high dietary fat content, under both isocaloric and hypercaloric conditions, compared with a low fat diet, on adiposity, glucose and lipid metabolism, and brain appetite regulators in rats. Male Sprague-Dawley rats were exposed to one of three diets: control (14% fat), ad lib high-fat palatable (HFD, 35% fat) or high-fat palatable restricted (HFD-R, matched to the energy intake of control) and were killed in the fasting state 11 weeks later. Body weight was increased by 28% in unrestricted HFD fed rats, with an almost tripling of caloric intake and fat mass (P < 0.001) and double the plasma triglycerides of controls. Glucose intolerance and increased insulin levels were observed. HFD-R animals calorie matched to control had double their fat mass, plasma insulin and triglycerides (P < 0.05). Only ad lib consumption of the HFD increased the hypothalamic mRNA expression of the appetite-regulating peptides, neuropeptide Y and pro-opiomelanocortin. Although restricted consumption of palatable HFD had no significant impact on hypothalamic appetite regulators or body weight, it increased adiposity and circulating triglycerides, suggesting that the proportion of dietary fat, independent of caloric intake, affects fat deposition and the metabolic profile. Topics: Adiposity; Animals; Blood Glucose; Body Weight; Diet; Dietary Fats; Energy Intake; Fasting; Glucose; Hormones; Hypothalamus; Insulin; Leptin; Lipid Metabolism; Male; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Triglycerides | 2009 |
Leptin-dependent control of glucose balance and locomotor activity by POMC neurons.
Leptin plays a pivotal role in regulation of energy balance. Via unknown central pathways, leptin also affects peripheral glucose homeostasis and locomotor activity. We hypothesized that, specifically, pro-opiomelanocortin (POMC) neurons mediate those actions. To examine this possibility, we applied Cre-Lox technology to express leptin receptors (ObRb) exclusively in POMC neurons of the morbidly obese, profoundly diabetic, and severely hypoactive leptin receptor-deficient Lepr(db/db) mice. Here, we show that expression of ObRb only in POMC neurons leads to a marked decrease in energy intake and a modest reduction in body weight in Lepr(db/db) mice. Remarkably, blood glucose levels are entirely normalized. This normalization occurs independently of changes in food intake and body weight. In addition, physical activity is greatly increased despite profound obesity. Our results suggest that leptin signaling exclusively in POMC neurons is sufficient to stimulate locomotion and prevent diabetes in the severely hypoactive and hyperglycemic obese Lepr(db/db) mice. Topics: Animals; Blood Glucose; Body Weight; Eating; Leptin; Mice; Mice, Knockout; Motor Activity; Neurons; Pro-Opiomelanocortin; Receptors, Leptin; Signal Transduction | 2009 |
Insulin-like growth factor-I, insulin-like growth factor binding protein-3 and growth in obese children before and after reduction of overweight.
Little longitudinal information is available on changes of growth, insulin-like growth factor-I (IGF-I), its main binding protein (IGFBP-3) and their relationships to leptin and insulin in obese children reducing their overweight. We compared these parameters between baseline and after participating in a one-year lifestyle intervention in 319 obese children. The control group comprised 52 lean children. Obese children demonstrated significantly increased IGFBP-3, leptin, and insulin concentrations and were taller compared to the lean children, while they did not differ in respect to their IGF-I concentrations. Reduction of overweight was associated with a significant decrease of IGFBP-3 SDS, leptin, and insulin concentrations. IGF-I SDS and height SDS did not change after weight loss.. IGFBP-3, leptin and insulin concentrations are increased in obese children and normalized in weight loss demonstrating the reversibility of these alterations. Weight loss due to lifestyle intervention was not associated with growth disturbances. Topics: Adolescent; Body Constitution; Body Height; Body Weight; Child; Female; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Life Style; Male; Obesity; Weight Loss | 2009 |
Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice.
Rapamycin is an immunosuppressant drug used to prevent organ rejection in transplant patients. In this study, we investigated the metabolic effects of rapamycin in an obese animal model, KK/HlJ mice. Mice were treated with a daily intraperitoneal injection of rapamycin at 2 mg/kg or vehicle for 42 days on a high-fat diet. Treated mice lost body weight and adiposity, reduced weight gain and retroperitoneal and epididymal fat pads/body weight, decreased serum leptin and plasma triglyceride levels and had lower liver fat concentration. However, treated mice had higher serum insulin levels and food intake. Dissection of rapamycin-treated mice revealed a marked reduction in fatty liver scores and fat cell size in retroperitoneal and epididymal adipocytes. Moreover, Western blot analysis revealed that rapamycin treatment resulted in decreasing adipophilin expression, as a marker of lipid accumulation, and reducing phosphorylation of mTOR downstream targets S6K1 compared to control group. Unfortunately, rapamycin-treated animals showed a marked decline in glucose tolerance as judged by the 180-min. area under the curve for plasma glucose levels, paralleled by increased generation of plasma reactive oxygen species. These results suggest that continual rapamycin administration may help to prevent diet-induced obesity, while prolonged use of rapamycin may exacerbate glucose intolerance. Topics: Adipocytes; Adipose Tissue, White; Adiposity; Animals; Body Weight; Dietary Fats; Eating; Glucose; Glucose Tolerance Test; Immunosuppressive Agents; Insulin; Leptin; Male; Mice; Obesity; Sirolimus | 2009 |
Maintenance on a ketogenic diet: voluntary exercise, adiposity and neuroendocrine effects.
Adherence to low-carbohydrate, ketogenic diets (KDs) has been associated with greater weight loss in the short-term than low-fat, calorie-restricted diets. However, consumption of KDs may result in decreased voluntary exercise and thus render long-term weight loss and maintenance of weight loss difficult.. Rats were maintained on either a non-ketogenic chow (CH) diet or a low-carbohydrate, KD for 6 weeks. Half of each dietary group was sedentary, whereas the other half was given access to a running wheel. Running wheel activity (total distance and meters per minute), plasma leptin and insulin, adiposity, and hypothalamic mRNA for neuropeptide Y and proopiomelanocortin (POMC) were measured to assess activity-related effects in animals maintained on KD.. With access to a running wheel, rats on KD engaged in similar levels of voluntary activity as CH rats and both dietary groups decreased caloric intake. Caloric intake increased over time such that it was significantly greater than sedentary controls after 1 month of access to the wheels, however body weight remained decreased. Sedentary rats maintained on KD had increased adiposity and plasma leptin levels and decreased hypothalamic POMC mRNA, as compared to sedentary CH rats. KD rats with access to a running wheel had similar levels of adiposity and plasma leptin levels as CH rats with access to running wheels, but significantly increased POMC mRNA in the arcuate.. We demonstrate that maintenance on KD does not inhibit voluntary activity in a running wheel. Furthermore, prevention of KD-related increased adiposity and plasma leptin, as measured in sedentary KD rats, significantly increases levels of the anorexigenic neuropeptide POMC mRNA. Topics: Adiposity; Animals; Body Weight; Diet, Carbohydrate-Restricted; Diet, Ketogenic; Hypothalamus; Insulin; Leptin; Male; Motor Activity; Neuropeptide Y; Physical Conditioning, Animal; Pro-Opiomelanocortin; Rats; Rats, Long-Evans; RNA, Messenger; Signal Transduction | 2009 |
Effects of topiramate on weight and metabolism in children with epilepsy.
To explore the mechanism of topiramate-induced weight loss in epilepsy children by monitoring metabolism indices.. Children with epilepsy were treated with topiramate at their first clinical visit. Metabolism indices including body mass index (BMI) and its SD scores, leptin, adiponectin, leptin/adiponectin (L/A), lipid profile-insulin and Homeostasis Model Assessments (HOMA) index were collected before and after treatment.. Topiramate treatment significantly reduced L/A (t = 2.156, p = 0.031), and markedly increased the serum level of adiponectin (t = 3.124, p = 0.002). Moreover, there were no relationships between the metabolism indices and dosages of topiramate (p > 0.05).. Our studies find that topiramate treatment in epilepsy children increases energy metabolism, resulting in weight loss. It has been demonstrated that adiponectin play a significant role in metabolic regulations. Topics: Adiponectin; Anti-Obesity Agents; Blood Glucose; Body Mass Index; Body Weight; Case-Control Studies; Child; Epilepsy; Female; Fructose; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Metabolism; Statistics, Nonparametric; Topiramate | 2009 |
Regulation of the fibrosis and angiogenesis promoter SPARC/osteonectin in human adipose tissue by weight change, leptin, insulin, and glucose.
Matricellular Secreted Protein, Acidic and Rich in Cysteine (SPARC), originally discovered in bone as osteonectin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines.. Serum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 +/- 3.7 kg). Another six lean subjects underwent fast-food-based hyperalimentation for 4 weeks (weight gain: 7.2 +/- 1.6 kg). Finally, visceral adipose tissue explants were cultured with recombinant leptin, insulin, and glucose, and SPARC mRNA and protein expression determined by Western blot analyses.. SPARC expression in human adipose tissue correlated with fat mass and was higher in SCAT. Weight loss induced by very-low-calorie diet lowered SPARC expression by 33% and increased by 30% in adipose tissue of subjects gaining weight after a fast-food diet. SPARC expression was correlated with leptin independent of fat mass and correlated with homeostasis model assessment-insulin resistance. In vitro experiments showed that leptin and insulin potently increased SPARC production dose dependently in visceral adipose tissue explants, while glucose decreased SPARC protein.. Our data suggest that SPARC expression is predominant in subcutaneous fat and its expression and secretion in adipose tissue are influenced by fat mass, leptin, insulin, and glucose. The profibrotic effects of SPARC may contribute to metabolic dysregulation in obesity. Topics: Adipose Tissue; Adult; Bariatric Surgery; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Diet, Reducing; Female; Gene Expression Regulation; Humans; Insulin; Leptin; Male; Middle Aged; Neovascularization, Physiologic; Obesity; Obesity, Morbid; Osteonectin | 2009 |
Postnatal stress produces hyperglycemia in adult rats exposed to hypoxia-ischemia.
Fetal or early postnatal stressors may predispose infants to develop diabetes, metabolic syndrome, or stroke. We hypothesized that postnatal stress will predispose animals to develop metabolic syndrome and impair the physiologic response to hypoxic-ischemic brain injury. We characterized the short- and long-term physiologic responses to postnatal stress by examining corticosterone (CS), glucose metabolism, and brain injury in neonatal and adult rats exposed to hypoxia-ischemia (H-I). Rat pups were divided into three levels of postnatal stress from postnatal day (P) 3 to P7. All rats underwent unilateral brain injury on either P7 or P134. We measured brain injury, growth, blood pressure, urine/plasma CS, plasma leptin, insulin, and glucose before and after H-I. Postnatal stress increased neonatal CS production, exacerbated neonatal white matter injury, and was associated with adult hyperglycemia after H-I despite increased insulin production. There were no group differences in adult weight, blood pressure, or leptin. Postnatal stress exacerbated brain injury and produced adult hyperglycemia, triggered after hypoxia exposure, consistent with the hypotheses that neonates exposed to early stress are more vulnerable to hypoxia and may be predisposed to develop metabolic syndrome in adulthood. Prolonged maternal separation produced more hyperglycemia than did brief daily handling. Topics: Animals; Animals, Newborn; Blood Glucose; Blood Pressure; Body Weight; Brain Injuries; Corticosterone; Female; Humans; Hyperglycemia; Hypoxia-Ischemia, Brain; Insulin; Leptin; Pregnancy; Rats; Rats, Sprague-Dawley; Stress, Physiological | 2009 |
Disruption of protein kinase A in mice enhances healthy aging.
Mutations that cause a reduction in protein kinase A (PKA) activity have been shown to extend lifespan in yeast. Loss of function of mammalian RIIbeta, a regulatory subunit of PKA expressed in brain and adipose tissue, results in mice that are lean and insulin sensitive. It was therefore hypothesized that RIIB null (RIIbeta(-/-)) mice would express anti-aging phenotypes. We conducted lifespan studies using 40 mutant and 40 wild type (WT) littermates of equal gender numbers and found that both the median and maximum lifespans were significantly increased in mutant males compared to WT littermates. The median lifespan was increased from 884 days to 1005 days (p = 0.006 as determined by the log rank test) and the 80% lifespan (defined here as 80% deaths) was increased from 941 days to 1073 days (p = 0.004 as determined by the Wang-Allison test). There was no difference in either median or 80% lifespan in female genotypes. WT mice of both genders became increasingly obese with age, while mutant mice maintained their lean phenotype into old age. Adiposity was found to correlate with lifespan for males only. 50% of male mice between 30 and 35 g, corresponding to about 5% body fat, for either genotype lived over 1000 days. No male mouse outside of this weight range achieved this lifespan. During their last month of life, WT mice began losing weight (a total of 8% and 15% of body weight was lost for males and females, respectively), but RIIbeta(-/-) male mice maintained their lean body mass to end of life. This attenuation of decline was not seen in female mutant mice. Old male mutant mice were insulin sensitive throughout their life. Both genders showed modestly lower blood glucose levels in old mutants compared to WT. Male mutants were also resistant to age-induced fatty liver. Pathological assessment of tissues from end of life male mutant mice showed a decrease in tumor incidence, decreased severity of renal lesions, and a trend towards a decrease in age-related cardiac pathology. These findings help establish the highly conserved nature of PKA and suggest that disruption of PKA affects physiological mechanisms known to be associated with healthy aging. Topics: Adipose Tissue; Aging; Animals; Body Weight; Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; Cyclic AMP-Dependent Protein Kinases; Female; Genotype; Leptin; Longevity; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Sex Factors | 2009 |
Ghrelin treatment protects lactotrophs from apoptosis in the pituitary of diabetic rats.
Poorly controlled diabetes is associated with hormonal imbalances, including decreased prolactin production partially due to increased lactotroph apoptosis. In addition to its metabolic actions, ghrelin inhibits apoptosis in several cell types. Thus, we analyzed ghrelin's effects on diabetes-induced pituitary cell death and hormonal changes. Six weeks after onset of diabetes in male Wistar rats (streptozotocin 70 mg/kg), minipumps infusing saline or 24 nmol ghrelin/day were implanted (jugular). Rats were killed two weeks later. Ghrelin did not modify body weight or serum glucose, leptin or adiponectin, but increased total ghrelin (P<0.05), IGF-I (P<0.01) and prolactin (P<0.01) levels. Ghrelin decreased cell death, iNOS and active caspase-8 (P<0.05) and increased prolactin (P<0.05), Bcl-2 (P<0.01) and Hsp70 (P<0.05) content in the pituitary. In conclusion, ghrelin prevents diabetes-induced death of lactotrophs, decreasing caspase-8 activation and iNOS content and increasing anti-apoptotic pathways such as pituitary Bcl-2 and Hsp70 and serum IGF-I concentrations. Topics: Adiponectin; Animals; Apoptosis; Biomarkers; Body Weight; Caspases; Cytoprotection; Diabetes Mellitus, Experimental; Ghrelin; HSP70 Heat-Shock Proteins; In Situ Nick-End Labeling; Insulin; Insulin-Like Growth Factor I; Lactotrophs; Leptin; Nitric Oxide Synthase Type II; Prolactin; Proto-Oncogene Proteins c-bcl-2; Rats; Weight Gain; X-Linked Inhibitor of Apoptosis Protein | 2009 |
Thylakoids suppress appetite by increasing cholecystokinin resulting in lower food intake and body weight in high-fat fed mice.
Thylakoids are membranes isolated from plant chloroplasts which have previously been shown to inhibit pancreatic lipase/colipase catalysed hydrolysis of fat in vitro and induce short-term satiety in vivo. The purpose of the present study was to examine if dietary supplementation of thylakoids could affect food intake and body weight during long-term feeding in mice. Female apolipoprotein E-deficient mice were fed a high-fat diet containing 41% of fat by energy with and without thylakoids for 100 days. Mice fed the thylakoid-enriched diet had suppressed food intake, body weight gain and body fat compared with the high-fat fed control mice. Reduced serum glucose, serum triglyceride and serum free fatty acid levels were found in the thylakoid-treated animals. The satiety hormone cholecystokinin was elevated, suggesting this hormone mediates satiety. Leptin levels were reduced, reflecting a decreased fat mass. There was no sign of desensitization in the animals treated with thylakoids. The results suggest that thylakoids are useful to suppress appetite and body weight gain when supplemented to a high-fat food during long-term feeding. Topics: Adipose Tissue; Animals; Appetite; Appetite Depressants; Blood Glucose; Body Weight; Chlorophyll; Cholecystokinin; Dietary Fats; Eating; Fatty Acids; Female; Leptin; Lipase; Mice; Mice, Knockout; Satiety Response; Spinacia oleracea; Thylakoids; Triglycerides | 2009 |
Short- and long-term effects of maternal nicotine exposure during lactation on body adiposity, lipid profile, and thyroid function of rat offspring.
Epidemiological studies show a higher prevalence of obesity in children from smoking mothers and smoking may affect human thyroid function. To evaluate the mechanism of smoking as an imprinting factor for these dysfunctions, we evaluated the programming effects of maternal nicotine (NIC) exposure during lactation. Two days after birth, osmotic minipumps were implanted in lactating rats, divided into: NIC (6 mg/kg per day s.c.) for 14 days; Control - saline. All the significant data were P<0.05 or less. Body weight was increased from 165 days old onwards in NIC offspring. Both during exposure (at 15 days old) and in adulthood (180 days old), NIC group showed higher total fat (27 and 33%). In addition, NIC offspring presented increased visceral fat and total body protein. Lipid profile was not changed in adulthood. Leptinemia was higher at 15 and 180 days old (36 and 113%), with no changes in food intake. Concerning the thyroid status, the 15-days-old NIC offspring showed lower serum-free tri-iodothyronine (FT(3)) and thyroxine (FT(4)) with higher TSH. The 180-days-old NIC offspring exhibited lower TSH, FT(3), and FT(4)). In both periods, liver type 1 deiodinase was lower (26 and 55%). We evidenced that NIC imprints a neonatal thyroid dysfunction and programs for a higher adiposity, hyperleptinemia, and secondary hypothyroidism in adulthood. Our study identifies lactation as a critical period to NIC programming for obesity, with hypothyroidism being a possible contributing factor. Topics: Adipose Tissue; Animals; Animals, Suckling; Body Weight; Dyslipidemias; Female; Infusion Pumps, Implantable; Lactation; Leptin; Lipids; Male; Nicotine; Nicotinic Agonists; Pregnancy; Rats; Rats, Wistar; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine | 2009 |
Maternal influence of prolyl endopeptidase on fat mass of adult progeny.
Maternal genotype has lifetime effects on progeny, but few specific genes, and no proteases, are known to underlie maternal effects. Prolyl endopeptidase (PREP) is a serine protease with putative substrates that regulate appetite or milk production.. To test effects of PREP on obesity phenotypes in mice.. Mice with a gene trap (GT) of PREP (PREP(gt/gt)) on the C57BL/6J (B6) background were generated. Minimal PREP protein was detected by western blot. In Experiment 1, direct effects of PREP were measured in littermate mice derived from intercrosses of heterozygotes (PREP(WT/gt)). In Experiment 2, maternal effects of PREP were measured in reciprocal crosses of heterozygous (PREP(WT/gt)) and wild-type (WT) (PREP(WT/WT)) males and females. DIETS: Mice were fed either low-fat (LF, Experiments 1 and 2) or high-fat (HF, Experiment 1) defined diets.. Adiposity index (AI) was calculated from body weight (BW) and weights of four fat depots measured in 120-day-old mice. Fasting plasma glucose, insulin and leptin were measured. In vivo plasma alpha-MSH levels were measured by targeted quantitative peptidomics.. Experiment 1-In intercross mice, there were significant diet effects, but few genotype effects. There were no genotype effects on BW or AI in males or females on either diet. Experiment 2-In contrast, reciprocal crosses of heterozygous males or females with WT B6 revealed highly significant parent of origin effects on all traits except body length. Progeny (WT and heterozygous genotypes and both sexes) born to female PREP(WT/gt) heterozygotes had fat pads that weighed as much as -twofold more at 120 days old than progeny born to male heterozygotes.. Heterozygosity for PREP GT results in highly significant maternal effects, whereas homozygosity for the PREP(gt/gt) mutation has a much more limited direct effect. Topics: Animals; Blood Glucose; Blotting, Western; Body Size; Body Weight; Crosses, Genetic; Fasting; Female; Genotype; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Prolyl Oligopeptidases; Serine Endopeptidases; Serine Proteases | 2009 |
Dietary manipulation of Bos indicus x heifers during gestation affects the reproductive development of their heifer calves.
The effect of nutrition during the first and second trimesters of pregnancy in composite beef heifers on reproductive parameters of their female calves was determined in the present study. At artificial insemination, heifers were assigned to one of four treatment groups (i.e. HH, HL, LowH and LL) depending on the level of crude protein intake (H = high; L = low) for first and second trimesters of pregnancy. Gonadotrophin concentrations and ovarian parameters were measured in their female calves at 5 and 23 months of age. Crude protein intake was positively associated with dam plasma urea (P < 0.001). The density of healthy follicles in heifers at the time of death was negatively correlated with dam plasma urea at Day 179 (P = 0.009). Heifers from LowH dams had a smaller-sized prepubertal largest ovarian follicle (P = 0.03) and lower densities of primordial and primary follicles (P = 0.02) and healthy antral follicles (P = 0.009) when they were killed. There was a positive correlation between plasma FSH concentrations at 5 and 23 months of age (P = 0.02), as well as between the sizes of the largest ovarian follicles at 6 and 23 months of age (P = 0.01). In conclusion, the reproductive development of heifers may be affected by prenatal nutrition during early and mid-gestation. Topics: Aging; Animals; Animals, Newborn; Body Weight; Breeding; Cattle; Dietary Proteins; Female; Follicle Stimulating Hormone; Gestational Age; Gonadotropins; Hypothalamo-Hypophyseal System; Insemination, Artificial; Leptin; Luteinizing Hormone; Maternal Nutritional Physiological Phenomena; Ovarian Follicle; Ovary; Pituitary-Adrenal System; Pregnancy; Prenatal Exposure Delayed Effects; Somatomedins; Urea; Uterus | 2009 |
Serum brain-derived neurotrophic factor and peripheral indicators of the serotonin system in underweight and weight-recovered adolescent girls and women with anorexia nervosa.
Brain-derived neurotrophic factor (BDNF) mutant mice show hyperphagia and hyperleptinemia. Animal and cell-culture experiments suggest multiple interrelations between BDNF and the serotonin (5-HT) system. We studied serum BDNF in patients with anorexia nervosa and its associations with peripheral indicators of the 5-HT system. To control for secondary effects of acute malnutrition, we assessed acutely underweight patients with anorexia nervosa (acAN) in comparison to long-term weight-recovered patients with the disorder (recAN) and healthy controls.. We determined serum BDNF, platelet 5-HT content and platelet 5-HT uptake in 33 patients in the acAN group, 20 patients in the recAN group and 33 controls. Plasma leptin served as an indicator of malnutrition.. Patients in the acAN group were aged 14-29 years and had a mean body mass index (BMI) of 14.9 (standard deviation [SD] 1.4) kg/m(2). Those in the recAN group were aged 15-29 years and had a mean BMI of 20.5 (SD 1.3) kg/m(2) and the controls were aged 15-26 years and had a BMI of 21.4 (SD 2.1) kg/m(2). The mean serum BDNF levels were significantly increased in the recAN group compared with the acAN group (8820, SD 3074 v. 6161, SD 2885 pg/mL, U = 154.5, p = 0.001). There were no significant associations between BDNF and either platelet 5-HT content or platelet 5-HT uptake. Among patients with anorexia nervosa, we found significant positive linear relations between BDNF and BMI (r = 0.312, p = 0.023) and between BDNF and leptin (r = 0.365, p = 0.016).. We measured the signal proteins under study in peripheral blood.. Serum BDNF levels in patients with anorexia nervosa depend on the state of illness and the degree of hypoleptinemia. Upregulation of BDNF in weight-recovered patients with anorexia nervosa could be part of a regenerative process after biochemical and molecular neuronal injury due to prolonged malnutrition. Associations between the BDNF and the 5-HT system in humans remain to be established. Topics: Adolescent; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Brain-Derived Neurotrophic Factor; Case-Control Studies; Female; Humans; Leptin; Malnutrition; Serotonin | 2009 |
Difference in leptin hormone response to nutritional status in normal adult male albino rats.
The present study investigated the effect of 14 days diet, enriched in butter, vitamin E (vit. E) and green tea, on the major regulators of energy expenditure. Leptin is the product OB gene. This 16 KDa protein is produced by mature adipocytes and is secreted in plasma. Its plasma levels are strongly correlated with adipose mass in rodents as well as in humans. Leptin inhibit food intake, reduces body weight and stimulates energy expenditure. In order to evaluate the effect of diet enriched in butter, vit. E and green tea on body weight, adipose tissue weight and organs weight, serum lipids, lipoproteins content and serum leptin levels in male albino rats supplemented for 14 days on the previous diet. This study showed that high fat diet significantly increased body weight and adipose tissue weight, while vit. E and green tea enriched diet significantly lowered body weight and adipose tissue weight, kidney and spleen weights didn't show significant changes in all the experimental groups. While liver weight decreased in diet supplemented with high fat diet. Also, the results showed that high fat diet and vit. E supplemented diet induced significant increase in total cholesterol, LDLc., triglyceride level with significant decrease in HDLc. level as compared to normal control rats. Finally green tea supplemented diet induced significant decrease in total cholesterol, LDLc., triglyceride level with insignificant increase in HDLc. level in control rats. On the other hand, high fat supplemented diet significantly increased serum leptin levels in rats compared to control group, while vit. E and green tea enriched diet significantly lowered serum leptin levels at the end of experimental period. In conclusion, improving the biological activity of leptin by diet modification may exist as a practical strategy for the treatment of obesity and related disorders and a diet rich in green tea to reduce the risk of cardiovascular disease (CVD) obesity and also protect the liver against free radicals. Topics: Adipose Tissue; Animals; Antioxidants; Body Weight; Diet; Dietary Fats; Dietary Supplements; Energy Metabolism; Humans; Leptin; Male; Nutritional Status; Obesity; Organ Size; Rats; Tea; Vitamin E | 2009 |
Impact of obesity on renal structure and function in the presence and absence of hypertension: evidence from melanocortin-4 receptor-deficient mice.
The purpose of this study was to determine the long-term impact of obesity and related metabolic abnormalities in the absence and presence of hypertension on renal injury and salt-sensitivity of blood pressure. Markers of renal injury and blood pressure salt sensitivity were assessed in 52- to 55-wk-old normotensive melanocortin-4 receptor-deficient (MC4R-/-) mice and lean C57BL/6J wild-type (WT) mice and in 22-wk-old MC4R-/- and WT mice made hypertensive by N(G)-nitro-L-arginine methyl ester (L-NAME) in the drinking water for 8 wk. Old MC4R-/- mice were 60% heavier, hyperinsulinemic, and hyperleptinemic but had similar mean arterial pressure (MAP) as WT mice (115 +/- 2 and 117 +/- 2 mmHg) on normal salt diet (0.4% NaCl). A high-salt diet (4.0% NaCl) for 12 days did not raise MAP in obese or lean mice [DeltaMAP: MC4R (-/-) 4 +/- 2 mmHg; WT, 2 +/- 1 mmHg]. Obese MC4R-/- mice had 23% greater glomerular tuft area and moderately increased GFR compared with WT mice. Bowman's space, total glomerular area, mesangial matrix, urinary albumin excretion (UAE), renal TGF-beta and collagen expression were not significantly different between old MC4R-/- and WT mice. Renal lipid content was greater but renal macrophage count was markedly lower in MC4R-/- than WT mice. Mild increases in MAP during L-NAME treatment (approximately 16 mmHg) caused small, but greater, elevations in UAE, renal TGF-beta content, and macrophage infiltration in MC4R-/- compared with WT mice without significant changes in glomerular structure. Thus despite long-term obesity and multiple metabolic abnormalities, MC4R-/- mice have no evidence of renal injury or salt-sensitivity of blood pressure. These observations suggest that elevations in blood pressure may be necessary for obesity and related metabolic abnormalities to cause major renal injury or that MC4R-/- mice are protected from renal injury by mechanisms that are still unclear. Topics: Age Factors; Albuminuria; Animals; Biomarkers; Blood Pressure; Body Weight; Disease Models, Animal; Glomerular Filtration Rate; Heart Rate; Hyperinsulinism; Hypertension; Kidney; Kidney Diseases; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptor, Melanocortin, Type 4; Sodium Chloride, Dietary | 2009 |
Obese reversal by a chronic energy restricted diet leaves an increased Arc NPY/AgRP, but no alteration in POMC/CART, mRNA expression in diet-induced obese mice.
Weight regain after weight loss is a major hurdle for combating obesity. The aim of this study is to examine orexigenic and anorectic neuropeptides of the hypothalamic arcuate nucleus (Arc) in response to weight loss after chronic energy intake restriction. Thirty mice were fed with a high-fat diet for 8 weeks and then classified as diet-induced obese (DIO; n=10) or diet-resistant (DR; n=10) mice according to the highest and lowest body weight gainers. Five mice from DIO and DR groups were placed on an energy restricted diet or continued on their high-fat diet ad libitum for 6 weeks. An additional five mice were on a LF diet throughout the course of this study as controls. Results showed that a six-week energy restricted diet completely reversed the increased body weight, fat mass and leptin in the DIO mice to the levels of the LF and DR mice. Arc neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expression in DIO mice after obesity reversal were significantly higher than DIO mice without obesity reversal (17%, 47%, both p<0.05), while the Arc pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA showed no difference. Both NPY and AgRP expression in DIO mice were negatively correlated with plasma leptin (R=-0.78, p<0.05; R=-0.72, p<0.05). In conclusion, while chronic energy restriction will lead to weight loss, it can up-regulate hypothalamic orexigenic peptides, which may be an important contributing factor to weight regain after a weight loss program from an energy restricted diet. Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Body Weight; Diet; Diet, Reducing; Dietary Fats; Leptin; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger | 2009 |
Long term effects of high fat and sucrose diets on obesity and lymphocyte proliferation in mice.
To clarify the effect of prolonged feeding of a high-fat and sucrose, and to clarify the effect of sucrose instead of other carbohydrate on obesity and immunity in C57BL/6J mice.. We investigated the development of obesity and immune cell function in four groups of mice fed high-fat, high-fat plus high-sucrose, high-sucrose, and control diet for 7 months.. Mice fed high-fat and high-fat plus high-sucrose groups developed severe obesity. Body weight, adipose tissue weight, serum leptin, blood glucose, and insulin were significantly higher, while the level of serum soluble leptin receptor was significantly lower in mice fed high-fat and high-fat plus high-sucrose diets than in mice fed the control or high-sucrose diets. Splenocyte proliferation stimulated by T-cell mitogen (PHA, ConA, and anti-CD 3 antibody) and B-cell mitogen (LPS) was significantly lower in both obese, high-fat and high-fat plus high-sucrose groups than in control and high-sucrose groups. However, these parameters did not differ between high-fat and high-fat plus high-sucrose groups.. Long-term feeding of high-fat diet and high-fat plus high-sucrose diet similarly induced severe obesity in C57BL/6J mice. Not only T-cell, but also B-cell function may be impaired in mice made severely obese by the high-fat or high-fat plus high-sucrose diets. Topics: Adipose Tissue; Animals; B-Lymphocytes; Blood Glucose; Body Weight; Cell Proliferation; Diet; Dietary Fats; Dietary Sucrose; Female; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mitogens; Obesity; Organ Size; Receptors, Leptin; Spleen; T-Lymphocytes | 2009 |
Leptin-mediated changes in hepatic mitochondrial metabolism, structure, and protein levels.
Leptin reduces body weight in ob/ob mice by decreasing food intake and increasing energy expenditure; however, the mechanisms by which it does the latter are not known. Here we report that 30% of the weight loss induced by leptin treatment of ob/ob mice is due to changes in energy expenditure. In assessing leptin's effects on specific tissues, we found that hepatic basal metabolic rate was paradoxically decreased 1.7-fold with leptin treatment, which was the result of a 1.6-fold reduction in mitochondrial volume density and altered substrate oxidation kinetics. The altered kinetics were associated with a decrease in protein levels of 2 mitochondrial respiratory chain components--cytochrome c oxidase subunit VIa and cytochrome c oxidase subunit IV. In addition to reduced hepatic metabolism, there was reduced long chain fatty acid production and a 2.5-fold increase in hepatic lipid export, both of which explain the reduced steatosis in leptin-treated animals. These data help clarify the role of the liver in leptin-mediated weight loss and define the mechanisms by which leptin alters hepatic metabolism and corrects steatosis. Topics: Animals; Body Weight; Fatty Acids; Fatty Liver; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondria, Liver; Mitochondrial Proteins; Oxidation-Reduction; Oxygen Consumption; Phosphorylation; Proteomics | 2009 |
Feto-placental adaptations to maternal obesity in the baboon.
Maternal obesity is present in 20-34% of pregnant women and has been associated with both intrauterine growth restriction and large-for-gestational age fetuses. While fetal and placental functions have been extensively studied in the baboon, no data are available on the effect of maternal obesity on placental structure and function in this species. We hypothesize that maternal obesity in the baboon is associated with a maternal inflammatory state and induces structural and functional changes in the placenta. The major findings of this study were: 1) decreased placental syncytiotrophoblast amplification factor, intact syncytiotrophoblast endoplasmic reticulum structure and decreased system A placental amino acid transport in obese animals; 2) fetal serum amino acid composition and mononuclear cells (PBMC) transcriptome were different in fetuses from obese compared with non-obese animals; and 3) maternal obesity in humans and baboons is similar in regard to increased placental and adipose tissue macrophage infiltration, increased CD14 expression in maternal PBMC and maternal hyperleptinemia. In summary, these data demonstrate that in obese baboons in the absence of increased fetal weight, placental and fetal phenotype are consistent with those described for large-for-gestational age human fetuses. Topics: Adaptation, Physiological; Amino Acid Transport System A; Amino Acids; Animals; Body Weight; Chorionic Villi; Crown-Rump Length; Disease Models, Animal; Female; Fetal Blood; Inflammation; Kidney; Leptin; Leukocytes, Mononuclear; Lipopolysaccharide Receptors; Macrophages; Matched-Pair Analysis; Maternal-Fetal Exchange; Obesity; Organ Size; Papio; Placenta; Pregnancy; Pregnancy Complications; Trophoblasts | 2009 |
Association between leptin gene polymorphisms and growth traits in Limousin cattle.
A total of 129 Limousin calves were used to investigate how leptin gene polymorphisms affect growth traits, such as body weight, average daily gain, wither height, sacrum height and chest girth in beef cattle. Two single nucleotide polymorphisms (SNPs) were genotyped, including the Sau3AI polymorphism in intron 2 and the A59V polymorphism in exon 3. The genotype and allele frequencies for each SNP and the haplotype frequencies for both SNPs were estimated in the studied herd. Statistical analysis revealed that the A59V polymorphism significantly affected the body weight at 210 days of age (P < or = 0.01) and the average daily gain between 3 and 210 days of age (P < or = 0.05) with Tas a desirable allele. No associations were observed between the Sau3AI polymorphism and the growth traits mentioned above. However, the average daily gain between 3 and 210 days of age was significantly higher in the CT/CT haplotype animals compared with the CC/CC and CC/CT individuals. These results indicated that selection for the A59V TT animals might contribute to an improved body weight in Limousin cattle. Topics: Animals; Body Weight; Cattle; Leptin; Polymorphism, Single Nucleotide | 2009 |
Some cyclin-dependent kinase inhibitors-related genes are regulated by vitamin C in a model of diet-induced obesity.
The aim of this research was to investigate differential gene expression of cyclin-dependent kinase inhibitors (CKIs) in white adipose tissue (WAT) and liver from high-fat fed male Wistar rats with or without vitamin C (VC) supplementation (750 mg/kg of body weight). After 56 d of experimentation, animals fed on a cafeteria diet increased significantly body weights and total body fat. Reverse transcription-polymerase chain reaction (RT-PCR) studies showed that cafeteria diet decreased p21 and p57 mRNA expression in subcutaneous WAT and increased p21 mRNA in liver. Overall, these data provide new information about the role of high fat intake on mRNA levels of several CKIs with implications in adipogenesis, cell metabolism and weight homeostasis. Interestingly, VC supplementation partially prevented diet-induced adiposity and increased p27 mRNA in liver without any changes in the other tissues and genes analyzed. Thus, hepatic mRNA changes induced by ascorbic acid indicate a possible role of these genes in diet-induced oxidative stress processes. Topics: Adipogenesis; Adipose Tissue, White; Animals; Antioxidants; Ascorbic Acid; Body Weight; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinase Inhibitor p57; Cyclin-Dependent Kinase Inhibitor Proteins; Dietary Fats; Disease Models, Animal; Energy Intake; Gene Expression Regulation; Leptin; Liver; Male; Malondialdehyde; Obesity; Organ Size; Oxidative Stress; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2009 |
Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding.
The lateral hypothalamic area (LHA) acts in concert with the ventral tegmental area (VTA) and other components of the mesolimbic dopamine (DA) system to control motivation, including the incentive to feed. The anorexigenic hormone leptin modulates the mesolimbic DA system, although the mechanisms underlying this control have remained incompletely understood. We show that leptin directly regulates a population of leptin receptor (LepRb)-expressing inhibitory neurons in the LHA and that leptin action via these LHA LepRb neurons decreases feeding and body weight. Furthermore, these LHA LepRb neurons innervate the VTA, and leptin action on these neurons restores VTA expression of the rate-limiting enzyme in DA production along with mesolimbic DA content in leptin-deficient animals. Thus, these findings reveal that LHA LepRb neurons link anorexic leptin action to the mesolimbic DA system. Topics: Animals; Body Weight; Dopamine; Eating; Gene Knock-In Techniques; Hypothalamic Area, Lateral; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Receptors, Leptin; Ventral Tegmental Area | 2009 |
Maternal and postweaning diet interaction alters hypothalamic gene expression and modulates response to a high-fat diet in male offspring.
Epidemiological data and results from animal studies indicate that imbalances in maternal nutrition impact the expression of metabolic disorders in the offspring. We tested the hypothesis that consumption of excess saturated fats during pregnancy and lactation contributes to adult metabolic dysfunction and that these disturbances can be further influenced by the postweaning diet. Adult male offspring from chow-fed dams were compared with males from dams fed a diet high in saturated fat (45 kcal/100 kcal) before mating, pregnancy, and lactation. Offspring were weaned to a standard chow diet or high fat diet. Animals were killed at 120 days after a 24-h fast. Body weight, energy intake, fat deposition, serum leptin, and insulin were significantly higher in offspring from control or high-fat dams if fed a high-fat diet from weaning to adulthood. Only fat-fed offspring from fat-fed dams were hyperglycemic. Leptin receptor, proopiomelanocortin, and neuropeptide Y (NPY) were also significantly increased in offspring exposed to excess saturated fat during gestation and into adulthood, whereas NPY(1) receptor was downregulated. Signal transducer and activator of transcription 3 mRNA level was significantly higher in offspring from high-fat-fed dams compared with controls; however, no change was detected in cocaine and amphetamine-regulated transcript or suppressor of cytokine signaling 3. An increase in agouti-related protein expression did not reach significance. A significant reduction in phosphatidylinositol 3-kinase regulatory subunit (p85alpha) coupled to an upregulation of protein kinase B was observed in offspring from high-fat-fed dams transitioned to chow food, whereas p85alpha expression was significantly increased in high-fat offspring weaned to the high-fat diet. These data support the hypothesis that early life exposure to excess fat is associated with changes in hypothalamic regulation of body weight and energy homeostasis and that postweaning diet influences development of metabolic dysfunction and obesity. Topics: Adiposity; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Dietary Fats; Energy Metabolism; Female; Gene Expression Regulation; Gestational Age; Hyperglycemia; Hypothalamus; Insulin; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Metabolic Diseases; Neuropeptides; Nutritional Status; Obesity; Phosphatidylinositol 3-Kinases; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; RNA, Messenger; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Weaning | 2009 |
Circulating triglycerides after a high-fat meal: predictor of increased caloric intake, orexigenic peptide expression, and dietary obesity.
Recent studies in normal-weight rats have linked circulating triglycerides (TG), when elevated by a high-fat (HF) compared to equicaloric low-fat (LF) meal, to an increase in subsequent food intake and hypothalamic expression of orexigenic peptides. The present study tested whether natural variations between rats in their TG levels after a small HF meal can also be related to their individual patterns of eating and peptide expression. In tail vein blood collected on three separate days 60 min after a HF meal, levels of TG were found to be strongly, positively correlated within rats from day to day but were highly variable between rats (75-365 mg/dl), allowing distinct subgroups (33% lowest or highest) to be formed. Compared to "Low-TG responders" with post-meal levels averaging 109 mg/dl, "High-TG responders" with 240 mg/dl showed in two separate experiments a significant increase in caloric intake in a subsequent laboratory chow meal. Before this larger meal, these rats with elevated TG consistently exhibited higher expression levels and synthesis of the orexigenic peptides, enkephalin, orexin and melanin-concentrating hormone, as revealed using real-time quantitative PCR, radiolabeled in situ hybridization, and immunofluorescence histochemistry. Over the long-term, the High-TG responders also showed an increased propensity to overeat, gain weight and accumulate excess body fat on a chronic HF diet. This simple measure of TG levels after a HF meal may offer a useful tool for identifying subpopulations with increased risk for overeating and dietary obesity and detecting early signs of brain disturbances that may contribute to this high-risk phenotype. Topics: Adipose Tissue; Agouti-Related Protein; Animals; Body Weight; Dietary Fats; Eating; Energy Intake; Feeding Behavior; Fluorescent Antibody Technique; Hypothalamic Hormones; Hypothalamus; Image Processing, Computer-Assisted; In Situ Hybridization; Insulin; Leptin; Male; Melanins; Microscopy, Fluorescence; Neuropeptides; Obesity; Pituitary Hormones; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Triglycerides | 2009 |
Diet-induced obesity is associated with hyperleptinemia, hyperinsulinemia, hepatic steatosis, and glomerulopathy in C57Bl/6J mice.
Obesity and obesity-related illnesses are global epidemics impacting the health of adults and children. The purpose of the present work is to evaluate a genetically intact obese mouse model that more accurately reflects the impact of aging on diet-induced obesity and type 2 diabetes in humans. Male C57Bl/6J mice consumed either a control diet or one in which 60% kcal were due to lard beginning at 5-6 weeks of age. Body weight and fat measurements were obtained and necropsy performed at 15, 20, 30, and 40 weeks of age. Serum chemistry, histopathology, gene expression of the liver, and renal and hepatic function were also evaluated. In concert with significant increases in percent body fat and weight, mice fed the high-fat versus control diet had significantly increased levels of serum cholesterol. At ages 20 and 30 weeks, serum glucose was significantly higher in obese versus controls, while serum insulin levels were >/=4-fold higher in obese mice at ages 30 and 40 weeks. The effect of age exacerbated the effects of consuming a high-fat diet. In addition to being hyperinsulinemic and leptin resistant, older obese mice exhibited elevated hepatic PAI-1 and downregulation of GLUT4, G6PC, IGFBP-1, and leptin receptor mRNA in the liver, steatosis with subsequent inflammation, glomerular mesangial proliferation, elevated serum ALT, AST, and BUN, and increased numbers of pancreatic islets. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Diet, Atherogenic; Fatty Liver; Glucose Tolerance Test; Hyperinsulinism; Insulin; Kidney Diseases; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Obesity | 2009 |
C-terminal deletion of the atrophin-1 protein results in growth retardation but not neurodegeneration in mice.
Dentatorubral-pallidoluysian atrophy (DRPLA) is a dominant hereditary neurodegenerative disorder caused by the expansion of a poly-glutamine (poly-Q) repeat in Atrophin-1 protein. Ectopic expression of a poly-Q expanded human Atrophin-1 is sufficient to induce DRPLA phenotypes in mice. However, it is still unclear whether the dominant effect of poly-Q expansion is due to the functional interference with wild-type Atrophin-1 proteins, which exist in both patients and transgenic mice. Here we report the generation and analysis of an Atrophin-1 targeting allele that expresses a truncated protein lacking both the poly-Q repeat and following C-terminal peptides. Homozygous mutants exhibit growth retardation and progressive male infertility, but no obvious signs of neurodegeneration. Moreover, the mutant allele neither blocked nor enhanced the neurodegenerative phenotypes caused by a poly-Q expanded transgene. These results support the model that poly-Q expanded Atrophin-1 proteins cause DRPLA in a manner independent of any functional interaction with wild-type Atrophin-1 proteins. Topics: Animals; Body Weight; Brain; DNA Repeat Expansion; Eating; Fertility; Gene Expression Regulation, Developmental; Humans; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myoclonic Epilepsies, Progressive; Nerve Degeneration; Nerve Tissue Proteins; Peptides; Phenotype; Rotarod Performance Test; Sequence Deletion; Survival Rate; Testis | 2009 |
Early maternal hyperleptinemia programs adipogenic phenotype in rats.
We have previously reported on the treatment of maternal rats with leptin during the three last days of lactation program for overweight and leptin hypothalamic resistance in the offspring. Here we have investigated whether treatment of maternal rats with leptin in the first ten days of lactation can program metabolic dysfunctions on the adult offspring. Lactating rats were divided into 2 groups: rats (LEP) injected with recombinant mouse leptin (8 microg/100 g/body weight, daily during the first 10 days of lactation) and control group (C) that received the same volume of saline. After weaning, all pups had free access to normal diet, their body weight and food intake were monitored at 4 days interval until 180 days, when they were tested for food intake and response to either leptin (0.5 mg/kg body weight, ip) or saline. The offspring from leptin-treated mothers gained more weight from day 69 onward and had higher food intake from day 145 onward, higher amount of visceral adipose tissue (57%), higher serum glucose (10%), and higher serum leptin (135%) at 180 days compared to control group. The food intake was not reduced as expected after acute injection of leptin in these animals, suggesting resistance to the anorexigenic effect of leptin. We conclude that maternal hyperleptinemia in early lactation programed higher food intake, body weight gain due to higher total and visceral fat mass, and resistance to anorexigenic effect of leptin in the adult offspring even when this hyperleptinemia occurred at the beginning of lactation. Topics: Adipogenesis; Adiposity; Animals; Animals, Newborn; Blood Glucose; Body Weight; Feeding Behavior; Female; Insulin; Insulin Resistance; Lactation; Leptin; Maternal Exposure; Maternal Nutritional Physiological Phenomena; Mice; Nutritional Status; Phenotype; Rats | 2009 |
Antiobesity and antidiabetic effects of biotransformed blueberry juice in KKA(y) mice.
Biotransformation of blueberry juice by the Serratia vaccinii bacterium gave rise to adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and glucose uptake in muscle cells and adipocytes, but inhibited adipogenesis. This study investigated the antiobesity and antidiabetic potential of biotransformed blueberry juice (BJ) in KKA(y) mice, rodent model of leptin resistance.. BJ was incorporated in drinking water of KKA(y) mice. Parameters of body weight, food intake, plasma glucose, insulin, leptin, and adiponectin were measured. Before and after therapy, animals were subjected to an oral glucose tolerance test. At the end of treatment, liver, muscle, kidney, epididymal fat pad, abdominal fat pad, and dorsal fat pad were collected and weighed.. Incorporating BJ in drinking water protected young KKA(y) mice from hyperphagia and significantly reduced their weight gain. Moreover, BJ protected young KKA(y) mice against the development of glucose intolerance and diabetes mellitus. Chronic BJ administration in obese and diabetic KKA(y) mice reduced food intake and body weight. This effect could not fully explain the associated antidiabetic effect because BJ-treated mice still showed lower blood glucose level when compared with pair-fed controls. The adipokines pathway also seems to be involved because BJ significantly increased adiponectin levels in obese mice.. This study shows that BJ decreases hyperglycemia in diabetic mice, at least in part by reversing adiponectin levels. BJ also protects young pre-diabetic mice from developing obesity and diabetes. Thus, BJ may represent a novel complementary therapy and a source of novel therapeutic agents against diabetes mellitus. Topics: Adiponectin; Animals; Beverages; Blueberry Plants; Body Weight; Diabetes Mellitus; Hyperglycemia; Hyperphagia; Hypoglycemic Agents; Leptin; Male; Mice; Obesity | 2009 |
Leptin increases maternal investment.
The primary goal of virtually all organisms is to produce genetic offspring, thereby passing on their genes to future generations. Offspring production, however, is limited by available resources within an environment. Moreover, distributing sufficient energy among competing physiological systems is challenging and can result in trade-offs between self-maintenance and offspring investment when resources are limited. In the current study, we tested the hypothesis that the adipose hormone leptin is involved in mediating energetic trade-offs between competing physiological systems. Specifically, we tested the effects of elevated maternal leptin on investment into offspring production versus self maintenance (immune function), in the Siberian hamster (Phodopus sungorus). The current study provides the first evidence that leptin serves as a signal to mothers of available energy resulting in epigenetic effects. Therefore, elevated leptin allows females to retain more embryos to parturition, and rear more offspring to weaning via reduced maternal infanticide. Innate immune response was suppressed seemingly as a result of these enlarged litters, suggesting that the observed fitness increase is not without costs to the mother. Collectively, these findings suggest that leptin plays a critical role in allowing mothers to determine how much energy to invest in the production and care of young versus self-maintenance. Topics: Adipose Tissue; Animals; Body Weight; Cricetinae; Energy Metabolism; Feeding Behavior; Female; Immunity; Leptin; Phodopus; Reproduction; Uterus | 2009 |
Effects of maternal genotype and diet on offspring glucose and fatty acid-sensing ventromedial hypothalamic nucleus neurons.
Maternal obesity accentuates offspring obesity in dams bred to develop diet-induced obesity (DIO) on a 31% fat, high-sucrose, high-energy (HE) diet but has no effect on offspring of diet-resistant (DR) dams. Also, only DIO dams become obese when they and DR dams are fed HE diet throughout gestation and lactation. We assessed glucose and oleic acid (OA) sensitivity of dissociated ventromedial hypothalamic nucleus (VMN) neurons from 3- to 4-wk old offspring of DIO and DR dams fed chow or HE diet using fura-2 calcium imaging to monitor intracellular calcium fluctuations as an index of neuronal activity. Offspring of DIO dams fed chow had approximately 2-fold more glucose-inhibited (GI) neurons than did DR offspring. This difference was eliminated in offspring of DIO dams fed HE diet. At 2.5 mM glucose, offspring of chow-fed DIO dams had more GI neurons that were either excited or inhibited by OA than did DR offspring. Maternal HE diet intake generally increased the percentage of neurons that were excited and decreased the percentage that were inhibited by OA in both DIO and DR offspring. However, this effect was more pronounced in DIO offspring. These data, as well as concentration-dependent differences in OA sensitivity, suggest that genotype, maternal obesity, and dietary content can all affect the sensitivity of offspring VMN neurons to glucose and long-chain fatty acids. Such altered sensitivities may underlie the propensity of DIO offspring to become obese when fed high-fat, high-sucrose diets. Topics: Animals; Animals, Newborn; Blood Glucose; Body Weight; Calcium; Dietary Fats; Dietary Sucrose; Disease Models, Animal; Fatty Acids; Female; Genotype; Insulin; Leptin; Male; Neurons; Obesity; Oleic Acid; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains; Ventromedial Hypothalamic Nucleus | 2009 |
Lack of laterality in the effects of right and left amygdala kindling on weight gain in female rats.
Women with epilepsy often suffer from weight gain. A similar phenomenon is seen in female rats that are kindled from the amygdala. Interestingly, it has been reported that kindling of the left amygdala causes more weight gain than kindling of the right amygdala. The present study was designed to confirm and extend that effect.. Female Wistar rats were kindled from the left or right basolateral amygdala to a criterion of 40 stage 5 seizures. Control subjects were handled but not stimulated. Subjects were weighed weekly for the duration of the study. Twenty-four hours following the last kindled seizure, kindled subjects and their yoked controls were sacrificed and their brains and serum were extracted.. Kindled subjects weighed significantly more than controls at the end of the kindling procedure and had significantly higher serum levels of leptin. No laterality effects were seen in either weight gain or leptin levels, however.. Amygdala kindling increases weight gain and serum leptin levels in rats, but in the present study no laterality effects were seen. Topics: Amygdala; Analysis of Variance; Animals; Body Weight; Disease Progression; Electric Stimulation; Electrodes, Implanted; Estrous Cycle; Female; Functional Laterality; Kindling, Neurologic; Leptin; Rats; Rats, Wistar; Seizures; Weight Gain | 2009 |
Central overexpression of leptin antagonist reduces wheel running and underscores importance of endogenous leptin receptor activity in energy homeostasis.
We used recombinant adeno-associated virus (rAAV)-mediated gene delivery to overexpress a mutant of rat leptin yielding a protein that acts as a neutral leptin receptor antagonist. The long-term consequences of this overexpression on body weight homeostasis and physical activity, as assessed by voluntary wheel running (WR), were determined in F344 x Brown Norway (BN) rats. Leptin antagonist overexpression was confirmed by examination of mRNA levels in the hypothalamus. Food consumption and body weight gain were exacerbated in the antagonist group during both chow and high-fat feeding periods over the 192-day experiment. In a second experiment, a lower dose of antagonist vector was used that resulted in no change in food consumption but still increased body weight. The degree of antagonist overexpression was sufficient to partially block signal transducer and activator of transcription 3 (STAT3) phosphorylation due to administration of an acute submaximal dose of leptin. Rats were provided free access to running wheels for 4 days during both the chow and high-fat feeding periods. With both antagonist doses and during both chow and high-fat feeding, WR was substantially less with antagonist overexpression. In contrast, when leptin was overexpressed in the hypothalamus, WR activity was increased by greater than twofold. At death, adiposity and serum leptin levels were greater in the antagonist group. These data indicate that submaximal central leptin receptor blockade promotes obesity and diminishes WR activity. These findings underscore the critical role of unrestrained leptin receptor activity in long-term energy homeostasis and suggest that even minor disruption of leptin receptor function can promote obesity. Topics: Adenoviridae; Adiposity; Animals; Body Weight; Eating; Energy Metabolism; Homeostasis; Hypothalamus; Ion Channels; Leptin; Male; Mitochondrial Proteins; Models, Animal; Obesity; Physical Conditioning, Animal; Rats; Rats, Inbred BN; Rats, Inbred F344; Receptors, Leptin; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Uncoupling Protein 1 | 2009 |
Adult type 3 adenylyl cyclase-deficient mice are obese.
A recent study of obesity in Swedish men found that polymorphisms in the type 3 adenylyl cyclase (AC3) are associated with obesity, suggesting the interesting possibility that AC3 may play a role in weight control. Therefore, we examined the weight of AC3 mice over an extended period of time.. We discovered that AC3(-/-) mice become obese as they age. Adult male AC3(-/-) mice are about 40% heavier than wild type male mice while female AC3(-/-) are 70% heavier. The additional weight of AC3(-/-) mice is due to increased fat mass and larger adipocytes. Before the onset of obesity, young AC3(-/-) mice exhibit reduced physical activity, increased food consumption, and leptin insensitivity. Surprisingly, the obesity of AC3(-/-) mice is not due to a loss of AC3 from white adipose and a decrease in lipolysis.. We conclude that mice lacking AC3 exhibit obesity that is apparently caused by low locomotor activity, hyperphagia, and leptin insensitivity. The presence of AC3 in primary cilia of neurons of the hypothalamus suggests that cAMP signals generated by AC3 in the hypothalamus may play a critical role in regulation of body weight. Topics: Adenylyl Cyclases; Adipocytes; Adipose Tissue; Animals; Body Weight; Cyclic AMP; Female; Hypothalamus; Leptin; Male; Mice; Neurons; Obesity; Polymorphism, Genetic; Sex Factors | 2009 |
Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity.
Leptin-stimulated Stat3 activation in proopiomelanocortin (POMC)-expressing neurons of the hypothalamus plays an important role in maintenance of energy homeostasis. While Stat3 activation in POMC neurons is required for POMC expression, the role of elevated basal Stat3 activation as present in the development of obesity has not been directly addressed. Here, we have generated and characterized mice expressing a constitutively active version of Stat3 (Stat3-C) in POMC neurons (Stat3-C(POMC) mice). On normal chow diet, these animals develop obesity as a result of hyperphagia and decreased POMC expression accompanied by central leptin and insulin resistance. This unexpected finding coincides with POMC-cell-specific, Stat3-mediated upregulation of SOCS3 expression inhibiting both leptin and insulin signaling as insulin-stimulated PIP(3) (phosphatidylinositol-3,4,5 triphosphate) formation and protein kinase B (AKT) activation in POMC neurons as well as with the fact that insulin's ability to hyperpolarize POMC neurons is largely reduced in POMC cells of Stat3-C(POMC) mice. These data indicate that constitutive Stat3 activation is not sufficient to promote POMC expression but requires simultaneous PI3K (phosphoinositide 3-kinase)-dependent release of FOXO1 repression. In contrast, upon exposure to a high-fat diet, food intake and body weight were unaltered in Stat3-C(POMC) mice compared with control mice. Taken together, these experiments directly demonstrate that enhanced basal Stat3 activation in POMC neurons as present in control mice upon high-fat feeding contributes to the development of hypothalamic leptin and insulin resistance. Topics: Agouti-Related Protein; Animals; Body Composition; Body Weight; Disease Models, Animal; Eating; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Feedback; Gene Expression Regulation; Glucose Tolerance Test; Green Fluorescent Proteins; Hypothalamus; In Vitro Techniques; Insulin; Insulin Resistance; Leptin; Leukemia Inhibitory Factor; Membrane Proteins; Mice; Mice, Transgenic; Neural Inhibition; Neurons; Neuropeptide Y; Obesity; Patch-Clamp Techniques; Phosphatidylinositol 3-Kinases; Pro-Opiomelanocortin; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transfection | 2009 |
Conjugated linoleic acid induces uncoupling protein 1 in white adipose tissue of ob/ob mice.
Conjugated linoleic acid (CLA) reduces body weight and adipose mass in a variety of species. The mechanisms by which CLA depletes adipose mass are unclear, but two independent microarray analyses indicate that in white adipose tissue (WAT), uncoupling protein 1 (UCP1) was among genes most changed by CLA. The objective of this study was to determine whether CLA induces ectopic expression of UCP1 in WAT, which may contribute to increased energy expenditure and weight loss. Six-week old, male ob/ob mice were fed either a control diet (CON) or a diet supplemented with 1.5% mixed isomer CLA (CLA) for 4 weeks. A third group of mice (LEPTIN) was fed the control diet and received daily injections of recombinant leptin as a positive control for adipose depletion in ob/ob mice. CLA did not alter several mRNA markers of lipid oxidation in epididymal white adipose tissue (eWAT) , but significantly increased carnitine palmitoyltransferase-1b (CPT1b) and PPAR gamma coactivator-1alpha (PGC1alpha) expression. Notably, CLA increased both mRNA and protein expression of uncoupling protein-1 (UCP1). beta3-adrenoceptor mRNA and phosphorylated-p38 mitogen activated protein kinase (MAPK) protein levels were not affected by CLA, but were upregulated by LEPTIN. These data suggest the increased CPT1b, PGC1alpha, and UCP1, in WAT of CLA-fed mice may contribute to the depletion of adipose, and CLA does not appear to increase UCP1 through beta3-adrenergic signaling. Future studies will focus on understanding how CLA increases mitochondrial oxidation and energy dissipation in white adipose tissue. Topics: Adipose Tissue, White; Animals; Body Weight; Carnitine O-Palmitoyltransferase; Energy Metabolism; Ion Channels; Leptin; Linoleic Acids, Conjugated; Male; Mice; Mice, Transgenic; Mitochondrial Proteins; Obesity; RNA, Messenger; Uncoupling Protein 1 | 2009 |
Plant growth regulator (4-chlorophenoxy acetic acid) increases apoptosis in gonads of rats without changing hormonal levels.
Plant growth regulators are considered to leave minimal amounts of remnants and therefore cause no significant side effects in humans. In this study, we aimed to investigate the hormonal and histopathological effects of 4-chlorophenoxy acetic acid (4-CPA), a commonly used plant growth regulator, on the gonadal functions of rats.. The study was implemented on 64 Wistar albino rats (20 days old). Forty-eight rats received 4-CPA every day until 50 days of age. The rats were randomized into 4 groups (a control group and three 4-CPA groups with doses of 25, 50 and 100 mg/kg/day); each group was further divided into males and females, making a total of 8 groups. The levels of FSH, LH, testosterone, estradiol, leptin, inhibin-B and neuropeptide-Y were measured. Histopathological examination of the testes and ductus deferens in male rats, and ovaries and uterus of female rats (caspase-3 and -9 immunoreactivity) was performed.. Although hormone levels were similar between the groups, rats that received 4-CPA showed significantly higher degrees of apoptosis compared to the control group (p < 0.001) and increased doses of 4-CPA were directly correlated with the amount of apoptosis (p < 0.001).. 4-CPA induced apoptosis in the gonads of rats without concurrent changes in plasma hormone levels. Topics: 2,4-Dichlorophenoxyacetic Acid; Animals; Apoptosis; Body Weight; Dose-Response Relationship, Drug; Endocrine Disruptors; Female; Gonadal Hormones; Gonads; Inhibins; Leptin; Male; Neuropeptide Y; Organ Size; Ovary; Plant Growth Regulators; Rats; Rats, Wistar; Sex Characteristics; Sexual Maturation; Testis; Uterus; Vas Deferens | 2009 |
Development of obesity in the Otsuka Long-Evans Tokushima Fatty rat.
Understanding the early factors affecting obesity development in males and females may help to prevent obesity and may lead to the discovery of more effective treatments for those already obese. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of obesity is characterized by hyperphagia-induced obesity, due to a spontaneous lack of CCK(1) receptors. In the present study, we focused on the behavioral and physiological aspects of obesity development from weaning to adulthood. We examined body weight, feeding efficiency, fat pad [brown, retroperitoneal, inguinal and epydidimal (in males)] weight, inguinal adipocyte size and number, leptin and oxytocin levels, body mass index, waist circumference, and females' estrous cycle structure. In the males, central hypothalamic gene expression was also examined. OLETF rats presented overall higher fat and leptin levels, larger adipocytes, and increased waist circumference and BMI from weaning until adulthood, compared with controls. Analysis of developmental patterns of gene expression for hypothalamic neuropeptides revealed peptide-specific patterns that may underlie or be a consequence of the obesity development. Analysis of the developmental trajectories toward obesity within the OLETF strain revealed that OLETF females developed obesity in a more gradual manner than the males, presenting delayed obesity-related "turning points," with reduced adipocyte size but larger postweaning fat pads and increased adipocyte hyperplasia compared with the males. Intake decrease in estrus vs. proestrus was significantly less in OLETF vs. Long-Evans Tokushima Otsuka females. The findings highlight the importance of using different sex-appropriate approaches to increase the efficacy of therapeutic interventions in the treatment and prevention of chronic early-onset obesity. Topics: Adipocytes; Adipose Tissue; Age Factors; Aging; Animals; Blood Glucose; Body Mass Index; Body Weight; Chronic Disease; Disease Models, Animal; Disease Progression; Eating; Estrus; Feeding Behavior; Female; Gene Expression Regulation, Developmental; Hyperphagia; Hypothalamus; Leptin; Male; Neuropeptides; Obesity; Oxytocin; Rats; Rats, Inbred OLETF; Receptor, Cholecystokinin A; RNA, Messenger | 2009 |
Effect of leptin on vascular calcification in apolipoprotein E-deficient mice.
The adipocytokine leptin has been proposed to increase cardiovascular risk in both obese and diabetic individuals. In the current study, therefore, we used apoE-deficient mice to examine the effects of leptin on both lesion size and calcification.. Mice were treated with once daily intraperitoneal injections of leptin (125 microg/mouse/d) for 2 months. The mice were then euthanized, and sections of the aortic root and thoracic aorta analyzed histomorphometrically. Measurements of lesion size and surface area occupied by atherosclerotic lesions did not reveal any differences between nontreated and leptin-treated animals. However, von Kossa staining of the aortic root demonstrated an 8.3+/-2.0-fold increase in lesion calcification as well as a 2.5+/-0.6-fold increase in valvular calcification in those animals treated with leptin. In addition, the percent total lesion area demonstrating ALP-positive staining was 5.4+/-2.1-fold greater in leptin-treated mice when compared to nontreated control mice. This increase in ALP staining was also accompanied by an increase in the expression of the osteoblast-specific markers, osteocalcin, and osteopontin.. Based on these observations, we conclude that leptin may increase cardiovascular risk by promoting osteogenic differentiation and thus vascular calcification. Topics: Alkaline Phosphatase; Animals; Aorta; Aortic Valve; Apolipoproteins E; Atherosclerosis; Body Weight; Calcinosis; Cattle; Cell Differentiation; Cells, Cultured; Disease Models, Animal; Female; Humans; Leptin; Lipids; Mice; Mice, Knockout; Myocytes, Smooth Muscle; Osteoblasts; Osteocalcin; Osteopontin; Recombinant Proteins; Risk Factors | 2009 |
Palatable high-energy diet decreases the expression of cannabinoid type 1 receptor messenger RNA in specific brain regions in the rat.
In laboratory rodents, a palatable high-energy diet (PHED) is usually consumed in a higher quantity than a standard laboratory diet, leading to the development of an obese phenotype. The central effects of PHED are not fully understood. Nonetheless, the long-term consumption of PHED can decrease cannabinoid type 1 receptor (CB1R) protein density in particular brain regions. However, little is known about the diet-dependent regulation of the brain expression of CB1R mRNA. The present study aimed to investigate the effects of the long-term consumption of PHED and short-term (12 h) food deprivation on the brain expression of CB1R mRNA. For 13 weeks, rats were fed a standard laboratory chow or PHED presented as a free choice of chow, shortcake biscuits and pork spread. In total, the food intake of PHED rats was higher than that of chow-fed animals. Expectedly, PHED rats demonstrated higher body weight than chow-fed animals. The difference in body weight between PHED- and chow-fed rats was as result of the fat but not the lean mass. PHED-fed rats had significantly higher plasma levels of leptin and insulin and significantly higher levels of expression of suppressor of cytokine signalling 3 (SOCS-3) in the arcuate hypothalamic nucleus. The long-term consumption of PHED significantly decreased the levels of CB1R mRNA expression in the cingulate (Cg) cortex, ventromedial hypothalamic nucleus and the descending/autonomic divisions of the parvocellular hypothalamic nucleus (PVH), the ventrolateral parvocellular PVH and, to a lesser extent, the dorsomedial parvocellular PVH. Acute food deprivation decreased the levels of CB1R transcript in the Cg and ventrolateral parvocellular PVH. Altogether, the present results demonstrate that long-term PHED leads to an increase in the hypothalamic expression of SOCS-3 mRNA and a decrease in expression of CB1R mRNA in the Cg cortex and specific hypothalamic regions. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Brain; Diet; Eating; Energy Intake; Food Deprivation; Insulin; Leptin; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Time Factors | 2009 |
Does hypothalamic inflammation cause obesity?
Obesity-induced inflammation causes cellular resistance to both insulin and leptin. In this issue, Brüning and colleagues (Kleinridders et al., 2009) add to growing evidence that this response occurs in the hypothalamus, as well as in peripheral tissues, which helps to explain how high-fat feeding induces a gradual increase in defended body weight. Topics: Animals; Body Weight; Dietary Fats; Energy Metabolism; Hypothalamus; Insulin; Leptin; Mice; Myeloid Differentiation Factor 88; Obesity | 2009 |
Activation of hypothalamic NPY, AgRP, MC4R, AND IL-6 mRNA levels in young Lewis rats with early-life diet-induced obesity.
Obesity represents a low-grade inflammatory disease and appears a risk factor for insulin resistance, but little is known on whether this may contribute to the development of autoimmune inflammatory diseases. The aim of this work was to study the early-life diet-induced obesity in Lewis rats which are known to be highly susceptible to autoimmunity.. Obesity was induced by reduced litter size (4 pups per litter) followed by high-fat diet (SHF rats). Control rats (8 pups per litter) were fed with standard diet (CN rats). Oral glucose tolerance test (3 g glucose per kg b.w.) was performed by intra-gastric tube in conscious rats after 12 h fast. Adipocyte size was assessed by light microscope after collagenase digestion. Hypothalamic arcuate (ARC) and paraventricular nuclei (PVN) were isolated by the punching technique. Target mRNAs were quantified by real-time PCR with the use of TaqMan probes and primers. Serum hormones (leptin, ghrelin, adiponectin, visfatin and insulin) were assayed by specific RIAs .. During the experimental period SHF rats had the same body weight gain and caloric intake as CN rats. At the age of 8 weeks SHF rats showed increased epididymal fat mass and adipocyte volume, impaired glucose tolerance, normal basal fasting insulin, visfatin, and ghrelin level, but decreased adiponectin and high leptin level. In the ARC, the SHF rats showed increased expression of mRNA for orexigenic neuropeptide Y (NPY), agouti-related protein (AgRP) and anorexigenic pro-inflammatory cytokine IL-6. In the PVN, the SHF rats showed increased expression of mRNA for anorexigenic melanocortin 4 receptor (MC4R) and IL-6.. Overexpression of orexigenic NPY and AgRP in the ARC indicates leptin resistance in SHF rats. The increased expression of MC4R in PVN points to the activation of melanocortin anorexigenic system which, along with increased hypothalamic IL-6, might prevent the animals from overfeeding. Higher adiposity in these rats results from the high fat-diet composition and not from increased caloric intake. Furthermore, enhanced leptin production appears the main factor indicating the predisposition to autoimmunity in these overfed rats. Topics: Adipocytes, White; Adiponectin; Adipose Tissue, White; Adiposity; Aging; Agouti-Related Protein; Analysis of Variance; Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Area Under Curve; Body Weight; Cell Size; Dietary Fats; Energy Intake; Feeding Behavior; Gene Expression; Ghrelin; Glucose Intolerance; Insulin; Interleukin-6; Leptin; Litter Size; Male; Neuropeptide Y; Nicotinamide Phosphoribosyltransferase; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred Lew; Receptor, Melanocortin, Type 4; RNA, Messenger | 2009 |
Alcohol intake modifies leptin, adiponectin and resistin serum levels and their mRNA expressions in adipose tissue of rats.
Alcohol intake is known to interfere with endocrine system functions thus inducing hormonal and metabolic imbalance. The aim was to investigate the impact of chronic intake of mild alcohol concentration on serum leptin, adiponectin and resistin and their gene expression in epididymal adipose tissue (EAT) of rats.. The 28 days study was based on 3 experimental groups of adult male Wistar rats: 1/ ad libitum intake of 6 % ethanol solution and pelleted diet (A), 2/ pair fed animals (PF) fed pelleted diet in the same caloric amount as A rats on previous day (alcohol+diet), 3/ control rats (C) with unrestricted intake of water and pelleted diet. RT-PCR method was used for determination of adipokines gene expression in epididymal adipose tissue, serum levels were measured by ELISA kits.. The animals of A group were characterized by reduced food and energy intake (-10 % vs C), lower body mass gain, reduced epididymal fat mass with smaller adipocytes. Alcohol consumption significantly increased glycemia, serum insulin was not affected. The raise of NEFA in A and PF rats gives the evidence of intensified lipolysis due to the deficiency of energy intake. Alcohol consumption significantly increased serum leptin and resistin, elevated adiponectin was present in A and PF rats. In parallel with increased serum levels the expression of adiponectin gene in epididymal adipose tissue was elevated in the same A and PF rats. Leptin and resistin mRNA levels were similar as in C regardless of alcohol intake or pair-fed feeding. Increased leptin and resistin levels positively correlated with glycemia and negatively with the size of adipocytes. Elevated serum leptin and resistin together with high adiponectin after chronic moderate alcohol intake could contribute to alteration of energy metabolism either individually or in reciprocal coordination.. 28 days consumption of 6 % ethanol solution changed the nutritional status of rats and induced significant elevation of serum leptin and resistin, while elevated gene expression in epididymal adipose tissue was proved for adiponectin only. Elevated serum adipokines could contribute to increased glycemia and altered glucose homeostasis. Topics: Abdominal Fat; Adipocytes, White; Adiponectin; Adiposity; Alcohol Drinking; Analysis of Variance; Animals; Blood Glucose; Body Weight; Cell Size; Diet; Energy Intake; Epididymis; Fatty Acids, Nonesterified; Gene Expression; Insulin; Leptin; Male; Rats; Rats, Wistar; Resistin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2009 |
Obesity and the associated mediators leptin, estrogen and IGF-I enhance the cell proliferation and early tumorigenesis of breast cancer cells.
Breast cancer continues to be a major cause of cancer deaths in women. Estrogen, which is also produced by the adipose tissue, is held responsible for the elevated risk of breast cancer in obese women. However, the adipose tissue secrets hormones and adipokines such as leptin and IGF-I and these substances could also contribute to an increased breast cancer risk for obese women. In this study, the impact of obesity on cell proliferation was investigated. The carcinogen 7, 12, dimethylbenz[a]anthracene (DMBA) was administered to normal weight and diet-induced obese female Sprague-Dawley rats. Cell proliferation was evaluated by immunohistological staining of BrdU-incorporation. In the mammary glands and inguinal lymphatic nodes of the obese rats, cell proliferation was significantly increased, indicating a significant influence of obesity on breast cancer. Effects of leptin, estrogen, and IGF-I on the proliferation of MCF-7 cells in vitro were assessed using an MTT assay. Cell culture experiments demonstrated a mitogenic role of these three mediators on cell proliferation. Our data demonstrate a stimulative effect of substances produced by the adipose tissue on breast cancer. Body weight specific cell proliferation suggests that obesity-related adipokines and mediators enhance cell proliferation and increase the risk for breast cancer. Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Analysis of Variance; Animals; Body Weight; Breast Neoplasms; Carcinogens; Cell Line, Tumor; Cell Proliferation; Dietary Fats; Disease Models, Animal; Estradiol; Female; Groin; Humans; Immunohistochemistry; Insulin-Like Growth Factor I; Leptin; Lymph Nodes; Lymphatic Metastasis; Mammary Neoplasms, Experimental; Obesity; Random Allocation; Rats; Rats, Sprague-Dawley; Time Factors | 2009 |
Leptin: back and forward.
The discovery of leptin resulted in a gear change in obesity research. Exploiting its therapeutic potential has proved to be a long game, although encouraging progress is now being made with leptin monotherapy in conditions of relative deficiency, and with combination therapy against common obesity. Leptin's role in early brain development constitutes an exciting area for mechanistic study with potential therapeutic implications. Topics: Aging; Animals; Body Weight; Brain; Eating; Humans; Leptin; Mice; Obesity | 2009 |
Hepcidin in obese children as a potential mediator of the association between obesity and iron deficiency.
Obesity and iron deficiency are two of the most common nutritional disorders worldwide. Several studies found higher rates of iron deficiency in obese than in normal-weight children. Hepcidin represents the main inhibitor of intestinal iron absorption, and its expression is increased in adipose tissue of obese patients. Leptin is able, in vitro, to raise hepcidin expression.. Aims of this work were 1) to assess the association between poor iron status and obesity, 2) to investigate whether iron homeostasis of obese children may be modulated by serum hepcidin variations, and 3) to assess the potential correlation between leptin and serum hepcidin variations.. Iron status and absorption as well as hepcidin, leptin, and IL-6 levels were studied in 60 obese children and in 50 controls.. Obese children showed lower iron and transferrin saturation (both P < 0.05) and higher hepcidin levels (P = 0.004) compared with controls. A direct correlation between hepcidin and obesity degree (P = 0.0015), and inverse correlations between hepcidin and iron (P = 0.04), hepcidin and transferrin saturation (P = 0.005), and hepcidin and iron absorption (P = 0.003) were observed. A correlation between leptin and hepcidin (P = 0.006) has been found. The correlation remained significant when adjusted for body mass index, sex, pubertal stage, and IL-6 values.. We propose that in obese patients, increased hepcidin production, at least partly leptin mediated, represents the missing link between obesity and disrupted iron metabolism. Topics: Absorption; Adolescent; Antimicrobial Cationic Peptides; Biomarkers; Body Height; Body Mass Index; Body Weight; Child; Female; Hepcidins; Humans; Interleukin-6; Iron; Iron Deficiencies; Italy; Leptin; Male; Nutritional Status; Obesity; Transferrin | 2009 |
Serum leptin concentrations in patients with intestinal parasites.
Leptin is a protein hormone controlling food intake and energy expenditure. In all infections including parasitic infections there is loss of appetite and anorexia. The aim of the present study was to clarify the relationship between intestinal parasites and serum leptin concentrations in children and adults. Forty patients with intestinal parasites and 34 healthy subjects took part in this study. Body weight, height and body mass index (BMI) were measured for all patients and controls. Patients were grouped according to age and parasitic infections (Giardia intestinalis, Blastocystis hominis, Enterobius vermicularis, Entamoeba histolytica/Entamoeba dispar, Entamoeba coli). Serum leptin concentrations were detected by immunoenzymometric assay using the Biosource Leptin EASIA kit. Statistical analysis was made by Mann-Whitney-U test using SPSS version 10.0. In children, the serum leptin levels were not statistically significant (patient: 1.49+/-1.97 ng/ml, control: 3.48+/-4.97; p=0.854) But for adults, although the BMI of patients were similar to that of the control group; the leptin levels of patients were low. These levels were not significant (patients: 9.06+/-10.34; controls: 4.7+/-9.02 ng/ml; p=0.271). There was no statistical difference for leptin levels in patient groups, children and adults due to intestinal parasitic infections. Further investigations are needed. Topics: Adolescent; Adult; Age Factors; Blastocystis Infections; Body Mass Index; Body Weight; Child; Child, Preschool; Dysentery, Amebic; Enterobiasis; Feeding and Eating Disorders; Female; Giardiasis; Humans; Intestinal Diseases, Parasitic; Leptin; Male; Middle Aged; Young Adult | 2009 |
The effect of high-fat diet on plasma ghrelin and leptin levels in rats.
Ghrelin and leptin regulate appetite and energy homeostasis in humans and rodents. The effects of different nutritional factors on ghrelin and leptin secretion are not well documented in rats. Therefore, the aim of our study was to investigate the effect of a high-fat diet on plasma ghrelin and leptin levels and on adiposity. Twenty male Wistar rats, body weight 220-260 g, were used in the study. Rats were randomized either on a standard chow diet (n=10) or on a high-fat diet (a mixture of nuts) for ad libitum 11-week period. Body weight was measured once per week. At the end of the nutritional period, rats were sacrificed. Blood was collected for determination of lipids and glucose, as well as plasma ghrelin and leptin levels by ELISA method. The weight of different organs was determined. Rats fed on a high-fat diet showed significant increase in total body weight compared to control group. The long-term intake of high-fat diet caused hyperleptinemia and hypoghrelinemia. There was a significant positive correlation between plasma leptin levels and epididymal fat mass, liver and heart. In contrast, ghrelin levels showed inverse correlation with epididymal fat mass and liver weight. In conclusion, long-term intake of high-fat diet induced changes in plasma ghrelin and leptin in male rats, as well as in epididymal fat mass, liver and heart weights. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Dietary Fats; Epididymis; Ghrelin; Leptin; Male; Rats; Rats, Wistar; Triglycerides | 2009 |
Involvement of adipokines in rimonabant-mediated insulin sensitivity in ob/ob mice.
It has been recently reported that blockade of type 1 cannabinoid (CB1) receptors by specific antagonists or genetic manipulation alleviates dyslipidaemia, hyperglycaemia and insulin resistance in animal models of obesity and type 2 diabetes. However, the precise role of adipokines in the insulin-sensitising effects of the CB1 antagonist rimonabant is not clear.. ob/ob mice were treated with different doses of rimonabant and then subjected to an oral glucose tolerance test. The expression of different adipokines in white adipose tissue was analysed by quantitative real-time PCR.. Rimonabant (30 mg/kg) significantly inhibited body weight and fat pad weight gain (P < 0.05) and improved glucose tolerance. Gene expression analysis indicated that tumour necrosis factor-alpha, visfatin and retinol binding protein-4 were downregulated in the adipose tissue of ob/ob mice treated with rimonabant compared with controls, whereas adiponectin was significantly upregulated.. Rimonabant-mediated alteration of adipokines in white adipose tissues may play a role in improving insulin sensitivity in obese animals. Topics: Adipokines; Adiponectin; Adipose Tissue; Adipose Tissue, White; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Down-Regulation; Female; Gene Expression; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Mice; Mice, Knockout; Models, Animal; Nicotinamide Phosphoribosyltransferase; Obesity; Organ Size; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Retinol-Binding Proteins, Plasma; Reverse Transcriptase Polymerase Chain Reaction; Rimonabant; RNA, Messenger; Tumor Necrosis Factor-alpha | 2009 |
PACAP neurons in the hypothalamic ventromedial nucleus are targets of central leptin signaling.
The adipose-derived hormone, leptin, was discovered over 10 years ago, but only now are we unmasking its downstream pathways which lead to reduced energy intake (feeding) and increased energy expenditure (thermogenesis). Recent transgenic models have challenged the long-standing supposition that the hypothalamic arcuate nucleus (Arc) is omnipotent in the central response to leptin, and research focus is beginning to shift to examine roles of extra-arcuate sites. Dhillon et al. (2006) demonstrated that targeted knock out of the signaling form of the leptin receptor (lepr-B) in steroidogenic factor 1 (SF-1) cells of the hypothalamic ventromedial nucleus (VMN) produces obesity of a similar magnitude to the pro-opiomelanocortin (POMC)-driven lepr-B deleted mouse, via a functionally distinct mechanism. These findings reveal that SF-1 cells of the VMN could be equally as important as POMC cells in mediating leptin's anti-obesity effects. However, the identification of molecular and cellular correlates of this relationship remains tantalizingly unknown. Here, we have shown that mRNA expression of the VMN-expressed neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is regulated according to energy status and that it exerts catabolic effects when administered centrally to mice. Furthermore, we have shown that SF-1 and PACAP mRNAs are colocalized in the VMN, and that leptin signaling via lepr-B is required for normal PACAP expression in these cells. Finally, blocking endogenous central PACAP signaling with the antagonist PACAP(6-38) markedly attenuates leptin-induced hypophagia and hyperthermia in vivo. Thus, it appears that PACAP is an important mediator of central leptin effects on energy balance. Topics: Animals; Appetite Regulation; Body Weight; Energy Metabolism; Fever; Leptin; Male; Mice; Neurons; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Leptin; Signal Transduction; Steroidogenic Factor 1; Ventromedial Hypothalamic Nucleus | 2009 |
Dietary supplementation with arachidonic acid but not eicosapentaenoic or docosahexaenoic acids alter lipids metabolism in C57BL/6J mice.
In order to investigate the effects of dietary supplementation rich in omega 3 and omega 6 fatty acids, we set up an experiment of twenty four C57BL/6J male mice segregated into 3 groups: normal diet (ND), omega 3 polyunsaturated fatty acid (n-3 PUFA,) and omega 6 (n-6 PUFA). At the end of the experiment that lasted for 1 month, food consumption of ND and n-3 PUFA were similar while it decreased in n-6 PUFA group. Total cholesterol, triglycerides, free fatty acids, and phospholipids profiles were increased in n-6 PUFA. LDL decreased in n-3 PUFA while increased in n-6 PUFA fed mice comparing to control group. On the other hand, there was no difference between treatments in HDL and glucose levels. Expression of leptin (ob) gene transcripts in epididymal fat were significantly elevated in n-6 PUFA mice compared to ND and n-3 PUFA groups while hypothalamic ob receptor A (obRa) mRNA did not changed in response to diet regimes. Transmission and scanning electron microscopy showed different degrees in fatty changes in the liver of both PUFA groups including lipid droplet infiltration and Ito cells with over accumulated lipids. In conclusion, under PUFA dietary supplementation, the hyperlipidemic status and elevated ob expression of n-6 PUFA but not n-3 PUFA fed mice suggests altered lipid metabolism between PUFA groups and/or different endocrine involvement. Moreover, the coincidently structural changes observed in liver of this group direct us to call for further studies to investigate the anti-obesity effect and safety of these PUFA under high supplementation condition. Topics: Animals; Arachidonic Acid; Blood; Body Weight; Diet; Dietary Fats, Unsaturated; Dietary Supplements; Docosahexaenoic Acids; Eating; Eicosapentaenoic Acid; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Glyceraldehyde-3-Phosphate Dehydrogenases; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Random Allocation; Receptors, Leptin | 2009 |
Effects of metformin on serum levels of sex hormone, leptin and insulin in ovariectomized Sprague-Dawley rats.
The aim of the present experiment was to study the effects of metformin (MF) on serum concentrations of sex hormone, leptin and insulin in ovariectomized (OVX) Sprague-Dawley (SD) rats. The serum estradiol (E2), progesterone (P), leptin and insulin concentrations were measured with radioimmunoassay (RIA). Compared with SHAM operated rats, the serum concentrations of E2 and P were significantly lower (P < 0.01), but leptin and insulin were significantly higher in OVX rats (P < 0.01). MF (135mg kg(-1) d(-1), ig, 30 d) had no evident effects on serum concentrations of E2, P, leptin and insulin in OVX rats. MF (270 mg kg(-1) d(-1), ig, 30 d) markedly increased serum concentrations of E2 and P (P < 0.05) while decreased serum concentrations of leptin and insulin (P < 0.05 and P < 0.01) in OVX rats. We concluded that long-term treatment of high dose MF cannot only significantly decrease serum concentrations of leptin and insulin, but also increase E2 and P in OVX SD rats. Topics: Animals; Body Weight; Estradiol; Female; Gonadal Steroid Hormones; Hypoglycemic Agents; Insulin; Leptin; Metformin; Ovariectomy; Progesterone; Rats; Rats, Sprague-Dawley | 2009 |
Decrease in leptin production by the adipose tissue in obesity associated with severe metabolic syndrome.
To evaluate the associations between leptinemia and the components of metabolic syndrome (MetS).. Fifty-one obese adults (9 men; 36.7 +/- 10.0 years; body mass index (BMI) 46.2 +/- 10.0 kg/m(2)) were submitted to clinical examination, determinations of body fat mass (BF, bioimpedance) and resting energy expenditure (REE, indirect calorimetry), and to hormonal and biochemical analysis. Patients were categorized into three groups, according to the number of criteria for MetS: Group I: none or 1; Group II: 2; and Group III: 3 or 4 criteria.. Absolute leptinemia (LepA; 37.5 +/- 16.9 ng/mL) was directly correlated with BMI (r = 0.48; p = 0.0004), waist circumference (r = 0.31; p = 0.028) and BF (r = 0.52; p = 0.0001). Leptinemia adjusted for BF (LepBF) was inversely correlated with weight (r = -0.41; p=0.027), REE (r = -0.34; p = 0.01) and number of MetS criteria (r = -0.32; p = 0.02). There was no difference in LepA among the groups. LepBF in Group III (0.58 +/- 0.27 ng/mL/kg) was significantly lower compared to Group I (0.81 +/- 0.22 ng/mL/kg; p = 0.03) and Group II (0.79 +/- 0.30 ng/mL/kg; p = 0.02).. Leptin production by the adipose tissue is decreased in obese subjects fulfilling three or more criteria of MetS, suggesting a state of relative leptin deficiency in obesity associated with advanced stages of MetS. Topics: Adipose Tissue; Adult; Body Mass Index; Body Weight; Energy Metabolism; Epidemiologic Methods; Female; Humans; Leptin; Male; Metabolic Syndrome; Obesity; Risk Factors; Waist Circumference | 2009 |
Influence of smoking and body weight on adipokines in middle aged women.
Quitting smoking was associated with an undesirable weight gain. Both, cigarette smoking and obesity were accompanied by subclinical systemic inflammation. This may cause unfavourable changes in (plasma) adipokine concentration. The aim of the present study was to establish the influence of moderate cigarette smoking on the concentration of the adipokines leptin and adiponectin and the pro-inflammatory factors CRP, SAA, IL-6 and TNF-a in non-obese (n=138) and obese (n=175) perimenopausal women of the DRECAN-2005 survey.. Among non-obese women, adiponectin was significantly lower in smokers than in non-smokers (16.88 +/-6.85 vs. 20.63 +/-10.04 microg/ml; P<0.05). Leptin tended to lower values, too. Among obese women, none significant differences in adiponectin or leptin concentration were observed between smokers and non-smokers. In obese smokers and obese non-smokers, the adiponectin concentrations were significantly lower and the leptin concentrations were significantly higher than in non-obese non-smokers. Non-obese smokers showed significantly higher leukocyte count (6.50 +/- 1.83 vs. 5.51 +/- 1.31 GPT/l; P<0.001) and serum amyloid A concentration (7.81 +/- 1.25 vs. 4.22 +/- 1.43 mg/l; P<0.05) than non-obese non-smokers. There were only tendencies to higher concentration of CRP, IL-6, and TNF-alpha. In obese women, moderate cigarette smoking was not associated with higher leukocyte count or concentration of SAA. Among non-smokers, overweight was associated higher concentration of leptin (22.16 +/- 12.16 vs. 11.49 +/- 6.37 ng/ml; P<0.001) and with significantly lower concentration of adiponectin (16.29 +/- 8.01 vs. 20.77 +/- 9.99 microg/ml; P<0.001). Among smokers, overweight was associated with higher leptin concentration only (obese: 18.62 +/- 13.46 vs. non-obese: 8.84 +/- 4.92 ng/ml; P<0.01).. In non-obese middle aged women, even moderate cigarette smoking adversely influences the serum concentration of adiponectin and SAA. Overweight hides possible effects of smoking on cytokines and adipokines. Topics: Adipokines; Adiponectin; Adult; Aged; Body Mass Index; Body Weight; C-Reactive Protein; Female; Humans; Interleukin-6; Leptin; Middle Aged; Serum Amyloid A Protein; Smoking; Tumor Necrosis Factor-alpha | 2009 |
Psychopathology in underweight and weight-recovered females with anorexia nervosa.
To compare general and eating disorder-specific psychopathology in patients with acute anorexia nervosa (acAN), weight-recovered patients (recAN) and healthy control women (HCW).. One hundred anorexia nervosa patients (66 acAN and 34 recAN) and 88 HCW were included in our study. Psychopathology was assessed by self-report questionnaires [Symptom Check List 90 Revised (SCL-90-R), Eating Disorder Inventory-2 (EDI- 2)] as well as by interview [Structured Interview of Anorexia Nervosa and Bulimic Syndromes (SIAB-EX)] and compared using multivariate analysis of variance. Plasma leptin levels were determined using enzyme linked immunosorbent assay.. Mean comparisons indicated highly significant differences between acAN and recAN subjects on all psychopatholgy variables, except for perfectionism. RecAN subjects did not differ from HCW. Partial weight recovery was associated with decreasing levels of psychopathology. Correlational analyses suggested strong negative associations between leptin levels and psychopathology.. Prolonged malnutrition, as indicated by suppressed plasma leptin levels, is strongly related to eating disorder-specific as well as general psychopathological symptoms. Weight recovery is associated with the absence of psychopathology. These data emphasize the interaction between somatic and psychological variables. Topics: Adaptation, Psychological; Adolescent; Adult; Anorexia Nervosa; Biomarkers; Body Weight; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interview, Psychological; Leptin; Multivariate Analysis; Surveys and Questionnaires; Thinness; Young Adult | 2009 |
Altered food consumption in mice lacking lysophosphatidic acid receptor-1.
The release of lysophosphatidic acid (LPA) by adipocytes has previously been proposed to play a role in obesity and associated pathologies such as insulin resistance and diabetes. In the present work, the sensitivity to diet-induced obesity was studied in mice lacking one of the LPA receptor subtype (LPA1R). Conversely to what was observed in wild type (WT) mice, LPA1R-KO-mice fed a high fat diet (HFD) showed no significant increase in body weight or fat mass when compared to low fat diet (LFD). In addition, in contrast to what was observed in WT mice, LPA1R-KO mice did not exhibit over-consumption of food associated with HFD. Surprisingly, when fed a LFD, LPA1R-KO mice exhibited significant higher plasma leptin concentration and higher level of adipocyte leptin mRNA than WT mice. In conclusion, LPA1R-KO mice were found to be resistant to diet-induced obesity consecutive to a resistance to fat-induced over-consumption of food that may result at least in part from alterations in leptin expression and production. Topics: Adipocytes; Adipose Tissue; Animal Feed; Animals; Behavior, Animal; Body Weight; Dietary Fats; Feeding Behavior; Food; Gene Expression Regulation; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Lysophosphatidic Acid | 2009 |
Differential adipokine response in genetically predisposed lean and obese rats during inflammation: a role in modulating experimental colitis?
The relationship between a predisposition to obesity and the development of colitis is not well understood. Our aim was to characterize the adipokine response and the extent of colitis in diet-induced obese (DIO) rats. DIO and control, diet-resistant (DR) animals were administered either saline or trinitrobenzene sulfonic acid (TNBS) to induce colitis. Macroscopic damage scores and myeloperoxidase (MPO) activity were measured to determine the extent of inflammation. Trunk blood was collected for the analysis of plasminogen activator inhibitor-1 (PAI-1) as well as leptin, ghrelin, and adiponectin. Colonic epithelial physiology was assessed using Ussing chambers. DIO rats had a modestly increased circulating PAI-1 before TNBS treatment; however, during colitis, DR animals had more than a fourfold increase in circulating PAI-1 compared with DIO rats. Circulating leptin was higher in DIO rats compared with DR animals, in the inflamed and noninflamed states. These changes in TNBS-induced adipokine profile were accompanied by decreased macroscopic tissue damage score in DIO animals compared with DR tissues. Furthermore, TNBS-treated DR animals lost significantly more weight than DIO rats during active inflammation. Colonic epithelial physiology was comparable between groups, as was MPO activity. The factors contributing to the decreased colonic damage are almost certainly multifold, driven by both genetic and environmental factors, of which adipokines are likely to play a part given the increasing body of evidence for their role in modulating intestinal inflammation. Topics: Adipokines; Adiponectin; Animals; Body Weight; Colitis, Ulcerative; Colon; Eating; Electric Impedance; Electrophysiological Phenomena; Genetic Predisposition to Disease; Ghrelin; Inflammation; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Peroxidase; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred Strains; Serpin E2; Serpins; Thinness; Trinitrobenzenesulfonic Acid | 2009 |
Effects of high-fat high-sucrose feeding, energy restriction, and trans-10,cis-12 conjugated linoleic acid on visfatin and apelin in hamsters.
To analyze the effects of high-fat high-sucrose (HFHS) feeding, energy restriction, and trans-10,cis-12 conjugated linoleic acid (CLA) on visfatin and apelin.. A randomized dietary intervention study.. Free-living individuals studied in metabolic cages.. Thirty-two male Syrian Golden hamsters (82.6 +/- 1.4 g).. Standard and HFHS feeding for 7 weeks. After that, some hamsters fed the HFHS diet were submitted for 3 weeks to a 25% energy restriction with or without trans-10,cis-12 CLA supplementation (0.5%).. Feeding animals an HFHS diet resulted in increased body fat and reduced insulin sensitivity. No changes were observed in the expression and serum levels of visfatin and apelin, or in peroxisome proliferator-activated receptor (PPAR)gamma and Sirt1 expression. Energy restriction reduced body fat and normalized insulin sensitivity. Visfatin showed increased serum levels without changes in expression. No modifications were found as far as apelin was concerned. Sirt1 expression was increased, and PPARgamma remained unchanged. With regard to trans-10,cis-12 CLA, no changes were induced by its addition to the restricted diet.. Insulin function impairment induced by HFHS feeding is not mediated by visfatin and apelin. However, visfatin can play a role in improving insulin sensitivity associated with energy restriction. These results suggest that visfatin may not have evolved as a molecule that reserves the action of insulin when food is widely available, but rather that its function seems to be associated with energy restriction adaptation. In general terms, trans-10,cis-12 CLA did not modify changes induced by energy restriction. Topics: Adipose Tissue; Analysis of Variance; Animals; Body Weight; Carrier Proteins; Cricetinae; Dietary Fats; Dietary Sucrose; Enzyme-Linked Immunosorbent Assay; Insulin; Insulin Resistance; Leptin; Linoleic Acid; Male; Mesocricetus; Nicotinamide Phosphoribosyltransferase; PPAR gamma; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction | 2009 |
Exogenous leptin promotes the recovery of regressed ovary in fasted ducks.
The present study was undertaken to examine the effect of administered recombinant mouse leptin on the recovery of regressed ovary in fasted ducks. Twenty-eight ducks were divided into five groups: fed ad libitum (control; n=5), fasted control (FC; n=5), fasted+low dose of leptin (F+L; n=5), fasted+medium dose of leptin (F+M; n=5) and fasted+high dose of leptin (F+H; n=3). All four fasted groups were fasted for 2 days and then ad libitum and the ducks were treated with leptin at doses of 0 (control and FC), 50 (F+L), 250 (F+M) and 1000 (F+H) microg/kg body weight/day on day 3-5. Results showed that a moderate dose of leptin (250 microg/kg body weight/day) injected during the re-feeding period: (i) promoted the recovery of the regressed ovary as evidenced by an increase in ovary weight and recovery of yellow hierarchical follicles; (ii) elevated the plasma 17beta-estradiol (E(2)) level; (iii) increased the mRNA levels of ovary follicle-stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR) and estrogen receptor-beta (ER-beta). Furthermore, the results also showed that a high dose of leptin (1000 microg/kg body weight/day) may have a negative effect on the recovery of the regressed ovary. In conclusion, this study indicates that, in ducks, leptin may be involved in the recovery of the regressed ovary caused by 2 days of fasting. This effect may be related to increased plasma E(2) levels and stimulation of the mRNA levels of ovarian FSHR, LHR and especially ER-beta. Topics: Animals; Body Weight; Ducks; Estradiol; Estrogen Receptor beta; Female; Food Deprivation; Leptin; Ovary; Oviposition; Receptors, FSH; Receptors, LH; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2009 |
Adiponectin is involved in the protective effect of DHEA against metabolic risk in aged rats.
The aim of the present work was to analyze the effect of dehydroepiandrosterone (DHEA) on several metabolic risk factors, including cardiovascular health and insulin resistance, in aged rats submitted to a high-fat diet. For that, weaned rats were fed on a high-fat diet until 20 months of age. In the last 13 weeks of life, a group (n=11) received the diet supplemented with DHEA (0.5%, w/w), serving the rest (n=10) as controls. Body weight, body fat, serum lipids (triglycerides, total cholesterol and non-esterified fatty acids (NEFA)), HOMA index, n-6/n-3 polyunsaturated fatty acid (PUFA) ratios, serum adiponectin, leptin, resistin and TNF-alpha, as well as adiponectin expression in adipose tissue, were measured. A stepwise discriminant test was used to analyze these variables, and an index of overall metabolic risk was generated from them. DHEA treatment resulted in a significantly lower overall metabolic risk index, as generated by the discriminant test (P<0.01). The DHEA group had lower body fat and n-6/n-3 polyunsaturated fatty acid (PUFA) ratios than the control group (P<0.01), and the same trends were observed for serum cholesterol, triglycerides and HOMA index; in contrast, adiponectin expression in adipose tissue increased in DHEA-treated rats (P<0.05). The discriminant analysis revealed that adiponectin, both from serum and adipose tissue, was the most influencing factor, followed by n-6/n-3 ratios in adipose tissue, and by body fat. Our results then suggest that adiponectin is involved in the protective effect of DHEA against metabolic risk demonstrated in the present work. Topics: Adiponectin; Adipose Tissue; Aging; Animals; Blood Glucose; Body Weight; Cholesterol; Dehydroepiandrosterone; Dietary Fats; Fasting; Fatty Acids, Nonesterified; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Female; Homeostasis; Insulin; Insulin Resistance; Leptin; Protective Agents; Rats; Rats, Sprague-Dawley; Resistin; Risk Factors; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha | 2008 |
Effect of des-acyl ghrelin on adiposity and glucose metabolism.
Ghrelin, a gastric peptide hormone, has been reported to regulate GH secretion and energy homeostasis. Here, we examined the effect of des-acyl ghrelin driven from the fatty acid-binding protein-4 (FABP4) promoter on adiposity and glucose metabolism. A high level of expression of des-acyl ghrelin (692 +/- 293 fmol/g fat) in adipose tissue was detected in FABP4-ghrelin transgenic mice, but not in wild-type littermates. Circulating des-acyl ghrelin was significantly higher in FABP4-ghrelin transgenic mice (8409 +/- 3390 pm) compared with wild-type mice (513 +/- 58 pm). No significant change was observed for plasma acylated ghrelin and obestatin. Epididymal and perirenal fat masses decreased 35 +/- 9 and 52 +/- 9%, respectively, in FABP4-ghrelin transgenic mice. FABP4-ghrelin transgenic mice are resistant to obesity induced by high-fat diet. Brown fat mass was not affected by overexpression of ghrelin in adipose tissue. Glucose tolerance tests showed glucose levels to be significantly lower in FABP4-ghrelin transgenic mice than in controls after glucose administration. Insulin sensitivity testing showed that FABP4-ghrelin transgenic mice had a 28 +/- 5% greater hypoglycemic response to insulin. Our study demonstrates that overexpression of ghrelin from the FABP4 promoter impairs the development of white adipose tissues, and alters glucose tolerance and insulin sensitivity in mice. Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Eating; Energy Metabolism; Fatty Acid-Binding Proteins; Ghrelin; Glucose; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Promoter Regions, Genetic | 2008 |
A study of anthropomorphic and biochemical characteristics in girls with central precocious puberty and thelarche variant.
Premature thelarche in later childhood may progress to central precocious puberty (CPP), which does not spontaneously resolve. Thelarche variant (TV) is a slowly progressive variant of precocious puberty.. To determine and compare levels of insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) and anthropomorphic measures in girls with TV and CPP.. Prepubertal controls and girls with TV and CPP.. Chronological and bone age, weight, height, BMI, height velocity (HV), and serum IGF-I, IGFBP-3, leptin, follicle-stimulating hormone (FSH) and lutenizing hormone (LH) levels were assessed.. Serum IGF-I levels, HV and IGF-I/ IGFBP-3 ratio were significantly higher in girls with CPP compared to both controls and girls with TV. IGFBP-3 values for bone age (IGFBP-3BA) were significantly higher in the TV group compared to both controls and girls with CPP. FSH and LH concentrations were significantly higher in the CPP group compared to TV.. HV, IGF-I, LH and FSH levels and IGF-I/IGFBP-3 ratio are elevated in girls with CPP compared to those with TV. Topics: Age Determination by Skeleton; Anthropometry; Body Height; Body Weight; Breast; Child; Female; Follicle Stimulating Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Luteinizing Hormone; Puberty, Precocious | 2008 |
Effects of chronic central leptin infusion on proopiomelanocortin and neurotensin gene expression in the rat hypothalamus.
Leptin signaling in the hypothalamus is critical for normal food intake and body weight regulation. While hyperleptinemia in obese people suggests a state of leptin resistance, the mechanism is not clearly understood. In a rat model of central leptin infusion in which animals develop resistance to the satiety action of leptin, orexigenic peptide producing neuropeptide Y neurons in the hypothalamus develop leptin resistance. However, it is still unknown if increased hypothalamic leptin tone caused by central leptin infusion results in the development of leptin resistance in anorexigenic peptide producing proopiomelanocortin (POMC) and neurotensin (NT) neurons. To this end, male rats were infused chronically with leptin (160 ng/h) or vehicle into the lateral cerebroventricle for 16 days. On day 4 of leptin infusion when food intake was decreased, POMC and NT mRNA levels, as determined by RNAse protection assay, were significantly increased as compared to control. By contrast, on day 16 of leptin infusion, when food intake was mostly normalized, both POMC and NT mRNA levels remained unchanged compared with control. These findings suggest the development of leptin resistance in the POMC and NT neurons following chronic elevation of hypothalamic leptin tone, which may be involved in the development of resistance to the satiety action of leptin following central infusion of this peptide hormone. Topics: Animals; Appetite Regulation; Body Weight; Eating; Gene Expression; Hypothalamus; Injections, Intraventricular; Leptin; Male; Neurons; Neurotensin; Nuclease Protection Assays; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors | 2008 |
Leptin receptor deficiency is associated with upregulation of cannabinoid 1 receptors in limbic brain regions.
Leptin receptor dysfunction results in overeating and obesity. Leptin regulates hypothalamic signaling that underlies the motivation to hyperphagia, but the interaction between leptin and cannabinoid signaling is poorly understood. We evaluated the role of cannabinoid 1 receptors (CB(1)R) in overeating and the effects of food deprivation on CB(1)R in the brain. One-month-old Zucker rats were divided into unrestricted and restricted (fed 70% of unrestricted rats) diet groups and maintained until adulthood (4 months). Levels of relative binding sites of CB(1)R (CB(1)R binding levels) were assessed using [(3)H] SR141716A in vitro autoradiography. These levels were higher (except cerebellum and hypothalamus) at 4 months than at 1 month of age. One month CB(1)R binding levels for most brain regions did not differ between Ob and Lean (Le) rats (except in frontal and cingulate cortices in Le and in the hypothalamus in Ob). Four month Ob rats had higher CB(1)R binding levels than Le in most brain regions and food restriction was associated with higher CB(1)R levels in all brain regions in Ob, but not in Le rats. CB(1)R binding levels increased between adolescence and young adulthood which we believe was influenced by leptin and food availability. The high levels of CB(1)R in Ob rats suggest that leptin's inhibition of food-intake is in part mediated by downregulation of CB(1)R and that leptin interferes with CB(1)R upregulation under food-deprivation conditions. These results are consistent with prior findings showing increased levels of endogenous cannabinoids in the Ob rats corroborating the regulation of cannabinoid signaling by leptin. Topics: Age Factors; Animals; Autoradiography; Body Weight; Cannabinoid Receptor Modulators; Eating; Food Deprivation; Hyperphagia; Leptin; Limbic System; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Receptors, Leptin; Rimonabant; Tritium; Up-Regulation | 2008 |
Differences in trabecular bone of leptin-deficient ob/ob mice in response to biomechanical loading.
It is known that bone mineral density (BMD) and the strength of bone is predicted by body mass. Fat mass is a significant predictor of bone mineral density which correlates with body weight. This suggests that body fat regulates bone metabolism first by means of hormonal factors and second that the effects of muscle and loading are signaling factors in mechanotransduction. Leptin, a peptide hormone produced predominantly by white fat cells, is one of these hormonal factors. The aim of this study was to investigate and measure by micro-CT the different effects of weight-bearing on trabecular bone formation in mice without the stimulation of leptin.. Animals with an ad-libitum-diet (Group A) were found to increase body weight significantly at the age of six weeks in comparison with lean mice (Group B). From this point on, the difference increased constantly. At the age of twenty weeks the obese mice were almost twice as heavy as the lean mice. Significant statistical differences are shown between the two groups for body weight and bone mineral density. Examination of trabecular bone (BV/TV, trabecular number (Tb.N.), trabecular thickness (Tb.Th.)) revealed that the only statistically significant difference between the two groups was the Tb.N. for the proximal femur. High weight-bearing insignificantly improved all trabecular bone parameters in the obese mice. Compared with the control-diet Group B, the BV/TV and Tb.N. were slightly higher in the controlled-diet Group A, but not the Tb.Th.. However, correlation was found between Tb.N. and BMD on the one hand and body weight on the other hand.. biomechanical loading led to decreased bone mineral density by a decrease in the number of trabeculae. Trabecular thickness was not increased by biomechanical loading in growing mice. Decreased body weight in leptin-deficient mice protects against bone loss. This finding is consistent with the principle of light-weight construction of bone. Differences in cortical and trabecular bone will be examined in later studies. It is not possible to conclude that these results also apply to human beings. Topics: Animals; Biomechanical Phenomena; Body Composition; Body Weight; Bone and Bones; Bone Density; Bone Remodeling; Female; Image Processing, Computer-Assisted; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Stress, Mechanical; Tomography, X-Ray Computed | 2008 |
Voluntary exercise improves insulin sensitivity and adipose tissue inflammation in diet-induced obese mice.
Exercise promotes weight loss and improves insulin sensitivity. However, the molecular mechanisms mediating its beneficial effects are not fully understood. Obesity correlates with increased production of inflammatory cytokines, which in turn, contributes to systemic insulin resistance. To test the hypothesis that exercise mitigates this inflammatory response, thereby improving insulin sensitivity, we developed a model of voluntary exercise in mice made obese by feeding of a high fat/high sucrose diet (HFD). Over four wk, mice fed chow gained 2.3 +/- 0.3 g, while HFD mice gained 6.8 +/- 0.5 g. After 4 wk, mice were subdivided into four groups: chow-no exercise, chow-exercise, HFD-no exercise, HFD-exercise and monitored for an additional 6 wk. Chow-no exercise and HFD-no exercise mice gained an additional 1.2 +/- 0.3 g and 3.3 +/- 0.5 g respectively. Exercising mice had higher food consumption, but did not gain additional weight. As expected, GTT and ITT showed impaired glucose tolerance and insulin resistance in HFD-no exercise mice. However, glucose tolerance improved significantly and insulin sensitivity was completely normalized in HFD-exercise animals. Furthermore, expression of TNF-alpha, MCP-1, PAI-1 and IKKbeta was increased in adipose tissue from HFD mice compared with chow mice, whereas exercise reversed the increased expression of these inflammatory cytokines. In contrast, expression of these cytokines in liver was unchanged among the four groups. These results suggest that exercise partially reduces adiposity, reverses insulin resistance and decreases adipose tissue inflammation in diet-induced obese mice, despite continued consumption of HFD. Topics: Adiponectin; Adipose Tissue; Animals; Body Composition; Body Weight; Cytokines; Diet; Dietary Fats; Glucose Tolerance Test; Hepatitis; Inflammation; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Physical Conditioning, Animal; Retinol-Binding Proteins, Plasma; Reverse Transcriptase Polymerase Chain Reaction | 2008 |
A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis.
Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient (LepOb), and obese hyperleptinemic (LepDb) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 microg/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1beta and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: LepOb mice were heaviest; however, LepDb mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity. Topics: Acute Disease; Adipokines; Adiponectin; Amylases; Animals; Blood Glucose; Body Weight; Ceruletide; Chemokines; Cytokines; Disease Models, Animal; Female; Insulin; Leptin; Lung; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pancreas; Pancreatitis; Peroxidase; Severity of Illness Index | 2008 |
Neonatal food restriction permanently alters rat body dimensions and energy intake.
Neonatal food restriction (FR) in rats, by means of increased litter size, has been used as a model for developmental programming by several investigators. However, the results reported have been inconsistent and difficult to compare between studies. In the present study, we aim to characterize the effects of this model throughout life in both sexes of one particular strain. On the second day of life, Wistar rat pups were randomly assigned to a litter of 10 (control) or 20 (FR). All litters had an equal number of males and females, and pups were weaned on day 25. Body dimensions and food intake were measured regularly until the age of one year. Serum leptin levels were determined in four subsets of different ages. FR acutely reduced growth in all body dimensions and serum leptin levels. Despite catch-up after weaning, all these parameters remained reduced throughout life. Male and female FR rats had a significantly reduced absolute energy intake throughout life. Male FR rats had significantly higher energy intake adjusted for body weight immediately after weaning. During catch-up growth, both FR males and females showed significantly enhanced feed efficiency. These results suggest that neonatal food restriction programmed both male and female Wistar rats to remain small and lean in adult life, with a lower food intake. Low neonatal leptin levels may play a mechanistic role in this process. Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Body Composition; Body Mass Index; Body Weight; Eating; Energy Intake; Female; Food Deprivation; Leptin; Male; Nutritional Status; Pregnancy; Radioimmunoassay; Random Allocation; Rats; Rats, Wistar; Sex Factors | 2008 |
Leptin regulated calcium channels of neuropeptide Y and proopiomelanocortin neurons by activation of different signal pathways.
The fat-derived hormone leptin regulates food intake and body weight in part by modulating the activity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC). To investigate the electrophysiological activity of these neurons and their responses to leptin, we recorded whole-cell calcium currents on NPY and POMC neurons in the ARC of rats, which we identified by morphologic features and immunocytochemical identification at the end of recording. Leptin decreased the peak amplitude of high voltage-activated calcium currents (I(HVA)) in the isolated neurons from ARC, which were subsequently shown to be immunoreactive for NPY. The inhibition was prevented by pretreatment with inhibitors of Janus kinase 2 (JAK2) and mitogen-activated protein kinases (MAPK). In contrast, leptin increased the amplitude of I(HVA) in POMC-containing neurons. The stimulations of I(HVA) were inhibited by blockers of JAK2 and phosphatidylino 3-kinase (PI3-k). Both of these effects were counteracted by the L-type calcium channel antagonist nifedipine, suggesting that L-type calcium channels were involved in the regulation induced by leptin. These data indicated that leptin exerted opposite effects on these two classes of neurons. Leptin directly inhibited I(HVA) in NPY neurons via leptin receptor (LEPR) -JAK2-MAPK pathways, whereas evoked I(HVA) in POMC neurons by LEPR-JAK2-PI3-k pathways. These neural pathways and intracellular signaling mechanisms may play key roles in regulating NPY and POMC neuron activity, anorectic action of leptin and, thereby, feeding. Topics: Animals; Animals, Newborn; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Body Weight; Calcium Channel Blockers; Calcium Channels, L-Type; Cells, Cultured; Dose-Response Relationship, Drug; Feeding Behavior; Janus Kinase 2; Leptin; MAP Kinase Signaling System; Membrane Potentials; Neurons; Neuropeptide Y; Patch-Clamp Techniques; Phosphatidylinositol 3-Kinases; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Signal Transduction | 2008 |
Anti-obesity effects of Juniperus chinensis extract are associated with increased AMP-activated protein kinase expression and phosphorylation in the visceral adipose tissue of rats.
This study evaluates the protective effect of Juniperus chinensis hot water extract (JCE) against high-fat-diet (HFD)-induced obesity and its molecular mechanisms in the visceral adipose tissue of rats. JCE supplementation significantly lowered body weight gain, visceral fat-pad weights, blood lipid levels, and blood insulin and leptin levels of rats rendered obese by an HFD. Feeding with JCE significantly reversed the HFD-induced down-regulation of the epididymal adipose tissue genes implicated in adipogenesis, such as the peroxisome proliferator-activated receptors gamma2 (PPARgamma2), adipocyte protein 2 (aP2), sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FAS), and HMG-CoA reductase (HMGR), as well as those involved in uncoupled respiration, such as the uncoupling protein 2 (UCP2) and uncoupling protein 3 (UCP3). Dietary supplementation with JCE also reversed the HFD-induced decreases in the AMP-activated protein kinase (AMPK) and the acetyl-CoA carboxylase 2 (ACC2) expressions at both the mRNA and protein levels and restored the HFD-induced inhibitions in the AMPK and ACC2 phosphorylation, which are related to fatty acid beta-oxidation, in the epididymal adipose tissue. This study reports, for the first time, that the JCE can have an anti-obesity effect in a rodent model with HFD-induced obesity through an enhanced gene transcription of the uncoupling protein as well as an elevated AMPK protein expression and phosphorylation in the visceral adipose tissue. Topics: Acetyl-CoA Carboxylase; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; Blotting, Western; Body Weight; Diet; Dietary Fats; Eating; Insulin; Juniperus; Leptin; Lipids; Male; Multienzyme Complexes; Obesity; Phosphorylation; Plant Extracts; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA; Wood | 2008 |
Beneficial effect of chungkukjang on regulating blood glucose and pancreatic beta-cell functions in C75BL/KsJ-db/db mice.
The current study investigated the antidiabetic effect of chungkukjang, a widely used traditional Korean soybean fermentation food, in a type 2 diabetic animal model, C57BL/KsJ-db/db mice. After a 2-week acclimation period, the db/db mice (male, 5 weeks old) were divided into three groups: diabetic control (AIN-76 diet), chungkukjang (5 g/100 g of diet), and rosiglitazone (0.005 g/100 g of diet). The supplementation of chungkukjang induced a significant reduction of blood glucose and glycosylated hemoglobin level, and it improved insulin tolerance compared to the diabetic control group. Plasma and pancreatic insulin levels of the chungkukjang-supplemented group were significantly higher than those of the diabetic control mice, and the plasma glucagon level was also significantly different. The supplementation of chungkukjang and rosiglitazone significantly elevated hepatic glucokinase activity with a simultaneous reduction of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activity in the db/db mice compared to the diabetic control mice. In addition, the chungkukjang-supplemented group had an increased hepatic glycogen content compared to the diabetic control and rosiglitazone-supplemented groups. Consequently, these results suggest that chungkukjang may be beneficial in improving insulin resistance and hyperglycemia in type 2 diabetic animals that are partly medicated by the regulation of hepatic glucose enzymes and insulin sensitivity in peripheral tissues. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Fermentation; Glucagon; Glucokinase; Glycated Hemoglobin; Glycine max; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Isoflavones; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Pancreas; Rosiglitazone; Soybean Proteins; Thiazolidinediones | 2008 |
Influence of increased adiposity on mitochondrial-associated proteins of the rat colon: a proteomic and transcriptomic analysis.
Epidemiological studies report obesity to be an important risk factor influencing colon pathologies, yet mechanism(s) are unknown. Recent studies have shown significant elevation of insulin, leptin and triglycerides associated with increased adipose tissue. In situ hybridisation studies have located insulin, leptin and adiponectin receptor expression in the colon epithelia. The influence of increased adiposity and associated deregulation of insulin and adipokines on regulation of the colon epithelium is unknown. Altered adipokine and insulin signalling associated with obesity has an impact on mitochondrial function and mitochondrial dysfunction is increasingly recognised as a contributing factor in many diseases. Proteomics and transcriptomics are potentially powerful methods useful in elucidating the mechanisms whereby obesity increases risk of colon diseases as observed epidemiologically. This study investigated colon mitochondrial-associated protein profiles and corresponding gene expression in colon in response to increased adiposity in a rat model of diet induced obesity. Increased adiposity in diet-induced obese sensitive rats was found to be associated with altered protein expression of 69 mitochondrial-associated proteins involved in processes associated with calcium binding, protein folding, energy metabolism, electron transport chain, structural proteins, protein synthesis and degradation, redox regulation, and transport. The changes in these mitochondrial protein profiles were not correlated with changes at the gene expression level assessed using real-time PCR arrays. Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Calmodulin; Colon; Diet; Electron Transport; Energy Metabolism; Gene Expression Profiling; Hormones; Insulin; Leptin; Male; Mitochondrial Proteins; Obesity; Principal Component Analysis; Protein Folding; Protein Transport; Proteomics; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Triglycerides | 2008 |
Guanethidine treatment does not block the ability of central leptin administration to decrease blood glucose concentrations in streptozotocin-induced diabetic rats.
Leptin, administered either into the ventricles of the brain or systemically, has been shown to normalize blood glucose concentrations in streptozotocin (STZ)-induced diabetic rats. We hypothesized that an intact sympathetic nervous system is necessary for centrally administered leptin to normalize or attenuate high blood glucose concentrations in STZ-induced diabetic rats. Young male Wistar rats (approximately 50 g) were treated every other day with either s.c. guanethidine (100 mg/kg) or vehicle for 2 weeks. Rats were then implanted with an intracerebroventricular cannula directed to the lateral ventricle and made diabetic with an i.v. injection of STZ (50 mg/kg). Half of the animals in each group were given daily injections of leptin (10 microl), while the remaining animals received vehicle injections. Blood glucose concentrations were measured daily and tissue norepinephrine content was determined by high performance liquid chromatography at the end of the study. Guanethidine pretreatment did not block the ability of centrally administered leptin to decrease blood glucose concentrations in diabetic rats. This suggests that the sympathetic nervous system does not mediate the leptin-induced attenuation of high blood glucose concentrations observed in diabetic rats. Topics: Adipose Tissue, Brown; Adipose Tissue, White; Adrenergic Agents; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Guanethidine; Leptin; Liver; Male; Norepinephrine; Rats; Rats, Wistar; Spleen; Sympathetic Nervous System | 2008 |
Binge-type eating attenuates corticosterone and hypophagic responses to restraint stress.
Binge eating has been associated with stress responses. Data in rats suggest that activation of the hypothalamic-pituitary-adrenal (HPA) axis is suppressed by consumption of a high sucrose diet, and is increased with exposure to a high fat diet. Additionally, the choice to consume a highly palatable food following exposure to a stressor results in reduced corticosterone levels. To test the effects of intermittent access to a high sugar/high fat food on stress hormone levels, rats were given either unrestricted (UR) access to a sucrose-vegetable shortening mixture (SVS) or 2 hour SVS access 7 days (7D) or 3 days (3D) per week for 4 weeks. Rats on the UR and 3D schedules consumed significantly more calories per day than did controls with no access to SVS, and the 7D and 3D rats consumed as many SVS calories in the 2 hour access period as did the UR rats with 24 hour access to SVS. After 4 weeks of access to SVS (UR, 7D, and 3D), rats were briefly restrained. Control and UR rats had elevated corticosterone during and following restraint, whereas there were no differences in corticosterone levels of 7D and 3D rats in response to restraint, as compared to baseline. Post-restraint consumption of chow was significantly decreased in all groups, and consumption of SVS was reduced in the UR, but not the 7D and 3D rats. These data demonstrate that intermittent access to SVS dampens the corticosterone response to restraint stress and that stressful events do not induce bingeing in non-bingeing animals with access to a high sucrose/high fat food. Topics: Analysis of Variance; Animals; Anorexia; Behavior, Animal; Body Weight; Bulimia; Corticosterone; Energy Intake; Feeding Behavior; Leptin; Male; Rats; Rats, Long-Evans; Restraint, Physical; Stress, Psychological; Time Factors | 2008 |
Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats.
Endocrine disrupting chemicals can induce malformations and impairment of reproductive function in experimental animals and may have similar effects in humans. Recently, the environmental obesogen hypothesis was proposed, suggesting that environmental chemicals contribute to the development of obesity and insulin resistance. These effects could be related to chemical interaction with nuclear receptors such as the peroxisome proliferator activated receptors (PPARs). As several testosterone-reducing drugs are PPAR activators, we aimed to examine whether four PPAR agonists were able to affect fetal testosterone production and masculinization of rats. Additionally, we wished to examine whether these chemicals affected fetal plasma levels of insulin and leptin, which play important roles in the developmental programming of the metabolic system. Pregnant Wistar rats were exposed from gestation day (GD) 7-21 to diisobutyl phthalate (DiBP), butylparaben, perfluorooctanoate, or rosiglitazone (600, 100, 20, or 1 mg/kg bw/day, respectively). Endocrine endpoints were studied in offspring at GD 19 or 21. DiBP, butylparaben and rosiglitazone reduced plasma leptin levels in male and female offspring. DiBP and rosiglitazone additionally reduced fetal plasma insulin levels. In males, DiBP reduced anogenital distance, testosterone production and testicular expression of Insl-3 and genes related to steroidogenesis. PPARalpha mRNA levels were reduced by DiBP at GD 19 in testis and liver. In females, DiBP increased anogenital distance and increased ovarian aromatase mRNA levels. This study reveals new targets for phthalates and parabens in fetal male and female rats and contributes to the increasing concern about adverse effects of human exposure to these compounds. Topics: Adrenal Glands; Animals; Body Weight; Dibutyl Phthalate; Estradiol; Female; Fetus; Gene Expression; Gestational Age; Immunohistochemistry; Insulin; Leptin; Liver; Male; Ovary; Peroxisome Proliferator-Activated Receptors; PPAR alpha; PPAR gamma; Pregnancy; Rats; Rats, Wistar; RNA, Messenger; Steroids; Testis; Testosterone | 2008 |
Long-term cigarette smoke exposure increases uncoupling protein expression but reduces energy intake.
The appetite suppressing effect of tobacco is a major driver of smoking behaviour; however few studies have addressed the effects of chronic cigarette smoke exposure (SE) on appetite, body weight and metabolic markers. We compared the effects of SE to equivalent food restriction (pair-fed, PF), against sham-exposure, on body weight, adiposity, cytokines, and levels of uncoupling proteins (UCP) and brain neuropeptide Y (NPY) in male Balb/C mice. SE rapidly induced anorexia, and after 12 weeks, SE and PF groups were lighter than control animals (23.9+/-0.2, 25.5+/-0.5, 26.8+/-0.4 g respectively, P<0.05). White fat (WAT) masses were reduced by both SE and PF. Plasma leptin and insulin were reduced in SE mice; insulin was further reduced by PF. Brown fat UCP1 and 3 mRNA were increased in SE animals relative to PF animals, possibly promoting thermogenesis. WAT mRNA expression of the inflammatory cytokine, TNFalpha was doubled by SE, while IL-6 was reduced by both PF and SE. Hypothalamic NPY content was increased by SE (89.3+/-2.8 vs. 75.9+/-2.4 ng control, P<0.05), and more by PF (100.7+/-3.4 ng, P<0.05 compared to both groups), suggesting disinhibition due to reduced adipose derived leptin. In contrast to equivalent food restriction, cigarette smoke exposure reduced body weight and total hypothalamic NPY, and increased thermogenesis and markers of inflammation. The suppressed hypothalamic NPY and increased UCPs may contribute to the spontaneous hypophagia and extra weight loss in SE animals. These findings contribute to our understanding of weight loss in smoking-related lung disease, suggesting a greater impact than that due to anorexia alone. Topics: Adipose Tissue, Brown; Adipose Tissue, White; Adiposity; Analysis of Variance; Animals; Body Weight; Corticosterone; Cytokines; Energy Intake; Gene Expression Regulation; Insulin; Interleukin-6; Ion Channels; Leptin; Male; Mice; Mice, Inbred BALB C; Mitochondrial Proteins; Neuropeptide Y; Nicotiana; Radioimmunoassay; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Smoke; Time Factors; Tumor Necrosis Factor-alpha; Uncoupling Protein 1 | 2008 |
Effects of sucrose, glucose and fructose on peripheral and central appetite signals.
In the Western world, consumption of soft drinks has increased the last three decades and is partly responsible for the epidemic-like increase in obesity. Soft drinks, originally sweetened by sucrose, are now sweetened by other caloric sweeteners, such as fructose. In this study, we investigated the short-term effect of sucrose, glucose or fructose solutions on food intake and body weight in rats, and on peripheral and central appetite signals. Rats received water containing either of the sugars and standard rat chow for two weeks. Rats receiving water alone and standard chow were controls. All rats offered the sugar solutions increased their total caloric intake. The increased caloric intake occurred despite the fact that the rats offered either of the sugar solutions consumed less chow. As a consequence of the increased caloric intake, the sugar-drinking rats had elevated serum levels of free fatty acids, triglycerides and cholesterol. In addition, consuming sugar solutions resulted in increased serum leptin, decreased serum PYY and down-regulated hypothalamic NPY mRNA. Serum ghrelin was increased in rats receiving fructose solution. Moreover, consumption of sucrose or fructose solution resulted in up-regulated hypothalamic CB1 mRNA. Hypothalamic POMC mRNA was down-regulated in rats receiving glucose or fructose. In conclusion, consumption of glucose, sucrose or fructose solution results in caloric overconsumption and body weight gain through activation of hunger signals and depression of satiety signals as well as activation of reward components. The weight-promoting effect of these sugar solutions may possibly be ameliorated by the down-regulation of NPY mRNA and increased serum leptin. Topics: Administration, Oral; Animals; Appetite; Blood Glucose; Body Weight; Cholesterol; Dietary Carbohydrates; Eating; Energy Intake; Fatty Acids, Nonesterified; Female; Fructose; Gene Expression Regulation; Ghrelin; Glucose; Hypothalamus; Leptin; Neuropeptide Y; Peptide YY; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; RNA, Messenger; Solutions; Sucrose; Sweetening Agents; Triglycerides | 2008 |
Hypothalamic suppressor-of-cytokine-signalling 3 mRNA is elevated and pro-opiomelanocortin mRNA is reduced during pregnancy in Brandt's voles (Lasiopodomys brandtii ).
Leptin acts within the hypothalamus to diminish food intake. In Brandt's voles (Lasiopodomys brandtii), both circulating leptin levels and food intake are elevated during pregnancy, suggesting an ineffectiveness of leptin to reduce food intake. Diminished hypothalamic leptin receptors and impaired leptin signal transduction are characteristic of central leptin resistance. The present study aimed to determine whether these characteristic modulations of leptin sensitivity occurred in pregnant Brandt's voles. The mRNA expression of the long form of the leptin receptor (Ob-Rb), suppressor-of-cytokine-signalling 3 (SOCS3), neuropeptide Y (NPY), agouti-related protein (AgRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus were examined on dioestrous, day 5, day 10 and day 18 of pregnancy. Compared to controls, there was no significant change in hypothalamic Ob-Rb mRNA during the pregnancy. SOCS3 mRNA was increased significantly by 68% on day 10% and 93% on day 18 of pregnancy compared to controls. Despite elevated leptin levels, POMC mRNA was decreased significantly by 60% on day 18 of pregnancy, whereas no differences were found in the mRNA expression of NPY, AgRP and CART in pregnant voles compared to controls. The elevation of SOCS3 mRNA together with disrupted leptin regulation of neuropeptides in the hypothalamus suggests that leptin resistance may develop in pregnant Brandt's voles. Topics: Adipose Tissue; Agouti-Related Protein; Animals; Arvicolinae; Body Weight; Eating; Female; Gene Expression Regulation; Hypothalamus; Leptin; Nerve Tissue Proteins; Neuropeptide Y; Pregnancy; Pregnancy, Animal; Pro-Opiomelanocortin; Receptors, Leptin; RNA, Messenger; Suppressor of Cytokine Signaling Proteins | 2008 |
Circadian rhythm drives the responsiveness of leptin-mediated hypothalamic pathway of cholecystokinin-8.
Cholecystokinin (CCK) and leptin act coordinately in the brain to regulate food intake and energy balance. Recently we have reported that CCK enhances the permeability of brain barriers to leptin and we have proposed that CCK enhances energy expenditure in rats by activating in the hypothalamus the janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway, which is coupled to leptin receptors. Because plasma leptin concentration follows a circadian rhythm (plasma leptin concentration rise maximal values during the night, after rats start eating), we have hypothesized that the interaction between leptin and CCK should be more intense in animals receiving CCK during the night, i.e., during periods of positive energy balance. In order to further characterize the physiological relevance of the interplay between leptin and CCK we have compared the effect of diurnal vs. nocturnal administration of the C-terminal octapeptide of CCK (CCK-8) on (i) body weight and food intake, and (ii) STAT3 activation, by analyzing phosphorylated STAT3 (pSTAT3) immunostaining within the arcuate nucleus of the hypothalamus. Our results show that CCK decreases body weight and food intake only after p.m. administration. Accordingly pSTAT3 immunostaining within the hypothalamus was more intense in p.m. than in a.m.-treated animals. These data suggest that the effect of CCK on leptin pathways follows a circadian rhythm linked to the energy balance status and gives further support to the interaction between leptin and CCK. Topics: Animals; Behavior, Animal; Body Weight; Circadian Rhythm; Dose-Response Relationship, Drug; Eating; Gene Expression Regulation; Hypothalamus; Leptin; Male; Rats; Rats, Sprague-Dawley; Signal Transduction; Sincalide; STAT3 Transcription Factor | 2008 |
Impaired anorectic effect of leptin in neurotensin receptor 1-deficient mice.
Neurotensin plays a role in regulating feeding behavior. Central injection of neurotensin reduces food intake and the anorectic effect of neurotensin is mediated through neurotensin receptor 1 (Ntsr1). Ntsr1-deficient mice are characterized by mild hyperphagia and overweight without hyperleptinemia. The mechanism by which Ntsr1-deficient mice develop these metabolic abnormalities is not well understood. Leptin, secreted by adipocytes, regulates food intake by acting on hypothalamic neurons including neurotensin-producing neurons. Since the anorectic effect of leptin is blocked by neurotensin receptor antagonist, we hypothesized that the anorectic effect of leptin is mediated through Ntsr1 in the central nervous system and that decreased sensitivity to the anorectic effect of leptin contributes to metabolic perturbations in Ntsr1-deficient mice. To address this hypothesis, we examined the effect of intracerebroventricular (i.c.v.) administration of leptin on food intake in Ntsr1-deficient mice. A single i.c.v. injection of leptin caused robust reductions in food intake in wild-type mice. These effects were markedly attenuated in Ntsr1-deficient mice. These data are consistent with our hypothesis that the anorectic effect of leptin is at least partly mediated through central Ntsr1 and that the leptin-Ntsr1 signaling pathway is involved in the regulation of food intake. Our data also suggest that the lack of Ntsr1 reduces sensitivity to the anorectic action of leptin, causing hyperphagia and abnormal weight gain. Topics: Analysis of Variance; Animals; Appetite Depressants; Behavior, Animal; Blood Glucose; Body Temperature; Body Weight; Calorimetry; Eating; Gene Expression Regulation; Hyperphagia; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Neurotensin; Receptors, Neurotensin | 2008 |
Effects of cold exposure, exogenous melatonin and short-day treatment on the weight-regulation and body temperature of the Siberian hamster (Phodopus sungorus).
To investigate how winter acclimatization (WA), exogenous melatonin (MEL) or endogenous melatonin (SD) affect plasma leptin and ghrelin concentrations and how leptin and ghrelin contribute to the regulation of different adaptations to wintering in the Siberian hamster.. The plasma leptin and insulin and testicular testosterone concentrations were lower in the WA, MEL and SD groups, whereas the plasma ghrelin concentration was higher due to the WA treatment. In the treated hamsters, body temperatures during photo- and scotophase were lower throughout the study and torpor bouts were observed. The absolute and relative body fat masses were lower in all treated groups.. Siberian hamsters reduce their feeding in winter, although just the opposite is suggested by the lower leptin concentrations in all treated groups and the higher ghrelin concentration in the WA group. The positive correlation between plasma leptin and testicular testosterone indicates a possible interaction between them. Torpor bouts were related to a lowered body mass and plasma leptin concentration. Exposure to short photoperiod did not induce elevated plasma ghrelin levels; the response required a low ambient temperature together with short day length. Topics: Acclimatization; Animals; Body Temperature; Body Weight; Cricetinae; Female; Ghrelin; Insulin; Leptin; Male; Melatonin; Phodopus; Photoperiod; Seasons; Testis; Testosterone | 2008 |
Effect of chronic hypoxia on leptin, insulin, adiponectin, and ghrelin.
The endocrine system plays an important role in the adaptation to hypoxia. The aim of this study was to assess the effect of chronic hypoxia on insulin, adiponectin, leptin, and ghrelin levels in a neonatal animal model. Sprague-Dawley rats were placed in a normobaric hypoxic environment at birth. Controls remained in room air. Rats were killed at 2 and 8 weeks of life. Insulin, adiponectin, leptin, and ghrelin were measured. At 2 weeks of life, there was no significant difference in insulin, adiponectin, and leptin levels between the hypoxic and control rats. The only statistically significant difference was found in ghrelin levels, which were lower in the hypoxic group (3.19 +/- 3.35 vs 24.52 +/- 5.09 pg/mL; P < .05). At 8 weeks of life, insulin was significantly higher in the hypoxic group (0.72 +/- 0.14 vs 0.44 +/- 0.26 ng/mL; P < .05) and adiponectin was significantly lower (1257.5 +/- 789.5 vs 7817.3 +/- 8453.7 ng/mL; P < .05). Leptin and ghrelin did not show significant difference in this age group, but leptin level per body weight was higher in the hypoxic group. Finally, we conclude that 2 weeks of continuous neonatal hypoxic exposure leads to a decrease in plasma ghrelin only with no significant change in insulin, adiponectin, and leptin and that 8 weeks of hypoxia leads to a decrease in adiponectin with an increase in insulin despite a significant decrease in weight. Topics: Adiponectin; Animals; Animals, Newborn; Body Weight; Disease Models, Animal; Female; Ghrelin; Hematocrit; Hypoxia; Insulin; Leptin; Pregnancy; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric | 2008 |
Impact of single nucleotide polymorphisms in leptin, leptin receptor, growth hormone receptor, and diacylglycerol acyltransferase (DGAT1) gene loci on milk production, feed, and body energy traits of UK dairy cows.
The impact of 9 single nucleotide polymorphisms (SNP) in the leptin (LEP), leptin receptor (LEPR), growth hormone receptor (GHR), and diacylglycerol acyltransferase (DGAT1) gene loci on daily milk production, feed intake, and feed conversion, and weekly measures of live weight, BCS, and body energy traits was evaluated using genetic and phenotypic data on 571 Holstein cows raised at the Langhill Dairy Cattle Research Center in Scotland. Six SNP were typed on the LEP gene and 1 on each of the other 3 loci. Of the 6 LEP SNP, 3 were in very high linkage disequilibrium, meaning there is little gain in typing all of them in the future. Seven LEP haplotypes were identified by parsimony-based analyses. Random-regression allele-substitution models were used to assess the impact of each SNP allele or haplotype on the traits of interest. Diacylglycerol acyltransferase had a significant effect on milk yield, whereas GHR significantly affected feed intake, feed conversion, and body energy traits. There was also evidence of dominance in allelic effects on milk yield and BCS. The LEP haplotype CCGTTT (corresponding to leptin SNP C207T, C528T, A1457G, C963T, A252T, and C305T, respectively) significantly affected milk yield and feed and dry matter intake. Animals carrying this haplotype produced 3.13 kg more milk daily and consumed 4.64 kg more feed. Furthermore, they tended to preserve more energy than average. Such results may be used to facilitate genetic selection in animal breeding programs. Topics: Animals; Body Composition; Body Weight; Cattle; Dairying; Diacylglycerol O-Acyltransferase; Eating; Female; Gene Frequency; Haplotypes; Lactation; Leptin; Male; Milk; Polymorphism, Single Nucleotide; Proteins; Receptors, Leptin; Receptors, Somatotropin; Regression Analysis; United Kingdom | 2008 |
Differences in endocrine parameters and psychopathology in girls with premature adrenarche versus on-time adrenarche.
Girls with premature adrenarche (PA) are at risk for multiple problems related to exaggerated androgen synthesis. Whether PA carries a risk of psychopathology remains unknown. This study examined group differences in: (a) anthropometric and endocrine parameters, and (b) mood and behavior problems, in 6-8 year-old girls with PA (n = 40) compared to on-time adrenarche girls (n = 36). PA girls were taller (p < or =0.05) and heavier (p < or =0.01) than the on-time adrenarche girls but body mass index showed no difference. PA girls had significantly (p <0.05) higher adrenal androgen and testosterone concentrations but not cortisol or leptin. PA girls also had significantly more oppositional defiant disorder, and higher symptom counts reflecting anxiety, mood or disruptive behavior disorders. PA girls may be more vulnerable to psychopathology than on-time adrenarche girls. The challenge of future studies is to determine which PA girls are at risk for psychopathology and which are more resilient. Topics: Adrenarche; Affect; Androgens; Anxiety; Body Height; Body Weight; Case-Control Studies; Child; Female; Humans; Hydrocortisone; Leptin; Puberty, Precocious; Testosterone | 2008 |
Whole-body vibration slows the acquisition of fat in mature female rats.
To evaluate the effects of whole-body vibration on fat, bone, leptin and muscle mass.. Thirty 7-month-old female 344 Fischer rats were randomized by weight into three groups (baseline, vibration or control; n=8-10 per group). Rats in the vibration group were placed inside individual compartments attached to a Pneu-Vibe vibration platform (Pneumex, Sandpoint, ID, USA) and vibrated at 30-50 Hz (6 mm peak to peak) for 30 min per day, 5 days per week, for 12 weeks. The vibration intervention consisted of six 5-min cycles with a 1-min break between cycles.. There were significant body composition differences between the whole-body vibration and the control group. The whole-body vibration group weighed approximately 10% less (mean+/-s.d.; 207+/-10 vs 222+/-15 g, P<0.03) and had less body fat (20.8+/-3.8 vs 26.8+/-5.9 g, P<0.05), a lower percentage of body fat (10.2+/-1.7 vs 12+/-2.0%, P<0.05), and lower serum leptin levels (1.06+/-0.45 vs 2.27+/-0.57 ng ml(-1), P<0.01) than the age-matched controls. No differences were observed for total lean mass, bone mineral content (BMC), bone mineral density (BMD), insulin-like growth factor-I (IGF-I) or soleus (SOL) and extensor digitorum longus (EDL) mass or function. Regional high-resolution dual-energy X-ray absoptiometry scans of the lumbar spine (L1-4) revealed that the whole-body vibration group had significantly greater BMC (0.33+/-0.05 vs 0.26+/-0.03 g, P<0.01) and BMD (0.21+/-0.01 vs 0.19+/-0.01 g cm(-2), P<0.01) than the control group. No differences between the groups were observed in the amount of food consumed.. These findings show that whole-body vibration reduced body fat accumulation and serum leptin without affecting whole body BMC, BMD or lean mass. However, the increase in vertebral BMC and BMD suggests that vibration may have resulted in local increases in bone mass and density. Also, whole-body vibration did not affect muscle function or food consumption. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Bone Density; Eating; Female; Insulin-Like Growth Factor I; Leptin; Lumbar Vertebrae; Muscle Contraction; Muscle, Skeletal; Organ Size; Rats; Rats, Inbred F344; Vibration | 2008 |
Impaired energetic metabolism after central leptin signaling leads to massive appendicular bone loss in hindlimb-suspended rats.
We previously showed in rats that the leptin effects on bone were dose dependent. Positive effects were observed when serum leptin concentration was in a physiological range. In contrast, important increases in serum leptin levels led to negative effects on bone formation similar to those reported after intracerebroventricular leptin administration in mice. To clarify whether leptin effects on bone depend on administration route and/or animal model, female rats were hindlimb unloaded or not and treated either with intracerebroventricular infusion of leptin or vehicle for 14 days. By increasing cerebrospinal fluid (CSF) leptin concentration, intracerebroventricular infusion of leptin significantly reduced food intake and consequently body weight, abdominal fat, and lean mass of the animals. Leptin infusion inhibited bone elongation over the 14 days and blunted cortical bone thickening at the femoral diaphysis site. Interestingly, leptin effects were site dependent in the cancellous bone envelopes, because tibia metaphysis BMD was lower and lumbar spine BMD was higher under intracerebroventricular leptin. Treated groups showed reduced bone remodeling independently of hindlimb unloading. Multiple downstream pathways were implicated in the mediation of these negative leptin effects on bone including not only stimulation of the sympathetic nervous system but also a decrease in somatotropic axis activity. Therefore, the intracerebroventricular leptin-induced bone loss could be largely related to the concurrent alteration of energetic and metabolic status. In summary, our study supports the hypothesis of a concentration-dependent balance between peripheral and central control of leptin on bone. Topics: Animals; Body Weight; Bone and Bones; Cell Lineage; Densitometry; Dose-Response Relationship, Drug; Female; Hindlimb; Leptin; Osteoblasts; Rats; Rats, Wistar; Signal Transduction; Tibia; Time Factors | 2008 |
Obesity and non-insulin-dependent diabetes mellitus in Swiss-Webster mice associated with late-onset hepatocellular carcinoma.
Genetic mutations resulting in obesity and type 2 diabetes mellitus (T2D) are described for both inbred and outbred mice. However, no known mouse model completely recapitulates human T2D and its comorbidities. We identified a cohort of obese, male, outbred Swiss-Webster (SW) mice as polyuric, polydipsic, glucosuric, and hyperglycemic. Prevalence of glucosuria in the SW colony reached 60% (n=70) in males 8 weeks to 6 months of age. Despite severe obesity in some females, no females were diabetic. Pathologic findings in affected males included cachexia, dilated gastrointestinal tracts with poor muscular tone, pancreatic islet degeneration and atrophy with compensatory metaplasia and/or neogenesis, bacterial pyelonephritis, membranous glomerulopathy, and late-onset hepatic tumors with macrosteatosis, microsteatosis, and hydropic change in aged males. Serum insulin correlated with blood glucose in a nonlinear pattern, suggestive of islet exhaustion. Circulating leptin levels showed a weak inverse correlation with glucose. Diabetic males were bred with obese colony females to produce 20 male and 20 female offspring. Prevalence of diabetes in male offspring was 80% (16/20) with a median age of onset of 18 weeks. By contrast, no diabetic females were identified, despite being significantly more obese than males. Male predominance is likewise a feature of T2D in humans. To our knowledge, this is the first documentation of hepatocellular carcinoma and islet metaplasia and/or neogenesis in a spontaneous outbred mouse model of T2D. The SW availability and histopathologic features represent a promising new model for the study of T2D. Topics: Animals; Blood Glucose; Body Weight; Carcinoma, Hepatocellular; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Glucose Tolerance Test; Glycosuria; Immunohistochemistry; Insulin; Kaplan-Meier Estimate; Leptin; Male; Mice; Obesity | 2008 |
Amylin-mediated restoration of leptin responsiveness in diet-induced obesity: magnitude and mechanisms.
Previously, we reported that combination treatment with rat amylin (100 microg/kg.d) and murine leptin (500 microg/kg.d) elicited greater inhibition of food intake and greater body weight loss in diet-induced obese rats than predicted by the sum of the monotherapy conditions, a finding consistent with amylin-induced restoration of leptin responsiveness. In the present study, a 3 x 4 factorial design was used to formally test for a synergistic interaction, using lower dose ranges of amylin (0, 10, and 50 microg/kg.d) and leptin (0, 5, 25, and 125 microg/kg.d), on food intake and body weight after 4 wk continuous infusion. Response surface methodology analysis revealed significant synergistic anorexigenic (P < 0.05) and body weight-lowering (P < 0.05) effects of amylin/leptin combination treatment, with up to 15% weight loss at doses considerably lower than previously reported. Pair-feeding (PF) experiments demonstrated that reduction of food intake was the predominant mechanism for amylin/leptin-mediated weight loss. However, fat loss was 2-fold greater in amylin/leptin-treated rats than PF controls. Furthermore, amylin/leptin-mediated weight loss was not accompanied by the counterregulatory decrease in energy expenditure and chronic shift toward carbohydrate (rather than fat) utilization observed with PF. Hepatic gene expression analyses revealed that 28 d treatment with amylin/leptin (but not PF) was associated with reduced expression of genes involved in hepatic lipogenesis (Scd1 and Fasn mRNA) and increased expression of genes involved in lipid utilization (Pck1 mRNA). We conclude that amylin/leptin interact synergistically to reduce body weight and adiposity in diet-induced obese rodents through a number of anorexigenic and metabolic effects. Topics: Amyloid; Animals; Blood Glucose; Body Weight; Caloric Restriction; Diet; Drug Evaluation, Preclinical; Drug Resistance; Drug Synergism; Eating; Islet Amyloid Polypeptide; Leptin; Lipids; Lipogenesis; Liver; Obesity; Rats; Rats, Sprague-Dawley; Signal Transduction | 2008 |
Selective inactivation of Socs3 in SF1 neurons improves glucose homeostasis without affecting body weight.
Suppressor of cytokine signaling 3 (Socs3) has been identified as a mediator of central leptin resistance, but the identity of specific neurons in which Socs3 acts to suppress leptin signaling remains elusive. The ventromedial hypothalamus (VMH) was recently shown to be an important site for leptin action because deleting leptin receptor within VMH neurons causes obesity. To examine the role of VMH Socs3 in leptin resistance and energy homeostasis, we generated mice lacking Socs3 specifically in neurons positive for steroidogenic factor 1 (SF1), which is expressed abundantly in the VMH. These mice had increased phosphorylation of signal transducer and activator of transcription-3 in VMH neurons, suggesting improved leptin signaling, and consistently, food intake and weight-reducing effects of exogenous leptin were enhanced. Furthermore, on either chow or high-fat diets, these mice had reduced food intake. Unexpectedly, energy expenditure was reduced as well. Mice lacking Socs3 in SF1 neurons, despite no change in body weight, had improved glucose homeostasis and were partially protected from hyperglycemia and hyperinsulinemia induced by high-fat diets. These results suggest that Socs3 in SF1 neurons negatively regulates leptin signaling and plays important roles in mediating leptin sensitivity, glucose homeostasis, and energy expenditure. Topics: Animals; Body Weight; Eating; Energy Metabolism; Glucose; Homeostasis; Insulin; Leptin; Male; Mice; Mice, Transgenic; Neurons; Organ Specificity; Phosphorylation; STAT3 Transcription Factor; Steroidogenic Factor 1; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Ventromedial Hypothalamic Nucleus | 2008 |
High-circulating leptin levels are associated with greater risk of hypertension in men independently of body mass and insulin resistance: results of an eight-year follow-up study.
We previously reported a significant association between plasma leptin (LPT) concentration and blood pressure (BP), which was partly independent of serum insulin levels and insulin resistance. The aims of this study were to detect whether serum LPT levels predict the development of hypertension (HPT) in the 8-yr follow-up investigation of a sample of an adult male population (the Olivetti Heart Study), and to evaluate the role of body mass index (BMI) and insulin resistance in this putative association.. The study population was made up of 489 untreated normotensive subjects examined in 1994-1995 (age: 50.1 +/- 6.7 yr; BMI: 26.3 +/- 2.8 kg/m(2); BP: 120 +/- 10/78 +/- 6 mm Hg; and homeostatic model assessment index: 2.1 +/- 1.6).. The HPT incidence over 8 yr was 35%. The participants with incident HPT had similar age but higher BMI (P < 0.001), serum LPT (P < 0.001), and BP (P < 0.01) at baseline. One sd positive difference in baseline serum LPT log was associated at univariate analysis with a 49% higher rate of HPT [95% confidence interval (CI) 22-83; P < 0.001]). In three different models of multivariable logistical regression analysis, LPT was respectively associated with a 41% greater risk to develop HPT (95% CI 15-74; P < 0.001) upon adjustment for age and baseline BP, with a 48% (95% CI 20-81) greater risk when adding the homeostatic assessment model index to the model, and with 33% greater risk (95% CI 6-67; P < 0.02) upon adjustment for BMI.. In this sample of originally normotensive men, circulating LPT level was a significant predictor of the risk to develop HPT over 8 yr, independently of BMI and insulin resistance. Topics: Adult; Aged; Blood Pressure; Body Mass Index; Body Weight; Case-Control Studies; Follow-Up Studies; Humans; Hypertension; Insulin Resistance; Leptin; Male; Middle Aged; Risk Factors | 2008 |
Fibroblast growth factor 21 corrects obesity in mice.
Fibroblast growth factor 21 (FGF21) is a metabolic regulator that provides efficient and durable glycemic and lipid control in various animal models. However, its potential to treat obesity, a major health concern affecting over 30% of the population, has not been fully explored. Here we report that systemic administration of FGF21 for 2 wk in diet-induced obese and ob/ob mice lowered their mean body weight by 20% predominantly via a reduction in adiposity. Although no decrease in total caloric intake or effect on physical activity was observed, FGF21-treated animals exhibited increased energy expenditure, fat utilization, and lipid excretion, reduced hepatosteatosis, and ameliorated glycemia. Transcriptional and blood cytokine profiling studies revealed effects consistent with the ability of FGF21 to ameliorate insulin and leptin resistance, enhance fat oxidation and suppress de novo lipogenesis in liver as well as to activate futile cycling in adipose. Overall, these data suggest that FGF21 exhibits the therapeutic characteristics necessary for an effective treatment of obesity and fatty liver disease and provides novel insights into the metabolic determinants of these activities. Topics: Adiposity; Animals; Body Weight; Dietary Fats; Energy Intake; Energy Metabolism; Fibroblast Growth Factors; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity | 2008 |
Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats.
There is emerging evidence that angiotensin stimulates adipocyte differentiation and lipogenesis. This study tested the hypothesis that inhibition of angiotensin II by treatment with an angiotensin-converting enzyme inhibitor, perindopril, would reduce fat mass in rats.. After a 12-day baseline, rats were divided into two groups: one was untreated and the other received perindopril (1.2 mg kg(-1) per day) in drinking water for 26 days.. In total, 16 male Sprague-Dawley rats aged 10 weeks at the start of the study.. Plasma leptin was measured in samples collected at baseline, half-way through and at the end of treatment. Body weight, food and water intake were measured daily throughout the experiment. Body fat mass, bone and lean mass were determined by dual energy X-ray absorptiometry (DEXA) at the end of the treatment period.. Daily food intake was the same in both groups throughout the study. By the end of treatment, animals receiving perindopril showed a modest reduction in weight gain relative to the untreated animals (62.4+/-5.0 g vs 73.0+/-4.0 g; P<0.05). DEXA analysis showed that body composition was greatly altered and the perindopril-treated group had 26% less body fat mass than the untreated group (61.0+/-5.2 g vs 44.4+/-4.2 g; P<0.01). The reduction in body fat mass was correlated with reductions in the weight of both the epididymal and retroperitoneal fat pads (P<0.001). Similarly, plasma leptin was reduced by perindopril treatment (4.64+/-0.56 ng ml(-1)) compared to the untreated group (8.27+/-1.03 ng ml(-1); P<0.001). In contrast, there were no differences in lean or bone mass between the two groups.. Oral treatment with perindopril selectively reduced body fat mass without influencing daily food intake. In contrast, there were no differences in lean or bone mass between the two groups. Topics: Absorptiometry, Photon; Adipose Tissue; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Composition; Body Weight; Bone Density; Eating; Leptin; Male; Perindopril; Rats; Rats, Sprague-Dawley | 2008 |
Functional potentiation of leptin-signal transducer and activator of transcription 3 signaling by the androgen receptor.
Hypogonadism is associated with increased fat mass and dysregulation of metabolic homeostasis in men. Our previous study revealed that androgen receptor (AR)-null male mice (ARL-/Y) develop late-onset obesity and are leptin-resistant. The present study evaluated how hypothalamic AR contributes to central leptin-signal transducer and activator of transcription 3 (STAT3) signaling. We evaluated leptin action in wild-type and ARL-/Y mice, the anatomic co-relationship between AR and leptin signaling in the hypothalamus, and the effects of AR on leptin-mediated STAT3 transactivation and nuclear translocation. AR deletion in male mice results in a weaker leptin-induced suppression of food intake and body weight drop even before the onset of overt obesity. In wild-type male but not female mice, AR was highly expressed in various hypothalamic nuclei that also expressed the long-form leptin receptor (OBRB) and co-resided with OBRB directly in the arcuate neurons. In vitro, AR significantly enhanced STAT3-mediated transcription of leptin target genes including POMC and SOCS3. This effect relied on the AR N-terminal activation function-1 (AF-1) domain and was specific to AR in that none of the other sex steroid hormone receptors tested showed similar effects. AR enhanced the low concentrations of leptin-induced STAT3 nuclear translocation in vitro, and ARL-/Y mice receiving leptin had impaired STAT3 nuclear localization in the arcuate neurons. These findings indicate that AR in the hypothalamus functions as a regulator of central leptin-OBRB-STAT3 signaling and has a physiological role in energy homeostasis and metabolic regulation in male mice. Topics: Animals; Biological Transport; Blotting, Western; Body Weight; Cell Line; Chlorocebus aethiops; COS Cells; Eating; Female; Immunohistochemistry; Leptin; Male; Mice; Mice, Knockout; Microscopy, Confocal; Pro-Opiomelanocortin; Receptors, Androgen; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcriptional Activation | 2008 |
Early undernutrition leads to long-lasting reductions in body weight and adiposity whereas increased intake increases cardiac fibrosis in male rats.
Previous studies suggest that both overfeeding and undernutrition during development increase the risk of obesity and hypertension in adulthood. In this study, we examined both short- (24 d) and long- (16 wk) term effects of early postnatal over- and underfeeding in rats on body weight, body composition, plasma hormones, adiposity markers, and hypothalamic neuropeptide Y content. Cardiovascular changes were also examined by measuring blood pressure and cardiac fibrosis. Rats raised in litters of 3, 12, or 18 pups per mother were used to model early onset overfeeding, control, and underfeeding, respectively. At 24 d of age, pups raised in small litters (SL) were 10% heavier than pups from normal litters, accompanied by increased organ mass and fat mass, elevated plasma leptin, corticosterone, and uncoupling protein-1 mRNA in brown adipose tissue. On the other hand, pups raised in large litters were 17% lighter with no significant changes in plasma leptin. Overfeeding during the first 3 wk of life led to increased plasma leptin concentration in adulthood, whereas underfed rats remained significantly lighter throughout the study, with no evidence of catch-up growth. Rats raised in SL were more susceptible to developing cardiac fibrosis with a 22% increase in collagen deposition compared with control rats at 16 wk of age (P < 0.05). This was independent of any changes in blood pressure. This study demonstrates that nutritional changes early in postnatal development can have long-lasting effects on body weight, adiposity, and some mediators involved in energy homeostasis and can also lead to structural changes in the heart in adulthood. This highlights the importance of identifying potential early life risk factors involved in the modulation of childhood nutrition. Topics: Adiposity; Aging; Animals; Animals, Newborn; Blood Pressure; Body Weight; Corticosterone; Energy Intake; Female; Fibrosis; Food Deprivation; Heart Diseases; Hyperphagia; Hypothalamus; Insulin; Leptin; Litter Size; Longitudinal Studies; Male; Neuropeptide Y; Obesity; Random Allocation; Rats; Rats, Sprague-Dawley | 2008 |
Myocardial ischemic-reperfusion injury in a rat model of metabolic syndrome.
Hearts of NaCl-induced hypertensive-glucose intolerant (HGI) rats develop reduced infarcts after ischemia-reperfusion injury (IRI) than their hypertensive (H) counterparts. Because high intake of saturated fat is a major risk factor for ischemic heart disease, we tested the hypothesis that chronic (18 weeks) consumption of a high saturated fat diet increases susceptibility to IRI, an effect more marked in the HGI rats than in the H rats. The fat-fed H (HFAT) rat displayed significantly higher body weight and plasma leptin content compared to the H, HGI, or fat-fed HGI (HGIFAT) rats which all showed similar values. In contrast, plasma triglyceride concentration was significantly higher in the HGIFAT rat than in the other three groups. Plasma insulin concentration was similar in the two H groups but higher than that of the two HGI groups. Compared to the H rat, the HGI rat was markedly glucose intolerant, with fat feeding causing comparable worsening of glucose intolerance in each group. The HGIFAT rats displayed a reduction in baseline myocardial contractility and relaxation and a higher end-diastolic pressure compared to the other three groups. Infarct size was significantly lower in the HGI rats than in the H rats. Although fat feeding did not affect infarct size of the H rat, it worsened that of the HGIFAT rat thereby abrogating the differential that existed between the H and HGI rats. In conclusion, excess fat feeding impairs myocardial function of HGI rats and increases their susceptibility to IRI. These findings are of relevance to the metabolic syndrome that manifests as a cluster of insulin resistance, dyslipidemia, and systemic hypertension. Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Dietary Fats; Disease Models, Animal; Glucose Intolerance; Hypertension; Insulin; Leptin; Male; Metabolic Syndrome; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Rats; Rats, Inbred WKY; Sodium Chloride, Dietary; Streptozocin; Time Factors; Triglycerides; Ventricular Pressure | 2008 |
The effects of high fat on central appetite genes in Wistar rats: a microarray analysis.
To evaluate the effects of high fat on central appetite regulatory genes in Wistar rats by microarray.. Sixteen male Wistar rats were randomly assigned to control (15% energy from fat) and high-fat (60% energy from fat) diets for 12 weeks. Body weight and food intake were recorded. Plasma leptin, ghrelin and insulin were measured by radioimmunoassay method. The expression of 111 appetite regulatory genes in the hypothalamus was evaluated by microarray and six genes, including leptin receptor, insulin receptor, orexin, NPY, AgRP, MC-4R, were further evaluated by real-time RT-PCR.. Body weight increased significantly in HF group compared with control group, whereas energy intake was similar in the two groups. HF had a time dependent effect on plasma leptin, but insulin and ghrelin level remained stable throughout the study. A positive relation was also found between body weight and plasma leptin (r=0.88, P<0.01). The expression of 27 appetite genes in the hypothalamus was significantly affected by HF diet. However, only the expression of leptin receptor was confirmed lower in HF group than that in control by real-time PCR, which suggested that lower expression of leptin receptor might be another reason for leptin resistance.. HF diet fed rats demonstrated leptin resistance, which could be targeted for obesity treatment. Topics: Animals; Appetite Regulation; Body Weight; Dietary Fats; Eating; Feeding Behavior; Gene Expression Profiling; Gene Expression Regulation; Ghrelin; Insulin; Leptin; Male; Microarray Analysis; Rats; Rats, Wistar | 2008 |
Temporal and site-specific brain alterations in CB1 receptor binding in high fat diet-induced obesity in C57Bl/6 mice.
The cannabinoid CB1 receptor has been implicated in the regulation of appetite and the consumption of palatable foods. This experiment aimed to explore the involvement of the CB1 receptor in the early and late stages of high fat diet-induced obesity in C57BL/6 mice. The C57Bl/6 mice were placed on a high fat (HF) or low fat/high carbohydrate (LF) diet for 3 or 20 weeks. Quantitative autoradiography revealed that binding of [3H] CP-55,940 (CB1 receptor ligand) was elevated following 3 weeks of HF feeding in areas including the medial/ventral anterior olfactory nucleus (22.1%), agranular insular cortex (24.0%) and the hypothalamus (31.5%) compared to LF controls. This increased level of binding was correlated with an increase in plasma leptin in the hypothalamus, raising the possibility that this hormone may exert inhibitory control over endocannabinoid signalling at this stage of obesity. Mice fed a HF diet for 20 weeks were obese, hyperphagic and had decreased CB1 receptor binding levels in the substantia nigra (12.8%) and ventral tegmental area (17.1%) compared to LF controls. The low [3H] CP-55,940 binding density seen in these reward-related areas in the late stage of obesity may be indicative of increased endocannabinoid release due to the chronic HF diet consumption. Topics: Animals; Body Weight; Brain; Cannabinoids; Cyclohexanols; Diet; Dietary Fats; Energy Intake; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Receptor, Cannabinoid, CB1 | 2008 |
Body weight and plasma levels of ghrelin and leptin during treatment with olanzapine.
Although enhanced appetite and weight gain are potential side effects of treatment with antipsychotic agents, particularly olanzapine and clozapine, the mechanisms underlying these side effects are poorly understood. Leptin and ghrelin were recently identified as hormones that play crucial roles in the regulation of energy balance and glucose metabolism. To elucidate relationships between weight change and plasma levels of ghrelin and leptin, we investigated the circulating ghrelin and leptin levels and body weight during olanzapine treatment. Twenty-four patients with schizophrenia were examined during 6-month administration of olanzapine. Ghrelin, leptin, weight and body mass index (BMI) were measured before and after 2, 4, 8, 12, 16, and 24 weeks of olanzapine treatment. The concentration of glucose and various lipid metabolic parameters were measured at baseline and at 24 weeks. Significant increases in weight, BMI and leptin were observed at week 24. On the other hand, the serum levels of ghrelin decreased significantly after olanzapine treatment. In addition, the level of ghrelin was negatively correlated with the leptin level, BMI and weight. The leptin level was positively correlated with both BMI and weight. Ghrelin is associated with metabolic changes, in combination with leptin, during olanzapine treatment. However, further large-scale and longitudinal studies are warranted to elucidate the metabolic changes involving ghrelin, leptin and insulin during treatment with antipsychotics. Topics: Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Ghrelin; Humans; Leptin; Male; Olanzapine; Schizophrenia | 2008 |
Correlates of serum leptin and insulin-like growth factor-I concentrations in normal weight and overweight/obese Iranian women.
Leptin and insulin-like growth factor-I (IGF-I) are two interrelated hormones that are implicated in the development or progression of coronary artery disease (CAD) and some cancers. The aim of this study was to investigate the relation between serum leptin and total IGF-I concentrations and to identify their correlations with age or anthropometric and body composition variables in healthy normal weight and overweight/obese Iranian women.. The percent of body fat (BF%), fat mass (FM), fat-free mass (FFM), and waist/hip ratio (WHR) were determined in 51 healthy normal weight (body mass index [BMI] 18.5-24.9 kg/m(2)) and 50 overweight/obese (BMI > or = 25 kg/m(2)) Iranian reproductive-age women. Serum leptin and total IGF-I concentrations were measured by double-antibody sandwich assay and enzyme-linked immunosorbent assay (ELISA), respectively. Statistical analysis was performed by Mann-Whitney U test and Spearman's rank-correlation test. Multivariate linear regression analysis was performed with ranked-transformed data to obtain partial correlation coefficient.. In this group of healthy, premenopausal Iranian women, variance of serum leptin concentration was independently explained by FM (partial rho = 0.295, p < 0.01), and variance of the total IGF-I concentration was explained by age (partial rho = -0.214, p = 0.037) and BMI (partial rho = 0.229, p = 0.026). Overweight/obese women had higher leptin and total IGF-I concentrations than normal weight women (p < 0.01). The serum leptin and total IGF-I concentrations were differentially correlated with age and anthropometric and body composition variables in the two groups. Whereas in normal weight women, leptin was negatively related to BMI (partial rho = -0.356, p = 0.015), in overweight/obese women, BMI, BF%, and FM independently contributed to the serum leptin variability (partial rho = 0.370, p = 0.013; partial rho = -0.320, p = 0.034; partial rho = 0.421, p < 0.01, respectively). There was a weak association between age and total IGF-I concentration in normal weight women, which did not reach statistical significance (partial rho = -0.255, p = 0.091). None of the variables was associated with the total IGF-I in overweight/obese women (p > 0.05).. Although the studied anthropometric and body composition variables could explain approximately half of the leptin variance in Iranian women, they explained only a small proportion of total IGF-I variability. Our results indicated that the serum leptin and total IGF-I concentrations are differentially regulated in healthy normal weight and overweight/obese Iranian women. Topics: Adult; Anthropometry; Body Fat Distribution; Body Mass Index; Body Weight; Case-Control Studies; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Insulin-Like Growth Factor I; Iran; Leptin; Linear Models; Middle Aged; Overweight; Waist-Hip Ratio | 2008 |
Study of hypothalamic leptin receptor expression in low-birth-weight piglets and effects of leptin supplementation on neonatal growth and development.
Low birth weight resulting from intrauterine growth retardation (IUGR) is a risk factor for further development of metabolic diseases. The pig appears to reproduce nearly all of the phenotypic pathological consequences of human IUGR and is likely to be more relevant than rodents in studies of neonatal development. In the present work, we characterized the model of low-birth-weight piglets with particular attention to the hypothalamic leptin-sensitive system, and we tested whether postnatal leptin supplementation can reverse the precocious signs of adverse metabolic programming. Our results demonstrated that 1) IUGR piglets present altered postnatal growth and increased adiposity; 2) IUGR piglets exhibit abnormal hypothalamic distribution of leptin receptors that may be linked to further disturbance in food-intake behavior; and 3) postnatal leptin administration can partially reverse the IUGR phenotype by correcting growth rate, body composition, and development of several organs involved in metabolic regulation. We conclude that IUGR may be characterized by altered leptin receptor distribution within the hypothalamic structures involved in metabolic regulation and that leptin supplementation can partially reverse the IUGR phenotype. These results open interesting therapeutic perspectives in physiopathology for the correction of defects observed in IUGR. Topics: Adipocytes, White; Adipose Tissue, White; Animals; Animals, Newborn; Birth Weight; Blood Glucose; Body Composition; Body Size; Body Weight; Female; Fetal Growth Retardation; Gene Expression; Hypothalamus; In Situ Hybridization; Leptin; Receptors, Leptin; Sus scrofa; Triglycerides; Weight Gain | 2008 |
Downregulation of melanocortin-4 receptor during refeeding and its modulation by adrenalectomy in rats.
Melanocortin system and corticotropin releasing hormone (CRH) are implicated in the control of feeding behavior. Besides its anorexigenic effect on food intake, CRH is one of the most important regulators of hypothalamic-pituitary-adrenal (HPA) axis activity. Therefore, there could be an interplay between HPA axis activity and melanocortin system. We investigated the expression of melanocortin-4 receptor (MC4-R) mRNA in the hypothalamus of rats after 14 days of food restriction or after a fasting-refeeding regimen, in sham or adrenalectomized rats. Male Wistar rats were subjected to free access to food or food ingestion restricted for 2 h a day (8-10 AM) during 14 d, when plasma corticosterone, ACTH, insulin, leptin concentrations, and MC4-R mRNA expression were determined before and after refeeding. Another set of rats was fasted for 48 h, followed by refeeding during 2 or 4 h on the seventh day after adrenalectomy (ADX) or sham surgery. On the day of the experiment, rats were anesthetized and perfused and the brain processed for MC4-R mRNA by in situ hybridization. Long-term reduction of food intake, either secondary to food restriction or adrenalectomy, reduced body weight gain and also leptin and insulin plasma concentrations. Food ingestion reduced MC4-R expression in the paraventricular nucleus in naive rats subjected to food restriction and also in sham rats fasted for 48 h. However, after ADX, MC4-R expression was not changed by refeeding. In conclusion, the present data indicate that MC4-R expression is downregulated by food ingestion and this response could be modulated by glucocorticoid withdrawal. Topics: Adrenalectomy; Adrenocorticotropic Hormone; Animals; Body Weight; Corticosterone; Eating; Fasting; In Situ Hybridization; Insulin; Leptin; Male; Melanocyte-Stimulating Hormones; Radioimmunoassay; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; RNA, Messenger | 2008 |
The effect of intermittent hypoxia on bodyweight, serum glucose and cholesterol in obesity mice.
This article tests mice's indicators of body nutritional metabolism under tolerable hypoxic conditions, in order to explore the effects of moderate intermittent hypoxia on the bodyweight, blood sugar and blood cholesterol of obese mice and to identify the role of leptin in these effects; this study applies high-fat diet to establish Mice Obesity Models and observes the intervention effects of intermittent hypoxic training in this Model. Small healthy mice are classified in 4 groups at random, that is, Group A (Normal), Group B (Normal Hypoxia) fed with normal foods and undergoing Intermittent Hypoxic Training (IHT), Group C (Fatty-diet) fed with High-Fat and High-Sugar (HFHS) foods without IHT and Group D (Fatty-diet and Hypoxia) fed with HFHS foods with IHT. After 40 days of feeding and hypoxic training, weigh the mice, measure the levels of blood sugar and blood cholesterol with a full automatic biochemical analyzer, measure serum leptin concentration by enzyme-linked immunosorbent assay (ELISA) technique, inspect liver leptin receptor expression and liver fat slice by immunohistochemistry. It is found that compared to control group, after experiment, the average bodyweight, blood sugar, blood cholesterol and serum leptin concentration in Group C is increased significantly and numerous fat cells are distributed in the liver, which indicates that hyperlipemia model has been successfully established; after intermittent hypoxic training, the average bodyweight, blood sugar, blood cholesterol and liver fat cells distribution density and scope in Group B and D are lower than those in Group A and C, while serum leptin concentration is increased significantly; liver leptin receptor expression in Group D is higher than that in Group C. And hypoxia groups have no trauma conclusion. Moderate intermittent hypoxia can reduce bodyweight by increasing leptin concentration and enhancing liver leptin expression and it can also reduce the level of blood sugar and blood cholesterol and meanwhile prevent steatosis in liver cells effectively. Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Female; Hypoxia; Leptin; Liver; Mice; Models, Biological; Obesity; Oxygen; Pressure; Receptors, Leptin; Tissue Distribution | 2008 |
Mechanisms mediating renal sympathetic activation to leptin in obesity.
Leptin plays a critical role in the control of energy homeostasis. The sympathetic cardiovascular actions of leptin have emerged as a potential link between obesity and hypertension. We previously demonstrated that in mice, modest obesity induced by 10 wk of a high-fat diet is associated with preservation of leptin ability to increase renal sympathetic nerve activity (SNA) despite the resistance to the metabolic effects of leptin. Here, we examined whether selective leptin resistance exists in mice with late-stage diet-induced obesity (DIO) produced by 20 wk of a high-fat diet. The decrease in food intake and body weight induced by intraperitoneal or intracerebroventricular injection of leptin was significantly attenuated in the DIO mice. Regional SNA responses to intravenous leptin were also attenuated in DIO mice. In contrast, intracerebroventricularly administered leptin caused contrasting effects on regional SNA in DIO mice. Renal SNA response to intracerebroventricular leptin was preserved, whereas lumbar and brown adipose tissue SNA responses were attenuated. Intact renal SNA response to leptin combined with the increased cerebrospinal fluid leptin levels in DIO mice represents a potential mechanism for the adverse cardiovascular consequences of obesity. Lastly, we examined the role of phosphoinositol-3 kinase (PI3K) and melanocortin receptors (MCR) in mediating the preserved renal SNA response to leptin in obesity. Presence of PI3K inhibitor (LY294002) or MC3/4R antagonist (SHU9119) significantly attenuated the renal SNA response to leptin in DIO and agouti obese mice. Our results demonstrate the importance of PI3K and melanocortin receptors in the transduction of leptin-induced renal sympathetic activation in obesity. Topics: Adipose Tissue, Brown; Animals; Body Weight; Chromones; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Injections, Intraperitoneal; Injections, Intraventricular; Kidney; Leptin; Lumbar Vertebrae; Male; Melanocyte-Stimulating Hormones; Mice; Mice, Inbred C57BL; Mice, Obese; Morpholines; Obesity; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Receptors, Melanocortin; Signal Transduction; Sympathetic Nervous System; Time Factors | 2008 |
A hypercaloric pellet-diet cycle induces obesity and co-morbidities in Wistar rats.
The present study was carried to develop and analyze the consequences of hypercaloric pellet-diet cycle that promotes obesity in rats. Male Wistar rats were randomly distributed into two groups that received either normal diet (ND; n =32; 3,5 Kcal/g) or a hypercaloric diet (HD; n =32; 4,6 Kcal/g). The ND group received commercial Labina rat feeding while the HD animals received a cycle of five hypercaloric diets over a 14-week period. The effects of the diets were analyzed in terms of body weight, body composition, hormone-metabolite levels, systolic arterial pressure and glucose tolerance at the 5% significance level. The hypercaloric pellet diet cycle promoted an increase in body weight and fat, systolic arterial pressure and a high serum level of glucose, triacylglycerol, insulin and leptin. The HD group also presented an impaired glucose tolerance. In conclusion, the results of this study show that the hypercaloric pellet-diet cycle promoted obesity in Wistar rats and displayed several characteristics that are commonly associated with human obesity, such as high arterial pressure, insulin resistance, hyperglycaemia, hyperinsulinaemia, hyperleptinaemia and dyslipidaemia. Topics: Analysis of Variance; Animals; Blood Pressure; Body Composition; Body Weight; Dietary Fats; Disease Models, Animal; Dyslipidemias; Energy Intake; Humans; Hyperglycemia; Hyperinsulinism; Hypertension; Leptin; Male; Obesity; Random Allocation; Rats; Rats, Wistar | 2008 |
Autoadjusting-CPAP effect on serum leptin concentrations in obstructive sleep apnoea patients.
Leptin is an hormone that regulates body weight. Studies have shown increasing leptin concentrations according to body mass index (BMI) and intermittent hypoxia. Our aim is to evaluate the basal leptin levels in OSA patients and its possible relation to OSA severity, independently of confounders and investigate the Autoadjusting-CPAP effect on leptin values.. In ninety eight male patients with moderate to severe OSA leptin serum levels were evaluated before therapy, 9 days and 6 months after therapy.. In this group mean age was 55.3 years, mean BMI was 33.2 Kg/m2 and mean Apnoea- Hypopnea Index (AHI) was 51.7/h. Mean basal serum leptin value was 12.1 ug/L. Univariate analysis showed a significant correlation between serum leptin values and BMI (R = 0.68; p < 0.001), waist-hip ratio (R = 0.283; p = 0.004) and AHI (R = 0.198; p = 0.048); in stepwise multiple regression analysis only BMI (p < 0.001) was a predictor of serum leptin values. One week after therapy, mean leptin serum level decreased to 11.0 ug/L and 6 months after it was 11.4 ug/L. (p = 0.56 and p = 0.387, respectively). Baseline leptin serum levels positively correlate with BMI, fat distributio and OSA severity. BMI is the only predictor of basal leptin levels.Treatment with Autoadjusting-CPAP has a small effect on leptin levels. Topics: Aged; Body Mass Index; Body Weight; Continuous Positive Airway Pressure; Follow-Up Studies; Humans; Leptin; Male; Middle Aged; Obesity; Prospective Studies; Regression Analysis; Severity of Illness Index; Sleep Apnea, Obstructive | 2008 |
Frequency of abnormal correlation between leptin and the body mass index during first and second generation antipsychotic drug treatment.
Leptin dysregulation has been implicated in the body weight gain and metabolic dysfunction observed with the second generation antipsychotic drugs (SGAD) olanzapine and clozapine.. This study quantified the frequency of subjects with abnormal correlation between leptin and the body mass index controlling for gender (defined as being out of the upper or lower 95% confidence interval in the regression line when combining each group with the drug-free subjects) after prolonged treatment with olanzapine (n=126), clozapine (n=62), first generation antiypsychotics (n=91), other SGAD (n=22), other psychotropic drugs (n=65) and drug-free subjects (n=229).. None of the analysis was significant (p>0.05). In fact, in 17 out of 20 comparisons, the drug-free group had numerically higher frequencies of outliers than the corresponding treatment group. There were 28 outliers (4.7% of the total sample). In agreement with previous studies, cross-sectional analysis did not report gross alterations in serum leptin levels during olanzapine or clozapine administration.. Longitudinal studies should focus on leptin regulation early on treatment, on the frequency of abnormal leptin receptor sensitivity and/or specific polymorphisms in the leptin allele and on several confounding factors in order to design personalized preventive and therapeutic measures. Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Mass Index; Body Weight; Clozapine; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Leptin; Male; Mental Disorders; Middle Aged; Olanzapine; Outliers, DRG; Receptors, Leptin; Schizophrenia; Sex Factors; Weight Gain | 2008 |
How long will my mouse live? Machine learning approaches for prediction of mouse life span.
Prediction of individual life span based on characteristics evaluated at middle-age represents a challenging objective for aging research. In this study, we used machine learning algorithms to construct models that predict life span in a stock of genetically heterogeneous mice. Life-span prediction accuracy of 22 algorithms was evaluated using a cross-validation approach, in which models were trained and tested with distinct subsets of data. Using a combination of body weight and T-cell subset measures evaluated before 2 years of age, we show that the life-span quartile to which an individual mouse belongs can be predicted with an accuracy of 35.3% (+/-0.10%). This result provides a new benchmark for the development of life-span-predictive models, but improvement can be expected through identification of new predictor variables and development of computational approaches. Future work in this direction can provide tools for aging research and will shed light on associations between phenotypic traits and longevity. Topics: Algorithms; Animals; Artificial Intelligence; Body Weight; Cataract; Female; Genetic Heterogeneity; Insulin-Like Growth Factor I; Leptin; Life Expectancy; Longevity; Male; Mice; Mice, Inbred Strains; Models, Statistical; T-Lymphocyte Subsets; Thyroxine | 2008 |
Effect of food availability and leptin on the physiology and hypothalamic gene expression of the golden spiny mouse: a desert rodent that does not hoard food.
Food availability and quality in desert habitats are spatially and temporally unpredictable, and animals face periods of food shortage. The golden spiny mouse (Acomys russatus) is an omnivorous desert rodent that does not hoard food, requiring it to withstand such periods by physiological means alone. In response to food restriction, plasma leptin concentrations, core body temperature, and energy expenditure of the spiny mouse decrease significantly after 24 h, and most spiny mice are able to maintain their body mass to approximately 85% of ad libitum for a prolonged period of time. Both 1-day food deprivation and long-term food restriction had a significant effect on body mass and plasma leptin concentrations, which decreased significantly with a high correlation, as well as on the orexigenic agouti-related protein, which increased significantly as a result of the 24-h food deprivation; and on neuropeptide Y (NPY), in which the increase was more pronounced under long-term food restriction. Food restriction and food deprivation had no effect, however, on the anorexigenic pro-opiomelanocortin and cocaine and amphetamine-related transcript. Leptin administration to food-restricted spiny mice did not affect food intake or the rate of decrease in body mass, indicating that it cannot overcome the drive to eat when food is scarce. However, it did result in a significant decrease in NPY levels, and the spiny mice spent less time at low body temperatures compared with PBS-treated golden spiny mice. These results show that in food-restricted golden spiny mice, leptin affects thermogenesis, but not food consumption, and suggest that the thermoregulatory effects of leptin are mediated by NPY. Topics: Adaptation, Physiological; Agouti Signaling Protein; Animals; Body Temperature Regulation; Body Weight; Desert Climate; Eating; Energy Metabolism; Feeding Behavior; Food Deprivation; Gene Expression Regulation; Hypothalamus; Infusions, Parenteral; Leptin; Male; Murinae; Nerve Tissue Proteins; Neuropeptide Y; Pro-Opiomelanocortin; RNA, Messenger; Time Factors | 2008 |
Nutrition-induced catch-up growth at the growth plate.
The effect of 40% food restriction (FR) and replenishment on the growth hormone (GH) and insulin-like growth factor-I (IGF-I) axis in the epiphyseal growth plate (EGP) was examined in a mouse model. Changes in RNA and protein levels were evaluated with real time PCR and immunohistochemistry, respectively, and serum levels of IGF-I and leptin were measured with radioimmunoassay. Dramatic changes in weight, tibial length and EGP height were observed following 10 days of 40% FR. The protein levels of IGF-I receptor (IGF-IR) and GH receptor (GHR), which were reduced during FR, increased during catch-up growth without an apparent change in the level of their RNA. The levels of type II and X collagens were unchanged. Serum IGF-I and leptin levels were reduced during FR and increased during catch-up growth. Following 40% FR, there was a significant decrease in the level of GHR and IGF-IR in the EGP which may explain the reduced effect of GH treatment in malnourished animals and children. Topics: Animals; Body Weight; Cell Proliferation; Chondrocytes; Eating; Growth Hormone; Growth Plate; Hypertrophy; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred ICR; Nutritional Physiological Phenomena; Receptor, IGF Type 1; Receptors, Somatotropin; Tibia | 2008 |
Common genetic components of obesity traits and serum leptin.
To estimate common and distinct genetic influences on a panel of obesity-related traits and serum leptin level in adults. In a cross-sectional study of 625 Danish, adult, healthy, monozygotic, and same-sex dizygotic twin pairs of both genders, we carried out detailed anthropometry (height, weight, waist and hip, and skin-fold thickness, body composition assessment by bioimpedance (fat mass and fat-free mass), and measurement of serum leptin level. Bivariate variance component analyses estimated the additive genetic correlations between these measurements. The genetic correlations between the traits for overall fatness (BMI and fat mass index, kg/m(2)) were 0.94 in men and 0.98 in women, and their correlations with the various local fatness measures ranged from 0.49 to 0.83 in men and from 0.70 to 0.87 in women. The correlations between the truncal measures (waist circumference and truncal skin folds) and between the peripheral measures (hip circumference and peripheral skin folds) were 0.57 and 0.47 in men and 0.71 and 0.70 in women, respectively. The correlations between the truncal and peripheral measures ranged between 0.49 and 0.72 in men and between 0.61 and 0.82 in women. For leptin vs. the various measures of overall and local fatness the correlations ranged from 0.54 to 0.74 in men and from 0.48 to 0.75 in women. All correlations were significantly <1.00. The study supports control of overall fat mass and peripheral and truncal fat mass by both shared and different genetic components, which suggests that it is important to distinguish between the different phenotypes in the search for genes involved in the development of obesity. Topics: Adipose Tissue; Adult; Body Composition; Body Mass Index; Body Weight; Cross-Sectional Studies; Denmark; Diseases in Twins; Environment; Female; Humans; Leptin; Male; Middle Aged; Obesity; Phenotype; Skinfold Thickness; Twins, Dizygotic; Twins, Monozygotic; Waist Circumference; Young Adult | 2008 |
High-fat feeding alters the clock synchronization to light.
High-fat feeding in rodents leads to metabolic abnormalities mimicking the human metabolic syndrome, including obesity and insulin resistance. These metabolic diseases are associated with altered temporal organization of many physiological functions. The master circadian clock located in the suprachiasmatic nuclei controls most physiological functions and metabolic processes. Furthermore, under certain conditions of feeding (hypocaloric diet), metabolic cues are capable of altering the suprachiasmatic clock's responses to light. To determine whether high-fat feeding (hypercaloric diet) can also affect resetting properties of the suprachiasmatic clock, we investigated photic synchronization in mice fed a high-fat or chow (low-fat) diet for 3 months, using wheel-running activity and body temperature rhythms as daily phase markers (i.e. suprachiasmatic clock's hands). Compared with the control diet, mice fed with the high-fat diet exhibited increased body mass index, hyperleptinaemia, higher blood glucose, and increased insulinaemia. Concomitantly, high-fat feeding led to impaired adjustment to local time by photic resetting. At the behavioural and physiological levels, these alterations include slower rate of re-entrainment of behavioural and body temperature rhythms after 'jet-lag' test (6 h advanced light-dark cycle) and reduced phase-advancing responses to light. At a molecular level, light-induced phase shifts have been correlated, within suprachiasmatic cells, with a high induction of c-FOS, the protein product of immediate early gene c-fos, and phosphorylation of the extracellular signal-regulated kinases I/II (P-ERK). In mice fed a high-fat diet, photic induction of both c-FOS and P-ERK in the suprachiasmatic nuclei was markedly reduced. Taken together, the present data demonstrate that high-fat feeding modifies circadian synchronization to light. Topics: Abdominal Fat; Administration, Oral; Animals; Biological Clocks; Blood Glucose; Body Temperature; Body Weight; Circadian Rhythm; Corticosterone; Dietary Fats; Extracellular Signal-Regulated MAP Kinases; Insulin; Leptin; Light; Male; Mice; Mice, Inbred C57BL; Motor Activity; Phosphorylation; Photic Stimulation; Proto-Oncogene Proteins c-fos; Suprachiasmatic Nucleus; Telemetry | 2008 |
Leptin gene, leptin gene receptor polymorphisms and body weight in pregnant women with type 1 diabetes mellitus.
Leptin, as well as many other hormones, may play an important role in the pathogenesis of obesity. Several genetic variants of both leptin and its receptor genes may influence human body weight. To investigate the role of leptin gene polymorphism promotion region (-2548G/A) and leptin gene receptor polymorphism (668 A/G) in regulation of body weight in the group of women with type 1 diabetes (PGDM-1).. 78 PGDM-1 first trimester pregnant women were qualified for the study group (SG). They were divided into normal and overweight subgroups, based on pre-pregnancy BMI. Control group (CG) consisted of first trimester healthy pregnant women with normal pre-pregnancy body weight Genetic variants of leptin gene and its receptor were analyzed with the help of PCR-RFLP assays. In the SG, the following metabolic parameters were estimated: MBG, HbA1c, insulin dose, LDL, HDL, T-CHOL, triglycerids, creatinine, creatinine clearance and blood pressure.. A tendency for the majority of homozygous A and G variants in LEP -2548 G/A and LEPR 668 A/G was found in overweight and obese patients, in comparison to normal-weight subjects. No specific differences in selected first trimester metabolic parameters were found in relation to patients' genotypes in the diabetic group. Topics: Adult; Body Mass Index; Body Weight; Case-Control Studies; Diabetes Mellitus, Type 1; DNA Mutational Analysis; Female; Humans; Leptin; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; Pregnancy; Pregnancy in Diabetics; Receptors, Leptin | 2008 |
Correlation between body weight (epididymal fat) and permeation rate of serum leptin through the blood-brain barrier (BBB) in male rats aged 8 months.
In this study, in order to clarify the kinetics of leptin, we focused on the ratio of leptin concentrations in cerebrospinal fluid and serum in aged male rats, and examined the weight of epididymal fat, and the passage rate of leptin through the blood-brain barrier. In the lighter animals, the epididymal fat weight was low, while leptin concentrations in the serum and cerebrospinal fluid were also low. Conversely, in the heavier animals, the weight of epididymal fat and leptin concentrations in the serum and cerebrospinal fluid were higher. With regard to the ratio of leptin in the cerebrospinal fluid and serum, the passage rate of leptin through the blood-brain barrier was lower in the heavier animals than in the lighter animals. Topics: Adipose Tissue; Aging; Animals; Blood-Brain Barrier; Body Weight; Epididymis; Leptin; Male; Rats | 2008 |
Centrally applied ghrelin affects feeding dynamics in male rats.
Ghrelin is 28-amino acid peptide, which is produced mainly in the stomach. Since plasma ghrelin are strictly dependent on food intake, this hormone has significant effects on appetite and energy balance. The aim of this investigation was to examine the effects of centrally applied ghrelin on feeding dynamism by measuring the approaches to food container and the amount of food and water intake within 2 hours immediately after ghrelin or PBS injections. Body weight was obtained daily, while ending retroperitoneal (RP) and epididymal (EPI) white adipose tissue (WAT) contents as well as blood levels of leptin and insulin were measured. Five injections of rat ghrelin or PBS (n = 8 per group) were administered once per day (1 microg = 0.15 nmol of ghrelin in 5 microL of PBS), into lateral cerebral ventricle (ICV) of free feeding adult male rats. Results showed that in the first and the second 30-min intervals number of approaches to food container were significantly increased already after the 2(nd) ICV ghrelin application (p < 0.05), by 50% and 67% respectively, in comparison with control rats. Centrally applied ghrelin increased body weight after the 2(nd) injection till the end of treatment (p < 0.05), which was followed by increased food and water intake (p < 0.05). At the end of treatment, RP and EPI WAT contents were increased (by 221%, p < 0.01 and 82%, p < 0.05, respectively). Serum insulin levels were elevated (by 41%, p < 0.05) while serum leptin levels were decreased (by 75%, p < 0.05). These data and the available literature strongly support the opinion that repetitive subnanomolar doses of central ghrelin administration play essential role in food initiation and feeding dynamics in freely feeding adult male rats. Topics: Adipose Tissue, White; Animals; Body Weight; Drinking; Eating; Enzyme-Linked Immunosorbent Assay; Epididymis; Feeding Behavior; Ghrelin; Injections, Intraventricular; Insulin; Leptin; Male; Rats; Rats, Wistar; Retroperitoneal Space | 2008 |
Effects of peripheral or central GLP-1 receptor blockade on leptin-induced suppression of appetite.
Leptin and glucagon-like peptide-1 (GLP-1) were proved to act in concert to control the activity of feeding centres. Since leptin receptor was identified in the gut endocrine L cells and neurons producing GLP-1, we have checked whether GLP-1 mediates the effects of leptin on feeding and drinking behaviour. To this aim, an intraperitoneal or intracerebroventricular injection of exendin (9 - 39), a GLP-1 antagonist, (50 or 10 microg per rat, respectively) followed by leptin (100 or 5 microg per rat, respectively) was made and 24-hour food intake and body weight changes were measured. Previous injection of exendin (9-39) completely abolished the supressory effect of peripheral leptin on food intake and body weight gain. Moreover, exendin (9-39) significantly attenuated the effect of intracerebroventricular leptin on food but not water consumption. It is concluded that intact GLP-1 signalling is necessary to mediate the effect of leptin on food intake in the rat. Conversely, leptin seems to affect the thirst center function independently of GLP-1. Also, these findings produce further evidence for close interactions between long- and short-term factors regulating the activity of feeding centres. Topics: Analysis of Variance; Animals; Appetite Depressants; Body Weight; Central Nervous System; Drinking; Eating; Glucagon-Like Peptide-1 Receptor; Injections, Intraventricular; Leptin; Male; Peptide Fragments; Peripheral Nervous System; Rats; Rats, Wistar; Receptors, Glucagon | 2008 |
Leptin gene, leptin gene polymorphisms and body weight in pregnant women with diabetes mellitus type I.
There have been several genetic causes of obesity discussed by past authors, among others leptin, that have provided information regarding signaling pathways in energy expenditure in humans. Genetic variants of the leptin gene and its receptor may influence body weight.. To investigate the role of the leptin gene's polymorphism promotion region (2548 G/A) and the leptin gene receptor polymorphism (668 A/G) and its associations with body weight in pregnant women with type 1 diabetes (PGDM-1).. 78 PGDM-1 were qualified to the study group (SG) which was divided into normal and over-weight individuals according to BMI criteria. The control group (CG) consisted of first trimester healthy pregnant women with normal body weight. Genetic variants of the leptin gene and its receptor were analyzed using PCR-RFLP assays. Within the SG, the following metabolic parameters were estimated: MBG, HbA1C, insulin dose, LDL, HDL, T-CHOL, creatinine, creatinine clearance and blood pressure.. There was a trend found among the majority of homozygous A and G variants in LEP -2548 G/A and LEPR 668 A/G in over-weight and obese individuals in comparison to normal-weight subjects (CG). There were no specific differences found in selected first trimester metabolic parameters in relation to patients' genotypes. Topics: Body Mass Index; Body Weight; Diabetes Mellitus, Type 1; Female; Genotype; Humans; Leptin; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; Pregnancy; Pregnancy in Diabetics; Promoter Regions, Genetic; Receptors, Leptin | 2008 |
Leptin responses to long-term cardiorespiratory exercise training without concomitant weight loss: a prospective study.
The aims of the present study were to examine 1) whether changes in circulating leptin levels occur in response to six months of aerobic exercise training (ET) without concomitant weight loss; 2) whether there is a different response with respect to gender; and 3) the relationship between age and leptin and whether this relationship has any impact on the response to ET without weight-loss.. Thirty-eight healthy, sedentary men and women (age 38.43+/-2.24, range 18-59 years) participated in 6 months of supervised, moderate intensity (ET) performed 4 days per week. Maintenance of usual dietary practices were encouraged to minimize weight-loss. Participants were evaluated for circulating fasting leptin, body mass, body fat percentage and maximal aerobic power (VO2max) prior to and after ET.. There was no decrease in body weight or leptin concentration (17.69+/-2.67 vs 16.85+/-3.12 ng dL(-1)). Gender did not affect the response to exercise training. The bivariate correlation between leptin and age was not significant, but the relationship reached significance after controlling for body fat percentage and VO2max (r = -0.358, P < 0.05). Age did not affect the response of leptin concentration to ET.. It is probable that changes in leptin concentration reported previously with ET may be attributable to concomitant weight loss, but age does not play a role in how leptin responds to ET. Topics: Adipose Tissue; Adolescent; Adult; Age Factors; Anthropometry; Body Mass Index; Body Weight; Cardiovascular Physiological Phenomena; Exercise; Exercise Tolerance; Female; Humans; Leptin; Male; Middle Aged; Prospective Studies; Respiration; Respiratory System; Time Factors; Weight Loss; Young Adult | 2008 |
Different transcriptional control of metabolism and extracellular matrix in visceral and subcutaneous fat of obese and rimonabant treated mice.
The visceral (VAT) and subcutaneous (SCAT) adipose tissues play different roles in physiology and obesity. The molecular mechanisms underlying their expansion in obesity and following body weight reduction are poorly defined.. C57Bl/6 mice fed a high fat diet (HFD) for 6 months developed low, medium, or high body weight as compared to normal chow fed mice. Mice from each groups were then treated with the cannabinoid receptor 1 antagonist rimonabant or vehicle for 24 days to normalize their body weight. Transcriptomic data for visceral and subcutaneous adipose tissues from each group of mice were obtained and analyzed to identify: i) genes regulated by HFD irrespective of body weight, ii) genes whose expression correlated with body weight, iii) the biological processes activated in each tissue using gene set enrichment analysis (GSEA), iv) the transcriptional programs affected by rimonabant.. In VAT, "metabolic" genes encoding enzymes for lipid and steroid biosynthesis and glucose catabolism were down-regulated irrespective of body weight whereas "structure" genes controlling cell architecture and tissue remodeling had expression levels correlated with body weight. In SCAT, the identified "metabolic" and "structure" genes were mostly different from those identified in VAT and were regulated irrespective of body weight. GSEA indicated active adipogenesis in both tissues but a more prominent involvement of tissue stroma in VAT than in SCAT. Rimonabant treatment normalized most gene expression but further reduced oxidative phosphorylation gene expression in SCAT but not in VAT.. VAT and SCAT show strikingly different gene expression programs in response to high fat diet and rimonabant treatment. Our results may lead to identification of therapeutic targets acting on specific fat depots to control obesity. Topics: Abdominal Fat; Adipocytes; Animals; Blood Glucose; Body Weight; Cannabinoid Receptor Antagonists; Dietary Fats; Extracellular Matrix; Gene Expression Regulation; Insulin; Leptin; Lipoproteins, VLDL; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Rimonabant; Subcutaneous Fat; Transcription, Genetic | 2008 |
Physiological responses to divergent selection for phytate phosphorus bioavailability in a randombred chicken population.
An investigation was conducted to study insulin-like growth factor (IGF)-I, IGF-II, insulin, glucagon, leptin, triiodothyronine (T(3)), and thyroxine (T(4)) levels in a chicken population divergently selected for P bioavailability (PBA). There were differences in growth and feed efficiency between the 2 lines. Concentrations of IGF-I, IGF-II, and T(3) were significantly greater in the high PBA line compared with the low PBA line, whereas the reverse was true for glucagon. There were no correlations between IGF-I and II and PBA in either line, suggesting that the line differences may be the result of factors other than PBA. Glucagon and IGF-I have different relationships with feed conversion ratio in the high PBA line compared with the low PBA line. There was a significant correlation between PBA and T(3) in the low line and between PBA and T(4) in the high PBA line. Thyroid hormone levels may be an indirect indicator of PBA in growing chickens. The genes in the thyroid hormone pathway may be key in the identification of genes associated with PBA. Topics: Animals; Biological Availability; Body Weight; Chickens; Glucagon; Insulin; Leptin; Phytic Acid; Somatomedins; Thyroxine; Triiodothyronine | 2008 |
Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis.
p70 S6 kinase 1 (S6K) is a major downstream effector of the mammalian target of rapamycin (mTOR), primarily implicated in the control of protein synthesis, cell growth, and proliferation. Here we demonstrate that specific bidirectional molecular targeting of mediobasal hypothalamic (MBH) S6K activity in rats is sufficient to significantly alter food intake, body weight, hypothalamic orexigenic neuropeptide expression, hypothalamic leptin sensitivity, and the metabolic and feeding responses to a fast. In addition, adenoviral-mediated constitutive activation of MBH S6K improved cold tolerance and protected against high-fat diet-induced overeating, fat deposition, and insulin resistance. Our results provide direct evidence that MBH S6K activity bidirectionally drives behavioral and metabolic determinants of energy balance and promote the assessment of MBH S6K activity as a therapeutic target in metabolic diseases. Topics: Adenoviridae; Adipocytes, Brown; Animals; Body Weight; Calorimetry; Cold Temperature; Eating; Energy Metabolism; Fasting; Hypothalamus; Leptin; Phosphorylation; Protein Kinases; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Messenger; Time Factors; TOR Serine-Threonine Kinases | 2008 |
Platelet monoamine oxidase activity in underweight and weight-recovered females with anorexia nervosa.
Central serotonergic pathways may play an important role in the etiology of anorexia nervosa (AN). Although platelet monoamine oxidase activity (MAO-B) has been proposed as an index of cerebral serotonin activity, studies in patients with AN are scarce.. Platelet MAO-B activity was determined in 59 acutely underweight AN patients (acAN, aged 14-29 years, BMI=15.2+/-1.4), 35 weight-recovered AN patients (recAN, aged 15-29, BMI=20.8+/-2.2) and 59 healthy control women (HCW, aged 14-26, BMI=21.6+/-2.1). Plasma leptin served as an indicator of malnutrition. Results were compared by ANCOVA controlling for confounding variables.. Platelet MAO-B activity in acAN patients (5.2+/-1.4 nmol/10 (9)pltx15 min) was similar to HCW (5.5+/-1.9) but significantly lower in recAN patients (4.4+/-1.5). BMI and leptin showed a significant negative correlation with MAO-B activity in AN patients, but not in HCW.. Our results highlight the importance of malnutrition for the interpretation of abnormalities in neurotransmitter systems in AN. Whether low MAO-B activity in weight-recovered AN patients indicates a premorbid trait or a secondary change due to recovery remains to be elucidated. Topics: Adipocytes; Adolescent; Adult; Anorexia Nervosa; Blood Platelets; Body Weight; Eating; Energy Metabolism; Female; Gonads; Humans; Hypothalamo-Hypophyseal System; Leptin; Monoamine Oxidase; Nutritional Physiological Phenomena; Psychiatric Status Rating Scales; Serotonin; Thinness; Young Adult | 2008 |
Genes are differentially expressed in the epididymal fat of rats rendered obese by a high-fat diet.
The aim of present study was to identify the visceral adipose tissue genes differentially expressed in a well-characterized rat model of high-fat diet (HFD)-induced obesity. Male Sprague-Dawley rats were fed either the HFD (17 g lard + 3 g corn oil/100 g) or the normal diet (5 g corn oil/100 g) for 9 weeks. The HFD rats weighed 55% more and accumulated 85% to 133% greater visceral fats than did the normal-diet rats (P < .05). Animals given the HFD for 9 weeks acquired dyslipidemia, fatty liver, insulin resistance, and hyperleptinemia along with the overexpression of several obesity-related genes, such as leptin, tumor necrosis factor alpha, resistin, peroxisome proliferator-activated receptor gamma2, CCAAT/enhancer-binding protein alpha, and sterol regulatory element-binding protein-1c, in the epididymal adipose tissue. The differential gene expression profile obtained from the cDNA microarray analysis followed by the real-time polymerase chain reaction confirmation led to a recruitment of several uncharacterized adipose tissue genes responding to the HFD. We report herein, for the first time, that a series of genes which might be implicated in the insulin-stimulated glucose transporter 4 translocation, such as protein phosphatase 2 (formerly 2A), cell division cycle 42-interacting protein 4, syntaxin 6, linker of T-cell receptor pathways 10, as well as the genes which might be involved in cancer development, such as heat shock 10-kd protein 1, and ras-related C3 botulinum toxin substrate 1, were differentially expressed in the epididymal adipose tissue of rats rendered obese by an HFD. Topics: Animals; Body Weight; C-Peptide; Dietary Fats; Epididymis; Gene Expression Profiling; Gene Expression Regulation; Glucose; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Lipids; Liver; Male; Obesity; Oligonucleotide Array Sequence Analysis; Rats; Rats, Sprague-Dawley | 2008 |
Norepinephrine controls both torpor initiation and emergence via distinct mechanisms in the mouse.
Some mammals, including laboratory mice, enter torpor in response to food deprivation, and leptin can attenuate these bouts of torpor. We previously showed that dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), do not reduce circulating leptin upon fasting nor do they enter torpor. To test whether the onset of torpor in mice during a fast requires a NE-mediated reduction in circulating leptin, double mutant mice deficient in both leptin (ob/ob) and DBH (DBL MUT) were generated. Upon fasting, control and ob/ob mice entered torpor as assessed by telemetric core T(b) acquisition. While fasting failed to induce torpor in Dbh -/- mice, leptin deficiency bypassed the requirement for NE, as DBL MUT mice readily entered torpor upon fasting. These data indicate that sympathetic activation of white fat and suppression of leptin is required for the onset of torpor in the mouse. Emergence from torpor was severely retarded in DBL MUT mice, revealing a novel, leptin-independent role for NE in torpor recovery. This phenotype was mimicked by administration of a beta(3) adrenergic receptor antagonist to control mice during a torpor bout. Hence, NE signaling via beta(3) adrenergic receptors presumably in brown fat is the first neurotransmitter-receptor system identified that is required for normal recovery from torpor. Topics: Adipose Tissue, Brown; Adrenergic beta-3 Receptor Antagonists; Animals; Basal Metabolism; Behavior, Animal; Body Weight; Dopamine beta-Hydroxylase; Eating; Energy Metabolism; Fasting; Female; Leptin; Male; Mice; Mice, Knockout; Mice, Obese; Norepinephrine; Recovery of Function; Signal Transduction | 2008 |
Can maternal leptin level at early gestation be used as a predictor of postpartum weight retention?
Topics: Body Mass Index; Body Weight; Female; Humans; Leptin; Postpartum Period; Pregnancy | 2008 |
Evaluation of plasma leptin levels & BMI as predictor of postpartum weight retention.
Plasma leptin level during pregnancy has been reported as a biochemical predictor of postpartum weight retention. The objective of this study was to determine the relationship between pregnancy-related factors including plasma leptin and postpartum weight retention in Korean women.. A convenience sampling method was used among women attending a high-risk pregnancy clinic in Pusan National University Hospital, Busan, between March 2002 and February 2003. We investigated 75 women during pregnancy and 6 months postpartum. Plasma leptin levels were measured using an ELISA. The weight gain during pregnancy and postpartum weight retention, and the correlation between the plasma leptin levels and body weight were evaluated.. The plasma leptin levels at the 1(st) trimester and body weight at 24 wk of gestation, 6 wk, and 6 months postpartum differed significantly between the underweight and overweight groups and between the normal and overweight groups. Plasma leptin levels during the first trimester correlated with the initial BMI at first visit and term, and body weight at term, while the initial BMI significantly correlated with the body weight at term, 6 months postpartum, and 6 months postpartum.. Our findings suggest that the plasma leptin level in the first trimester is a predictor of maternal weight at term, while initial BMI is a better predictor of maternal weight at 6 wk and 6 months postpartum. Further, postpartum weight retention was more dependent on first pre-natal visit factors rather than weight changes during pregnancy. Anthropometric measures at first pre-natal visit to prevent postpartum obesity can be recommended. Topics: Adult; Body Mass Index; Body Weight; Female; Humans; Leptin; Postpartum Period; Pregnancy | 2008 |
The leptin/adiponectin ratio in mid-infancy correlates with weight gain in healthy term infants, but is unrelated to serum insulin concentrations, body mass index, or skin fold thickness.
Rapid growth in infancy may be associated with later onset childhood obesity. The aim in this study was to evaluate the relationships of adipokines to growth of infants at 6-10 months of age and to serum insulin, glucose, and auxological parameters of infants and their mothers.. Thirty-seven healthy term AGA formula fed infants, 21 males, mean age 7.0 +/- 1.2 (SD) months, were evaluated during a nutritional assessment at a county health department. Length, weight, head circumference, waist circumference, mid-arm circumference, and subscapular skin fold and triceps skin fold thickness were determined. Mothers were weighed and their height measured, birth weight recorded from clinic records, and the infant's dietary history reviewed. Following finger stick for assessment of hemoglobin, a bedside blood glucose was determined and 250 microl of additional serum taken for assay of total adiponectin, high molecular weight (HMW) adiponectin (n=12), leptin, and insulin.. The infants' total adiponectin to leptin ratio correlated significantly with the change in body weight from birth to mid-infancy (r = 0.349, p < 0.05). The mean total adiponectin was 34.2 - 16.6 microg/ml (n=37), mean HMW adiponectin 12.2 +/- 9.0 microg/ml (n=12), mean HMW/total adiponectin ratio 34.3 +/- 17.6%, and mean leptin 1.3 +/- 1.2 ng/ml. Neither total nor HMW adiponectin, leptin, nor the leptin/adiponectin ratio, correlated with serum insulin, glucose/insulin ratio, hemoglobin, birth weight, or auxological determinations of the infants or mothers.. As leptin and adiponectin are both insulin sensitizing hormones that change inversely with acquisition of body fat, and the leptin/adiponectin ratio correlates significantly with weight gain in mid-infancy, we postulate that this ratio might provide a marker relating to infantile growth and later adiposity. Topics: Adiponectin; Adipose Tissue; Adiposity; Biomarkers; Body Mass Index; Body Weight; Cohort Studies; Female; Humans; Infant; Insulin; Leptin; Male; Nutrition Assessment; Skinfold Thickness; Weight Gain | 2008 |
Interaction of GH polymorphism with body weight and endocrine functions in Japanese black calves.
We assessed the interaction of GH gene polymorphisms (AA, AB and BB genotypes) with body weight and measures of endocrine function in Japanese black calves at 10 months of age. The average body weight for the BB genotype (281+/-5 kg) was significantly lower (P=0.0017, ANOVA) than those for the AA (324+/-9 kg) and AB (317+/-7 kg) genotypes. Plasma concentrations of insulin and IGF-I were greater for the AA genotype than for the AB genotype, and AB and BB genotypes, respectively. There were significant differences in the triglyceride and cholesterol concentrations among the GH genotypes. The area under the basal GH concentration was significantly greater (P=0.0314) for the AA genotype than for the two other genotypes. The incremental area over the basal GH concentrations in response to intravenous GHRH injection (0.4 microg/kg BW) was significantly smaller (P=0.0005) for the BB genotype than for the two other genotypes. In addition, linear regression analysis between GH incremental area induced by GHRH and body weight demonstrated that there was a positive linear correlation (r=0.6496, P<0.002) for incremental areas less than 600 ng min/ml, but a negative correlation (r=0.6473, P<0.05) for incremental areas over 600 ng min/ml. These findings indicate that the GH genotypes of the animals could be associated with difference in the GH response in Japanese black cattle at 10 months of age. We also observed a relationship between genotype and animal performances, but other studies on more animals in different conditions must be realized to make a definite conclusion. Topics: Animals; Area Under Curve; Blood Glucose; Blood Urea Nitrogen; Body Weight; Cattle; Cholesterol; Endocrine System; Fatty Acids, Nonesterified; Genotype; Growth Hormone; Growth Hormone-Releasing Hormone; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Polymorphism, Single Nucleotide; Triglycerides | 2008 |
Postprandial blood hormone and metabolite concentrations influenced by feeding frequency and feeding level in veal calves.
This study hypothesized that increased feeding frequency (FF) decreases problems with glucose homeostasis seen at high feeding levels (FL) in heavy veal calves. Effects of FF and FL on hormone and metabolite concentrations were studied in 15 heavy veal calves fed once (FF1; at 12:00), twice (FF2; at 12:00 and 24:00) or four times daily (FF4; at 06:00, 12:00, 18:00 and 24:00). In period 1, all calves were fed at a low FL (FL(low); 1.5 x metabolizable energy requirements for maintenance, ME(m)). In period 2, FF2 and FF4 calves were fed at high FL (FL(high); 2.5 x ME(m)), whereas FF1 calves were still fed at FL(low). Blood was sampled every 30 min from 12:00 to 18:00 and postprandial integrated plasma hormone and metabolite concentrations (AUC(12-18 h)) were calculated. Glucose AUC(12-18 h) increased with increasing FL, but decreased with increasing FF, urea AUC(12-18 h) increased with increasing FL, whereas non-esterified fatty acid AUC(12-18 h) were unaffected by FL and FF. Insulin AUC(12-18 h) decreased with increasing FF and decreasing FL. Glucagon AUC(12-18 h) increased with increasing FL and FF. Growth hormone AUC(12-18 h) decreased, whereas insulin-like growth factor-1 and leptin AUC(12-18 h) increased with increasing FL. Mean thyroxine and 3,5,3'-triiodothyronine concentrations were modified by FF and FL. There were no FF x FL interactions, except for plasma glucose. In conclusion, postprandial hormone and metabolite responses were differentially affected by FF and (or) FL. Glucose and insulin concentrations were maximally increased at high FL and low FF. Hyperglycemia, glucosuria and excessive insulinemia were prevented by increasing FF and decreasing FL. Topics: Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Body Weight; Cattle; Fatty Acids, Nonesterified; Feeding Behavior; Glucagon; Growth Hormone; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Postprandial Period; Thyroxine; Triiodothyronine; Urea | 2008 |
Opioid-dependent anticipatory negative contrast and binge-like eating in rats with limited access to highly preferred food.
Binge eating and an increased role for palatability in determining food intake are abnormal adaptations in feeding behavior linked to eating disorders and body weight dysregulation. The present study tested the hypothesis that rats with limited access to highly preferred food would develop analogous opioid-dependent learned adaptations in feeding behavior, with associated changes in metabolism and anxiety-like behavior. For this purpose, adolescent female Wistar rats were daily food deprived (2 h) and then offered 10-min access to a feeder containing chow followed sequentially by 10-min access to a different feeder containing either chow (chow/chow; n=7) or a highly preferred, but macronutrient-comparable, sucrose-rich diet (chow/preferred; n=8). Chow/preferred-fed rats developed binge-like hyperphagia of preferred diet from the second feeder and anticipatory chow hypophagia from the first feeder with a time course suggesting associative learning. The feeding adaptations were dissociable in onset, across individuals, and in their dose-response to the opioid-receptor antagonist nalmefene, suggesting that they represent distinct palatability-motivated processes. Chow/preferred-fed rats showed increased anxiety-like behavior in relation to their propensity to binge as well as increased feed efficiency, body weight, and visceral adiposity. Chow/preferred-fed rats also had increased circulating leptin levels and decreased growth hormone and 'active' ghrelin levels. Thus, the short-term control of food intake in rats with restricted access to highly preferred foods comes to rely more on hedonic, rather than nutritional, properties of food, through associative learning mechanisms. Such rats show changes in ingestive, metabolic, endocrine, and anxiety-related measures, which resemble features of binge eating disorders or obesity. Topics: Adiposity; Animals; Anxiety; Behavior, Animal; Body Weight; Eating; Feeding Behavior; Female; Food; Food Preferences; Ghrelin; Growth Hormone; Leptin; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Rats; Rats, Wistar | 2008 |
Increased leptin permeation across the blood-brain barrier after chronic alcohol ingestion.
Leptin, a polypeptide mainly produced in the periphery, crosses the blood-brain barrier (BBB) by receptor-mediated transport to exert multiple central nervous system actions including decreased food intake. The reciprocal interactions between leptin transport and alcohol drinking are not clear. In this study, we tested whether alcohol increases leptin entry into brain and, if this occurs, whether it is a consequence of a generalized increase in the permeability of the BBB. BBB permeability to albumin, the increased permeation of which indicates BBB disruption, as well as to leptin was measured after alcohol ingestion. CD1 and B6 mice ingested a 5% liquid alcohol diet or its isocaloric control for 2 weeks. Alcohol ingestion resulted in increased blood-alcohol levels, decreased blood-leptin concentrations, and increased permeation of radioactively labeled leptin across the BBB as shown by in situ perfusion. Although the increased influx of the vascular marker albumin into brain showed partial disruption of the BBB, the influx of (125)I-leptin still could be suppressed by excess unlabeled leptin, indicating persistence of its saturable transport system. When given a choice of either alcohol or control diet, even the alcohol-preferring B6 mice showed a significantly greater preference for the control liquid diet, and there was no evidence of BBB disruption or alterated leptin transport. Furthermore, acute alcohol intoxication induced by intraperitoneal injection of 20% alcohol did not result in BBB disruption or increased leptin permeation 4 h later. Thus, partial disruption of the BBB and increased permeation of leptin in both CD1 and B6 mice were only induced by chronic alcohol ingestion. The results showing increased leptin permeation across the BBB lead to the speculation that leptin may serve as a homeostatic feeding signal in these mice. Topics: Alcohol Drinking; Animals; Behavior, Animal; Blood-Brain Barrier; Body Weight; Central Nervous System Depressants; Drinking; Eating; Ethanol; Leptin; Male; Mice; Mice, Inbred Strains; Time Factors | 2008 |
Brain neuropeptide Y and CCK and peripheral adipokine receptors: temporal response in obesity induced by palatable diet.
Palatable food disrupts normal appetite regulation, which may contribute to the etiology of obesity. Neuropeptide Y (NPY) and cholecystokinin play critical roles in the regulation of food intake and energy homeostasis, while adiponectin and carnitine palmitoyltransferase (CPT) are important for insulin sensitivity and fatty acid oxidation. This study examined the impact of short- and long-term consumption of palatable high-fat diet (HFD) on these critical metabolic regulators.. Male C57BL/6 mice were exposed to laboratory chow (12% fat), or cafeteria-style palatable HFD (32% fat) for 2 or 10 weeks. Body weight and food intake were monitored throughout. Plasma leptin, hypothalamic NPY and cholecystokinin, and mRNA expression of leptin, adiponectin, their receptors and CPT-1, in fat and muscles were measured.. Caloric intake of the palatable HFD group was 2-3 times greater than control, resulting in a 37% higher body weight. Fat mass was already increased at 2 weeks; plasma leptin concentrations were 2.4 and 9 times higher than control at 2 and 10 weeks, respectively. Plasma adiponectin was increased at 10 weeks. Muscle adiponectin receptor 1 was increased at 2 weeks, while CPT-1 mRNA was markedly upregulated by HFD at both time points. Hypothalamic NPY and cholecystokinin content were significantly decreased at 10 weeks.. Palatable HFD induced hyperphagia, fat accumulation, increased adiponectin, leptin and muscle fatty acid oxidation, and reduced hypothalamic NPY and cholecystokinin. Our data suggest that the adaptive changes in hypothalamic NPY and muscle fatty acid oxidation are insufficient to reverse the progress of obesity and metabolic consequences induced by a palatable HFD. Topics: Adiponectin; Animals; Body Weight; Cholecystokinin; Dietary Fats; Eating; Energy Metabolism; Hyperphagia; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Receptors, Adiponectin; RNA, Messenger | 2008 |
Microvascular transplantation of adipose tissue and serum level of adipocyte products.
Topics: Adipocytes; Adipose Tissue; Body Weight; Feedback; Humans; Leptin; Microcirculation; Microsurgery | 2008 |
Effect of Acute Administration of Recombinant Human Leptin during the Neonatal Period on Body Temperature and Endocrine Profile of the Piglet.
Leptin is produced predominantly by white adipocytes; in adults it regulates appetite and energy expenditure but its role in the neonate remains to be fully established.. To examine the effects of acute administration of recombinant human leptin on the endocrine profile and thermoregulation of neonatal pigs.. 24 pairs of siblings (n = 48) were administered with either a single dose (4 microg ml(-1) kg(-1) body weight) of leptin (L: n = 24) or a placebo (P: n = 24) on day 6 of neonatal life. Rectal temperature was recorded, and tissue samples were taken at 1 (n = 12), 2 (n = 12), 4 (n = 12) or 6 (n = 12) hours post-administration. Plasma concentrations of hormones and metabolites were determined in conjunction with messenger RNA (mRNA) for leptin and uncoupling protein-2.. Plasma leptin increased following leptin administration, and differences in concentrations of insulin, thyroxine and non-esterified fatty acids were observed between the two groups. Initially, rectal temperature decreased in L pigs but returned to start values by 1.5 h. This decline in rectal temperature was delayed in placebo animals, resulting in differences between treatments at 1.5 and 2 h.. Acute leptin administration alters the endocrine profile of pigs and influences the thermoregulatory ability of the neonate. Topics: 3-Hydroxybutyric Acid; Animals; Animals, Newborn; Blood Glucose; Body Composition; Body Temperature Regulation; Body Weight; Endocrine System; Fatty Acids, Nonesterified; Female; Insulin; Ion Channels; Lactates; Leptin; Male; Mitochondrial Proteins; Random Allocation; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA; Swine; Thyroxine; Triglycerides; Triiodothyronine; Uncoupling Protein 2 | 2008 |
Conjugated linoleic acid fails to worsen insulin resistance but induces hepatic steatosis in the presence of leptin in ob/ob mice.
Conjugated linoleic acid (CLA) induces insulin resistance preceded by rapid depletion of the adipokines leptin and adiponectin, increased inflammation, and hepatic steatosis in mice. To determine the role of leptin in CLA-mediated insulin resistance and hepatic steatosis, recombinant leptin was coadministered with dietary CLA in ob/ob mice to control leptin levels and to, in effect, negate the leptin depletion effect of CLA. In a 2 x 2 factorial design, 6 week old male ob/ob mice were fed either a control diet or a diet supplemented with CLA and received daily intraperitoneal injections of either leptin or vehicle for 4 weeks. In the absence of leptin, CLA significantly depleted adiponectin and induced insulin resistance, but it did not increase hepatic triglyceride concentrations or adipose inflammation, marked by interleukin-6 and tumor necrosis factor-alpha mRNA expression. Insulin resistance, however, was accompanied by increased macrophage infiltration (F4/80 mRNA) in adipose tissue. In the presence of leptin, CLA depleted adiponectin but did not induce insulin resistance or macrophage infiltration. Despite this, CLA induced hepatic steatosis. In summary, CLA worsened insulin resistance without evidence of inflammation or hepatic steatosis in mice after 4 weeks. In the presence of leptin, CLA failed to worsen insulin resistance but induced hepatic steatosis in ob/ob mice. Topics: Adiponectin; Animals; Body Weight; Dietary Fats, Unsaturated; Fatty Liver; Glucose; Insulin; Insulin Resistance; Interleukin-6; Leptin; Linoleic Acids, Conjugated; Lipid Metabolism; Macrophages; Male; Mice; Mice, Mutant Strains; Mice, Obese; Obesity; Recombinant Proteins; Tumor Necrosis Factor-alpha | 2008 |
Changes in leptin, ghrelin, growth hormone and neuropeptide-Y after an acute model of MDMA and methamphetamine exposure in rats.
Club drug abuse is a growing problem in the United States. Beyond addiction and toxicity are endocrine effects which are not well characterized. Specifically, the changes in appetite following exposure to drugs of abuse are an interesting but poorly understood phenomenon. Serum hormones such as leptin, ghrelin, growth hormone (GH), and neuropeptide-Y (NP-Y) are known to affect appetite, but have not been studied extensively with drugs of abuse. In this work, we examine the effects of club drugs 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) and methamphetamine (METH) (doses of 5, 20 and 40 mg/kg) on serum concentrations of these hormones in adult male Sprague-Dawley rats 6, 12, 24 and 48 hours after drug administration. In a dose-dependent manner, MDMA was shown to cause transient significant decreases in serum leptin and GH followed by a base line recovery after 24 hours. Conversely, serum ghrelin increased and normalized after 24 hours. Interestingly, serum NP-Y showed a steady decrease in both treatment of MDMA and METH at different time points and dosages. In humans, abuse of these drugs reduces eating. As evident from these data, acute administration of METH and MDMA had significant effects on different serum hormone levels involved in appetite regulation. Future studies should be performed to see how chronic, low dose drug administration would affect hormone levels and try to answer questions about the physiological mechanisms involved in the anorexic paradigm observed in drug use. Topics: Adrenergic Uptake Inhibitors; Amphetamine-Related Disorders; Animals; Appetite; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Ghrelin; Growth Hormone; Leptin; Male; Methamphetamine; N-Methyl-3,4-methylenedioxyamphetamine; Neuropeptide Y; Radioimmunoassay; Rats; Rats, Sprague-Dawley | 2008 |
A new model for nonalcoholic steatohepatitis in the rat utilizing total enteral nutrition to overfeed a high-polyunsaturated fat diet.
We have used total enteral nutrition (TEN) to moderately overfeed rats high-polyunsaturated fat diets to develop a model for nonalcoholic steatohepatitis (NASH). Male Sprague-Dawley rats were fed by TEN a 187 kcal.kg(-3/4).day(-1) diet containing 5% (total calories) corn oil or a 220 kcal.kg(-3/4).day(-1) diet in which corn oil constituted 5, 10, 25, 35, 40, or 70% of total calories for 21 or 65 days. Rats fed the 5% corn oil, 220 kcal.kg(-3/4).day(-1)diet had greater body weight gain (P < or = 0.05), fat mass (P < or = 0.05), and serum leptin and glucose levels (P < or = 0.05), but no liver pathology. A dose-dependent increase in hepatic triglyceride deposition occurred with increase in percent corn oil in the 220 kcal.kg(-3/4).day(-1) groups (P < or = 0.05). Steatosis, macrophage infiltration, apoptosis, and focal necrosis were present in the 70% corn oil group, accompanied by elevated serum alanine aminotransferase (ALT) levels (P < or = 0.05). An increase in oxidative stress (thiobarbituric acid-reactive substances) and TNF-alpha expression (P < or = 0.05) was observed in the 70% corn oil group, as well as an increase in hepatic CYP2E1 and CYP4A1 expression (P < or = 0.05). Significant positive correlations were observed between the level of dietary corn oil and the degree of pathology, ALTs, oxidative stress, and inflammation. Liver pathology was progressive with increased necrosis, accompanied by fibrosis, observed after 65 days of TEN. Increased expression of CD36 and l-fabp mRNA suggested development of steatosis was associated with increased fatty acid transport. These data suggest that intragastric infusion of a high-polyunsaturated fat diet at a caloric level of 17% excess total calories results in pathology similar to clinical NASH. Topics: Adiposity; Alanine Transaminase; Animals; Apoptosis; Blood Glucose; Body Weight; CD36 Antigens; Corn Oil; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP4A; Disease Models, Animal; Enzyme Induction; Fatty Acid-Binding Proteins; Fatty Acids; Fatty Liver; Leptin; Liver; Macrophages; Male; Necrosis; Overnutrition; Oxidative Stress; Parenteral Nutrition, Total; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha | 2008 |
Comparison of the obesity phenotypes related to monosodium glutamate effect on arcuate nucleus and/or the high fat diet feeding in C57BL/6 and NMRI mice.
In this study, susceptibility of inbred C57BL/6 and outbred NMRI mice to monosodium glutamate (MSG) obesity or diet-induced obesity (DIO) was compared in terms of food intake, body weight, adiposity as well as leptin, insulin and glucose levels. MSG obesity is an early-onset obesity resulting from MSG-induced lesions in arcuate nucleus to neonatal mice. Both male and female C57BL/6 and NMRI mice with MSG obesity did not differ in body weight from their lean controls, but had dramatically increased fat to body weight ratio. All MSG obese mice developed severe hyperleptinemia, more remarkable in females, but only NMRI male mice showed massive hyperinsulinemia and an extremely high HOMA index that pointed to development of insulin resistance. Diet-induced obesity is a late-onset obesity; it developed during 16-week-long feeding with high-fat diet containing 60 % calories as fat. Inbred C57BL/6 mice, which are frequently used in DIO studies, both male and female, had significantly increased fat to body weight ratio and leptin and glucose levels compared with their appropriate lean controls, but only female C57BL/6 mice had also significantly elevated body weight and insulin level. NMRI mice were less prone to DIO than C57BL/6 ones and did not show significant changes in metabolic parameters after feeding with high-fat diet. Topics: Adiposity; Age Factors; Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Dietary Fats; Disease Models, Animal; Disease Susceptibility; Eating; Female; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Phenotype; Sodium Glutamate; Species Specificity | 2008 |
Protein kinase C deficiency increases fatty acid oxidation and reduces fat storage.
Metabolic syndrome is common in the general population, but there is little information available on the underlying signaling mechanisms regulating triglyceride (TG) content in the body. In the current study, we have uncovered a role for protein kinase Cbeta (PKCbeta) in TG homeostasis by studying the consequences of a targeted disruption of this kinase. PKCbeta(-/-) mutant mice were considerably leaner and the size of white fat depots was markedly decreased compared with wild-type littermates. TG content in the liver and skeletal muscle of PKCbeta(-/-) mice was also significantly low. Interestingly, mutant animals were hyperphagic and exhibited higher food intake and reduced feed efficiency versus wild type. The protection from obesity involves elevated oxygen consumption/energy expenditure and increased fatty acid oxidation in adipose tissue with concurrent increased mitochondria genesis, up-regulation of PGC-1alpha and UCP-2, and down-regulation of perilipin. The ability of PKCbeta deficiency to promote fat burning in adipocytes may suggest novel therapeutic strategies for obesity and obesity-related disorders. Topics: Adipocytes; Adipose Tissue; Adiposity; Animals; Body Weight; Carbon Dioxide; Fats; Fatty Acids; Leptin; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Mitochondria; Muscle, Skeletal; Oleic Acid; Oxidation-Reduction; Oxygen Consumption; Protein Kinase C; Protein Kinase C beta; Triglycerides | 2008 |
Changes in body mass, serum leptin, and mRNA levels of leptin receptor isoforms during the premigratory period in Myotis lucifugus.
Migration and hibernation in mammals may be preceded by a period of leptin resistance, which may in part account for the increasing adiposity and body mass that occurs during these periods. We hypothesized that hypothalamic expression of leptin receptor mRNA would decrease during the premigration (PM) period in the little brown myotis, Myotis lucifugus. Body mass of M. lucifugus increased during the PM period, but serum leptin levels did not change during that time. Hypothalamic mRNA levels for both the short (ObRa) and fully active long (ObRb) forms of the leptin receptor increased during PM, but the relative increase in ObRa was larger and occurred sooner than ObRb. mRNA levels of an inhibitor of leptin signaling (protein inhibitor of activated STAT3: PIAS3) increased in hypothalami during the PM period in bats. Adiponectin is an adipokine that has been linked to obesity in rodents; normally, serum levels of adiponectin decrease in obesity. In M. lucifugus, adiponectin mRNA levels decreased in adipose tissue during the period of mass gain, but circulating adiponectin levels did not change. We conclude that the relative changes in leptin receptor isoform expression during the PM fattening period may favor binding of leptin to the less active short isoform. Coupled with increased expression of PIAS3 and the dissociation of serum leptin levels from body mass and adiposity, these changes could account in part for the adaptive fattening during the PM period. In addition, the adipokine profiles of M. lucifugus during the PM period and that of obesity in non-hibernating mammals are strikingly dissimilar. Topics: Adaptation, Physiological; Adiponectin; Adipose Tissue; Animal Migration; Animals; Body Weight; Chiroptera; Female; Hypothalamus; Isomerism; Leptin; Male; Receptors, Leptin; RNA, Messenger; Seasons | 2008 |
Three weeks of early-onset exercise prolongs obesity resistance in DIO rats after exercise cessation.
We assessed the effect of early-onset exercise as a means of preventing childhood obesity using juvenile male rats selectively bred to develop diet-induced obesity (DIO) or to be diet resistant (DR) when fed a 31% fat high-energy diet. Voluntary wheel running begun at 36 days of age selectively reduced adiposity in DIO vs. DR rats. Other 4-wk-old DIO rats fed a high-energy diet and exercised (Ex) for 13 wk increased their core temperature, gained 22% less body weight, and had 39% lighter fat pads compared with sedentary (Sed) rats. When wheels were removed after 6 wk (6 wk Ex/7 wk Sed), rats gained less body weight over the next 7 wk than Sed rats and still had comparable adipose pad weights to 13-wk-exercised rats. In fact, only 3 wk of exercise sufficed to prevent obesity for 10 wk after wheel removal. Terminally, the 6-wk-Ex/7-wk-Sed rats had a 55% increase in arcuate nucleus proopiomelanocortin mRNA expression vs. Sed rats, suggesting that this contributed to their sustained obesity resistance. Finally, when Sed rats were calorically restricted for 6 wk to weight match them to Ex rats (6 wk Rstr/7 wk Al), they increased their intake and body weight when fed ad libitum and, after 7 wk more, had higher leptin levels and adiposity than Sed rats. Thus, early-onset exercise may favorably alter, while early caloric restriction may unfavorably influence, the development of the hypothalamic pathways controlling energy homeostasis during brain development. Topics: Adipose Tissue; Animal Feed; Animals; Body Weight; Brain-Derived Neurotrophic Factor; Caloric Restriction; Eating; Hypothalamus; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Physical Conditioning, Animal; Pro-Opiomelanocortin; Rats; Rats, Inbred Strains; Receptors, Leptin; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins | 2008 |
Long-term effects of central leptin and resistin on body weight, insulin resistance, and beta-cell function and mass by the modulation of hypothalamic leptin and insulin signaling.
To determine the long-term effect of central leptin and resistin on energy homeostasis, peripheral insulin resistance, and beta-cell function and mass, intracerebroventricular (ICV) infusion of leptin (3 ng/h), resistin (80 ng/h), leptin plus resistin, and cerebrospinal fluid (control) was conducted by means of an osmotic pump for 4 wk on normal rats and 90% pancreatectomized diabetic rats fed 40% fat-energy diets. Overall, the effects were greater in diabetic rats than normal rats. Leptin infusion, causing a significant reduction in food intake, decreased body weight and epididymal fat. However, resistin and leptin plus resistin reduced epididymal fat with decreased serum leptin levels in comparison with the control. Unlike serum leptin, only resistin infusion lowered serum resistin levels. Central leptin increased glucose infusion rates during euglycemic hyperinsulinemic clamp and suppressed hepatic glucose production in the hyperinsulinemic state in comparison with the control. However, central leptin did not affect glucose-stimulated insulin secretion and beta-cell mass. Central resistin infusion also increased peripheral insulin sensitivity, but not as much as leptin. Unlike leptin, resistin significantly increased first-phase insulin secretion during hyperglycemic clamp and beta-cell mass by augmenting beta-cell proliferation. These metabolic changes were associated with hypothalamic leptin and insulin signaling. ICV infusion of leptin potentiated signal transducer and activator of transcription 3 phosphorylation and attenuated AMP kinase in the hypothalamus, but resistin had less potent effects than leptin. Leptin enhanced insulin signaling by potentiating IRS2-->Akt pathways, whereas resistin activated Akt without augmenting insulin receptor substrate 2 phosphorylation. In conclusion, long-term ICV infusion of leptin and resistin independently improved energy and glucose homeostasis by modulating in different ways hypothalamic leptin and insulin signaling. Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Cell Division; Eating; Glucose Clamp Technique; Glucose Tolerance Test; Hyperinsulinism; Hypothalamus; Injections, Intraventricular; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Like Growth Factor I; Insulin-Secreting Cells; Leptin; Male; Pancreatectomy; Rats; Rats, Sprague-Dawley; Resistin; Signal Transduction | 2008 |
Oral supplementation with physiological doses of leptin during lactation in rats improves insulin sensitivity and affects food preferences later in life.
We have previously described that neonate rats supplemented with physiological doses of oral leptin during lactation become more protected against overweight in adulthood. The purpose of this study was to characterize further the long-term effects on glucose and leptin homeostasis and on food preferences. Neonate rats were supplemented during lactation with a daily oral dose of leptin or the vehicle. We followed body weight and food intake of animals until the age of 15 months, and measured glucose, insulin, and leptin levels under different feeding conditions: ad libitum feeding, 14-h fasting, and 3-h refeeding after fasting. An oral glucose tolerance test and a leptin resistance test were performed. Food preferences were also measured. Leptin-treated animals were found to have lower body weight in adulthood and to eat fewer calories than their controls. Plasma insulin levels were lower in leptin-treated animals than in their controls under the different feeding conditions, as was the increase in insulin levels after food intake. The homeostatic model assessment for insulin resistance index was significantly lower in leptin-treated animals, and the oral glucose tolerance test also indicated higher insulin sensitivity in leptin-treated animals. In addition, these animals displayed lower plasma leptin levels under the different feeding conditions and were also more responsive to exogenous leptin administration. Leptin-treated animals also showed a lower preference for fat-rich food than their controls. These observations indicate that animals supplemented with physiological doses of oral leptin during lactation were more protected against obesity and metabolic features of the metabolic syndrome. Topics: Administration, Oral; Animals; Animals, Newborn; Animals, Suckling; Blood Glucose; Body Weight; Female; Food Preferences; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Insulin Resistance; Lactation; Leptin; Male; Milk; Obesity; Pregnancy; Rats; Rats, Wistar | 2008 |
Short-term exercise improves beta-cell function and insulin resistance in older people with impaired glucose tolerance.
There is a high prevalence of diabetes and impaired glucose tolerance (IGT) in the older population. Normal aging is associated with insulin resistance and impaired insulin secretion, with greater defects in people with IGT. Short-term exercise has been found to increase insulin sensitivity, but little is known about acute exercise effects on beta-cell function in older people with IGT.. We assessed the effects of 7 consecutive days of supervised aerobic exercise (1 h/d at 60-70% heart rate reserve) in 12 sedentary older people with IGT. Screening included oral glucose tolerance test, stress/maximal O(2) uptake test, and dual-energy x-ray absorptiometry scan. Participants had a frequently sampled iv glucose tolerance test at baseline and 15-20 h after the seventh exercise session. Insulin sensitivity (S(I)), glucose disappearance constant (Kg, a measure of iv glucose tolerance), acute insulin response to glucose (AIRg), and disposition index (AIRg x S(I)), a measure of beta-cell function in relation to insulin resistance, were calculated.. Exercise was well tolerated. Body weight, fasting glucose, fasting insulin, and iv glucose tolerance were unchanged with exercise. S(I) increased by 59%, AIRg decreased by 12%, and disposition index increased by 31%. There was no significant change in fasting lipid, catecholamine, leptin, or adiponectin levels.. Short-term exercise not only improved insulin resistance but also significantly enhanced beta-cell function in older people with IGT. These effects of short-term exercise on beta-cell function cannot be explained by changes in body weight or circulating levels of lipids, leptin, adiponectin, or catecholamines. Topics: Adiponectin; Aged; Blood Glucose; Body Weight; Catecholamines; Exercise; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Leptin; Male; Oxygen Consumption; Triglycerides | 2008 |
Maternal perinatal undernutrition drastically reduces postnatal leptin surge and affects the development of arcuate nucleus proopiomelanocortin neurons in neonatal male rat pups.
A growing body of evidence suggests that maternal undernutrition sensitizes the offspring to the development of energy balance metabolic disorders such as type 2 diabetes, dyslipidemia, and obesity. The present study aimed at examining the impact of maternal undernutrition on leptin plasma levels in newborn male rats and on the arcuate nucleus proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons that are major leptin targets. Using a model of perinatal maternal 50% food-restricted diet (FR50) in the rat, we evaluated leptin plasma levels and hypothalamic POMC and NPY gene expression from postnatal day (PND) 4 to PND30 in both control and FR50 offspring. In control rats, a postnatal peak of plasma leptin was observed between PND4 and PND14 that reached a maximal value at PND10 (5.17 +/- 0.53 ng/ml), whereas it was dramatically reduced in FR50 pups with the higher concentration at PND7 (0.93 +/- 0.23 ng/ml). In FR50 animals, using semiquantitative RT-PCR and in situ hybridization, we showed that the hypothalamic POMC mRNA level was decreased from PND14 until PND30, whereas NPY gene expression was not significantly modified. In PND21 FR50 animals, we observed strikingly reduced immunoreactive beta-endorphin nerve fibers projecting to the hypothalamic paraventricular nucleus without affecting NPY projections. Our data showed that maternal undernutrition drastically reduces the postnatal surge of plasma leptin, disturbing particularly the hypothalamic wiring as well as the gene expression of the anorexigenic POMC neurons in male rat pups. These alterations might contribute to the adult metabolic disorders resulting from perinatal growth retardation. Topics: Age Factors; Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Body Weight; Feeding Behavior; Female; Fetal Nutrition Disorders; Gene Expression; Leptin; Male; Nerve Fibers; Neurons; Pregnancy; Prenatal Exposure Delayed Effects; Pro-Opiomelanocortin; Rats; Rats, Wistar | 2008 |
Factors contributing to obesity in bombesin receptor subtype-3-deficient mice.
Mice with a targeted disruption of bombesin receptor subtype-3 (BRS-3 KO) develop hyperphagia, obesity, hypertension, and impaired glucose metabolism. However, the factors contributing to their phenotype have not been clearly established. To determine whether their obesity is a result of increased food intake or a defect in energy regulation, we matched the caloric intake of BRS-3 KO mice to wild-type (WT) ad libitum (ad lib)-fed controls over 21 wk. Although BRS-3 KO ad lib-fed mice were 29% heavier, the body weights of BRS-3 KO pair-fed mice did not differ from WT ad lib-fed mice. Pair-feeding BRS-3 KO mice normalized plasma insulin but failed to completely reverse increased adiposity and leptin levels. Hyperphagia in ad lib-fed KO mice was due to an increase in meal size without a compensatory decrease in meal frequency resulting in an increase in total daily food intake. An examination of neuropeptide Y, proopiomelanocortin, and agouti-related peptide gene expression in the arcuate nucleus revealed that BRS-3 KO mice have some deficits in their response to energy regulatory signals. An evaluation of the satiety effects of cholecystokinin, bombesin, and gastrin-releasing peptide found no differences in feeding suppression by these peptides. We conclude that hyperphagia is a major factor leading to increased body weight and hyperinsulinemia in BRS-3 KO mice. However, our finding that pair-feeding did not completely normalize fat distribution and plasma leptin levels suggests there is also a metabolic dysregulation that may contribute to, or sustain, their obese phenotype. Topics: Adiposity; Animals; Body Weight; Bombesin; Cholecystokinin; Eating; Energy Metabolism; Gastrin-Releasing Peptide; Glucose; Hyperinsulinism; Hyperphagia; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Knockout; Obesity; Receptors, Bombesin; Satiation; Weight Gain | 2008 |
Hypothalamic phosphatidylinositol 3-kinase pathway of leptin signaling is impaired during the development of diet-induced obesity in FVB/N mice.
Phosphatidylinositol 3-kinase (PI3K) pathway of leptin signaling plays an important role in transducing leptin action in the hypothalamus. Obesity is usually associated with resistance to the effect of leptin on food intake and energy homeostasis. Although central leptin resistance is thought to be involved in the development of diet-induced obesity (DIO), the mechanism behind this phenomenon is not clearly understood. To determine whether DIO impairs the effect of leptin on hypothalamic PI3K signaling, we fed 4-wk-old FVB/N mice a high-fat diet (HFD) or low-fat diet (LFD) for 19 wk. HFD-fed mice developed DIO in association with hyperleptinemia, hyperinsulinemia, and impaired glucose and insulin tolerance. Leptin (ip) significantly increased hypothalamic PI3K activity and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) levels in LFD-fed mice but not in DIO mice. Immunocytochemical study confirmed impaired p-STAT3 activation in various hypothalamic areas, including the arcuate nucleus. We next tested whether both PI3K and STAT3 pathways of leptin signaling were impaired during the early period of DIO. Leptin failed to increase PI3K activity in DIO mice that were on a HFD for 4 wk. However, leptin-induced p-STAT3 activation in the hypothalamus measured by Western blotting and immunocytochemistry remained comparable between LFD- and HFD-fed mice. These results suggest that the PI3K pathway but not the STAT3 pathway of leptin signaling is impaired during the development of DIO in FVB/N mice. Thus, a defective PI3K pathway of leptin signaling in the hypothalamus may be one of the mechanisms of central leptin resistance and DIO. Topics: Animals; Body Weight; Dietary Fats; Disease Models, Animal; Eating; Hypothalamus; Leptin; Male; Mice; Mice, Inbred Strains; Obesity; Phosphatidylinositol 3-Kinases; Signal Transduction; STAT3 Transcription Factor | 2008 |
Structure-effect relation of C18 long-chain fatty acids in the reduction of body weight in rats.
To investigate the relationship between chemical structure and physiological effect, the efficacy and the molecular mechanisms involved in the reduction of body weight by C18 fatty acids (stearic, elaidic, oleic, linoleic and 2-hydroxyoleic acids (2-OHOA)).. Ad libitum fed, lean Wistar Kyoto rats treated orally with up to 600 mg kg(-1) of the fatty acids or vehicle every 12 h for 7 days. Besides, starved rats and rats pairfed to the 2-OHOA-treated group served as additional controls under restricted feeding conditions.. Body weight, food intake, weight of various fat depots, plasma leptin, hypothalamic neuropeptides, uncoupling proteins (UCP) in white (WAT) and brown adipose tissue (BAT) and phosphorylation level of cyclic AMP (cAMP) response element-binding protein (CREB) in WAT.. Only treatment with oleic acid and 2-OHOA induced body weight loss (3.3 and 11.4%, respectively) through reduction of adipose fat mass. Food intake in these rats was lower, although hypothalamic neuropeptide and plasma leptin levels indicated a rise in orexigenic status. Rats pairfed to the 2-hydroxyoleic group only lost 6.3% body weight. UCP1 expression and phosphorylation of CREB was drastically increased in WAT, but not BAT of 2-OHOA-treated rats, whereas no UCP1 expression could be detected in WAT of rats treated with oleic acid.. Both cis-configured monounsaturated C18 fatty acids (oleic acid and 2-OHOA) reduce body weight, but the introduction of a hydroxyl group in position 2 drastically increases loss of adipose tissue mass. The novel molecular mechanism unique to 2-hydroxyoleic, but not oleic acid, implies induction of UCP1 expression in WAT by the cAMP/PKA pathway-dependent transcription factor CREB, most probably as part of a transdifferentiation process accompanied by enhanced energy expenditure. Topics: Adipose Tissue; Animals; Body Weight; Fatty Acids; Feeding Behavior; Immunoblotting; Leptin; Linoleic Acid; Neuropeptides; Oleic Acid; Oleic Acids; Random Allocation; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Stearic Acids; Structure-Activity Relationship | 2008 |
ICV leptin effects on spontaneous physical activity and feeding behavior in rats.
Although leptin causes negative energy balance by reducing food intake and increasing energy expenditure, the effect of leptin on spontaneous physical activity (SPA) is not clearly established. To test the hypothesis that leptin enhances SPA in rats, male Sprague-Dawley rats were injected intracerebroventricularly (ICV) with either 10mug of leptin or artificial cerebrospinal fluid (aCSF) before dark onset (12:00h) once daily for 5 successive days. The rats were individually housed in behavioral monitoring cages to measure feeding behavior and SPA throughout the study. Both groups had a diurnal pattern of SPA being low during the light period and high during the dark period. Specifically, there were two peaks of SPA during the dark period, with the first peak taking place around the dark onset and the second occurring approximately 6h towards the light onset. Leptin treatment resulted in a significant increase in SPA whether or not it was expressed in terms of light-dark, daily or diurnal basis. Increased SPA was consistently observed throughout the entire 5-day study in spite of the fact that the rats were consistently eating less and losing body weight. With reduction in weight of fat pads and increase in apoptosis of fat pads but no change in body temperature, leptin decreased size, duration and number of meals without altering eating rate, thereby increasing satiety. Our data show that increased activity is a key determinant in negative energy balance induced by leptin, which cannot be accounted for solely by the leptin-induced food intake reduction. Topics: Analysis of Variance; Animals; Appetite Regulation; Body Composition; Body Weight; Circadian Rhythm; Energy Metabolism; Feeding Behavior; Hunger; Injections, Intraventricular; Leptin; Male; Motor Activity; Rats; Rats, Sprague-Dawley | 2008 |
TrkB agonists ameliorate obesity and associated metabolic conditions in mice.
Mutations in the tyrosine kinase receptor trkB or in one of its natural ligands, brain-derived neurotrophic factor (BDNF), lead to severe hyperphagia and obesity in rodents and/or humans. Here, we show that peripheral administration of neurotrophin-4 (NT4), the second natural ligand for trkB, suppresses appetite and body weight in a dose-dependent manner in several murine models of obesity. NT4 treatment increased lipolysis, reduced body fat content and leptin, and elicited long-lasting amelioration of hypertriglyceridemia and hyperglycemia. After treatment termination, body weight gradually recovered to control levels in obese mice with functional leptin receptor. A single intrahypothalamic application of minute amounts of NT4 or an agonist trkB antibody also reduced food intake and body weight in mice. Taken together with the genetic evidence, our findings support the concept that trkB signaling, which originates in the hypothalamus, directly modulates appetite, metabolism, and taste preference downstream of the leptin and melanocortin 4 receptor. The trkB agonists mediate anorexic and weight-reducing effects independent of stress induction, visceral discomfort, or pain sensitization and thus emerge as a potential therapeutic for metabolic disorders. Topics: Animals; Body Weight; Disease Models, Animal; Eating; Energy Metabolism; Glucose; Homeostasis; Leptin; Lithium Chloride; Male; Melanocortins; Mice; Mice, Inbred C57BL; Mice, Obese; Nerve Growth Factors; Obesity; Rats; Rats, Sprague-Dawley; Receptor, trkB; Receptors, Leptin; Taste; Triglycerides | 2008 |
Leptin deficiency per se dictates body composition and insulin action in ob/ob mice.
Obese humans are often insulin- and leptin resistant. Since leptin can affect glucose metabolism, it is conceivable that a lack of leptin signal transduction contributes to insulin resistance. It remains unclear whether leptin affects glucose metabolism via peripheral and/or central mechanistic routes. In the present study, we aimed: (i) to determine the relative contributions of lack of leptin signal transduction and adiposity to insulin resistance and (ii) to establish the impact of central leptin action on glucose metabolism. To address the first point, ob/ob mice were subjected to severe calorie restriction, so that their body weight became similar to that of wild-type mice. Insulin sensitivity was measured in obese ob/ob, lean (food restricted) ob/ob and lean, weight-matched wild-type mice. To address the second point, leptin (or vehicle) was i.c.v. infused to the lateral cerebral ventricle of ob/ob mice and insulin sensitivity was determined. Hyperinsulinaemic euglyceamic clamps were used to quantify insulin sensitivity. Food restriction barely affected body composition, although it profoundly curtailed body weight. Insulin suppressed hepatic glucose production (HGP) to a greater extent in lean ob/ob than in obese ob/ob mice, but its impact remained considerably less than in wild-type mice (% suppression: 11.8 +/- 8.9 versus 1.3 +/- 1.1 versus 56.6 +/- 13.0%/nmol, for lean, obese ob/ob and wild-type mice, respectively; P < 0.05). The insulin-mediated glucose disposal (GD) of lean ob/ob mice was also in between that of obese ob/ob and wild-type mice (37.5 +/- 21.4 versus 25.1 +/- 14.6 versus 59.6 +/- 17.3 mumol/min/kg/nmol of insulin, respectively; P < 0.05 wild-type versus obese ob/ob mice). Leptin infusion acutely enhanced both hepatic insulin sensitivity (insulin-induced inhibition of HGP) and insulin-mediated GD (9.1 +/- 2.4 versus 5.0 +/- 2.7%/nmol of insulin, and 25.6 +/- 5.6 versus 13.6 +/- 4.8 mumol/min/kg/nmol of insulin, respectively; P < 0.05 for both comparisons) in ob/ob mice. Both a lack of leptin signals and adiposity may contribute to insulin resistance in obese individuals. Diminution of central leptin signalling can critically affect glucose metabolism in these individuals. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Fatty Acids, Nonesterified; Female; Food Deprivation; Glucose; Glucose Clamp Technique; Growth and Development; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Obesity | 2008 |
Comparison of the effect of an H(3)-inverse agonist on energy intake and hypothalamic histamine release in normal mice and leptin resistant mice with high fat diet-induced obesity.
Leptin is a key signal linking peripheral adiposity levels to the regulation of energy homeostasis in the brain. The injection of leptin decreases body weight and food intake in lean rodents; however, in a rodent model of high fat diet-induced obesity (DIO), the exogenous leptin cannot improve adiposity. This ineffectiveness is known as leptin resistance, and the factors downstream of leptin signaling have received attention as viable targets in the treatment of obesity. We previously reported that the histaminergic system is one of the targets of leptin. In the present study, the effect of an H(3)-receptor inverse agonist on hypothalamic histamine release and energy intake was investigated in normal and DIO mice. Leptin (1.3 mg/kg, i.p.) significantly increased hypothalamic histamine release and reduced 12 h-energy intake in normal mice, but had no such effects in DIO mice. In contrast, clobenpropit (5 mg/kg, i.p.), an H(3)-inverse agonist, elicited a significant increase in histamine release in both types of mice. Clobenpropit did not reduce 12 h-energy intake; however, it decreased 3 h-energy intake in both types of mice. These results suggest that lack of the activation of the histaminergic system partly contributes to obesity in DIO mice and direct activation of the histaminergic system circumvents leptin resistance. Topics: Analysis of Variance; Animals; Behavior, Animal; Body Weight; Chromatography, High Pressure Liquid; Electrochemistry; Energy Intake; Fats; Histamine; Histamine H3 Antagonists; Hypothalamus; Imidazoles; Leptin; Male; Mice; Mice, Inbred C57BL; Microdialysis; Obesity; Thiourea; Time Factors | 2008 |
Food deprivation-induced changes in body fat mobilization after neonatal monosodium glutamate treatment.
The reversal of obesity is a difficult feat at best and is a growing problem as the obesity epidemic increases worldwide. Considerable focus has been made on the arcuate nucleus (Arc) in the control of body and lipid mass and food intake. To test the role of the Arc in body fat mobilization, we compared the effects of food deprivation on white adipose tissue (WAT) mass in adult Siberian hamsters by making exocytotic lesions of the Arc via neonatal subcutaneous injections of monosodium glutamate (MSG). MSG-treated hamsters had significantly increased body mass, total and individual WAT pad masses, and serum leptin concentrations compared with their vehicle-injected counterparts. MSG produced marked reductions in Arc Nissl staining, tyrosine hydroxylase-immunoreactive (ir) neurons, and neuropeptide Y (NPY)- and agouti-related protein (AgRP)-ir fibers compared with controls. MSG significantly decreased hypothalamic paraventricular nucleus (PVN) NPY- and AgRP fiber-ir compared with controls, likely because of Arc projections to this nucleus. MSG treatment also reduced area postrema (AP) tyrosine hydroxylase (TH)-ir fibers compared with controls. MSG treatment did not, however, block food deprivation-induced decreases in WAT pad mass compared with controls. Thus, despite considerable damage to the Arc and some of its projections to the PVN, as well as the AP, body fat was mobilized apparently normally, bringing into question the necessity of these structures for food deprivation-induced lipid mobilization. These data support recent evidence that chronically decerebrate rats, in which the forebrain is surgically isolated from the caudal brainstem, show normal food deprivation responses, including lipid mobilization. Topics: Adipose Tissue; Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Area Postrema; Body Weight; Catecholamines; Cell Count; Cricetinae; Eating; Energy Metabolism; Female; Food Additives; Food Deprivation; Immunohistochemistry; Leptin; Lipid Metabolism; Neuropeptides; Paraventricular Hypothalamic Nucleus; Phodopus; Sodium Glutamate | 2008 |
Leptin-mediated hypothalamic pathway of cholecystokinin (CCK-8) to regulate body weight in free-feeding rats.
Regulation of body weight (BW) results from the interplay between different hormonal systems acting at central and peripheral level. This study aims at characterizing the involvement of cholecystokinin (CCK) in BW and energy balance regulation. We have characterized, in free-feeding rats, the effect of CCK-8 on 1) food intake, BW, and adiposity; 2) skeletal muscle metabolism; 3) leptin signaling pathway within the arcuate nucleus of the hypothalamus; and 4) the permeability of brain barriers to leptin. We demonstrate here that CCK-8 acutely decreases BW by a mechanism partially dependent on central leptin pathways, based on the following results: 1) the effect of CCK was less intense in rats lacking functional leptin receptors (Zucker fa/fa), 2) CCK-8 facilitated the uptake of leptin from peripheral circulation to cerebrospinal fluid (CSF), 3) the concentration of leptin in CSF of rats receiving CCK was more elevated in those animals showing higher loss of BW, and 4) CCK activated leptin signaling pathways within the hypothalamus as well as phosphorylation of AMP-activated protein kinase in skeletal muscle. We also suggest that gain of BW may be linked to individual susceptibility to the effect of CCK, because we observed that in animals treated with this hormone, the increase of BW negatively correlated with leptin concentration within the CSF. Our data show that CCK has a negative impact on energy balance and suggest that CCK facilitates the access of leptin to hypothalamic areas, thus allowing leptin to act on hypothalamic targets involved in BW control. Topics: Acetyl-CoA Carboxylase; Adipose Tissue; Adiposity; AMP-Activated Protein Kinases; Animals; Body Weight; Eating; Hypothalamus; Leptin; Male; Multienzyme Complexes; Muscle, Skeletal; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Sincalide; STAT3 Transcription Factor | 2008 |
Adipose-specific disruption of signal transducer and activator of transcription 3 increases body weight and adiposity.
To determine the role of STAT3 in adipose tissue, we used Cre-loxP DNA recombination to create mice with an adipocyte-specific disruption of the STAT3 gene (ASKO mice). aP2-Cre-driven disappearance of STAT3 expression occurred on d 6 of adipogenesis, a time point when preadipocytes have already undergone conversion to adipocytes. Thus, this knockout model examined the role of STAT3 in mature but not differentiating adipocytes. Beginning at 9 wk of age, ASKO mice weighed more than their littermate controls and had increased adipose tissue mass, associated with adipocyte hypertrophy, but not adipocyte hyperplasia, hyperphagia, or reduced energy expenditure. Leptin-induced, but not isoproterenol-induced, lipolysis was impaired in ASKO adipocytes, which may partially explain the increased cell size. Despite reduced adiponectin and increased liver triacylglycerol, ASKO mice displayed normal glucose tolerance. Overall, these findings demonstrate that adipocyte STAT3 regulates body weight homeostasis in part through direct effects of leptin on adipocytes. Topics: Adipocytes; Adiposity; Animals; Body Weight; Eating; Energy Metabolism; Female; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction; STAT3 Transcription Factor; Triglycerides | 2008 |
Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons.
Leptin is a fat-derived hormone that exerts pleiotropic effects on energy balance and neuroendocrine functions. Mice defective in leptin or its receptor [leptin receptor, isoform b (LepRb)] exhibit profound obesity, infertility, and reduced linear growth. Leptin binding to its receptor triggers multiple signaling pathways, including signal transducer and activator of transcription 3 (Stat 3), phosphatidylinositol-3-kinase, and ERK. A considerable amount of effort has been focused on how these signaling pathways mediate diverse leptin functions. Mice containing a mutant LepRb incapable of Stat3 signaling are obese but remain fertile with enhanced linear growth. In contrast, deletion of Stat3 in the whole brain with Nestin-Cre results in infertility and decreased linear growth, in addition to obesity. The additional phenotypes of the Nestin-mediated deletion could reflect Stat3 action in non-LepRb neurons or leptin-independent Stat3 actions in LepRb neurons. To resolve this discrepancy and to gain more insight into the metabolic actions of Stat3, we have generated mice in which Stat3 is disrupted specifically in LepRb neurons after the onset of leptin receptor expression. We show that mutant mice exhibit profound obesity with increased linear growth and normal fertility. In addition, impaired glycemic control in these animals correlates with their degree of obesity. These results demonstrate that Stat3 in LepRb neurons does not regulate linear growth or fertility. These results further suggest that leptin's effects on growth and reproduction are mediated by other signaling pathways, and that Stat3-mediated control of these functions is mediated independently of leptin and LepRb neurons. Topics: Agouti-Related Protein; Animals; Blood Glucose; Body Weight; Eating; Female; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; Neurons; Neuropeptide Y; Phosphorylation; Pro-Opiomelanocortin; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; STAT3 Transcription Factor | 2008 |
Intracerebroventricular administration of soy protein hydrolysates reduces body weight without affecting food intake in rats.
Some studies suggest that increased consumption of soy protein hydrolysates may cause body weight loss but the mechanism of action is unknown. The objective of this investigation was to determine whether intracerebroventricular (i.c.v.) infusion of soy protein hydrolysates decrease food intake and body weight. Adult male Sprague Dawley rats (n = 24) received i.c.v. injections of soy hydrolysate I (SH I) or soy hydrolysate II (SH II) three times weekly for 2 weeks. Krebs solution and leptin were used as negative and positive controls respectively. SH I (6.5-20 kDa with a strong band at 14 kDa) was produced by hydrolysis with alcalase, and SH II (approximately 2 kDa) was obtained by hydrolysis and ultrafiltration. Leptin successfully reduced body weight (-1.60 g) 24 h (p = 0.0093) after the third injection. SH I caused significant (p = 0.0009) decreases in body weight (-1.70 g) 24 h after the third injection but not after 48 h. SH II showed a tendency to prevent body weight gain but this effect was short of statistical significance (p < 0.40). Food intake was not affected by any of the soy hydrolysate treatments but leptin injection did cause significant decreases in food intake (p < 0.05). Data suggest that soy alcalase hydrolysate can decrease, in the short term, the rate of body weight gain independently of food consumption. This preliminary data show that soy peptides may play a role on body weight regulation, possibly by increasing energy utilization. Topics: Animals; Body Weight; Brain; Cross-Over Studies; Energy Intake; Energy Metabolism; Injections, Intraventricular; Leptin; Male; Obesity; Protein Hydrolysates; Random Allocation; Rats; Rats, Sprague-Dawley; Soybean Proteins; Time Factors; Weight Loss | 2008 |
Endothelial dysfunction and the development of renal injury in spontaneously hypertensive rats fed a high-fat diet.
Obesity and hypertension have been identified as cardiovascular risk factors that contribute to the progression of end-stage renal disease. To examine the mechanisms by which a high-fat diet and hypertension contribute to endothelial dysfunction and renal injury, 8-week-old male spontaneously hypertensive rats and Wistar rats were fed a high-fat (36% fat) or a normal-fat (7% fat) diet for 10 weeks. The high-fat diet increased body weight in Wistar and hypertensive rats by 25 and 31 g, respectively. Systolic blood pressure was higher in the hypertensive rats compared with Wistar rats; however, blood pressure was unaltered by the high-fat diet. Afferent arteriole response to acetylcholine was impaired in the high-fat groups after just 3 weeks. Renal macrophage infiltration was increased in the hypertensive high-fat group compared with others, and monocyte chemoattractant protein-1 excretion was increased in both of the high-fat-fed groups. Renal PCR arrays displayed significant increases in 2 inflammatory genes in hypertensive rats fed a normal diet, 1 gene was increased in high-fat-fed Wistar rats, whereas 12 genes were increased in high-fat-fed hypertensive rats. Urinary albumin excretion was increased in the hypertensive rats compared with the Wistar rats, which was further exacerbated by the high-fat diet. Glomerular nephrin expression was reduced and desmin was increased by the high-fat diet in the hypertensive rats. Our results indicate that endothelial dysfunction precedes renal injury in normotensive and spontaneously hypertensive rats fed a high-fat diet, and hypertension with obesity induces a powerful inflammatory response and disruption of the renal filtration barrier. Topics: Albuminuria; Animals; Arterioles; Biomarkers; Blood Glucose; Blood Pressure; Body Weight; Chemokine CCL2; Cholesterol; Cytokines; Dietary Fats; Dose-Response Relationship, Drug; Endothelium, Vascular; Gene Expression Profiling; Inflammation; Inflammation Mediators; Insulin Resistance; Kidney; Kidney Cortex; Leptin; Macrophages; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, CCR1; RNA, Messenger | 2008 |
PYY transgenic mice are protected against diet-induced and genetic obesity.
The gut-derived hormone, peptide YY (PYY) reduces food intake and enhances satiety in both humans and animals. Obese individuals also have a deficiency in circulating peptide YY, although whether this is a cause or a consequence of obesity is unclear. Our aims were to determine whether peptide YY (PYY) over-expression may have therapeutic effects for the treatment of obesity by altering energy balance and glucose homeostasis. We generated PYY transgenic mice and measured body weight, food intake, temperature, adiposity, glucose tolerance, circulating hormone and lipid concentrations and hypothalamic neuropeptide levels (neuropeptide Y; proopiomelanocortin, and thyrotropin-releasing hormone) under chow and high-fat feeding and after crossing these mice onto the genetically obese leptin-deficient ob/ob mouse background. PYY transgenic mice were protected against diet-induced obesity in association with increased body temperature (indicative of increased thermogenesis) and sustained expression of thyrotropin-releasing hormone in the paraventricular nucleus of the hypothalamus. Moreover, PYY transgenic mice crossed onto the genetically obese ob/ob background had significantly decreased weight gain and adiposity, reduced serum triglyceride levels and improved glucose tolerance compared to ob/ob controls. There was no effect of PYY transgenic over expression on basal or fasting-induced food intake measured at 11-12 weeks of age. Together, these findings suggest that long-term administration of PYY, PYY-like compounds or agents that stimulate PYY synthesis in vivo can reduce excess adiposity and improve glucose tolerance, possibly via effects on the hypothalamo-pituitary-thyroid axis and thermogenesis. Topics: Adiposity; Animals; Body Weight; Diet; Eating; Energy Metabolism; Glucose; Glucose Tolerance Test; Homeostasis; Hypothalamo-Hypophyseal System; In Situ Hybridization; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Paraventricular Hypothalamic Nucleus; Peptide YY; Reverse Transcriptase Polymerase Chain Reaction; Thermogenesis; Thyroid Gland; Thyrotropin | 2008 |
Disruption of the RIIbeta subunit of PKA reverses the obesity syndrome of Agouti lethal yellow mice.
Agouti lethal yellow (A(y)) mice express agouti ectopically because of a genetic rearrangement at the agouti locus. The agouti peptide is a potent antagonist of the melanocortin 4 receptor (MC4R) expressed in neurons, and this leads to hyperphagia, hypoactivity, and increased fat mass. The MC4R signals through Gs and is thought to stimulate the production of cAMP and activation of downstream cAMP effector molecules such as PKA. Disruption of the RIIbeta regulatory subunit gene of PKA results in release of the active catalytic subunit and an increase in basal PKA activity in cells where RIIbeta is highly expressed. Because RIIbeta is expressed in neurons including those in the hypothalamic nuclei where MC4R is prominent we tested the possibility that the RIIbeta knockout might rescue the body weight phenotypes of the A(y) mice. Disruption of the RIIbeta PKA regulatory subunit gene in mice leads to a 50% reduction in white adipose tissue and resistance to diet-induced obesity and hyperglycemia. The RIIbeta mutation rescued the elevated body weight, hyperphagia, and obesity of A(y) mice. Partial rescue of the A(y) phenotypes was even observed on an RIIbeta heterozygote background. These results suggest that the RIIbeta gene mutation alters adiposity and locomotor activity by modifying PKA signaling pathways downstream of the agouti antagonism of MC4R in the hypothalamus. Topics: Adipose Tissue; Animals; Body Weight; Cyclic AMP-Dependent Protein Kinase Type II; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Gene Expression Regulation; Heterozygote; Hypothalamus; Leptin; Mice; Mice, Knockout; Models, Biological; Motor Activity; Obesity; Phenotype; Receptor, Melanocortin, Type 4 | 2008 |
Gender-dependent differences in serum profiles of insulin and leptin in caloric restricted rats.
In the present study, we have investigated whether differences between male and female rats described in response to 40% caloric restriction (CR) were influenced by circulating level variations of sex hormones and/or insulin and leptin. Body weights (BW), organ weights, and adipose depot weights (ADW) were also measured. The most affected tissues by CR were the fat depots. Metabolically active organs were the least affected, especially more in females than in males (male weight lost: 24.3% vs. female: 17.3%). Testosterone and estradiol circulating levels did not show changes by CR. Insulin levels were decreased by CR in both genders, but was more evident in female rats than males. Leptin serum levels were higher in male rats than in females, and CR caused a circulating leptin level reduction only in males. In conclusion, our results indicate that leptin and insulin could be one of the keys of the different hormonal control of energy homeostasis in response to CR between female and male rats. In this sense, leptin serum levels correlated statistically with BW and with individual ADW only in male rats, whereas insulin serum levels correlated statistically with BW and with any of the ADW studied only in females. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Caloric Restriction; Female; Insulin; Leptin; Male; Organ Size; Rats; Rats, Wistar; Sex Characteristics | 2008 |
Visceral fat and total body fat mass correlate differently with hormones in rat.
Forty-eight 67-day-old male Wistar rats (330+/-5g) were fed ad libitum either with a lipid enriched diet or a standard laboratory chow. Half of each sub-group was submitted to training. Training and difference in diet composition induced nonsignificant changes in body adiposity. Visceral fat (perirenal adipose tissue mass) was correlated with leptin (r=0.35, p=0.02) and insulin (r=0.38, p=0.01). Total body fat mass (measured by DEXA) was correlated with leptin only (r=0.58, p=0.003). Other correlations between perirenal adipose tissue or fat mass and adiponectin or insulin like growth factor 1 were nonsignificant. These results suggest that, in rat like in human, visceral fat development is linked with insulin insensitivity. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Dietary Fats; Hyperlipidemias; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intra-Abdominal Fat; Leptin; Male; Organ Size; Physical Conditioning, Animal; Rats; Rats, Wistar | 2008 |
Differential long-term dietary regulation of adipokines, ghrelin, or corticosterone: impact on adiposity.
In the present experiment, we examined in Long-Evans rats the long-term effects of diets that differed in the energy provided by proteins (P) and fats (F) but provided a constant level of energy from carbohydrates (55%) on various hormones regulating feeding and metabolism. Sixty adult rats were fed for 2 months either a high-fat (protein-to-fat, PF 5/40), a control (PF 15/30), low-fat (PF 30/15), or high-protein (PF 40/5) diet ad libitum. Both the PF 30/15 and the PF 40/5 rats ate significantly less than their PF 5/40 and PF 15/30 counterparts throughout the experiment (P<0.001). PF 40/5 rats weighed less than PF 15/30 rats (PL=0.04). PF 40/5 and PF 30/15 rats had smaller epididymal and perirenal adipose tissue depots than PF 5/40 and PF 15/30 rats (P<0.05 or less). Adiponectin (+25-47%) and leptin levels in the PF 5/40 rats were higher than in the three other groups (P<0.0025 or less). Ghrelin concentration in the PF 30/15 group was also higher than in the three other groups (P<0.001 versus PF 5/40; P<0.05 versus PF 15/30 and PF 40/5). Corticosterone level was 2- to 2.5-fold higher in PF 40/5 rats than in the three other groups (P<0.01 or less). Immunoreactive insulin was not different between the four groups. Our current findings thus show that increases in the protein content resulted in a greater degree of leanness, but at sufficiently high levels, also activated the hypothalamo-pituitary axis. Ghrelin appeared to be down-regulated by increases in fat content and no obvious signs of insulin resistance were observed in any of the rats under study. Topics: Adipokines; Adiponectin; Adiposity; Animals; Blood Glucose; Body Weight; Corticosterone; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; Ghrelin; Homeostasis; Insulin; Leptin; Male; Rats; Rats, Long-Evans; Triglycerides | 2008 |
Effect of angiotensin converting enzyme inhibitor enalapril on body weight and composition in young rats.
Obesity is considered a worldwide public health problem showing an increased prevalence in developing countries, with urgent need for new and more efficient drugs and therapies. Enalapril, an angiotensin-I converting enzyme inhibitor (ACEi), is classically used in anti-hypertensive therapies, however, earlier publications have shown that this drug could also have significant impact on body weight in rats as well as in humans, besides reducing blood pressure. The effect of this drug in the white adipose tissue has been neglected for long time, even considering that most components of the renin-angiotensin and kallikrein-kinin system are expressed in this tissue. Furthermore, the adipose tissue is considered today as one of the most important sites for endocrine/inflammatory regulation of appetite and energy output and AngII has been linked to the metabolism in this tissue. Therefore, we analyzed the influence of chronic enalapril treatment in normotensive rats at earlier ages, evaluating body weight, energy homeostasis, lipid profile and serum levels of the hormones leptin and insulin, in the presence of a standard or a palatable hyperlipidic diet regimen for one month. Our results show that enalapril treatment is able to reduce body fat on both diets, without alteration in serum lipid profile. Furthermore, animals receiving enalapril showed reduction in food intake, leptin level and energy intake. In summary, these findings show for the first time that the ACEi enalapril reduces body fat in young normotensive rats and highlights a novel target to treat obesity and associated diseases. Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Body Composition; Body Weight; Enalapril; Energy Intake; Leptin; Lipids; Rats; Rats, Wistar | 2008 |
Thyroid function and body weight programming by neonatal hyperthyroidism in rats - the role of leptin and deiodinase activities.
Several authors have shown that secondary hypothyroidism was programed by neonatal thyroxine (T4) treatment. However, the associated changes of body weight (BW) were less studied, especially those related to the body fat proportion. Here, we have evaluated the effect of neonatal thyroxine treatment on BW, fat proportion, serum leptin, and thyroid function of 60-day-old rats. Wistar rats were treated with thyroxine (50 microg/100 g BW, ip) (T) or saline (S), during the first 10 days of life. BW, nose-rump length (NRL), and food consumption were monitored for 60 days, when the animals were sacrificed. Thyroid function was evaluated by thyroid radioiodine uptake (RAIU), serum T3, T4, TSH, and liver mitochondrial alpha-glycerophosphate dehydrogenase (mGPD) and type 1 and 2 deiodinases (D1 and D2) activities, which are thyroid hormone-dependent enzymes. T animals showed lower food intake, BW and NRL, but higher total fat mass (+33%) and serum leptin (+46%). They also showed lower serum T3 (-23%), T4 (-32%), TSH (-36%), RAIU (-29%) and mGPD activity (-22%). Hypothalamic and pituitary D2 activities were higher (+24% and 1.4 fold, respectively), while brown adipose tissue (BAT) D2 and skeletal muscle D1 activities were lower (-30% and -62%, respectively). Thus, neonatal hyperthyroidism programs for a higher fat proportion and hyperleptinemia, which can explain the lower food intake. The TH-dependent enzymes activities changed accordingly, except for the decrease in BAT D2, which may be due the role played by the hyperleptinemia. Finally, the decrease in peripheral deiodination may contribute to a lower me-tabolic rate that may increase the adiposity. Topics: Adipose Tissue; Animals; Animals, Newborn; Body Weight; Female; Glycerolphosphate Dehydrogenase; Hyperthyroidism; Iodide Peroxidase; Lactation; Leptin; Male; Mitochondria, Liver; Muscles; Pituitary Gland; Rats; Rats, Wistar; Thyroid Function Tests; Thyrotropin; Thyroxine; Triiodothyronine | 2008 |
Seasonal adiposity, correlative changes in metabolic factors and unique reproductive activity in a vespertilionid bat, Scotophilus heathi.
The aim of this study was to determine the effect of changes in body mass, fat reserves and feeding activity on circulating levels of lipids, glucose, protein and metabolic hormones in a vespertilionid bat, Scotophilus heathi. Furthermore, the relationship between changes in metabolic factors and hormones with the unique reproductive features of female S. heathi was also examined. The results of this study showed annual variation in body mass, fat reserve and feeding activity, which correlated significantly with circulating levels of lipids, protein and metabolic hormones. Increased corticosterone level during September-October in S. heathi promotes increased feeding activity, which in turn induces hyperinsulinemia in S. heathi during November. Hyperinsulinemia together with low body temperature in November facilitates fat accumulation in bat. Coinciding with the period of fat accumulation raises serum leptin level, which has been demonstrated to suppress ovarian activities thus causing delayed ovulation in S. heathi. Circulating levels of lipids were high during winter dormancy, which may provide energy to stored sperms. The study thus suggests that the unique reproductive features of female vespertilionid bat are strongly linked to fat deposition. Topics: Adiposity; Animals; Blood Glucose; Blood Proteins; Body Temperature; Body Weight; Chiroptera; Energy Metabolism; Feeding Behavior; Female; Glycogen; Insecta; Insulin; Leptin; Lipids; Reproduction; Seasons; Thyroid Hormones; Urea | 2008 |
Green tea extract protects leptin-deficient, spontaneously obese mice from hepatic steatosis and injury.
The incidence of nonalcoholic fatty liver disease (NAFLD) has risen along with the ongoing obesity epidemic. Green tea extract (GTE) inhibits intestinal lipid absorption and may regulate hepatic lipid accumulation. The objective of this study was to determine whether GTE protects against hepatic lipid accumulation during the development of NAFLD in an obese mouse model. Five-wk-old ob/ob (obese) mice and their lean littermates (8 mice x genotype(-1) x dietary treatment(-1)) were fed GTE at 0, 1, or 2% (wt:wt) for 6 wk. The body weights of obese mice and lean littermates fed diets containing GTE were 23-25% and 11-20% lower (P < 0.05) than their respective controls fed no GTE. Histologic evaluation showed a significant reduction in hepatic steatosis in GTE-fed obese mice only and histologic scores were correlated with hepatic lipid concentration (r = 0.84; P < 0.05), which was reduced dose dependently by GTE. GTE protected against hepatic injury as suggested by 30-41% and 22-33% lower serum alanine aminotransferase and aspartate aminotransferase activities, respectively. Hepatic alpha-tocopherol was 36% higher in obese mice than lean mice. GTE tended (P = 0.06) to lower hepatic alpha-tocopherol, which was not fully explained by the GTE-mediated reduction in hepatic lipid. Hepatic ascorbic acid was lower in obese mice than in lean mice (P < 0.05) and was unaltered by GTE. Obese mice had lower serum adiponectin than lean mice and this was not affected by GTE. The results suggest that GTE protects against NAFLD by limiting hepatic lipid accumulation and injury without affecting hepatic antioxidant status and adiponectin-mediated lipid metabolism. Further study is underway to define the events by which GTE protects against obesity-triggered NAFLD. Topics: Adiponectin; Aging; Animals; Antioxidants; Biomarkers; Body Weight; Camellia sinensis; Dose-Response Relationship, Drug; Eating; Energy Intake; Fatty Liver; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Plant Extracts | 2008 |
Diurnal profiles of hypothalamic energy balance gene expression with photoperiod manipulation in the Siberian hamster, Phodopus sungorus.
Hypothalamic energy balance genes have been examined in the context of seasonal body weight regulation in the Siberian hamster. Most of these long photoperiod (LD)/short photoperiod (SD) comparisons have been of tissues collected at a single point in the light-dark cycle. We examined the diurnal expression profile of hypothalamic genes in hamsters killed at 3-h intervals throughout the light-dark cycle after housing in LD or SD for 12 wk. Gene expression of neuropeptide Y, agouti-related peptide, proopiomelanocortin, cocaine- and amphetamine-regulated transcript, long-form leptin receptor, suppressor of cytokine signaling-3, melanocortin-3 receptor, melanocortin-4 receptor, and the clock gene Per1 as control were measured by in situ hybridization in hypothalamic nuclei. Effects of photoperiod on gene expression and leptin levels were generally consistent with previous reports. A clear diurnal variation was observed for Per1 in the suprachiasmatic nucleus in both photoperiods. Temporal effects on expression of energy balance genes were restricted to long-form leptin receptor in the arcuate nucleus and ventromedial nucleus, where similar diurnal expression profiles were observed, and melanocortin-4 receptor in the paraventricular nucleus; these effects were only observed in LD hamsters. There was no variation in serum leptin concentration. The 24-h profiles of hypothalamic energy balance gene expression broadly confirm photoperiodic differences that were observed previously, based on single time point comparisons, support the growing consensus that these genes have a limited role in seasonal body weight regulation, and further suggest limited involvement in daily rhythms of food intake. Topics: Animals; Body Weight; Circadian Rhythm; Cricetinae; Eating; Energy Metabolism; Gene Expression Regulation; Hypothalamus; Leptin; Male; Nerve Tissue Proteins; Neuropeptides; Nuclear Proteins; Phodopus; Photoperiod; Receptors, Cell Surface; RNA, Messenger; Seasons; Suppressor of Cytokine Signaling Proteins; Suprachiasmatic Nucleus | 2008 |
Atherogenecity of LDL and unfavorable adipokine profile in metabolically obese, normal-weight woman.
The relationship of visceral adiposity with adipocytokines and low-density lipoprotein (LDL) particle distribution and oxidation in Asian metabolically obese, normal-weight (MONW) individuals has not been evaluated. We aimed to investigate the association between visceral adiposity and adipocytokines and cardiovascular disease (CVD) risk factors in MONW Korean women with normal glucose tolerance.. We examined the metabolic characteristics of 135 non-obese (BMI <25 kg/m(2)) women aged 25-64 years. Twenty-five women (BMI <25 kg/m(2) and visceral fat adiposity (VFA) > or =100 cm(2)) were classified as MONW and 25 women (BMI <25 kg/m(2) and VFA <100 cm(2)), pair-matched for age, weight, height, and menopausal status, as control group. Plasma lipid profiles and adipocytokines were evaluated in these two groups.. MONW subjects had higher systolic (P < 0.05) and diastolic blood pressure (P < 0.005) and higher concentrations of triacylglycerol (TG) (P < 0.005), insulin (P < 0.01), and free fatty acid (FFA) (P < 0.05) than control subjects. There was no significant difference between two groups in LDL-cholesterol (LDL-C) concentrations; however, MONW subjects had smaller LDL particles (P < 0.01) and higher concentrations of oxidized LDL (ox-LDL) (P < 0.05) compared with controls. Moreover, MONW subjects had higher concentrations of tumor necrosis factor-alpha (TNF-alpha) (P < 0.05), interleukin-6 (IL-6) (P < 0.05) and leptin (P < 0.05), and lower plasma adiponectin concentrations (P < 0.05). Higher intake of saturated fat with lower ratio of polyunsaturated fatty acids (PUFAs) to saturated fatty acids (SFA) and lower fiber intake than normal subjects were found in MONW women.. We found an unfavorable inflammatory profile and a more atherogenic LDL profile in MONW female subjects even in the absence of a known CVD risk factors. Moreover, MONW consumed more saturated fat and less fiber than the control group. Topics: Adiponectin; Adult; Atherosclerosis; Blood Pressure; Body Weight; Cholesterol, LDL; Energy Intake; Fatty Acids, Nonesterified; Fatty Acids, Unsaturated; Female; Humans; Insulin; Intra-Abdominal Fat; Leptin; Lipoproteins, LDL; Middle Aged; Obesity; Particle Size; Risk Factors; Triglycerides | 2008 |
Keishibukuryogan ameliorates glucose intolerance and hyperlipidemia in Otsuka Long-Evans Tokushima Fatty (OLETF) rats.
Keishibukuryogan, one of the traditional herbal formulations, is used clinically to improve blood circulation. In this study, we examined the effects of keishibukuryogan on glucose and lipids metabolism in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. Forty-five-week-old male OLETF rats were divided into three groups: diabetic control rats given a standard chow; diabetic rats given keishibukuryogan (3%, w/w in chow); diabetic rats given pioglitazone (0.01%, w/w in chow). Oral administration of keishibukuryogan produced significant improvement against impaired glucose tolerance. On the other hand, fasting serum glucose and insulin levels, and the homeostasis index of insulin resistance did not change by keishibukuryogan treatment. Against lipid parameters, keishibukuryogan significantly lowered serum total cholesterol and triglyceride levels, and the hepatic total cholesterol level. Keishibukuryogan treatment also significantly reduced the serum leptin level, but it had no effect on the serum adiponectin level. Additionally, keishibukuryogan showed significant effects on epididymal adipose tissue by decreasing the size of fat cells and on skeletal muscle by reducing TNF-alpha protein content. From these results, it was suggested that keishibukuryogan exerts beneficial effects on the features associated with type 2 diabetes. Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Hyperlipidemias; Hypoglycemic Agents; Insulin; Leptin; Lipid Metabolism; Male; Organ Size; Phytotherapy; Pioglitazone; Rats; Rats, Inbred OLETF; Thiazolidinediones; Tumor Necrosis Factor-alpha | 2008 |
Gender-based dimorphic pattern for interleukin-1 receptor antagonist in type 2 diabetes mellitus.
Adipose tissue secretes a variety of cytokines, some of which are increased in the serum of obese patients. The anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) is the most highly elevated known cytokine in human obesity, and its serum levels are strongly associated with the degree of insulin resistance in non-diabetic patients.. The present study examined serum levels of IL-1Ra in type 2 diabetic patients (T2DM) and their relationships with three other adipokines (leptin, interleukin-6 [IL-6], adiponectin). Their correlation with anthropometric and biochemical variables was examined, as well as their intraindividual fluctuations.. Fifty T2DM patients, aged 58+/-13 years, were consecutively recruited among those electively hospitalized for a one-week intensive training course with our Diabetes Education Service. Anthropometric measurements and blood samples were taken after an overnight fast on admission (baseline) and after four days.. Mean serum levels of IL-1Ra and leptin, but not of IL-6 and adiponectin, were significantly higher in women than in men (P<0.0006), and this difference persisted after correction for body mass index (BMI) (P<0.0004). In addition, IL-1Ra and leptin were strongly correlated with the BMI (P<0.0004). By contrast, no significant correlations were observed between IL-1Ra and glucose-control parameters. Finally, all four adipokines exhibited wide interindividual variability, but with limited intraindividual fluctuations over the short time period.. IL-1Ra, leptin and adiponectin serum levels exhibit marked interindividual variation with high intraindividual consistency. A gender-based dimorphic pattern for IL-1Ra, independent of the degree of adiposity and glucose control, was also found. Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Body Weight; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Interleukin 1 Receptor Antagonist Protein; Leptin; Male; Middle Aged; Patient Selection; Sex Characteristics | 2008 |
A role for leptin in sustaining lymphopoiesis and myelopoiesis.
Although leptin is known for its regulation of food intake, it has many emerging roles in immune function. To better define the role of leptin in hematopoietic processes, a leptin-deficient obese mouse (ob/ob) and C57BL/6 lean wild-type controls were compared. Despite their large size and consumption of substantial amounts of nutrients, the ob/ob mice had only 60% as many nucleated cells in their marrow as controls. The greatest impact of leptin deficiency was on the B cell compartment that had 70% fewer cells, reducing the absolute number of pre-B and immature B cells to 21% and 12% of normal, respectively, and indicating a significant reduction in lymphopoiesis in ob/ob mice. Whereas the proportion of myeloids remained nearly normal in the obese mice, they also exhibited a reduction of 40% and 25%, respectively, in absolute numbers of granulocytes and monocytes. Seven days of provision of recombinant leptin promoted substantial lymphopoiesis, increasing the numbers of B cells in the marrow of the obese mice twofold, while doubling and tripling, respectively, the numbers of pre-B and immature B cells. Twelve days of supplementation brought these subpopulations to near-normal proportions. Leptin treatment also facilitated myelopoiesis such that the marrow of the obese mice contained normal numbers of monocytes and granulocytes after 7 days. Taken together, the data support an important role for leptin in sustaining lymphopoiesis and myelopoiesis. Topics: Animals; Body Weight; Feeding Behavior; Hematopoiesis; Leptin; Mice; Mice, Inbred C57BL; Obesity | 2008 |
AMPK and ACC phosphorylation: effect of leptin, muscle fibre type and obesity.
Leptin stimulates fatty acid oxidation via the phosphorylation of AMPK (AMP-activated protein kinase) and ACC (acetyl-CoA carboxylase). Obesity is associated with resistance to the effects of leptin. We determined the action of leptin on AMPKalpha and ACCbeta phosphorylation and lipid metabolism in soleus (SOL) and extensor digitorum longus (EDL) muscles from lean and obese Wistar rats after 1 and 100 nM leptin. Both leptin doses stimulated phosphorylation of AMPKalpha and ACCbeta (P Topics: Acetyl-CoA Carboxylase; Acyl Coenzyme A; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Body Weight; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Energy Metabolism; Enzyme Activation; Fatty Acids; Glycolysis; Humans; Insulin; Leptin; Male; Malonyl Coenzyme A; Multienzyme Complexes; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Oxidation-Reduction; Phosphorylation; Protein Serine-Threonine Kinases; Rats; Rats, Wistar | 2008 |
Reproducibility of serum leptin, insulin-like growth factor-I, and insulin-like growth factor-binding protein-3 measurements.
Many epidemiologic studies examine the effects of single measurements of hormones, including those related to obesity such as insulin-like growth factors (IGFs) or leptin, on disease associations; however, few studies have determined whether these single values accurately reflect measurements over time.. We examined the reproducibility of hormones associated with obesity, specifically leptin, IGF-I, and IGF-binding protein-3 (IGFBP-3). Two fasting blood samples, approximately four months apart, were collected from 38 participants from the Seattle metropolitan area; leptin, IGF-I, and IGFBP-3 concentrations were measured in previously unthawed serum samples. Unadjusted and adjusted intraclass correlation coefficients (ICC) were calculated to assess reproducibility.. Adjusting for age and sex, the ICCs for leptin, IGF-I, and IGFBP-3 were 0.73, 0.83 and 0.60, respectively. Weighted kappas yielded similar results.. These data suggest that for leptin, IGF-I, and IGFBP-3, a single fasting serum measurement can fairly reliably reflect the hormonal milieu over periods of months. Topics: Adult; Body Weight; Fasting; Female; Follow-Up Studies; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Randomized Controlled Trials as Topic; Reproducibility of Results; Research Design | 2008 |
Plasma obestatin levels in normal weight, obese and anorectic women.
Obestatin is a recently discovered peptide produced in the stomach, which was originally described to suppress food intake and decrease body weight in experimental animals. We investigated fasting plasma obestatin levels in normal weight, obese and anorectic women and associations of plasma obestatin levels with anthropometric and hormonal parameters. Hormonal (obestatin, ghrelin, leptin, insulin) and anthropometric parameters and body composition were examined in 15 normal weight, 21 obese and 15 anorectic women. Fasting obestatin levels were significantly lower in obese than in normal weight and anorectic women, whereas ghrelin to obestatin ratio was increased in anorectic women. Compared to leptin, only minor differences in plasma obestatin levels were observed in women who greatly differed in the amount of fat stores. However, a negative correlation of fasting obestatin level with body fat indexes might suggest a certain role of obestatin in the regulation of energy homeostasis. A significant relationship between plasma obestatin and ghrelin levels, independent of anthropometric parameters, supports simultaneous secretion of both hormones from the common precursor. Lower plasma obestatin levels in obese women compared to normal weight and anorectic women as well as increased ghrelin to obestatin ratio in anorectic women might play a role in body weight regulation in these pathologies. Topics: Adult; Anorexia; Body Composition; Body Weight; Fasting; Female; Ghrelin; Humans; Insulin; Leptin; Middle Aged; Obesity; Waist-Hip Ratio | 2008 |
Food restriction and simulated microgravity: effects on bone and serum leptin.
Leptin is responsible for linking energy metabolism to bone mass. Because astronauts are commonly in negative energy balance during spaceflight, this study was designed to assess individual and combined effects of food restriction and simulated microgravity on bone mass and serum leptin. Six-month-old male Sprague-Dawley rats were randomly assigned to four groups (n = 12 each): two hindlimb-unloading (HU) groups fed 100% (HU100) and 70% (HU70) and two cage-activity control (CC) groups fed 100% (CC100) and 70% (CC70) of their baseline food requirement. After 28 days, CC100 rats gained body weight, whereas all other groups lost body weight; this loss was greater in HU70 than in CC70 and HU100 rats. Serum leptin decreased in CC70 and HU100 (-60% and -27%, respectively) and was not detectable in HU70 animals. Percent osteoid surface in CC70 and HU100 was lower than that of CC100 (7.80%, 8.60% vs. 10.70%, respectively), and this decrease was more pronounced in HU70 animals (4.38%). Mineral apposition rate of CC70, HU100, and HU70 rats was lower than that of CC100 (1.5, 1.6, and 1.5 vs. 2.1 mum/day, respectively). Bone formation rate of CC70, HU100, and HU70 rats was lower than that of CC100 (13.4, 13.1, and 12.2 vs. 40.8 mm(3).mm(-2).day(-1), respectively). The change in bone formation rate was correlated with the change in serum leptin value over 28 days (r(2) = 0.69, P = 0.0007). We conclude that moderate caloric restriction may cause bone loss at susceptible bone sites to a similar degree as does the unloading effect of microgravity; serum leptin may be an important endocrine regulator contributing to this change in skeletal integrity. Topics: Animals; Body Weight; Bone and Bones; Bone Density; Bone Development; Caloric Restriction; Eating; Enzyme-Linked Immunosorbent Assay; Femur; Humerus; Leptin; Male; Rats; Rats, Sprague-Dawley; Tibia; Tomography, X-Ray Computed; Weightlessness Simulation | 2008 |
Leptin-adiposity relationship changes, plus behavioral and parental factors, are involved in the development of body weight in a Dutch children cohort.
The development of body weight is determined by different factors, namely genetic, behavioral, parental and physiological.. To investigate whether genetic, behavioral, parental and physiological factors are involved and the extent of involvement in the development of body weight at ages 12 and 13 y in a Dutch children cohort.. In a Dutch cohort of 94 children at ages 12 and 13 y, we determined anthropometric measurements, body composition, leptin concentrations, TFEQ scores, physical activity, as well as 3 polymorphisms, and in the parents we determined anthropometric measurements and TFEQ scores.. 11% of the children in the cohort were classified as overweight. The genotype frequency distributions of the PPARy2, GRL and CNTF genes at ages 12 and 13 y were not significantly different for the overweight children compared to the lean children. Overweight children showed higher dietary restraint and disinhibition scores. Overweight children's parents had a higher BMI, dietary restraint and disinhibition scores, compared to lean children's parents. A peak in leptin concentrations between 7 and 13 y was shown at 12 y. In lean boys, the decrease in leptin concentrations between 12 and 13 y was related to an increase in fat free mass. At the age of 12 y predominantly the physiological factors were predictors for body weight, and at the age of 13 y both the physiological and behavioral factors were predictors for body weight.. We conclude from this longitudinal study, that leptin appeared to play an important role in the development of body weight during puberty, in addition to behavioral and parental factors. Topics: Adiposity; Adolescent; Analysis of Variance; Attitude; Body Composition; Body Weight; Child; Child Behavior; Child Development; Cohort Studies; Feeding Behavior; Female; Humans; Leptin; Male; Netherlands; Overweight; Parent-Child Relations; Retrospective Studies; Sex Factors | 2008 |
The effects of wintertime undernutrition on plasma leptin and insulin levels in an arctic ruminant, the reindeer.
We examined the effects of prolonged undernutrition on plasma leptin and insulin levels and some serum protein metabolites in reindeer (Rangifer tarandus tarandus L.) during winter and spring. The reindeer (male <1 year) were fed their preferred winter feed, low-protein lichen ad libitum for 5 weeks, followed by 40% restriction of energy for 8 weeks and refeeding with high-protein pellets for 6 weeks. The control group received high-protein reindeer pellets ad libitum throughout the experiment. Plasma leptin decreased by 46% and insulin by 54% in the lichen group already during the ad libitum period between January and February, with parallel decreases in body weight, serum total proteins, albumin and urea. Leptin remained low during most of the energy restriction period in March and April, but increased at the end of April while body weight decreased. During the refeeding period in May and June, the body weight and insulin of the lichen group increased in parallel with total proteins and urea, but leptin remained unchanged. Similar significant reductions in plasma leptin (40%) as in the lichen group also took place in the control group fed high-protein pellets ad libitum in January and February, although their feed intake, serum total proteins and body weight remained unchanged. The results show that leptin decreases in reindeer during mid-winter, independent of food or protein intake, and suggest that the decrease may be cued by seasonal factors such as the short photoperiod. Topics: Animals; Arctic Regions; Blood Glucose; Body Weight; Creatinine; Insulin; Leptin; Malnutrition; Photoperiod; Reindeer; Seasons; Serum Albumin; Time Factors; Urea | 2008 |
Large litter size increases maternal energy intake but has no effect on UCP1 content and serum-leptin concentrations in lactating Brandt's voles (Lasiopodomys brandtii).
Lactation is the most energetically demanding period in the female mammal's life. We measured maternal energy intake, uncoupling protein 1 (UCP1) content in brown adipose tissue (BAT), serum-leptin concentration, and litter growth in lactating Brandt's voles (Lasiopodomys brandtii) with different litter sizes. Litter mass was positively related to litter size but there was no difference in pup mass at birth. Maternal gross energy intake at peak lactation was positively correlated with litter size and litter mass. Maternal resting metabolic rate (RMR) was positively correlated with litter mass, but not with litter size. No significant differences were detected in body-fat mass, serum-leptin concentration, or UCP1 in lactating voles with different litter sizes. Serum-leptin concentration was negatively correlated with energy intake during lactation. Our data did not support the hypothesis that there is a trade-off in energy allocation between maternal maintenance and offspring growth in lactating Brandt's voles, but support the idea that if the mothers with ten pups should have less energy available for their maintenance than mothers raising fewer pups. Also, leptin is probably not the only factor that induces the high energy intake in mothers with large litter sizes, although it was involved in the regulation of energy intake during lactation. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Animals, Suckling; Arvicolinae; Basal Metabolism; Body Composition; Body Weight; Energy Intake; Female; Ion Channels; Lactation; Leptin; Litter Size; Mitochondrial Proteins; Organ Size; Uncoupling Protein 1 | 2008 |
Effect of Lactobacillus acidophilus supernatants on body weight and leptin expression in rats.
Lactobacillus extracts and supernatants have been used as probiotics in human and veterinary medicine for their ability to enhance wound healing and immunity. Previous data from our laboratory demonstrated that Lactobacillus supernatant (LS) stimulated wound healing, angiogenesis and proliferation of embryonic cells after topical application. This current study shows that LS after its administration into the cerebral ventricles of male rats exerts systemic effects.. The right lateral cerebral ventricle of young male rats was accessed through intracerebroventricular cannulation (ICV) under anesthesia and aseptic conditions. One group of control rats received saline solution, a second control group received 0.8 M lactic acid solution (to control for acidity of LS), and a third group received LS. The animals were sacrificed 12, 24, 48, 96 and 120 hours after the injection. Selected tissues were collected, fixed in 10% buffered formalin and used for immunohistochemistry and in situ hybridization. Other tissues were frozen and extracted for immunoblotting. LS-injected animals had a slight decrease in body weight when compared to their initial weight and to both control groups. Using immunohistochemistry and in situ hybridization leptin expression was studied in multiple brain sections and peripheral adipose tissue of control and LS-injected rats. Strong cytoplasmic stain was observed by both techniques in neurons of the cerebral cortex, thalamus, hypothalamus, hippocampus and, to lesser degree, in the cells of the choroid plexus in the LS-injected rats. Control animals demonstrated much less intense staining in neurons located in the same regions using immunohistochemistry and almost no staining with in situ hybridization technique. Adipose tissue exhibited slight presence of leptin in LS-treated animals. In contrast no immunohistochemical staining for GM-CSF and TNFalpha was observed in brains from control and treated rats. Western blotting showed mild increase in leptin and leptin receptors in intestines and retroperitoneal adipose tissues of LS-injected rats.. This study demonstrates that direct administration of LS into rat CNS leads to a decrease in body weight of rats and an increase in the expression of leptin in specific areas of the brain and retroperitoneal adipose tissue. Topics: Adipose Tissue; Animals; Body Weight; Cerebral Ventricles; Lactic Acid; Lactobacillus acidophilus; Leptin; Male; Models, Animal; Neovascularization, Physiologic; Probiotics; Rats; Rats, Sprague-Dawley; Reference Values | 2008 |
Decreased clearance of serum retinol-binding protein and elevated levels of transthyretin in insulin-resistant ob/ob mice.
Serum retinol-binding protein (RBP4) is secreted by liver and adipocytes and is implicated in systemic insulin resistance in rodents and humans. RBP4 normally binds to the larger transthyretin (TTR) homotetramer, forming a protein complex that reduces renal clearance of RBP4. To determine whether alterations in RBP4-TTR binding contribute to elevated plasma RBP4 levels in insulin-resistant states, we investigated RBP4-TTR interactions in leptin-deficient ob/ob mice and high-fat-fed obese mice (HFD). Gel filtration chromatography of plasma showed that 88-94% of RBP4 is contained within the RBP4-TTR complex in ob/ob and lean mice. Coimmunoprecipitation with an RBP4 antibody brought down stoichiometrically equal amounts of TTR and RBP4, indicating that TTR was not more saturated with RBP4 in ob/ob mice than in controls. However, plasma TTR levels were elevated approximately fourfold in ob/ob mice vs. controls. RBP4 injected intravenously in lean mice cleared rapidly, whereas the t(1/2) for disappearance was approximately twofold longer in ob/ob plasma. Urinary fractional excretion of RBP4 was reduced in ob/ob mice, consistent with increased retention. In HFD mice, plasma TTR levels and clearance of injected RBP4 were similar to chow-fed controls. Hepatic TTR mRNA levels were elevated approximately twofold in ob/ob but not in HFD mice. Since elevated circulating RBP4 causes insulin resistance and glucose intolerance in mice, these findings suggest that increased TTR or alterations in RBP4-TTR binding may contribute to insulin resistance by stabilizing RBP4 at higher steady-state concentrations in circulation. Lowering TTR levels or interfering with RBP4-TTR binding may enhance insulin sensitivity in obesity and type 2 diabetes. Topics: Animals; Blotting, Western; Body Weight; Diabetes Mellitus, Type 2; Dietary Fats; Female; Injections, Intravenous; Insulin Resistance; Leptin; Metabolic Syndrome; Mice; Mice, Obese; Obesity; Prealbumin; Retinol-Binding Proteins, Plasma | 2008 |
Astrocyte leptin receptor (ObR) and leptin transport in adult-onset obese mice.
The agouti viable yellow (A vy) spontaneous mutation generates an unusual mouse phenotype of agouti-colored coat and adult-onset obesity with metabolic syndrome. Persistent production of agouti signaling protein in A vy mice antagonizes melanocortin receptors in the hypothalamus. To determine how this disruption of neuroendocrine circuits affects leptin transport across the blood-brain barrier (BBB), we measured leptin influx in A vy and B6 control mice after the development of obesity, hyperleptinemia, and increased adiposity. After iv bolus injection, (125)I-leptin crossed the BBB significantly faster in young (2 month old) B6 mice than in young A vy mice or in older (8 month old) mice of either strain. This difference was not observed by in situ brain perfusion studies, indicating the cause being circulating factors, such as elevated leptin levels or soluble receptors. Thus, A vy mice showed peripheral leptin resistance. ObRa, the main transporting receptor for leptin at the BBB, showed no change in mRNA expression in the cerebral microvessels between the age-matched (2 month old) A vy and B6 mice. Higher ObRb mRNA was seen in the A vy microvasculature with unknown significance. Immunofluorescent staining unexpectedly revealed that many of the ObR(+) cells were astrocytes and that the A vy mice showed significantly more ObR(+) astrocytes in the hypothalamus than the B6 mice. Although leptin permeation from the circulation was slower in the A vy mice, the increased ObR expression in astrocytes and increased ObRb mRNA in microvessels suggest the possibility of heightened central nervous system sensitivity to circulating leptin. Topics: Adipose Tissue; Age of Onset; Animals; Biological Transport; Blood-Brain Barrier; Body Weight; Disease Models, Animal; Glial Fibrillary Acidic Protein; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C3H; Mice, Obese; Obesity; Polymerase Chain Reaction; Receptors, Leptin; RNA | 2008 |
Hyperinsulinemia and insulin resistance in Wrn null mice fed a diabetogenic diet.
Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by mutations in the Werner (Wrn) gene. WS patients have increased incidence of a number of chronic conditions including insulin resistance and type 2 diabetes. Since ingestion of foods that are high in fat and sugar is associated with increased incidence of diabetes, we examined if Wrn mutations might affect metabolic response to a diabetogenic diet. Four-month-old mice with a null mutation for the Wrn gene were fed a diet consisting of 36% fat (lard), 33% table sugar, and 20% protein plus balanced vitamins and minerals. Wrn null mice had significantly increased body weights, increased serum insulin levels, impaired glucose tolerance, and insulin resistance during 4 months of eating the diabetogenic diet. Diffuse fatty infiltration of the liver and pancreatic islet hyperplasia was characteristic morphological features. These observations suggest that Wrn null mice have impaired glucose homeostasis and fat metabolism, and may be a useful model to investigate metabolic conditions associated with aging. Topics: Adiposity; Animal Feed; Animals; Body Weight; Diabetes Mellitus; Diet; Glucose Intolerance; Hyperglycemia; Hyperinsulinism; Hypertriglyceridemia; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; RecQ Helicases; Werner Syndrome Helicase | 2008 |
Effects of physical training on IL-1beta, IL-6 and IL-1ra concentrations in various brain areas of the rat.
There is increasing evidence that voluntary physical activity and exercise training have beneficial effects on brain function by facilitating neurovegetative, neuroadaptative and neuroprotective processes. Cytokines are chronically expressed at elevated levels within the CNS in many neurological disorders and may contribute to the histopathological, pathophysiological, and cognitive deficits associated with such disorders. In the present study, we examined the influence of seven weeks of physical training on IL-1b, IL-6 and IL-1ra concentrations in hypothalamus, pituitary, hippocampus, cerebellum and frontal cortex in rats. We determined circulating concentrations of cytokines, corticosterone, prolactin and leptin. Two groups of 10 rats were investigated: one group (trained rats) was progressively trained (5 days/week); the other group (sedentary rats) was used as a sedentary group. The training program induced a decrease of (i) IL-1b concentration in the hippocampus (0.7 +/- 0.16 versus 0.99 +/- 0.14 pg/mg protein; p < 0.05), (ii) IL-6 concentration in the cerebellum (10.7 +/- 1.00 in trained rats versus 14.8 +/- 1.34 pg/mg protein in sedentary rats; p < 0.05), (iii) IL-1ra concentration in the pituitary (245 +/- 14.31 versus 328 +/- 17.73 pg/mg protein; p < 0.01). We also found positive correlations between (i) serum prolactin and the concentration of IL-6 in the cerebellum, (ii) serum leptin and the concentration of IL-1ra in the pituitary. There was no effect of physical training on IL-1b, IL-6, and IL-1ra serum levels. These findings suggest that the decrease in particular pro-inflammatory, central cytokines such as IL-1b and IL-6 induced by the training program may play a role in the positive effects of regular physical activity on the central nervous system. Topics: Animals; Body Weight; Brain; Cerebellum; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Interleukin-6; Leptin; Male; Models, Biological; Physical Conditioning, Animal; Pituitary Gland; Rats; Rats, Wistar; Tissue Distribution | 2008 |
Serum concentrations and expressions of serum amyloid A and leptin in adipose tissue are interrelated: the Genobin Study.
Serum amyloid A (SAA) is a novel link between increased adipose tissue mass and low-grade inflammation in obesity. Little is known about the factors regulating its serum concentration and mRNA levels. We investigated the association between SAA and leptin in obese and normal weight subjects and analyzed the effect of weight reduction on serum SAA concentration and gene expression in adipose tissue of the obese subjects.. Seventy-five obese subjects (60+/-7 years, body mass index (BMI) 32.9+/-2.8 kg/m(2), mean+/-s.d.) with impaired fasting plasma glucose or impaired glucose tolerance and other features of metabolic syndrome, and 11 normal weight control subjects (48+/-9 years, BMI 23.7+/-1.9 kg/m(2)) were studied at the baseline. Twenty-eight obese subjects underwent a 12-week intensive weight reduction program followed by 5 months of weight maintenance. Blood samples and abdominal s.c. adipose tissue biopsies were taken at the baseline and after the follow-up. Gene expression was studied using real-time quantitative PCR.. The gene expressions in women and serum concentrations of leptin and SAA were interrelated independently of body fat mass in the obese subjects (r=0.54, P=0.001; r=0.24, P=0.039 respectively). In multiple linear regression analyses, leptin mRNA explained 38% of the variance in SAA mRNA (P=0.002) in the obese women. Weight loss of at least 5% increased SAA mRNA expression by 48 and 36% in men and women, but serum SAA concentrations did not change.. The association between SAA and leptin suggests an interaction between these two adipokines, which may have implications in inflammatory processes related to obesity and the metabolic syndrome. Topics: Adipocytes; Adipose Tissue; Aged; Body Weight; Female; Gene Expression; Glucose Intolerance; Humans; Inflammation; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; RNA, Messenger; Serum Amyloid A Protein; Weight Loss | 2008 |
Fat may fuel breast cancer growth.
Topics: Adipose Tissue; Biomarkers, Tumor; Body Mass Index; Body Weight; Breast Neoplasms; Disease-Free Survival; Estrogens; Exercise; Female; Humans; Inflammation; Insulin; Insulin-Like Growth Factor I; Leptin; Neoplasms; Obesity; Overweight; Recurrence; Risk Assessment; Risk Factors; United Kingdom; Weight Gain | 2008 |
Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome.
Bardet-Biedl syndrome (BBS) is a heterogeneous genetic disorder characterized by many features, including obesity and cardiovascular disease. We previously developed knockout mouse models of 3 BBS genes: BBS2, BBS4, and BBS6. To dissect the mechanisms involved in the metabolic disorders associated with BBS, we assessed the development of obesity in these mouse models and found that BBS-null mice were hyperphagic, had low locomotor activity, and had elevated circulating levels of the hormone leptin. The effect of exogenous leptin on body weight and food intake was attenuated in BBS mice, which suggests that leptin resistance may contribute to hyperleptinemia. In other mouse models of obesity, leptin resistance may be selective rather than systemic; although mice became resistant to leptin's anorectic effects, the ability to increase renal sympathetic nerve activity (SNA) was preserved. Although all 3 of the BBS mouse models were similarly resistant to leptin, the sensitivity of renal SNA to leptin was maintained in Bbs4 -/- and Bbs6 -/- mice, but not in Bbs2 -/- mice. Consequently, Bbs4 -/- and Bbs6 -/- mice had higher baseline renal SNA and arterial pressure and a greater reduction in arterial pressure in response to ganglionic blockade. Furthermore, we found that BBS mice had a decreased hypothalamic expression of proopiomelanocortin, which suggests that BBS genes play an important role in maintaining leptin sensitivity in proopiomelanocortin neurons. Topics: Animals; Bardet-Biedl Syndrome; Blood-Brain Barrier; Body Weight; Disease Models, Animal; Electrocardiography; Gene Expression Regulation; Group II Chaperonins; Hypertension; Leptin; Magnetic Resonance Imaging; Mice; Mice, Knockout; Microtubule-Associated Proteins; Molecular Chaperones; Obesity; Organ Size; Proteins | 2008 |
Different physiological roles of serum leptin in the regulation of energy intake and thermogenesis between pregnancy and lactation in primiparous Brandt's voles (Lasiopodomys brandtii).
Reproduction, especially lactation, is associated with major metabolic adaptive changes. In this study, we investigated the metabolic changes and the roles of leptin during different periods of reproduction in primiparous Brandt's voles (Lasiopodomys brandtii). Energy intake, thermogenic capacity and serum leptin levels were examined in non-reproductive, mid pregnant, late pregnant, early lactating and peak lactating voles. Voles increased body mass by nearly 70% during late pregnancy compared to the non-breeding controls. The increase in body mass was mainly due to the increase in body fat mass which increased by 56%, and the growth of the reproductive tissues and digestive organs. Lactating voles decreased body fat by nearly 27% at peak lactation compared to the controls, and 53% compared to late pregnant voles. At the same time they increased food intake significantly. Uncoupling protein 1 (UCP1) content in brown adipose tissue (BAT) decreased significantly at peak lactation. Serum leptin increased significantly in the mid pregnancy, at a time when there was no increase in body fat, and remained at this high level in late pregnancy. Leptin levels decreased after parturition and reached a nadir at peak lactation. Serum leptin was negatively correlated with energy intake during lactation, but not during pregnancy. These data suggest that Brandt's voles adjust energy intake, thermogenic capacity and body reserves to match the high energy demands for reproduction. Hyperleptinemia, without decreased energy intake suggests a state of leptin resistance during pregnancy, and hypoleptinemia during lactation might act as a signal to stimulate energy intake. Topics: Adaptation, Physiological; Adipose Tissue, Brown; Animals; Arvicolinae; Basal Metabolism; Body Composition; Body Weight; Eating; Electron Transport Complex IV; Energy Intake; Energy Metabolism; Female; Hyperphagia; Ion Channels; Lactation; Leptin; Mitochondria, Liver; Mitochondrial Proteins; Pregnancy; Thermogenesis; Time Factors; Uncoupling Protein 1 | 2008 |
Differential sympathetic drive to adipose tissues after food deprivation, cold exposure or glucoprivation.
Surplus energy is principally stored in white adipose tissue (WAT) as triacylglycerol and mobilized via lipolysis through norepinephrine (NE) released from sympathetic nervous system terminals innervating WAT. We demonstrated that central melanocortin receptor agonism provokes differential sympathetic drives across WAT pads and interscapular brown adipose tissue (IBAT). Here we tested for differential WAT and IBAT sympathetic drive to known lipolytic stimuli {glucoprivation [2-deoxy-D-glucose (2-DG)], cold exposure (5 degrees C), food deprivation (16 h), or both cold exposure and food deprivation} by measuring NE turnover (NETO). Only inguinal WAT NETO significantly increased across all stimuli. Dorsal subcutaneous WAT NETO only increased with glucoprivation. Retroperitoneal WAT NETO increased with glucoprivation, cold and cold + food deprivation, but not by food deprivation. Epididymal WAT NETO was unaffected by glucoprivation but increased with cold, cold + food deprivation or food deprivation, but to a small significant degree. IBAT NETO was unaffected by glucoprivation or food deprivation, but increased with cold and cold + food deprivation. Plasma glucose decreased with food deprivation and increased with 2-DG administration or cold exposure. Plasma glycerol was increased with food deprivation, cold, and their combination but not with 2-DG, whereas plasma free fatty acids increased with food deprivation, cold + food deprivation, and 2-DG. These data show differential sympathetic drive to WAT and BAT for four different lipolytic stimuli, exemplifying the fat pad-specific pattern of WAT sympathetic drive across lipid-mobilizing conditions and emphasizing the need to analyze multiple adipose depots for measures of NETO and likely most measures. Topics: Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Antimetabolites; Blood Glucose; Body Weight; Cold Temperature; Cricetinae; Deoxyglucose; Eating; Energy Metabolism; Epinephrine; Fatty Acids, Nonesterified; Food Deprivation; Glucose; Glycerol; Leptin; Male; Norepinephrine; Phodopus; Sympathetic Nervous System | 2008 |
Substance P as a novel anti-obesity target.
Substance P (SP) is an 11-amino acid peptide that belongs to the tachykinin family of peptides. SP acts in the brain and in the periphery as a neuropeptide, neurotransmitter, and hormone affecting diverse physiologic pathways, mainly via its high-affinity neurokinin-1 receptor (NK-1R). Its presence in the hypothalamus and other areas of the brain that regulate feeding as well as in the stomach and small intestine prompted us to investigate its role on appetite control and energy balance.. CJ 012,255 (CJ), a SP antagonist that binds to NK-1R, was injected into lean, diet-induced obese (DIO), and genetically obese (ob/ob) mice, and its effects on body weight, adiposity, and insulin sensitivity were investigated.. CJ administration prevented weight gain and accumulation of fat after 2 weeks of high-fat feeding, whereas similar CJ treatment in obese mice (following 3 months of high-fat diet) resulted in weight loss, reduction in adiposity, and improvement of insulin sensitivity, in part because of inhibition of food intake. The effects of SP in the control of energy balance are, at least in part, leptin independent because CJ treatment was also effective in leptin-deficient mice. Peripheral SP administration resulted in a mild, dose-dependent increase in food intake, evident 3 hours post-SP injection.. CJ reduces appetite and promotes weight loss in mice. We speculate that NK-1R antagonists, already tested in clinical trials for various diseases, may represent a potential target against obesity. Topics: Adiposity; Animals; Anti-Obesity Agents; Appetite Regulation; Blood Glucose; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Energy Metabolism; Feeding Behavior; Injections, Intraperitoneal; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neurokinin-1 Receptor Antagonists; Obesity; Receptors, Neurokinin-1; Substance P; Time Factors | 2008 |
Increased leptin expression selectively in the hypothalamus suppresses inflammatory markers CRP and IL-6 in leptin-deficient diabetic obese mice.
Low-grade systemic inflammation, as indicated by increased circulating levels of inflammatory markers CRP and IL-6, is linked to increased risks for cardiovascular diseases (CVD) and diabetes mellitus in obese subjects. Whereas hyperleptinemia in obesity are associated with increased CRP and IL-6 release, the hypothalamic versus peripheral site of leptin action has not been ascertained. The effects of increased leptin supply selectively in the hypothalamus by gene therapy on pro-inflammatory CRP and IL-6 levels and on markers of diabetes in the circulation of ob/ob mice displaying either age-related or dietary obesity were assessed. A recombinant adeno-associated viral vector encoding either green-fluorescent protein (control) or leptin gene was injected intracerebroventricularly. Five weeks later, one-half of each of the vector groups was switched to high-fat diet consumption and the other half continued to consume regular low-fat chow diet. Body weight and visceral white adipose tissue were drastically reduced and hyperinsulinemia and hyperglycemia were abrogated by leptin gene therapy, independent of the dietary fat content. The elevated plasma CRP and IL-6 levels seen in obese ob/ob mice receiving the control vector, regardless of the fat content of the diet, were markedly suppressed by increased hypothalamic leptin in both groups. The results show for the first time that leptin deficiency elevates and reinstatement of leptin selectively in the hypothalamus suppresses the release of pro-inflammatory biomarkers, a response likely to alleviate CVD associated with obesity. Topics: Animals; Biomarkers; Body Weight; C-Reactive Protein; Diabetes Complications; Genetic Vectors; Hypothalamus; Interleukin-6; Leptin; Male; Mice; Mice, Obese; Mice, Transgenic; Obesity | 2008 |
Up-regulation of rat adipose tissue adiponectin gene expression by long-term but not by short-term food restriction.
Beneficial effects of food restriction as well as elevated circulating adiponectin concentration on the cardiovascular system, lipid metabolism and non-insulin dependent diabetes have been reported. The present article indicates that the reduction in rat body and adipose tissue weight after long-term (1 month) food restriction (either 75% or 50% of ad libitum food intake) was accompanied by the increase in serum adiponectin concentration. The increase in serum adiponectin concentration is the result of the significant increase in white adipose tissue adiponectin gene expression. In contrast to long-term food restriction, short-term (3 days) food restriction (either 75% or 50% of ad libitum food intake) did not influence body and fat mass as well as serum adiponectin concentration and white adipose tissue adiponectin mRNA level. The obtained results suggest that long-term food restriction is necessary to increase in serum adiponectin concentration that could be beneficial, to prevent some disorders associated with low serum adiponectin concentration like obesity and obesity-related diseases. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Food Deprivation; Leptin; Male; Organ Size; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Up-Regulation | 2008 |
Peripheral ghrelin treatment stabilizes body weights of senescent male Brown Norway rats at baseline and after surgery.
Unintentional weight loss may occur spontaneously in older humans and animals. Further weight losses after surgery or illness in the older patients result in increased morbidity, mortality, and hospital readmission rate. A growing body of work has shown increased appetite and weight gain in response to administration of ghrelin, the "hunger hormone." We conducted two studies in senescent male Brown Norway rats to assess the ability of peripheral administration of ghrelin to increase body weight and food intake. One study assessed the effect of 2 wk of daily subcutaneous ghrelin administration (1 mg.kg(-1).day(-1)) to senescent rats in a baseline condition; a second study used the same administration protocol in an interventional experiment with aged rats subjected to a surgery with 10-15% blood loss as a model of elective surgery. In both studies, animals receiving ghrelin maintained their body weights, whereas control animals lost weight. Body weight stability was achieved in ghrelin-treated animals despite a lack of increase in daily or cumulative food intake in both experiments. Hormone and proinflammatory cytokine levels were measured before surgery and after 14 days of treatment. Ghrelin treatment appeared to blunt declining ghrelin levels and also to blunt cytokine increases seen in the surgical control group. The ability of peripheral ghrelin treatment to maintain body weights of senescent rats without concomitant increases in food intake may be due to its known ability to decrease sympathetic activity and metabolic rate, perhaps by limiting cytokine-driven inflammation. Topics: Aging; Animals; Body Composition; Body Weight; Cytokines; Eating; Ghrelin; Hormones; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Rats; Rats, Inbred BN; Surgical Procedures, Operative | 2008 |
Effects of a maternal low protein isocaloric diet on milk leptin and progeny serum leptin concentration and appetitive behavior in the first 21 days of neonatal life in the rat.
Suboptimal developmental environments program offspring to lifelong metabolic problems. We evaluated effects of maternal isocaloric low protein diet during pregnancy and/or lactation on milk quantity and leptin concentration at postnatal day 7, 14, and 21. Control mothers ate 20% casein (C) and restricted mothers (R) 10% casein to provide four groups: CC, RR, CR, and RC (first letter pregnancy and second lactation diet) to enable evaluation of effects influenced by maternal diet during pregnancy and lactation. Milk leptin was not a determinant of pup serum leptin. Pup serum leptin did not inhibit milk appetite at any postnatal age. Pup serum leptin did not correlate with pup adipose tissue. Finally, the normal postnatal leptin rise in pup serum was delayed by prenatal undernutrition. These data suggest that fetal nutrition modifies timing of neonatal leptin surge and may contribute to the development of altered appetite and metabolic disorders in later life. Topics: Aging; Animals; Animals, Newborn; Animals, Suckling; Appetitive Behavior; Body Weight; Diet, Protein-Restricted; Female; Leptin; Male; Milk; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar | 2008 |
Structural analysis and haplotype diversity in swine LEP and MC4R genes.
Knowledge about structural variation of candidate genes could be important to improve breeding selection scheme and preserve genetic variability in livestock species. Leptin (LEP) and melanocortin-4 receptor (MC4R) genes are involved in the energetic pathway and are obvious candidate genes for fatness. By sequencing LEP and MC4R genes in 72 pigs belonging to lean (Large White and Duroc), fat (Meishan and Casertana) breeds and also Wild Boar, 98 polymorphic sites, of which 91 were novel, were found in the Leptin sequence while only the previously described mutation was found in the MC4R gene. A total of 18 LEP haplotypes were observed and their distribution was unequal among the breeds. The phylogenetic analysis showed two haplotype branches distinguishing between lean and fat breeds. Topics: Animals; Animals, Wild; Base Sequence; Body Weight; Breeding; Chromosome Inversion; DNA; Female; Genetic Variation; Haplotypes; Leptin; Male; Molecular Sequence Data; Phylogeny; Polymorphism, Single Nucleotide; Receptor, Melanocortin, Type 4; Species Specificity; Sus scrofa; Swine | 2008 |
Alterations in male sexual behaviour, attractiveness and testosterone levels induced by an adult-onset calorie restriction regimen.
Despite an abundance of research on calorie restriction (CR) altering gonadal and appetite regulating hormones, the sexual behavioural consequences of CR remain to be examined systematically. This study compared the sexual behaviour, partner preference, serum testosterone and leptin levels of male adult Hooded Wistar rats administered a CR (continuous 25%, 50% CR or a temporary restriction) with ad libitum fed controls. The temporary restriction (Previous CR) failed to alter sexual behaviour, partner preference and levels of testosterone and leptin. The moderately 25% CR males did not demonstrate an impairment in sexual behaviour but did demonstrate a reduced level of attractiveness to females in one measure of partner preference. Sexual performance was affected by a substantial CR, as the CR 50% group exhibited a longer latency to the first intromission, indicating alteration in sexual arousal. Females also consistently demonstrated a clear preference for the control group compared to the CR 50% group. These findings indicate a possible reduction in the overall reproductive potential of the substantially CR animals. Testosterone levels were equally suppressed by both the 25% and 50% CR, while leptin levels were only reduced in the CR 50% group. Leptin, rather than testosterone, may have influenced the impairment in sexual behaviour only demonstrated by the substantially CR animals. Testosterone, may, however, play a role in modulating the preference of control over CR males, as attractiveness was totally reduced by a substantial CR, and partially reduced by a moderate restricted regimen. Topics: Analysis of Variance; Animals; Behavior, Animal; Body Weight; Caloric Restriction; Enzyme-Linked Immunosorbent Assay; Female; Leptin; Male; Ovariectomy; Rats; Rats, Wistar; Sex Characteristics; Sexual Behavior, Animal; Testosterone | 2008 |
Early postnatal leptin blockage leads to a long-term leptin resistance and susceptibility to diet-induced obesity in rats.
Using a recombinant rat leptin antagonist, we investigated the effects of early postnatal leptin disruption on long-term leptin sensitivity and metabolic phenotype.. Three groups of 10 newborn female Wistar rats were injected subcutaneously with either saline (control) or leptin antagonist (at 2.5 or 7.5 microg g(-1) day(-1)) from postnatal day 2 to day 13.. At weaning (day 28), antagonist-treated rats presented similar body weight (BW) compared to control animals. At 3 months of age, there was no significant change in BW, food intake and leptin or insulin levels between groups. Only a disturbed relationship between circulating insulin and glucose levels was observed in antagonist-treated animals. At 4 months of age, treated animals developed a leptin resistance appreciated by the lack of response to a 7-days leptin treatment (1 mg kg(-1) day(-1)) in term of decrease in food intake and BW. At 8 months of age, following 3 months of high-energy diet, rlepm7.5 animals presented higher BW gain associated with increased body fatness and striking hyperleptinaemia as compared to control animals.. The blockage of leptin action during the critical period of early life in rodents has long-term consequences by altering the capacity to respond to leptin during adulthood, thus predisposing the animals to obesity. These findings clearly demonstrate the physiological importance of the postnatal leptin surge for the optimal onset of the metabolic regulation, at least in rodents, and its implication in the prevention of unfavourable developmental programming. Topics: Animals; Animals, Newborn; Body Weight; Disease Susceptibility; Eating; Female; Insulin; Leptin; Obesity; Rats; Rats, Wistar; Recombinant Proteins; Time; Weaning | 2008 |
Appetite enhancement and weight gain by peripheral administration of TrkB agonists in non-human primates.
Loss of function mutations in the receptor tyrosine kinase TrkB pathway resulted in hyperphagia and morbid obesity in human and rodents. Conversely, peripheral or central stimulation of TrkB by its natural ligands BDNF or NT4 reduced body weight and food intake in mice, supporting the idea that TrkB is a key anorexigenic signal downstream of the melanocortin-4 receptor (Mc4r) system. Here we show that in non-human primates TrkB agonists were anorexigenic when applied centrally, but surprisingly orexigenic, leading to gain in appetite, body weight, fat deposits and serum leptin levels, when given peripherally. The orexigenic and pro-obesity effects of peripherally administered TrkB agonists appear to be dose dependent, not associated with fluid retention nor with evidence of receptor down regulation. Our findings revealed that TrkB signaling exerts dual control on energy homeostasis in the primates that could be targeted for the treatment of either wasting disorders or obesity. Topics: Animals; Appetite; Body Weight; Brain-Derived Neurotrophic Factor; Gene Deletion; Leptin; Ligands; Macaca mulatta; Mutation; Obesity; Receptor, Melanocortin, Type 4; Receptor, trkB; Recombinant Proteins; Signal Transduction; Weight Gain | 2008 |
Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice.
Normal food intake and body weight homeostasis require the direct action of leptin on hypothalamic proopiomelanocortin (POMC) neurons. It has been proposed that leptin action requires PI3K activity. We therefore assessed the contribution of PI3K signaling to leptin's effects on POMC neurons and organismal energy balance. Leptin caused a rapid depolarization of POMC neurons and an increase in action potential frequency in patch-clamp recordings of hypothalamic slices. Pharmacologic inhibition of PI3K prevented this depolarization and increased POMC firing rate, indicating a PI3K-dependent mechanism of leptin action. Mice with genetically disrupted PI3K signaling in POMC cells failed to undergo POMC depolarization or increased firing frequency in response to leptin. Insulin's ability to hyperpolarize POMC neurons was also abolished in these mice. Moreover, targeted disruption of PI3K blunted the suppression of feeding elicited by central leptin administration. Despite these differences, mice with impaired PI3K signaling in POMC neurons exhibited normal long-term body weight regulation. Collectively, these results suggest that PI3K signaling in POMC neurons is essential for leptin-induced activation and insulin-induced inhibition of POMC cells and for the acute suppression of food intake elicited by leptin, but is not a major contributor to the regulation of long-term organismal energy homeostasis. Topics: Animals; Body Weight; Eating; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Leptin; Mice; Mice, Knockout; Neurons; Patch-Clamp Techniques; Phosphatidylinositol 3-Kinases; Pro-Opiomelanocortin; Signal Transduction | 2008 |
Type 1 diabetes alters brain cannabinoid receptor expression and phosphorylation status in rats.
One of the most common symptoms of diabetes is extreme hunger, but the brain mechanism underlying this hyperphagia is unknown. The endocannabinoid system has emerged as one of the main food intake regulators in the brain. However, the effects of type 1 diabetes on the endocannabinoid system are not completely known. Thus, the aim of the present work is to establish the possible alterations induced by type 1 diabetes on the brain endocannabinoid system in rats. Western blot and immunocytochemistry were used to measure CB1 and phosphorylated CB1 receptor expression in several prosencephalic regions in streptozotocin-induced type 1 diabetic rats. Serum leptin levels were measured by ELISA. CB1 receptor expression was increased in striatum and hypothalamus of diabetic animals, with no changes in other brain areas studied. CB1 receptor phosphorylation was also increased in the same brain areas. Type 1 diabetes induced significant weight loss, and serum leptin levels were severely decreased. These results reinforce the possible role of the CB1 receptor as a pharmacological target for the clinical management of appetite in diabetic patients. Topics: Animals; Appetite; Blood Glucose; Body Weight; Brain; Diabetes Mellitus, Type 1; Eating; Leptin; Male; Phosphorylation; Protein Kinases; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1 | 2008 |
Changes in serum leptin, insulin, androstenedione and luteinizing hormone during ovarian cycle in the bat, Taphozous longimanus.
Detailed reproductive pattern and associated endocrine characteristics have been documented in only a few species of order Chiroptera. The aim of the present study was to examine the changes in body weight, serum insulin, leptin, androstenedione and luteinizing hormone (LH) concentrations during annual ovarian cycle in the sheath-tailed bat, Taphozous longimanus. Bats were sampled over three years. Leptin, a satiety hormone produced primarily by adipose tissue, provides information to feeding center of the brain about nutritional status, fat mass, appetite and energy expenditure. The circulating concentration of leptin begins to increase from October and attains a peak in December. The peak serum leptin concentration coincides with body weight in November before winter dormancy in December. The serum leptin levels dissociate from body weight during December. The other peaks of serum leptin levels coincide with late stages of the two successive pregnancies. The serum insulin concentration begins to increase from September and attains a peak during December. The insulin concentration remains low from January to August. The circulating androstenedione concentration begins to increase in October, reaching a peak in December. This increase in androstenedione concentration correlated with the period of heavy accumulation of abdominal fat and increase in body weight. There was a sharp decline in androstenedione concentration and body weight in January. The serum LH shows peaks, in November, coinciding with the peaked body weight, the other peaks in January and May, coinciding with ovulation for the two successive pregnancies. The high leptin and insulin levels might be responsible for the maintenance of reproductive response and gonadal function during adverse environmental condition in the winter, while high androstenedione, and associated body weight along with LH might be responsible for maintaining basal gonadal function. We conclude that high leptin, androstenedione and insulin serve, as signal for the reproductive functions in that sufficient body fat are available to meet the caloric demands and maintain normal function during adverse winter conditions. Topics: Androstenedione; Animals; Body Weight; Chiroptera; Energy Metabolism; Female; Insulin; Leptin; Luteinizing Hormone; Menstrual Cycle; Reproduction; Seasons | 2008 |
Signal transducer and activator of transcription-3 is required in hypothalamic agouti-related protein/neuropeptide Y neurons for normal energy homeostasis.
Signal transducer and activator of transcription (Stat)-3 signals mediate many of the metabolic effects of the fat cell-derived hormone, leptin. In mice, brain-specific depletion of either the long form of the leptin receptor (Lepr) or Stat3 results in comparable obese phenotypes as does replacement of Lepr with an altered leptin receptor locus that codes for a Lepr unable to interact with Stat3. Among the multiple brain regions containing leptin-sensitive Stat3 sites, cells expressing feeding-related neuropeptides in the arcuate nucleus of the hypothalamus have received much of the focus. To determine the contribution to energy homeostasis of Stat3 expressed in agouti-related protein (Agrp)/neuropeptide Y (Npy) arcuate neurons, Stat3 was deleted specifically from these cells, and several metabolic indices were measured. It was found that deletion of Stat3 from Agrp/Npy neurons resulted in modest weight gain that was accounted for by increased adiposity. Agrp/Stat3-deficient mice also showed hyperleptinemia, and high-fat diet-induced hyperinsulinemia. Stat3 deletion in Agrp/Npy neurons also resulted in altered hypothalamic gene expression indicated by increased Npy mRNA and decreased induction of suppressor of cytokine signaling-3 in response to leptin. Agrp mRNA levels in the fed or fasted state were unaffected. Behaviorally, mice without Stat3 in Agrp/Npy neurons were mildly hyperphagic and hyporesponsive to leptin. We conclude that Stat3 in Agrp/Npy neurons is required for normal energy homeostasis, but Stat3 signaling in other brain areas also contributes to the regulation of energy homeostasis. Topics: Adiposity; Agouti-Related Protein; Animals; Body Weight; Dietary Fats; Energy Metabolism; Homeostasis; Hypothalamus; Immunohistochemistry; Leptin; Mice; Neurons; Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Weight Gain | 2008 |
Desensitization of gonadotropin responses to kisspeptin in the female rat: analyses of LH and FSH secretion at different developmental and metabolic states.
Kisspeptins have emerged as potent elicitors of gonadotropin secretion and, therefore, putative targets for pharmacological intervention. In this context, desensitization of gonadotropin responses to continuous administration of kisspeptins has begun to be characterized, but information so far available is mostly restricted to LH responses in males, whereas the similar phenomenon in females, of obvious therapeutic interest, remains virtually unexplored. We report herein LH and FSH responses to continuous intracerebral administration of kisspeptin in female rats at different developmental and metabolic states. Infusion of kisspeptin-10 to adult female rats induced a transient elevation in serum LH concentrations, followed by a precipitous drop and normalization of LH levels thereafter. Elevation of LH after kisspeptin infusion was prolonged in underfed animals; a phenomenon mimicked by leptin administration. Conversely, FSH levels were persistently heightened along continuous kisspeptin infusion, but duration of this response was shortened by undernutrition. In pubertal females, LH and FSH levels remained elevated at the end of a 7-day infusion of kisspeptin; responses whose magnitude was augmented by subnutrition but not mimicked by leptin. In all settings, terminal gonadotropin-releasing hormone responses were fully preserved, suggesting that eventual desensitization must occur upstream from the pituitary. In summary, our current data document the pharmacological consequences of continuous administration of kisspeptin to female rats, with remarkable differences being detected between LH and FSH responses, in different developmental and metabolic states. These observations of potential pharmacological interest might help also to delineate the physiological roles of kisspeptins in the dynamic regulation of gonadotropin secretion in the female. Topics: Age Factors; Animals; Body Weight; Eating; Female; Follicle Stimulating Hormone; Kisspeptins; Leptin; Luteinizing Hormone; Oligopeptides; Rats; Rats, Wistar; Sexual Maturation | 2008 |
Novel black soy peptides with antiobesity effects: activation of leptin-like signaling and AMP-activated protein kinase.
To investigate the mechanisms underlying the antiobesity effects of a novel isoflavone-free peptide mixture (BSP) derived from black soybean.. Long-term effects of BSP were evaluated in diet-induced obese (DIO) mice fed a high-fat (HF) diet without or with BSP (2, 5 or 10% of energy) for 13 weeks, or for 8 weeks in combination with exercise. Acute effects of BSP on food intake and body weight in rats and leptin-deficient ob/ob mice were evaluated. Cell culture models or tissue extracts were used to investigate the mechanisms underlying the antiobesity effect.. Total food intake, body weight gain, white adipose tissue (WAT) mass, plasma concentrations of leptin, adiponectin, cholesterol and triglyceride were measured. Janus kinase 2 (JAK2)-dependent signal transducers and activators of the transcription 3 (STAT3) phosphorylation and AMP-activated protein kinase (AMPK) activity were determined using Western-blot in cultured cells or tissue extracts.. DIO mice fed an HF diet with BSP (2, 5 or 10%) for 13 weeks gained less body weight (21.4, 19.8 or 17.1 g, respectively) than the mice fed an HF diet without BSP (22.6 g) concurrent with inhibition of total food intake in a dose-dependent manner. BSP also significantly decreased food intake in rats and leptin-deficient ob/ob mice. The highest dose of BSP (10%) significantly elevated the plasma adiponectin and decreased plasma triglyceride. BSP activated JAK2-dependent STAT3 in a cell model, and elevated the level of hypothalamic phospho-STAT3 in ob/ob mice. BSP also phosphorylated AMPK and acetyl-CoA carboxylase of C2C12 myocytes in a dose-dependent manner. The antiobesity effect was augmented by low-intensity wheel-based exercise. In exercised mice, BSP significantly decreased periepididymal WAT mass and body weight gain.. These results provided evidences that BSP decreased appetite and HF diet-induced body weight gain particularly in combination with exercise, through leptin-like STAT3 phosphorylation and AMPK activation. Topics: Adipose Tissue; AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; Body Weight; Eating; Energy Metabolism; Enzyme Activation; Female; Janus Kinase 2; Leptin; Mice; Mice, Inbred C57BL; Multienzyme Complexes; Obesity; Phosphorylation; Protein Serine-Threonine Kinases; Signal Transduction; Soybean Proteins; STAT3 Transcription Factor; Triglycerides | 2008 |
Treatment of obesity and diabetes in mice by transplant of gut cells engineered to produce leptin.
Leptin injections evoke weight loss by causing a reduction in food consumption and an increase in energy expenditure. Also, the administration of leptin lowers blood glucose levels in some rodent models of diabetes and in humans with lipodystrophy. We explored the therapeutic potential of delivering leptin to obese, diabetic ob/ob mice and to mice fed on a high-fat diet (HFD), by transplanting gut-derived cells engineered to produce leptin, under the regulation of an inducing agent, mifepristone. These cells expressed and released leptin in a mifepristone dose-dependent and time-dependent manner. The engineered cells were either transplanted into the mice under the kidney capsule or were encapsulated in alginate and injected into the intraperitoneal cavity, while mifepristone was delivered by implanting 14-day release pellets. In ob/ob mice, leptin delivery by this method caused a significant reduction in food intake and profound weight loss, which was controllable by adjusting the dose of mifepristone. These transplants also achieved rapid and persistent amelioration of diabetes. However, mice fed on a HFD were resistant to the leptin therapy. These results indicate that gut cells can be modified to express leptin in an inducible manner and that the transplantation of these cells has a therapeutic effect in leptin-deficient mice, but not in mice fed on a HFD. Topics: Adipose Tissue; Animals; Body Weight; Cell Transplantation; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Insulin; Kidney; Leptin; Mice; Mice, Obese; Mifepristone; Obesity; RNA, Messenger; Transfection | 2008 |
Effect of restricted feeding and monopropylene glycol postpartum on metabolic hormones and postpartum anestrus in grazing dairy heifers.
This study was designed to determine the effects of feed restriction and monopropylene glycol (MPG) supplementation on the reproductive, milk production, and somatotropic axes in dairy heifers postpartum. At calving, 49 Holstein-Friesian heifers were allowed either unrestricted (UNR; n = 18) or restricted access to pasture with (RES+MPG; n = 13) or without (RES; n = 18) MPG supplementation (250 mL drenched twice daily for 150 d). The average body condition score (BCS) of the heifers was 5.3 +/- 0.2 on a scale from 1 to 10 (where 1 = emaciated and 10 = obese). Body condition score and body weight were similar among the groups at calving and decreased after calving for all groups. However, body weight loss was around 10% greater for the RES and RES+MPG groups from wk 3 to 12 compared with UNR group. The length of the postpartum anestrous interval was similar for all groups (47, 51, and 45 +/- 5 d for the UNR, RES, and RES+MPG, respectively). Average milk production, protein, fat, and lactose yields during the first 12 wk postpartum were greater in the UNR group than in the RES and RES+MPG groups. Feed restriction affected plasma concentrations of insulin, with lower concentrations in the RES group compared with the UNR group. There were no differences in plasma concentrations of insulin between the RES+MPG group and the UNR or RES groups. An effect of feed restriction was observed on insulin-like growth factor-I concentrations and also a treatment by time interaction with a changing pattern through time as concentrations in the UNR group increased relative to the RES and RES+MPG groups. There were no differences in growth hormone concentrations among the groups. Glucose concentrations were lower in the RES group when compared with RES+MPG and UNR groups and this difference lessened over time. Plasma concentrations of nonesterified fatty acids were greater in the RES group compared with the RES+MPG and UNR groups. Leptin concentrations in the UNR group were greater than in the RES and RES+MPG groups. Hepatic growth hormone receptor 1A, total growth hormone receptor, and insulin-like growth factor-I relative mRNA expressions decreased postpartum with no effect of feed restriction, MPG supplementation, or interaction between time and treatment. During a challenge with MPG, insulin secretion was stimulated but no effect on postpartum anestrous interval in the treatment groups was observed. It was concluded that restricted pasture availability postpartum in dair Topics: Anestrus; Animals; Blood Glucose; Body Composition; Body Weight; Cattle; Female; Food Deprivation; Hormones; Insulin; Insulin-Like Growth Factor I; Lactation; Leptin; Liver; Postpartum Period; Propylene Glycol; Receptors, Somatotropin; Reproduction; RNA, Messenger | 2008 |
Effects of a novel Y5 antagonist in obese mice: combination with food restriction or sibutramine.
To further address the function of the Y5 receptor in energy homeostasis, we investigated the effects of a novel spironolactone Y5 antagonist in diet-induced obese (DIO) mice.. Male C57BL/6 or Npy5r(-/-) mice were adapted to high-fat (HF) diet for 6-10 months and were submitted to three experimental treatments. First, the Y5 antagonist at a dose of 10 or 30 mg/kg was administered for 1 month to DIO C57BL/6 or Npy5r(-/-) mice. Second, the Y5 antagonist at 30 mg/kg was administered for 1.5 months to DIO C57BL/6 mice, and insulin sensitivity was evaluated using an insulin tolerance test. After a recovery period, nuclear magnetic resonance measurement was performed to evaluate body composition. Third, DIO mice were treated with the Y5 antagonist alone, or in combination with 10% food restriction, or with another anorectic agent, sibutramine at 10 mg/kg, for 1.5 months. Plasma glucose, insulin, and leptin levels, and adipose tissue weights were quantified.. The spironolactone Y5 antagonist significantly reduced body weight in C57BL DIO mice, but not in Npy5r(-/-) DIO mice. The Y5 antagonist produced a fat-selective loss of body weight, and ameliorated obesity-associated insulin resistance in DIO mice. In addition, the Y5 antagonist combined with either food restriction or sibutramine tended to produce greater body weight loss, as compared with single treatment.. These findings demonstrate that the Y5 receptor is an important mediator of energy homeostasis in rodents. Topics: Adiposity; Animals; Anti-Obesity Agents; Appetite Depressants; Blood Glucose; Body Weight; Caloric Restriction; Combined Modality Therapy; Cyclobutanes; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eating; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptors, Neuropeptide Y; Spiro Compounds; Spironolactone; Time Factors | 2008 |
Identification of ALOX5 as a gene regulating adiposity and pancreatic function.
We previously used an integrative genetics approach to demonstrate that 5-lipoxygenase (5-LO) deficiency in mice (Alox5 (-/-)) protects against atherosclerosis despite increasing lipid levels and fat mass. In the present study, we sought to further examine the role of 5-LO in adiposity and pancreatic function.. Alox5 (-/-) and wild-type (WT) mice were characterised with respect to adiposity and glucose/insulin metabolism using in vivo and in vitro approaches. The role of ALOX5 in pancreatic function in human islets was assessed through short interfering RNA (siRNA) knockdown experiments.. Beginning at 12 weeks of age, Alox5 (-/-) mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels (p<0.05). Although Alox5 (-/-) mice did not exhibit insulin resistance, they had impaired insulin secretion in response to a bolus glucose injection. Histological analyses revealed that Alox5 (-/-) mice had increased islet area, beta cell nuclear size, and numbers of beta cells/mm(2) islet (p<0.05), indicative of both hyperplasia and hypertrophy. Basal and stimulated insulin secretion in isolated Alox5 (-/-) islets were significantly lower than in WT islets (p<0.05) and accompanied by a three- to fivefold decrease in the expression of the genes encoding insulin and pancreatic duodenal homeobox 1 (Pdx1). Direct perturbation of ALOX5 in isolated human islets with siRNA decreased insulin and PDX1 gene expression by 50% and insulin secretion by threefold (p<0.05).. These results provide strong evidence for pleiotropic metabolic effects of 5-LO on adiposity and pancreatic function and may have important implications for therapeutic strategies targeting this pathway for the treatment of cardiovascular disease. Topics: 5-Lipoxygenase-Activating Proteins; Adipose Tissue; Animals; Arachidonate 5-Lipoxygenase; Blood Glucose; Body Composition; Body Weight; Carrier Proteins; Crosses, Genetic; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreas; RNA; RNA Interference; RNA, Small Interfering; Sex Characteristics; Tissue Donors | 2008 |
Fluoxetine alters feeding behavior and leptin levels in chronically-stressed rats.
Stress-induced alterations in feeding behavior are sexually dimorphic and have been related to changes in monoamine levels. Fluoxetine is commonly used as an antidepressant and has also been suggested as an adjunct to other strategies to treat obese individuals. Leptin may interact with stress hormones and with the brain serotonergic system, possibly affecting the feeding behavior of stressed rats. The aim of this study is to evaluate the interaction between chronic fluoxetine treatment and leptin levels in adult female Wistar rats submitted to chronic variable stress. After 30 days of stress, control and stressed groups were subdivided into two groups that received daily injections of vehicle or fluoxetine (8 mg/kg, i.p.). Body weight was evaluated before and after fluoxetine treatment. The animals gained weight with time, signifying that there is a difference in weight gain over time when fluoxetine-treated animals are, or not, subjected to the stress model. Both fluoxetine and stress induced a decrease in sweet food consumption. On the 60th day of fluoxetine treatment, leptin levels were decreased in fluoxetine-treated animals and there was no effect of stress. We conclude that chronic fluoxetine treatment induced a decreased intake of sweet food, as well as a reduction in leptin levels, and that this result could represent a compensatory response to reduced food intake rather than a direct anorectic mechanism. No interaction with chronic stress was observed. Topics: Animals; Body Weight; Chronic Disease; Estrous Cycle; Feeding Behavior; Female; Fluoxetine; Leptin; Nutritional Physiological Phenomena; Rats; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Stress, Psychological | 2008 |
Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines.
In obesity, decreases in adiponectin and increases in proinflammatory adipokines are associated with heart disease. Because adipocytes express mineralocorticoid receptor (MR) and MR blockade reduces cardiovascular inflammation and injury, we tested the hypothesis that MR blockade reduces inflammation and expression of proinflammatory cytokines in adipose tissue and increases adiponectin expression in adipose tissue and hearts of obese mice.. We determined the effect of MR blockade (eplerenone, 100 mg/kg per day for 16 weeks) on gene expression in retroperitoneal adipose and heart tissue from obese, diabetic db/db mice (n=8) compared with untreated obese, diabetic db/db mice (n=10) and lean, nondiabetic db/+ littermates (n=11). Expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, plasminogen activator inhibitor type 1, and macrophage protein CD68 increased, and expression of adiponectin and peroxisome proliferator-activated receptor-gamma decreased in retroperitoneal adipose tissue from obese versus lean mice. In addition, adiponectin expression in heart was reduced in obese versus lean mice. MR blockade prevented these obesity-related changes in gene expression. Furthermore, treatment of undifferentiated preadipocytes with aldosterone (10(-8) mol/L for 24 hours) increased mRNA levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 and reduced mRNA and protein levels of peroxisome proliferator-activated receptor-gamma and adiponectin, supporting a direct aldosterone effect on gene expression.. MR blockade reduced expression of proinflammatory and prothrombotic factors in adipose tissue and increased expression of adiponectin in heart and adipose tissue of obese, diabetic mice. These effects on adiponectin and adipokine gene expression may represent a novel mechanism for the cardioprotective effects of MR blockade. Topics: 3T3-L1 Cells; Adipokines; Adiponectin; Adipose Tissue; Aldosterone; Animals; Biomarkers; Body Weight; Diabetes Mellitus, Experimental; Homeostasis; Inflammation; Leptin; Male; Mice; Mice, Mutant Strains; Mineralocorticoid Receptor Antagonists; Myocardium; Obesity; PPAR gamma; Receptors, Mineralocorticoid; RNA, Messenger; Triglycerides | 2008 |
Age-specific effects of short- and long-term caloric restriction on the expression of adiponectin and adiponectin receptors: influence of intensity of food restriction.
Hormonal signals from adipose tissue regulate energy homeostasis and may be involved in anti-aging effects of caloric restriction (CR). The adipokine adiponectin is abundantly expressed in adipose tissue and directly sensitizes the body to insulin. The purpose of the current study was to investigate age-dependent effects of different levels of CR (16%, 2 months or 40%, 6 months) on adiponectin and on its receptors AdipoR1 and AdipoR2 in the left ventricle (LV). In young and senescent rats, 2 months of moderate CR reduced serum leptin. The same diet was sufficient to enhance serum adiponectin, adiponectin expression (visceral fat) and left ventricular AdipoR1 expression in young but not in senescent rats. The higher degree of CR, however, resulted in a mild induction of adiponectin expression in adipose tissue and release into plasma together with increased LV AdipoR1 also in old rats, while these effects were more pronounced in young rats. These changes in adiponectin activation were associated with reduced LV triglyceride content, suggesting an adiponectin-mediated reduced ectopic lipid deposition in nonadipose tissues. Thus, aging is associated with a loss of adiponectin inducibility by moderate CR. This reduction can only partially be overcome by increasing the degree and duration of CR. Topics: Adiponectin; Adipose Tissue; Aging; Animals; Body Weight; Caloric Restriction; Heart Ventricles; Leptin; Male; Organ Size; Rats; Rats, Sprague-Dawley; Receptors, Adiponectin; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Triglycerides | 2008 |
Prominent pancreatic endocrinopathy and altered control of food intake disrupt energy homeostasis in prion diseases.
Prion diseases are fatal neurodegenerative diseases that can induce endocrinopathies. The basis of altered endocrine function in prion diseases is not well understood, and the purpose of this study was to investigate the spatiotemporal relationship between energy homeostasis and prion infection in hamsters inoculated with either the 139H strain of scrapie agent, which induces preclinical weight gain, or the HY strain of transmissible mink encephalopathy (TME), which induces clinical weight loss. Temporal changes in body weight, feed, and water intake were measured as well as both non-fasted and fasted concentrations of serum glucose, insulin, glucagon, beta-ketones, and leptin. In 139H scrapie-infected hamsters, polydipsia, hyperphagia, non-fasted hyperinsulinemia with hyperglycemia, and fasted hyperleptinemia were found at preclinical stages and are consistent with an anabolic syndrome that has similarities to type II diabetes mellitus and/or metabolic syndrome X. In HY TME-infected hamsters, hypodipsia, hypersecretion of glucagon (in both non-fasted and fasted states), increased fasted beta-ketones, fasted hypoglycemia, and suppressed non-fasted leptin concentrations were found while feed intake was normal. These findings suggest a severe catabolic syndrome in HY TME infection mediated by chronic increases in glucagon secretion. In both models, alterations of pancreatic endocrine function were not associated with PrP(Sc) deposition in the pancreas. The results indicate that prominent endocrinopathy underlies alterations in body weight, pancreatic endocrine function, and intake of food. The prion-induced alterations of energy homeostasis in 139H scrapie- or HY TME-infected hamsters could occur within areas of the hypothalamus that control food satiety and/or within autonomic centers that provide neural outflow to the pancreas. Topics: Animals; Blood Glucose; Body Weight; Cricetinae; Drinking; Eating; Energy Metabolism; Glucagon; Glucose Tolerance Test; Homeostasis; Hypothalamus; Insulin; Leptin; Male; Mesocricetus; Pancreatic Diseases; Prion Diseases; PrPSc Proteins | 2008 |
Caloric restriction decreases cortical bone mass but spares trabecular bone in the mouse skeleton: implications for the regulation of bone mass by body weight.
Body weight is positively correlated with bone mass and density, and both muscle mass and body fat are thought to play a role in regulating bone metabolism. We examined bone metabolism in calorically restricted mice to determine how alterations in soft tissue mass affect bone mass, density, and strength.. Caloric restriction (CR) was initiated in male mice at 14 wk of age at 10% restriction, increased to 25% restriction at 15 wk, and then increased to 40% restriction at 16 wk, where it was maintained until 24 wk of age when the study was terminated. Control mice were fed ad libitum (AL). Body composition, BMD, and BMC were measured by DXA, BMD and BMC in the femoral metaphysis were measured by pQCT, femora were tested in three-point bending, serum leptin and IGF-1 were measured using immunoassay, and osteoblast and osteoclast numbers were determined using histomorphometry.. Body weight, lean mass, fat mass, percent body fat, serum leptin, and serum IGF-1 were all significantly lower in CR mice than AL mice. Whole body BMC and BMD did not differ significantly between the two groups. Femur BMC, BMD, cortical thickness, and fracture strength decreased significantly in CR mice, but trabecular bone volume fraction in the femur did not change with food restriction. Vertebral cortical thickness also decreased with caloric restriction, whereas spine BMC, BMD, and trabecular bone volume fraction were significantly increased with caloric restriction.. Caloric restriction and its related weight reduction are associated with marked decreases in lean mass, fat mass, serum leptin and IGF-1, and cortical bone mass. Consistent with the opposite effects of leptin on cortical and cancellous bone, trabecular bone mass is spared during food restriction. Topics: Animals; Biomarkers; Body Weight; Bone and Bones; Bone Density; Caloric Restriction; Insulin-Like Growth Factor I; Leptin; Male; Mice; Organ Size | 2008 |
Glucose transporter isoform-3-null heterozygous mutation causes sexually dimorphic adiposity with insulin resistance.
We examined male and female glucose transporter isoform-3 (GLUT3; placenta)-null heterozygous(+/-) mutation-carrying mice and compared them with age- and sex-matched wild-type(+/+) littermates. No difference in postnatal (1-2 days, 6-7 days, 12-13 days, 20-21 days), postsuckling (1-2 mo), and adult (3-6 mo) growth pattern was seen except for an increase in body weight of 9- to 11-mo-old male but not female GLUT3(+/-) mice. This change in male mutant mice was associated with increased total body fat mass, perirenal and epididymal white adipose tissue weight, and hepatic lipid infiltration. These minimally glucose-intolerant male mutant mice demonstrated no change in caloric intake but a decline in basal metabolic rate and insulin resistance. No perturbation in basal circulating glucose concentrations but an increase in insulin concentrations, triglycerides, and total cholesterol was observed in GLUT3(+/-) male mice. Tissue analysis in males and females demonstrated diminished GLUT3 protein in GLUT3(+/-) brain and skeletal muscle with no change in brain and adipose tissue GLUT1 protein concentrations. Furthermore, the male GLUT3(+/-) mice expressed decreased insulin-responsive GLUT4 in white adipose tissue and skeletal muscle sarcolemma. We conclude that the GLUT3(+/-) male mice develop adult-onset adiposity with insulin resistance. Topics: Adiposity; Animals; Animals, Newborn; Basal Metabolism; Blood Glucose; Body Composition; Body Weight; Eating; Female; Glucose Transporter Type 3; Histocytochemistry; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains | 2008 |
Anxiety-like behaviour in adult rats perinatally exposed to maternal calorie restriction.
Environmental stimuli such as caloric availability during the perinatal period exert a profound influence on the development of an organism. Studies in this domain have focused on the effects of under- and malnutrition while the effects of more mild levels of restriction have not been delineated. Rat dams and their offspring were subjected to one of five dietary regimens: control, CR50% for 3 days preconception, CR25% during gestation, CR25% during lactation, and CR25% during gestation, lactation, and post-weaning (lifelong). The pup retrieval test and maternal observations were conducted during lactation to quantify maternal care. In the pup retrieval test, dams that were concurrently experiencing CR (i.e., from the lactation and lifelong groups) displayed shorter latencies to retrieve all pups than the control and preconception groups and the lactation group constructed better nests than all groups. Adult offspring were tested in three tests of anxiety: the elevated plus maze, open field, and emergence test. No differences were observed in the elevated plus maze; however, in the open field preconception animals made fewer entries and spent more time in the central zone than controls. In addition, preconception offspring exhibited longer latencies to full body emergence, spent less time fully emerged, and spent more time engaged in risk assessment behaviours than all other groups. Offspring from the preconception group were also on average 11% heavier than control rats throughout life and displayed 37% higher serum leptin concentrations than controls. A potential role for leptin in the anxiogenic effect of preconception CR is discussed. Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Anxiety; Behavior, Animal; Body Weight; Caloric Restriction; Embryo, Mammalian; Exploratory Behavior; Female; Leptin; Male; Maternal Behavior; Maze Learning; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Video Recording | 2008 |
The impact of a leptin gene SNP on beef calf weaning weights.
Prior research indicates that a SNP at position 305 of exon 2 in the leptin gene affects milk production in dairy cows. Dairy cows with at least one copy of the T allele have been shown to have higher milk production than CC cows. If that effect carries over to beef breeds, it is reasonable to expect that CT and TT beef cows will wean heavier calves than CC beef cows. We tested this hypothesis for a herd of mixed breed cows using anova. Results indicated that both crossbred CT and TT beef cows wean significantly heavier beef calves than CC crossbred beef cows. A lack of observations generally hinders detection of significance in other breeds. However, two other comparisons were found to be significant. The results suggest further investigation into the link between leptin genotype and calf weaning weights. Aside from interest to animal scientists, these results have the potential to alter mating and replacement selection decisions by cow-calf producers, given the importance of weaning weights on profitability. Topics: Animals; Body Weight; Breeding; Cattle; Female; Genotype; Leptin; Polymorphism, Single Nucleotide; Weaning | 2008 |
The effects of age on uptake, serum half-life and bioavailability of mouse [D-Leu-4]OB3, a synthetic peptide amide with leptin-like activity, in male C57BL/6J mice.
We have previously shown that the activity of a synthetic peptide amide corresponding to amino acid residues 116-130 of mouse leptin is contained in a restricted sequence at the amino terminus of the peptide, between residues 116 and 122 (Ser-Cys-Ser-Leu-Pro-Glu-Thr). This peptide was named mouse OB3. The potency of OB3 was improved by replacing the L-leucine residue at position four with its D-isomer. Intraperitoneal administration (i.p.) of mouse OB3 or [D-Leu-4]OB3 to ob/ob and db/db mice reduces food intake, body weight gain and serum glucose levels, and enhances insulin sensitivity. These effects of OB3 and [D-Leu-4]OB3 are very pronounced in young mice and diminish with age. In the present study, we measured uptake, serum half-life, and bioavailability of mouse [D-Leu-4]OB3 in mice of different ages. Groups of male C57BL/6J mice, six and 25 weeks of age, were given a single i.p. injection of 1 mg mouse [D-Leu-4]OB3 in PBS. Five, 10, 20, 40, 60, 120, or 180 min after injection, the mice were anesthetized and exsanguinated. Serum samples were prepared and assayed for mouse [D-Leu-4]OB3 content by competitive ELISA. In six week-old mice, the maximum concentration of mouse [D-Leu-4]OB3 was reached in 10 min, and the serum half-life was approximately 52.5 min. In 25 week-old mice, however, mouse [D-Leu-4]OB3 peaked in 5 min, and the serum half-life was approximately 30.6 min. The relative bioavailability of mouse [D-Leu-4]OB3 in six and 25 week-old mice was determined by measuring the area under the uptake curves. Bioavailability of mouse [D-Leu-4]OB3 was approximately 20% greater in six week-old mice than in 25 week-old mice. The results of this study indicate that at least some pharmacokinetic parameters of peptide uptake change as mice age. They also suggest that differences in uptake, serum half-life, and relative bioavailability of mouse [D-Leu-4]OB3 may contribute, at least in part, to the reduced efficacy of bioactive leptin-related peptides we have consistently observed in ob/ob and db/db mice as they age. Topics: Aging; Animals; Area Under Curve; Biological Availability; Body Weight; Enzyme-Linked Immunosorbent Assay; Half-Life; Injections, Intraperitoneal; Leptin; Male; Metabolic Clearance Rate; Mice; Mice, Inbred C57BL; Peptide Fragments; Stereoisomerism | 2008 |
Effects of chronic food restriction and treatments with leptin or ghrelin on different reproductive parameters of male rats.
The existence of a close relationship between energy status and reproductive function is well-documented, especially in females, but its underlying mechanisms remain to be fully unfolded. This study aimed to examine the effects of restriction of daily calorie intake, as well as chronic treatments with the metabolic hormones leptin and ghrelin, on the secretion of different reproductive hormones, namely pituitary gonadotropins and prolactin, as well as testosterone, in male rats. Restriction (50%) in daily food intake for 20 days significantly reduced body weight as well as plasma PRL and T levels, without affecting basal LH and FSH concentrations and testicular weight. Chronic administration of leptin to rats fed ad libitum increased plasma PRL levels and decreased circulating T, while it did not alter other hormonal parameters under analysis. In contrast, in rats subjected to 50% calorie restriction, leptin administration increased plasma T levels and reduced testis weight. Conversely, ghrelin failed to induce major hormonal changes but tended to increase testicular weight in fed animals, while repeated ghrelin injections in food-restricted males dramatically decreased plasma LH and T concentrations and reduced testis weight. In sum, we document herein the isolated and combined effects of metabolic stress (50% food restriction) and leptin or ghrelin treatments on several reproductive hormones in adult male rats. Overall, our results further stress the impact and complex way of action of different metabolic cues, such as energy status and key hormones, in reproductive function also in the male. Topics: Animals; Body Weight; Caloric Restriction; Follicle Stimulating Hormone; Ghrelin; Immunoassay; Leptin; Luteinizing Hormone; Male; Organ Size; Prolactin; Rats; Rats, Wistar; Testis; Testosterone | 2008 |
Differential expression of hypothalamic CART mRNA in response to body weight change following different dietary interventions.
Cocaine- and amphetamine-regulated transcript (CART) peptide is widely expressed in the hypothalamus and is involved in the central regulation of energy balance. Using in situ hybridization, this study examined the roles of CART peptide in the hypothalamus of diet-induced obese (DIO) or diet-resistant (DR) mice under different dietary interventions including high-fat (HF), low-fat (LF) and pair-feeding (PF) diet for 6 weeks. Pair feeding the energy intake of the DIO and DR mice was used to determine whether there is an inherent difference in baseline CART expression that may cause the DIO and DR phenotypes. The results demonstrated that CART mRNA expression in the hypothalamus of the DIO mice responded differently on the high-fat diet compared to DR mice. The arcuate nucleus and paraventricular nucleus showed a significant reduction in CART mRNA expression in DIO mice compared to DR mice on the HF diet (-19.6%, p=0.019; -26.1%, p=0.003); whilst a profound increase in CART mRNA expression was observed in the dorsomedial nucleus and lateral hypothalamic area (+44.5%, p=0.007; +37.4%, p=0.033). Our study suggests that the decrease of CART mRNA expression in Arc and PVN regions of DIO mice may contribute to the development of high-fat diet-induced obesity. In addition, CART in the dorsomedial nucleus (DM) of hypothalamus and lateral hypothalamus (LH) may be involved in the activation of an orexigenic effect. Since pair feeding of the high-fat diet eliminated both the body weight and CART mRNA differences between the DIO and DR mice, it is likely that their alterations in gene expression were a consequence of their dissimilar body weight levels. Topics: Adipose Tissue; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Caloric Restriction; Dorsomedial Hypothalamic Nucleus; Eating; Energy Metabolism; Food, Formulated; Gene Expression Regulation; Hypothalamic Area, Lateral; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Obesity; Paraventricular Hypothalamic Nucleus; RNA, Messenger | 2008 |
Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies.
Body weight is regulated by complex neurohormonal interactions between endocrine signals of long-term adiposity (e.g., leptin, a hypothalamic signal) and short-term satiety (e.g., amylin, a hindbrain signal). We report that concurrent peripheral administration of amylin and leptin elicits synergistic, fat-specific weight loss in leptin-resistant, diet-induced obese rats. Weight loss synergy was specific to amylin treatment, compared with other anorexigenic peptides, and dissociable from amylin's effect on food intake. The addition of leptin after amylin pretreatment elicited further weight loss, compared with either monotherapy condition. In a 24-week randomized, double-blind, clinical proof-of-concept study in overweight/obese subjects, coadministration of recombinant human leptin and the amylin analog pramlintide elicited 12.7% mean weight loss, significantly more than was observed with either treatment alone (P < 0.01). In obese rats, amylin pretreatment partially restored hypothalamic leptin signaling (pSTAT3 immunoreactivity) within the ventromedial, but not the arcuate nucleus and up-regulated basal and leptin-stimulated signaling in the hindbrain area postrema. These findings provide both nonclinical and clinical evidence that amylin agonism restored leptin responsiveness in diet-induced obesity, suggesting that integrated neurohormonal approaches to obesity pharmacotherapy may facilitate greater weight loss by harnessing naturally occurring synergies. Topics: Adipose Tissue; Amyloid; Animals; Body Weight; Caloric Restriction; Disease Models, Animal; Hormones; Hypothalamus; Islet Amyloid Polypeptide; Leptin; Models, Biological; Obesity; Oxygen Consumption; Rats | 2008 |
Adaptation to lactation in OLETF rats lacking CCK-1 receptors: body weight, fat tissues, leptin and oxytocin.
To understand the adaptation to lactation of obese rats, by studying the interplay among the gut hormone cholecystokinin (CCK), the adiposity hormone leptin and the affiliation hormone oxytocin in modulating body mass and fat storage.. Strain differences were examined between Otsuka Long Evans Tokushima Fatty (OLETF) rats lacking expression of functional CCK-1 receptors and Long Evans Tokushima Otsuka (LETO) controls, tested as nulliparous dams, at the 7 and 15th lactation day, at weaning (lactation day 22) or 8 weeks postweaning.. We measured body mass, fat pads (brown, retroperitoneal and inguinal) and inguinal adipocytes. Plasma levels of leptin and oxytocin were determined.. Fat depots of LETO female rats were larger during lactation compared to the levels found in postweaning and nulliparous female rats. LETO female rats gained weight and accumulated fat during pregnancy and lactation, returning to their normal fat levels postweaning. In contrast, OLETF female rats presented lower body weight and fat depots during the lactation period than nulliparous dams, and regained the weight and fat postweaning. Plasma leptin and oxytocin were highly correlated and followed the same pattern. OLETF leptin levels were highly correlated with fat depot and inguinal cell surface. No significant correlation was found for LETO parameters.. Pregnancy and lactation are energy-consuming events, which naturally induce female rats to increase food intake and accumulate fat. When challenged by the demands of rapidly growing preobese OLETF pups, OLETF dams' fat stores are reduced to lean, LETO levels. During lactation, sensitivity of the oxytocinergic neurons descending from the paraventricular nuclei to the nucleus of the solitary tract to CCK is reduced. We theorized that this pathway is not available to OLETF female rats that lack functional CCK-1 receptors to mediate the signal. The current study contributes to the understanding of the female body's adaptation to lactation. Topics: Adaptation, Physiological; Adipocytes; Adipose Tissue; Animals; Body Weight; Disease Models, Animal; Female; Hypertrophy; Lactation; Leptin; Mutation; Obesity; Oxytocin; Rats; Rats, Inbred OLETF; Receptors, Cholecystokinin; Weaning; Weight Gain | 2008 |
Reduction of hypothalamic protein tyrosine phosphatase improves insulin and leptin resistance in diet-induced obese rats.
Protein tyrosine phosphatase (PTP1B) has been implicated in the negative regulation of insulin and leptin signaling. PTP1B knockout mice are hypersensitive to insulin and leptin and resistant to obesity when fed a high-fat diet. We investigated the role of hypothalamic PTP1B in the regulation of food intake, insulin and leptin actions and signaling in rats through selective decreases in PTP1B expression in discrete hypothalamic nuclei. We generated a selective, transient reduction in PTP1B by infusion of an antisense oligonucleotide designed to blunt the expression of PTP1B in rat hypothalamic areas surrounding the third ventricle in control and obese rats. The selective decrease in hypothalamic PTP1B resulted in decreased food intake, reduced body weight, reduced adiposity after high-fat feeding, improved leptin and insulin action and signaling in hypothalamus, and may also have a role in the improvement in glucose metabolism in diabetes-induced obese rats. Topics: Adiposity; Animals; Body Weight; Diet, Atherogenic; Drug Resistance; Eating; Glucose; Hypothalamus; Injections, Intraventricular; Insulin; Leptin; Male; Obesity; Oligonucleotides, Antisense; Protein Tyrosine Phosphatases; Rats; Rats, Wistar; Satiation; Signal Transduction | 2008 |
Effects of leptin deficiency on postnatal lung development in mice.
Leptin modulates energy metabolism and lung development. We hypothesize that the effects of leptin on postnatal lung development are volume dependent from 2 to 10 wk of age and are independent of hypometabolism associated with leptin deficiency. To test the hypotheses, effects of leptin deficiency on lung maturation were characterized in age groups of C57BL/6J mice with varying Lep(ob) genotypes. Quasi-static pressure-volume curves and respiratory impedance measurements were performed to profile differences in respiratory system mechanics. Morphometric analysis was conducted to estimate alveolar size and number. Oxygen consumption was measured to assess metabolic rate. Lung volume at 40-cmH(2)O airway pressure (V(40)) increased with age in each genotypic group, and V(40) was significantly (P < 0.05) lower in leptin-deficient (ob/ob) mice beginning at 2 wk. Differences were amplified through 7 wk of age relative to wild-type (+/+) mice. Morphometric analysis showed that alveolar surface area was lower in ob/ob compared with +/+ and heterozygote (ob/+) mice beginning at 2 wk. Unlike the other genotypic groups, alveolar size did not increase with age in ob/ob mice. In another experiment, ob/ob at 4 wk received leptin replacement (5 microg.g(-1) x day(-1)) for 8 days, and expression levels of the Col1a1, Col3a1, Col6a3, Mmp2, Tieg1, and Stat1 genes were significantly increased concomitantly with elevated V(40). Leptin-induced increases in V(40) corresponded with enlarged alveolar size and surface area. Gene expression suggested a remodeling event of lung parenchyma after exogenous leptin replacement. These data support the hypothesis that leptin is critical to postnatal lung remodeling, particularly related to increased V(40) and enlarged alveolar surface area. Topics: Aging; Air Pressure; Airway Resistance; Animals; Body Weight; Female; Leptin; Lung; Male; Mice; Mice, Knockout; Oxygen Consumption; Pulmonary Alveoli; Respiratory Mechanics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2008 |
Tea catechin ingestion combined with habitual exercise suppresses the aging-associated decline in physical performance in senescence-accelerated mice.
Catechins, which are abundant in green tea, possess a variety of biologic actions, and their clinical application has been extensively investigated. In this study, we examined the effects of tea catechins and regular exercise on the aging-associated decline in physical performance in senescence-accelerated prone mice (SAMP1) and age-matched senescence-accelerated resistant mice (SAMR1). The endurance capacity of SAMR1 mice, measured as the running time to exhaustion, tended to increase over the 8-wk experimental period, whereas that of SAMP1 mice decreased by 17%. On the other hand, the endurance capacity of SAMP1 mice fed 0.35% (wt/wt) catechins remained at the initial level and was significantly higher than that of SAMP1 mice not fed catechins. In SAMP1 mice fed catechins and given exercise, oxygen consumption was significantly increased, and there was an increase in skeletal muscle fatty acid beta-oxidation. The mRNA levels of mitochondria-related molecules, such as peroxisome proliferator-activated receptor-gamma coactivator-1, cytochrome c oxidase-II, III, and IV in skeletal muscle were also higher in SAMP1 mice given both catechins and exercise. Moreover, oxidative stress measured as thiobarbituric reactive substances was lower in SAMP1 groups fed catechins than in the SAMP1 control group. These results suggest that long-term intake of catechins, together with habitual exercise, is beneficial for suppressing the aging-related decline in physical performance and energy metabolism and that these effects are due, at least in part, to improved mitochondrial function in skeletal muscle. Topics: Adaptation, Physiological; Adiponectin; Aging; Animals; Blood Glucose; Body Weight; Catechin; Energy Metabolism; Fatty Acids; Gene Expression Profiling; Gene Expression Regulation; Insulin; Leptin; Male; Mice; Mice, Inbred Strains; Motor Activity; Physical Conditioning, Animal; Physical Endurance; RNA, Messenger; Running; Tea | 2008 |
Dehydroepiandrosterone prevents age-associated alterations, increasing insulin sensitivity.
The age decline in DHEA levels has been associated with the appearance of age-related disorders such as obesity and insulin resistance. The aim of this study was to analyse the effect of chronic administration (13 weeks) of DHEA (5 g/kg diet) to old female rats fed on a high-fat diet on body weight and adiposity, and concretely on the expression of the adipokines related to obesity and insulin resistance, such as leptin, adiponectin and resistin. DHEA treatment induced a decrease in body weight, adipose tissue mass and serum insulin, adiponectin and leptin levels. Adiponectin mRNA expression in visceral fat depots decreased with aging, but this reduction was attenuated by DHEA treatment. DHEA treatment also stimulated resistin gene expression in the ovaric and renal adipose depots, which is associated with an increase in its circulating levels. In conclusion, DHEA treatment decreases body weight and adiposity in old female rats fed a high-fat diet, leading to an improvement of the HOMA index for insulin sensitivity, with decreasing circulating insulin levels, and preventing the age-associated decline of visceral-adipose adiponectin expression. Topics: Adipocytes; Adiponectin; Aging; Animals; Appetite; Body Weight; Dehydroepiandrosterone; Energy Intake; Female; Insulin; Leptin; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Resistin; RNA, Messenger; RNA, Ribosomal, 18S | 2008 |
Dietary fructose during the suckling period increases body weight and fatty acid uptake into skeletal muscle in adult rats.
The suckling period is one potentially "critical" period during which nutritional intake may permanently "program" metabolism to promote increased adult body weight and insulin resistance in later life. This study determined whether fructose introduced during the suckling period altered body weight and induced changes in fatty acid transport leading to insulin resistance in adulthood in rats.. Pups were randomly assigned to one of four diets: suckle controls (SCs), rat milk substitute formula (Rat Milk Substitute), fructose-containing formula (Fructose), or galactose-containing formula (Galactose). Starting at weaning, all pups received the same diet; at 8 weeks of age, half of the SC rats began ingesting a diet containing 65% kcal fructose (SC-Fructose). This continued until animals were 12 weeks old and the study ended.. At weeks 8, 10, and 11, the Fructose group weighed more than SC and SC-Fructose groups (P < 0.05). At weeks 8 and 10 of age, the Fructose group had significantly higher insulin concentrations vs. rats in the SC-Fructose group. (3)H-Palmitate transport into vesicles from hind limb skeletal muscle was higher in Fructose vs. SC rats (P < 0.05). CD36 expression was increased in the sarcolemma but not in whole tissue homogenates from skeletal muscle from Fructose rats (P < 0.05) suggesting a redistribution of this protein associated with fatty acid uptake across the plasma membrane. This change in subcellular localization of CD36 is associated with insulin resistance in muscle.. Consuming fructose during suckling may result in lifelong changes in body weight, insulin secretion, and fatty acid transport involving CD36 in muscle and ultimately promote insulin resistance. Topics: Adipose Tissue; Aging; Animals; Animals, Suckling; Blood Glucose; Body Weight; CD36 Antigens; Dietary Carbohydrates; Fatty Acids; Female; Fructose; Insulin; Leptin; Liver; Male; Models, Animal; Muscle, Skeletal; Pregnancy; Rats; Rats, Sprague-Dawley; Triglycerides | 2008 |
High-fat diet-induced changes in body mass and hypothalamic gene expression in wild-type and leptin-deficient mice.
We tested whether diet-induced obesity results from increased energy consumption, is associated with changes in expression of genes involved in leptin signal transduction, and is altered by hyperleptinemia. C57BL/6 mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for up to 15 weeks. HFD mice weighed significantly more than LFD controls by 3 weeks, despite consuming less energy. HFD mice had significantly greater leptin, insulin, and glucose levels than LFD mice, suggesting leptin and insulin resistance. Adiponectin levels declined with age but were unaffected by diet. HFD was associated with altered hypothalamic expression of genes whose products regulate the activity or nuclear translocation of STAT3, an important mediator of leptin actions. Expression of two isoforms of the leptin receptor decreased at 15 weeks in hypothalami of HFD mice in a tissue-specific manner. The type of fat (saturated versus unsaturated) did not influence weight gain on an HFD, but animals on LFD gained significantly more weight and adiposity if the dietary fat consisted mostly of saturated fats; this occurred despite no difference in energy consumption or absorption. Replacement of leptin to leptin-deficient ob/ob mice decreased hypothalamic leptin receptor expression and did not prevent HFD-induced weight gain. It is concluded that (1) increased energy consumption is not required for HFD-induced obesity in C57BL/6 mice, (2) HFD results in weight gain partly by modulating hypothalamic leptin-signaling pathways, (3) saturated fats induce weight gain even when total fat content of the diet is low, and (4) the effects of HFD are manifest in the presence or absence of circulating leptin. Topics: Adiponectin; Adiposity; Animals; Blood Glucose; Body Composition; Body Weight; Dietary Fats; Energy Intake; Female; Gene Expression; Hypothalamus; Insulin; Intestinal Absorption; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Weight Gain | 2008 |
Impairment of nutritional regulation of adipose triglyceride lipase expression with age.
Fasting-induced lipolysis becomes less effective with age. We have studied whether nutritional regulation of adipose triglyceride lipase (ATGL)--with an important role in lipolysis in low energy states--is affected by age.. Wistar rats of different ages (from 1 to 13 months) were distributed in control and fasted groups (14 h-food deprivation). ATGL mRNA expression was measured in different adipose depots at different ages and in only one depot at 13 months by reverse transcription (RT)-PCR. ATGL protein levels were determined at 3 and 7 months (not at 13 months) by western blot. Nonesterified fatty acid (NEFA), insulin and leptin levels were assessed in serum by enzymatic assays.. ATGL expression was dependent on regional fat distribution, with higher levels in brown than in white adipose tissue depots; and was affected by age: ATGL mRNA was increased with age in the brown adipose tissue and was decreased in two of the studied white depots, the inguinal and retroperitoneal, not being affected in the epididymal and mesenteric. Age also affected ATGL nutritional regulation: fasting increased ATGL gene expression and protein levels in the different white adipose depots of the youngest rats (up to the age of 5 months), whereas there was no change in the oldest rats studied (7 and 13-months old). This was in agreement with the pattern of NEFA levels, which did not increase in serum of fasted rats in the oldest animals, whereas other homeostatic parameters, such as insulin and leptin, responded to fasting independently of age. ATGL expressed by brown adipose tissue was not affected by feeding conditions at any age.. Nutritional regulation of ATGL expression in white adipose tissue is impaired with age, which could contribute to the increased difficulty for mobilizing lipids when animals are exposed to nutritional stress such as fasting. Topics: Adipose Tissue; Adipose Tissue, White; Adiposity; Aging; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Fasting; Fatty Acids, Nonesterified; Gene Expression Regulation, Enzymologic; Insulin; Leptin; Lipase; Lipolysis; Male; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sterol Esterase | 2008 |
Assessment of adiponectin and leptin as biomarkers of positive metabolic outcomes after lifestyle intervention in overweight and obese children.
A number of metabolic changes are caused by childhood obesity, including insulin resistance, diabetes, and dyslipidemia. To counteract them, lifestyle modification with changes in dietary habits and physical activity is the primary intervention. Anthropometric parameters may not identify all positive changes associated with lifestyle modifications, whereas circulating adipokines may represent an alternative as biomarkers. The aim of this study was to evaluate adiponectin and leptin levels as markers of positive metabolic outcomes in childhood obesity.. Changes in clinical, anthropometric, and metabolic parameters, including adiponectin and leptin, were assessed in 104 overweight and obese children before and after 1 yr of lifestyle intervention. Obesity and overweight were defined according to the Italian body mass index reference tables for age and sex. Fifty-four normal-weight children were evaluated as controls. Forty-eight of the children (47.5%) returned for follow-up at 1 yr.. Compared with normal-weight children, overweight and obese subjects differed significantly at baseline for glycemia, insulinemia, homeostasis model assessment for insulin resistance, adiponectinemia (5.8 vs. 18.2 microg/ml in controls), low-density lipoprotein-cholesterol, and triglycerides. These parameters were all higher in the overweight/obese children. At follow-up, most parameters improved in overweight/obese children. The most significant changes were observed in adiponectin concentration, which increased by 245% (P < 0.0001), reaching the levels observed in normal-weight children. Leptin levels showed changes unrelated to positive metabolic outcomes, remaining high at 1 yr of follow-up in overweight/obese children. Regardless of changes in weight status, children with lifestyle intervention reported changes in homeostasis model assessment for insulin resistance and in adiponectin that were associated with loss of fat mass.. After lifestyle intervention, adiponectin increased regardless of changes in weight, whereas no consistent changes was observed in serum leptin. Therefore, circulating adiponectin may represent a good biomarker to evaluate the efficacy of lifestyle intervention in overweight/obese children. Topics: Adiponectin; Adolescent; Biomarkers; Body Weight; Child; Female; Humans; Insulin Resistance; Leptin; Life Style; Male; Obesity; Overweight | 2008 |
Thyroid hormones and their relation to weight status.
The aim of this study was to analyze thyroid hormones in female adolescents with obesity and anorexia nervosa (AN) before and after normalization of weight.. Thyroid-stimulating hormone (TSH), fT3, and fT4 were determined in 100 obese girls, 32 normal-weight girls and 20 girls with AN aged 14-18 years at baseline and 1 year later. Additionally, leptin, insulin, and the insulin resistance index HOMA were analyzed in the obese and normal-weight girls.. TSH and fT3 levels of girls with AN were significantly lower compared to TSH concentrations of normal-weight girls, while TSH and fT3 levels of the obese girls were significantly higher. The 21 obese females with weight loss >5% demonstrated a significant decrease in fT3 and TSH, while the 9 adolescents with AN and weight gain >5% showed a significant increase in fT3 and TSH. Insulin and HOMA were not significantly correlated to TSH, fT3 and fT4, while leptin was correlated to TSH and fT3 in both cross-sectional and longitudinal analysis.. Thyroid function seems to be reversibly related to weight status with increased TSH and fT3 concentrations in obesity and decreased TSH and fT3 levels in AN. We hypothesize that leptin may be the link between weight status and TSH. Topics: Adolescent; Anorexia Nervosa; Body Weight; Female; Follow-Up Studies; Humans; Insulin; Insulin Resistance; Leptin; Obesity; Thyrotropin; Thyroxine; Triiodothyronine | 2008 |
Loss of resistin ameliorates hyperlipidemia and hepatic steatosis in leptin-deficient mice.
Resistin has been linked to components of the metabolic syndrome, including obesity, insulin resistance, and hyperlipidemia. We hypothesized that resistin deficiency would reverse hyperlipidemia in genetic obesity. C57Bl/6J mice lacking resistin [resistin knockout (RKO)] had similar body weight and fat as wild-type mice when fed standard rodent chow or a high-fat diet. Nonetheless, hepatic steatosis, serum cholesterol, and very low-density lipoprotein (VLDL) secretion were decreased in diet-induced obese RKO mice. Resistin deficiency exacerbated obesity in ob/ob mice, but hepatic steatosis was drastically attenuated. Moreover, the levels of triglycerides, cholesterol, insulin, and glucose were reduced in ob/ob-RKO mice. The antisteatotic effect of resistin deficiency was related to reductions in the expression of genes involved in hepatic lipogenesis and VLDL export. Together, these results demonstrate a crucial role of resistin in promoting hepatic steatosis and hyperlipidemia in obese mice. Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Cholesterol; Cohort Studies; Fatty Liver; Hyperlipidemias; Immunohistochemistry; Insulin; Leptin; Lipoproteins, VLDL; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Resistin; Triglycerides | 2008 |
Gene expression in arcuate nucleus-median eminence of rats treated with leptin or ciliary neurotrophic factor.
Ciliary neurotrophic factor (CNTF) and leptin are cytokine-like% hormones and act on their corresponding receptors in the hypothalamic arcuate nucleus (ARC). The present study was designed to assess effects of intracerebroventricular (ICV) injection of leptin and CNTF on gene expression in micropunched hypothalamic arcuate nucleus-median eminence (ARC-ME) complex samples from rats. Male Sprague Dawley rats were implanted with lateral cerebroventricular cannulas for administration of control, 10 microg/d leptin or 5 microg/d CNTF for four days. Real-time Taqmantrade mark RT-PCR was used to quantitatively compare the mRNA levels of selected genes in the ARC-ME complex. Leptin and CNTF increased ARC-ME mRNA levels of signal transducer and activator of transcription 3 (STAT3) by 64.5 and 124.7% (p<0.01), suppressor of cytokine signaling 3 (SOCS3) by 258.9 and 1063.9% (p<0.01), cocaine and amphetamine regulated transcript (CART) by 102.7 and 123.1% (p<0.01), and proopiomelanocortin (POMC2) by 374.1 and 264.9% (p<0.01), respectively. Leptin increased growth hormone releasing hormone (GHRH) by 309.9% (p<0.01), while CNTF increased janus kinase 2 (JAK2) mRNA by 31.7% (p<0.01) and decreased gonadotropin releasing hormone 1 (GNRH1) by 59.7% (p<0.01), mitogen activated protein kinase 1 (MAPK1) by 19.4% (p<0.05) and tyrosine hydroxylase (TH) by 74.5% (p<0.05). Significant reduction in daily food intake and body weights by both the treatments was observed. Also, decrease in weights of fat pads was concomitant with lowered serum insulin and leptin levels. Our findings show that leptin and CNTF engage both convergent and divergent pathways involved in feeding, cellular signaling, inflammation, and other related regulatory systems. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Ciliary Neurotrophic Factor; Eating; Gene Expression; Gonadotropin-Releasing Hormone; Growth Hormone-Releasing Hormone; Injections, Intraventricular; Insulin; Janus Kinase 2; Leptin; Male; Median Eminence; Mitogen-Activated Protein Kinase 1; Nerve Tissue Proteins; Pro-Opiomelanocortin; Prostaglandin-E Synthases; Prostaglandin-Endoperoxide Synthases; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Tumor Necrosis Factor-alpha; Tyrosine 3-Monooxygenase | 2007 |
Dynamic changes of orexin A and leptin in obese children during body weight reduction.
In this study, we describe changes of plasma levels of the hypothalamic neuropeptide orexin A in obese children during the reduction of body weight and its relationship to other biochemical and anthropometrical parameters. We measured orexin A fasting plasma levels by the RIA method in 58 obese children--33 girls and 25 boys; mean age 13.1+/-0.38 years (range 7-18.5) before and after 5 weeks of weight-reduction therapy. Leptin, IGF-1, and IGFBP-3 levels were measured in all the subjects and were compared to orexin A levels and anthropometrical data. Average weight in subjects before weight-reduction was 74.2+/-2.79 kg and after weight-loss 67.4+/-2.60 kg (p<0.0001). Orexin A levels before the therapy were 33.3+/-1.97 pg/ml and after the therapy 51.7+/-3.07 pg/ml (p<0.0001). Levels of orexin A were not significantly different between girls and boys (p=0.7842). We found negative correlation between orexin A and age (r = -0.5395; p<0.0001), body height (r = -0.4751; p=0.0002), body weight (r = -0.4030; p=0.0017) and BMI (r = -0.2607; p=0.0481). No correlation was found between orexin A and IGF-1, IGFBP-3 or leptin. Orexin A plasma levels increased during body weight loss, whereas the reverse was true for leptin levels. These findings support the hypothesis that orexin A may be involved in regulation of nutritional status in children. Topics: Adolescent; Aging; Body Height; Body Mass Index; Body Weight; Child; Female; Humans; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptides; Nutritional Status; Obesity; Orexins; Radioimmunoassay; Weight Loss | 2007 |
Effect of nutrition during calfhood and peripubertal period on serum metabolic hormones, gonadotropins and testosterone concentrations, and on sexual development in bulls.
The objective of the present study was to characterize the effects of nutrition on circulating concentrations of metabolic hormones, gonadotropins, and testosterone during sexual development in bulls. Nutrition regulated the hypothalamus-pituitary-testes axis through effects on the GnRH pulse generator in the hypothalamus and through direct effects on the testes. Pituitary function (gonadotropin secretion after GnRH challenge) was not affected by nutrition. However, nutrition affected LH pulse frequency and basal LH concentration during the early gonadotropin rise (10-26 weeks of age). There were close temporal associations between changes in insulin-like growth factor-I (IGF-I) concentrations and changes in LH pulse frequency, suggesting a role for IGF-I in regulating the early gonadotropin rise in bulls. The peripubertal increase in testosterone concentration was delayed in bulls with lesser serum IGF-I concentrations (low nutrition), suggesting a role for IGF-I in regulating Leydig cell function. Serum IGF-I concentrations accounted for 72 and 67% of the variation in scrotal circumference and paired-testes volume, respectively (at any given age), indicating that IGF-I may regulate testicular growth. Bulls with a more sustained elevated LH pulse frequency during the early gonadotropin rise (high nutrition) had greater testicular mass at 70 weeks of age relative to the control group (medium nutrition), despite no differences in metabolic hormone concentrations after 26 weeks of age. Therefore, gonadotropin-independent mechanism regulating testicular growth might be dependent on previous gonadotropin milieu. Topics: Animals; Body Weight; Cattle; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Growth Hormone; Insulin; Insulin-Like Growth Factor I; Leptin; Luteinizing Hormone; Male; Nutritional Status; Random Allocation; Regression Analysis; Scrotum; Sexual Development; Testis; Testosterone | 2007 |
Changes in liver PPARalpha mRNA expression in response to two levels of high-safflower-oil diets correlate with changes in adiposity and serum leptin in rats and mice.
The ligand-dependent transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) is known to be activated by common fatty acids and to regulate the expression of genes of various lipid oxidation pathways and transport. High-fat diets provide more fatty acids, which presumably could enhance lipid catabolism through up-regulation of PPARalpha signaling. However, high intake of fat could also lead to obesity. To examine PPARalpha signaling in high-fat feeding and obesity, this study examined the hepatic mRNA expression of PPARalpha and some of its target genes in Wistar rats and C57BL/6J mice fed two levels (20% or 30% wt/wt) of high-safflower-oil (SFO; oleic-acid-rich) diets until animals showed significantly higher body weight (13 weeks for rats and 22 weeks for mice) than those of control groups fed a 5% SFO diet. At the end of these respective feeding periods, only the rats fed 30% SFO and the mice fed 20% SFO among the two groups fed high-fat diets showed significantly higher body weight, white adipose tissue weight, serum leptin and mRNA expression of PPARalpha (P<.05) compared to the respective control groups. Despite elevated acyl-CoA (a PPARalpha target gene) protein and activity in both groups fed high-fat diets, the mRNA expression level of most PPARalpha target genes examined correlated mainly to PPARalpha mRNA levels and not to fat intake or liver lipid levels. The observation that the liver PPARalpha mRNA expression in groups fed high-fat diets was significantly higher only in obese animals with elevated serum leptin implied that obesity and associated hyperleptinemia might have a stronger impact than dietary SFO intake per se on PPARalpha-regulated mRNA expression in the liver. Topics: Acyl-CoA Oxidase; Adipose Tissue; Adiposity; Animals; Body Weight; Cytochrome P-450 CYP4A; Dietary Fats, Unsaturated; Eating; Fatty Acids, Nonesterified; Gene Expression Regulation; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; PPAR gamma; Rats; Rats, Wistar; RNA, Messenger; Safflower Oil; Triglycerides | 2007 |
Difference in susceptibility to activity-based anorexia in two inbred strains of mice.
Food restricted rodents develop activity-based anorexia in the presence of a running wheel, characterised by increased physical activity, weight loss and decreased leptin levels. Here, we determined trait differences in the development of activity-based anorexia between C57BL/6J and DBA/2J inbred mouse lines previously reported as having low and high anxiety, respectively. C57BL/6J mice housed with running wheels and exposed to scheduled feeding reduced their wheel activity, in contrast to DBA/2J mice which exhibited increased behavioural activity under these conditions. Food restriction induced hypoleptinemia in both strains, but the decline in plasma leptin was stronger in DBA/2J mice and correlated with increased activity only in that strain. These data suggest that plasma leptin level dynamics rather than hypoleptinemia alone influences the development of activity-based anorexia and that recombinant inbred panels based on these progenitor lines offer opportunities for the identification of molecular determinants for anorexia nervosa related behavioural traits. Topics: Animals; Anorexia; Body Weight; Caloric Restriction; Eating; Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Motor Activity | 2007 |
Perinatal overfeeding in rats results in increased levels of plasma leptin but unchanged cerebrospinal leptin in adulthood.
To study the effect of perinatal programming and overfeeding on the hypothalamic control mechanisms of food intake in adult rats.. Neonatal programming effects on body weight, food intake, central and peripheral leptin levels, hypothalamic neuropeptides, leptin receptors and central leptin responsiveness in adult rats.. Plasma and cerebrospinal fluid (CSF) leptin levels were analyzed using radioimmunoassay. Neuropeptide mRNA levels were analyzed using in situ hybridization. Leptin receptor mRNA levels were analyzed using reverse transcriptase-polymerase chain reaction.. Perinatally overfed rats growing up in small litters (SL) maintain their obese and hyperleptinemic phenotype in adulthood. However, leptin levels in CSF are abnormally low considering the plasmatic hyperleptinemia. In contrast to the already reported changes in perinatally overfed juvenile rats, perinatally overfed adult rats did not show any alteration in the expression of leptin receptor isoforms and evaluated neuropeptides. Moreover, SL adult rats showed a normal sensitivity regarding the inhibitory effect of intracerebroventricular leptin administration on food intake.. Perinatal overfeeding does not induce alterations in either the anorectic response to central leptin administration or expression of leptin receptors and neuropeptides in adulthood. The leptin resistance to peripheral leptin in SL adult rats may be related to impaired leptin transport across the blood-brain barrier. Topics: Animals; Blood-Brain Barrier; Body Size; Body Weight; Eating; Female; Gene Expression Regulation; Hypothalamus; In Situ Hybridization; Leptin; Neuropeptides; Obesity; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2007 |
Energy expenditure adjusted for body composition differentiates constitutional thinness from both normal subjects and anorexia nervosa.
Constitutional thinness (CT) is characterized by a low and stable body mass index (BMI) without any hormonal abnormality. To understand the weight steadiness, energetic metabolism was evaluated. Seven CT, seven controls, and six anorexia nervosa (AN) young women were compared. CT and AN had a BMI <16.5 kg/m(2). Four criteria were evaluated: 1) energy balance including diet record, resting metabolic rate (RMR) (indirect calorimetry), total energy expenditure (TEE) (doubly labeled water), physical activity; 2) body composition (dual-energy X-ray absorptiometry); 3) biological markers (leptin, IGF-I, free T3); 4) psychological profile of eating behavior. The normality of free T3 (3.7 +/- 0.5 pmol/l), IGF-I (225 +/- 93 ng/ml), and leptin (8.3 +/- 3.4 ng/ml) confirmed the absence of undernutrition in CT. Their psychological profiles revealed a weight gain desire. TEE (kJ/day) in CT (8,382 +/- 988) was not found significantly different from that of controls (8,793 +/- 845) and AN (8,001 +/- 2,152). CT food intake (7,565 +/- 908 kJ/day) was found similar to that of controls (7,961 +/- 1,452 kJ/day) and higher than in AN (4,894 +/- 703 kJ/day), thus explaining the energy metabolism balance. Fat-free mass (FFM) (kg) was similar in CT and AN (32.5 +/- 2.9 vs. 34.1 +/- 1.9) and higher in controls (37.8 +/- 1.6). While RMR absolute values (kJ/day) were lower in CT (4,839 +/- 473) than in controls (5,576 +/- 209), RMR values adjusted for FFM were the highest in CT. TEE-to-FFM ratio was also higher in CT than in controls. Energetic metabolism balance maintains a stable low weight in CT. An increased energy expenditure-to-FFM ratio differentiates CT from controls and could account for the resistance to weight gain observed in CT. Topics: Adipose Tissue; Adolescent; Adult; Anorexia Nervosa; Basal Metabolism; Body Composition; Body Constitution; Body Mass Index; Body Weight; Diagnosis, Differential; Energy Metabolism; Female; Humans; Leptin; Thinness | 2007 |
Social defeat and footshock increase body mass and adiposity in male Syrian hamsters.
Obesity is a world-wide epidemic, and many factors, including stress, have been linked to this growing trend. After social stress (i.e., defeat), subordinate laboratory rats and most laboratory mice become hypophagic and, subsequently, lose body mass; the opposite is true of subordinate Syrian hamsters. After social defeat, Syrian hamsters become hyperphagic and gain body mass compared with nonstressed controls. It is unknown whether this increase in body mass and food intake is limited to subordinate hamsters. In experiment 1, we asked, do dominant hamsters increase food intake, body mass, and adiposity after an agonistic encounter? Subordinate hamsters increased food intake and body mass compared with nonstressed controls. Although there was no difference in food intake or absolute body mass between dominant and nonstressed control animals, cumulative body mass gain was significantly higher in dominant than in nonstressed control animals. Total carcass lipid and white adipose tissue (WAT) (i.e., retroperitoneal and epididymal WAT) masses were significantly increased in subordinate, but not dominant, hamsters compared with nonstressed controls. In experiment 2, we asked, does footshock stress increase food intake, body mass, and adiposity. Hamsters exposed to defeat, but not footshock stress, increased food intake relative to nonstressed controls. In animals exposed to defeat or footshock stress, body mass, as well as mesenteric WAT mass, increased compared with nonstressed controls. Collectively, these data demonstrate that social and nonsocial stressors increase body and lipid mass in male hamsters, suggesting that this species may prove useful for studying the physiology of stress-induced obesity in some humans. Topics: Adiposity; Agonistic Behavior; Animals; Body Composition; Body Weight; Cricetinae; Dominance-Subordination; Eating; Electroshock; Leptin; Male; Mesocricetus; Stress, Psychological; Testis; Testosterone; Weight Gain | 2007 |
Leptin gene transfer in the hypothalamus enhances longevity in adult monogenic mutant mice in the absence of circulating leptin.
Leptin, a product of the ob gene, is a pleiotropic signal implicated in regulation of multiple physiological functions in the periphery and centrally, including hypothalamic integration of energy homeostasis. Recessive mutations of ob gene result in early onset of hyperphagia, morbid obesity, metabolic disorders, early mortality and shortened life-span. Intracerebroventricular injection of recombinant adeno-associated virus vector (rAAV) encoding the leptin gene in adult obese ob/ob mice enhanced leptin transgene expression only in the hypothalamus, normalized food intake, body weight and more than doubled the life-span as compared to control cohorts and extended it to near that of normal wild type mice. These life-extending benefits were associated with drastic reductions in visceral fat, and blood glucose and insulin levels, but elevated ghrelin levels, the anti-aging biomarkers. Thus, bioavailability of leptin transduced by ectopic gene in the hypothalamus alone is both necessary and sufficient to normalize life-span. Evidently, site-specific ectopic gene expression with rAAV is durable and safe for alleviating neural disorders that stem from missing or functional disruption of a single gene. Topics: Adipose Tissue; Animals; Appetite Regulation; Blood Glucose; Body Weight; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Ghrelin; Hyperphagia; Hypothalamus; Injections, Intraventricular; Insulin; Leptin; Longevity; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Peptide Hormones | 2007 |
Leptin antagonist reveals that the normalization of caloric intake and the thermic effect of food after high-fat feeding are leptin dependent.
High-fat (HF) feeding induces a transient increase in caloric intake and enhances energy expenditure. We hypothesized that leptin is necessary for homeostatic restoration of the HF-enhanced caloric intake and may mediate the increase in uncoupling protein-1 (UCP1) in brown adipose tissue (BAT). We employed a leptin antagonist to examine the role of leptin in these biological processes. Simultaneous central administration of leptin and increasing doses of the leptin antagonist revealed a dose-dependent inhibition of leptin-induced hypothalamic signal transducer and activator of transcription-3 phosphorylation, and 7 days of infusion of the leptin antagonist produced the predicted increase in food intake and weight gain. When delivered with exogenous leptin in a 7-day infusion, the leptin antagonist blocked leptin-mediated anorexic effects as well as the increase in BAT UCP1 protein and signal transducer and activator of transcription-3 phosphorylation. Rats were then fed an HF diet (60% kcal as fat) or chow and simultaneously infused with antagonist (25 microg/day into the lateral ventricle) for 7 days and compared with vehicle-infused chow-fed rats. Daily caloric intake of both HF groups peaked on day 2. HF feeding elevated caloric intake, which nearly normalized by day 7, whereas in the presence of the antagonist, caloric intake remained elevated. Moreover, the HF-mediated augmentation in UCP1 in BAT was prevented by the antagonist. These results demonstrate that leptin is essential for the homeostatic restoration of caloric intake after HF feeding and that this leptin antagonist is able to block central leptin signaling and leptin-mediated UCP1 elevation. Topics: Adipose Tissue, Brown; Animals; Body Temperature Regulation; Body Weight; Diet; Dietary Fats; Energy Intake; Energy Metabolism; Food; Homeostasis; Hypothalamus; Ion Channels; Leptin; Male; Mitochondrial Proteins; Mutation; Phosphorylation; Rats; Rats, Inbred BN; Rats, Inbred F344; Signal Transduction; STAT3 Transcription Factor; Uncoupling Protein 1 | 2007 |
Circulating levels of adiponectin in preterm infants.
To determine circulating levels of adiponectin in preterm infants and examine possible associations with anthropometric measurements, weight gain, and leptin and insulin levels.. Prospective study.. A university hospital neonatal care unit.. 62 preterm (mean (SD) gestational age 32.0 (2.1) weeks) and 15 full-term infants (reference group).. Blood samples taken at discharge (40.9 (14.8) days of life) from the preterm infants and at a comparable postnatal age in full-term infants. All infants were fed the same commercial formula, but in nine preterms the formula contained long-chain polyunsaturated fatty acids (LCPUFAs).. Serum levels of adiponectin, leptin and insulin. Associations of adiponectin levels were tested only in the preterm group.. Serum levels of adiponectin were lower in preterm (40.9 (14.8) microg/ml) than full-term infants (53.1 (16.0) microg/ml, p<0.01). However, after adjustment for body weight, the influence of prematurity on adiponectin levels was no longer significant. In preterm infants, adiponectin levels independently correlated with being born small for gestational age (SGA) (beta=-0.35, p=0.01), weight gain (beta=0.28, p=0.03) and LCPUFA-supplemented formula (beta=0.34, p=0.009). Serum adiponectin levels did not correlate with insulin or leptin levels. However, insulin levels were higher in preterm than in full-term infants after adjustment for body weight.. Adiponectin levels are lower in preterm infants at discharge than full-term infants probably due to decreased adiposity. The levels are influenced by being born SGA, weight gain and, possibly, by dietary LCPUFAs. The importance of these findings in the development of insulin or leptin resistance in children born prematurely needs to be further studied. Topics: Adiponectin; Anthropometry; Birth Weight; Body Weight; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Insulin; Leptin; Male; Prospective Studies; Weight Gain | 2007 |
Leptin antagonist reveals an uncoupling between leptin receptor signal transducer and activator of transcription 3 signaling and metabolic responses with central leptin resistance.
Leptin-resistant rats have reduced leptin receptors and signaling and are refractory to exogenous leptin. However, it is unclear how leptin-mediated hypothalamic signal transducer and activator of transcription 3 (STAT3) signaling relates to the loss of physiological responsiveness. We hypothesized that if leptin resistance is associated with leptin receptors that are no longer functionally coupled to leptin responses, then a leptin antagonist should be less effective in leptin-resistant compared with leptin-responsive rats. Hypothalamic leptin resistance was induced in lean rats with a recombinant adeno-associated viral (rAAV) vector encoding leptin by intracerebroventricular injection. Following development of leptin resistance, at day 153, these rats and control rats were infused centrally either with vehicle or a rat leptin antagonist for 14 days. Food intake, body weight, adiposity, and uncoupling protein 1 expression increased with antagonist infusion in controls but elevated only marginally in leptin-resistant rats. Basal hypothalamic STAT3 signaling remained unchanged with antagonist infusion in control rats despite the pronounced orexigenic response in these animals. STAT3 phosphorylation in rats pretreated with rAAV-leptin to induce leptin resistance was elevated 2-fold. Paradoxically, in these leptin-resistant rats, the antagonist fully reversed the 2-fold elevated phosphorylated STAT3, but it evoked minimal physiological responses. These data reveal an uncoupling between leptin receptor activation and metabolic responses with central leptin resistance. Topics: Adiposity; Animals; Body Weight; Dependovirus; Eating; Hypothalamus; Ion Channels; Leptin; Male; Mitochondrial Proteins; Oxygen Consumption; Rats; Rats, Inbred BN; Rats, Inbred F344; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Uncoupling Protein 1 | 2007 |
Effect of human body weight changes on circulating levels of peptide YY and peptide YY3-36.
Recent findings suggest that low plasma peptide YY (PYY) levels may contribute to diet-induced human obesity and justify PYY replacement therapy. Although the pharmacological value of PYY is controversial, further study of the secretion of the precursor PYY(1-36) and the pharmacologically active PYY(3-36) is indicated to determine the potential role in energy balance regulation.. Our objective was to determine the effects of acute and chronic changes in human body weight on circulating levels of the putative satiety hormone peptide YY.. Total plasma PYY levels (PYY(1-36) + PYY(3-36)) were measured in 66 lean, 18 anorectic, 63 obese, and 16 morbidly obese humans. In addition, total PYY was measured in 17 of the obese patients after weight loss and in the 18 anorectic patients after weight gain. Fasting PYY(3-36) levels were measured in 17 lean and 15 obese individuals.. Fasting total plasma PYY levels were highest in patients with anorexia nervosa (80.9 +/- 12.9 pg/ml, P < 0.05) compared with lean (52.4 +/- 4.6 pg/ml), obese (43.9 +/- 3.8 pg/ml), or morbidly obese (45.6 +/- 11.2 pg/ml) subjects. In obese patients, weight loss of 5.4% was associated with a 30% decrease in fasting total PYY plasma levels. In anorectic patients, weight gain had no effect on fasting PYY. PYY(3-36) levels did not differ between lean (96.2 +/- 8.6 pg/ml) and obese (91.5 +/- 6.9 pg/ml) subjects.. Our findings do not support a role for abnormal circulating PYY in human obesity. We conclude that circulating PYY levels in humans are significantly elevated in anorexia nervosa and, given the controversially discussed anorectic effect of PYY, could theoretically contribute to that syndrome. Topics: Adult; Anorexia; Body Weight; Energy Intake; Fasting; Female; Humans; Leptin; Obesity, Morbid; Peptide Fragments; Peptide YY; Receptors, Cell Surface; Receptors, Leptin; Satiety Response; Weight Gain; Weight Loss | 2007 |
Dissociation between adipose tissue fluxes and lipogenic gene expression in ob/ob mice.
Recent evidence has been presented that expression of lipogenic genes is downregulated in adipose tissue of ob/ob mice as well as in human obesity, suggesting a functionally lipoatrophic state. Using (2)H(2)O labeling, we measured three adipose tissue biosynthetic processes concurrently: triglyceride (TG) synthesis, palmitate de novo lipogenesis (DNL), and cell proliferation (adipogenesis). To determine the effect of the ob/ob mutation (leptin deficiency) on these parameters, adipose dynamics were compared in ob/ob, leptin-treated ob/ob, food-restricted ob/ob, and lean control mice. Adipose tissue fluxes for TG synthesis, de novo lipogenesis (DNL), and adipogenesis were dramatically increased in ob/ob mice compared with lean controls. Low-dose leptin treatment (2 microg/day) via miniosmotic pump suppressed all fluxes to control levels or below. Food restriction in ob/ob mice only modestly reduced DNL, with no change in TG synthesis or adipogenesis. Measurement of mRNA levels in age-matched ob/ob mice showed generally normal expression levels for most of the selected lipid anabolic genes, and leptin treatment had, with few exceptions, only modest effects on their expression. We conclude that leptin deficiency per se results in marked elevations in flux through diverse lipid anabolic pathways in adipose tissue (DNL, TG synthesis, and cell proliferation), independent of food intake, but that gene expression fails to reflect these changes in flux. Topics: Adipogenesis; Adipose Tissue; Animals; Blood Glucose; Body Weight; Eating; Female; Food Deprivation; Gene Expression; Insulin; Leptin; Lipogenesis; Lipolysis; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Osmolar Concentration; Palmitates; Triglycerides | 2007 |
Regulation of adiponectin and its receptors in response to development of diet-induced obesity in mice.
Adiponectin and its receptors play an important role in energy homeostasis and insulin resistance, but their regulation remains to be fully elucidated. We hypothesized that high-fat diet would decrease adiponectin but increase adiponectin receptor (AdipoR1 and AdipoR2) expression in diet-induced obesity (DIO)-prone C57BL/6J and DIO-resistant A/J mice. We found that circulating adiponectin and adiponectin expression in white adipose tissue are higher at baseline in C57BL/6J mice compared with A/J mice. Circulating adiponectin increases at 10 wk but decreases at 18 wk in response to advancing age and high-fat feeding. However, adiponectin levels corrected for visceral fat mass and adiponectin mRNA expression in WAT are affected by high-fat feeding only, with both being decreased after 10 wk in C57BL/6J mice. Muscle AdipoR1 expression in both C57BL/6J and A/J mice and liver adipoR1 expression in C57BL/6J mice increase at 18 wk of age. High-fat feeding increases both AdipoR1 and AdipoR2 expression in liver in both strains of mice and increases muscle AdipoR1 expression in C57BL/6J mice after 18 wk. Thus advanced age and high-fat feeding, both of which are factors that predispose humans to obesity and insulin resistance, are associated with decreasing adiponectin and increasing AdipoR1 and/or AdipoR2 levels. Topics: Adiponectin; Adipose Tissue; Aging; Animals; Blood Glucose; Body Composition; Body Weight; Dietary Fats; Disease Susceptibility; Insulin; Leptin; Mice; Mice, Inbred A; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Receptors, Adiponectin; Receptors, Cell Surface; RNA, Messenger | 2007 |
Influence of serum leptin on weight and body fat growth in children at high risk for adult obesity.
Our objective was to examine serum leptin prospectively as a predictor of weight and body fat growth in children at high risk for adult obesity. We hypothesized that leptin measurements would be positively associated with increased growth of adipose tissue because children with high baseline leptin for their body fat mass have greater leptin resistance and thus would have greater susceptibility to weight gain.. Children ages 6-12 yr at high risk for adult obesity because of early-onset childhood overweight and/or parental overweight were recruited from 1996-2004. Growth in body mass index (BMI) was studied in 197 children, and growth in total body fat mass was examined in 149 children over an average follow-up interval of 4.4 yr (range, 1-8 yr). Longitudinal analyses accounted for sex, race, socioeconomic status, initial body composition, age, skeletal age, and physical activity and included all available interim visits for each individual so that a total of 982 subject visits were included in the analysis.. At baseline, 43% of children studied were overweight (BMI > or = 95th percentile); during follow-up, an additional 14% became overweight. Independent of initial body composition, baseline leptin was a statistically significant positive predictor of increased BMI (P = 0.0147) and increased total body fat mass (P < 0.007).. High serum leptin, independent of body fat, may be an indicator of increased leptin resistance, which predisposes children at high risk for adult obesity to somewhat greater growth in weight and body fat during childhood. Topics: Adipose Tissue; Adult; Body Fat Distribution; Body Mass Index; Body Weight; Child; Female; Humans; Leptin; Longitudinal Studies; Male; Obesity; Risk Factors | 2007 |
Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals.
Metabolic hormones, such as leptin, alter the input organization of hypothalamic circuits, resulting in increased pro-opiomelanocortin (POMC) tone, followed by decreased food intake and adiposity. The gonadal steroid estradiol can also reduce appetite and adiposity, and it influences synaptic plasticity. Here we report that estradiol (E2) triggers a robust increase in the number of excitatory inputs to POMC neurons in the arcuate nucleus of wild-type rats and mice. This rearrangement of synapses in the arcuate nucleus is leptin independent because it also occurred in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice, and was paralleled by decreased food intake and body weight gain as well as increased energy expenditure. However, estrogen-induced decrease in body weight was dependent on Stat3 activation in the brain. These observations support the notion that synaptic plasticity of arcuate nucleus feeding circuits is an inherent element in body weight regulation and offer alternative approaches to reducing adiposity under conditions of failed leptin receptor signaling. Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Body Weight; Estradiol; Estrogen Receptor alpha; Excitatory Postsynaptic Potentials; Female; Injections, Intraventricular; Leptin; Male; Melanocortins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Microscopy, Electron; Neurons; Obesity; Ovariectomy; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor | 2007 |
Maternal taurine supplementation in the late pregnant rat stimulates postnatal growth and induces obesity and insulin resistance in adult offspring.
An adequate supply of taurine during fetal life is important for normal beta-cell development and insulin action. An altered availability of taurine may programme glucose metabolism in utero and result in type 2 diabetes in adult age. We examined whether maternal taurine supplementation in late pregnant rats affects postnatal growth, adult body composition, insulin sensitivity and endogenous insulin secretion in intrauterine growth restricted (IUGR) and normal offspring. Uterine artery ligation or sham operations were performed on gestational day (GD) 19. Taurine supplementation was given to half of the dams from GD 18 until term, resulting in four groups of offspring: sham (n = 22), sham/taurine (n = 22), IUGR (n = 22) and IUGR/taurine (n = 24). The offspring were studied at 12 weeks of age. In offspring with normal birth weight, fetal taurine supplementation markedly stimulated postnatal growth. In sham/taurine females, fat depots, plasma free fatty acid and leptin concentrations were increased, and insulin sensitivity was reduced. Insulin sensitivity was unaltered in IUGR and IUGR/taurine offspring. However, whereas IUGR offspring showed little catch-up growth, 50% of IUGR/taurine animals displayed complete catch-up at 12 weeks of age, and these animals had increased fat depots and reduced insulin sensitivity. In conclusion, taurine supplementation in late gestation resulted in accelerated postnatal growth, which was associated with adult obesity and insulin resistance in both IUGR and normal offspring. This effect was particularly evident in females. These data suggest that fetal taurine availability is an important determinant for postnatal growth, insulin sensitivity and fat accumulation. Topics: Adipose Tissue; Animals; Animals, Newborn; Body Composition; Body Weight; Female; Gestational Age; Glucose Clamp Technique; Hyperglycemia; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Lipid Metabolism; Maternal Nutritional Physiological Phenomena; Obesity; Placental Insufficiency; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Taurine | 2007 |
Is leptin an important physiological regulator of CRP?
Topics: Animals; Body Weight; C-Reactive Protein; Eating; Hepatocytes; Humans; Leptin; Mice; Protein Binding | 2007 |
Is leptin an important physiological regulator of CRP?
Topics: Animals; Body Weight; C-Reactive Protein; Eating; Hepatocytes; Humans; Leptin; Mice; Protein Binding | 2007 |
Is leptin an important physiological regulator of CRP?
Topics: Animals; Body Weight; C-Reactive Protein; Eating; Hepatocytes; Humans; Leptin; Mice; Protein Binding | 2007 |
Relationships between leptin, insulin, IGF-1 and IGFBP-3 in children with energy malnutrition.
Leptin has a key role in energy homeostasis and there may be a link between leptin and insulin-like growth factor-1 (IGF-1) system. The aim of this study was to analyze the relationships between long-lasting insufficient caloric intake (marasmus), leptin and IGF-1 system.. The study group consisted of 30 marasmic children and control group included 28 healthy children. After an overnight fasting; leptin, insulin, IGF-1 and IGFBP-3 levels were measured.. Marasmic children had significantly lower body weight, height, mid-arm circumference (MAC), skinfold thickness, mean serum leptin, insulin, IGF-1 and IGFBP-3 levels compared with healthy subjects (P<0.05). Serum IGF-1 and IGFBP-3 levels were significantly correlated with insulin, MAC and height Z score in patients (P<0.05). In controls, significant positive correlations were found between BMI, IGF-1 and leptin (P<0.05).. Energy malnutrition is characterized by the important decreases in the leptin, insulin, IGF-1 and IGFBP-3 levels. Understanding details of these changes may lead to new therapeutic approaches in disease states associated with malnutrition. Topics: Body Height; Body Mass Index; Body Weight; Female; Humans; Infant; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Protein-Energy Malnutrition | 2007 |
Altered expression of SOCS3 in the hypothalamic arcuate nucleus during seasonal body mass changes in the field vole, Microtus agrestis.
We have previously shown that cold-acclimated (8 degrees C) male field voles (Microtus agrestis) transferred from short day (SD, 8 h light) to long day (LD, 16 h light) photoperiod exhibit an increase in body mass lasting 4 weeks, after which they stabilise at a new plateau approximately 7.5 g (24.8%) higher than animals maintained in SD. By infusing voles with exogenous leptin, we have also demonstrated that SD voles respond to the hormone by reducing body mass and food intake, whereas LD animals increasing body mass are resistant to leptin treatment. In the present study, we investigated whether seasonal changes in body mass could be linked to modulation of the leptin signal by suppressor of cytokine signalling-3 (SOCS3). We used in situ hybridisation to examine hypothalamic arcuate nucleus (ARC) expression of SOCS3, neuropeptide Y (NPY), agouti-related peptide (AgRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) genes in 90 voles exposed to either SD or LD for up to 11 weeks. LD voles increasing body mass had significantly higher levels of SOCS3 mRNA than SD or LD voles with a stable body mass. There were no associated changes in expression of NPY, AgRP, POMC and CART genes. These results suggest that voles that regulate body mass at either the lower (SD) or upper (LD) plateau remain sensitive to leptin action, whereas SOCS3-mediated leptin resistance is a short-term mechanism that enables animals to move between the stable body mass plateaus. Our data provide evidence that expression of SOCS3 in the ARC is involved in the modulation of the strength of the leptin signal to facilitate seasonal cycles in body mass and adiposity. Topics: Acclimatization; Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Arvicolinae; Body Weight; Gene Expression Regulation; Intercellular Signaling Peptides and Proteins; Leptin; Male; Nerve Tissue Proteins; Neuropeptide Y; Photoperiod; Pro-Opiomelanocortin; RNA, Messenger; Seasons; Signal Transduction; Suppressor of Cytokine Signaling Proteins | 2007 |
Serum leptin and insulin levels in lactating protein-restricted rats: implications for energy balance.
The present study analysed the effect of protein restriction on serum insulin and leptin levels and their relationship with energy balance during lactation. Four groups of rats received isocaloric diets containing 170 g protein/kg or 60 g protein/kg from pregnancy until the 14th day of lactation: control non-lactating, control lactating (both fed a control diet), low-protein non-lactating and low-protein lactating. Energy intake, body composition, energy balance, serum insulin and leptin concentrations and the relationship between these hormones and several factors related to obesity were analysed. Low-protein-intake lactating rats exhibited hypoinsulinaemia, hyperleptinaemia, hypophagia and decreased energy expenditure compared with control lactating rats. The protein level in the carcasses was lower in the low-protein lactating group than in the control lactating group, resulting in a higher fat content in the first group compared with the latter. Body fat correlated inversely with serum insulin and positively with serum leptin level. There was a significant negative correlation between serum leptin and energy intake, and a positive relationship between energy intake and serum insulin level in lactating rats and in the combined data from both groups. Energy expenditure was correlated positively with serum insulin and negatively with serum leptin in lactating rats and when data from control non-lactating and lactating rats were pooled. Lactating rats submitted to protein restriction, compared with lactating control rats, showed that maternal reserves were preserved owing to less severe negative energy balance. This metabolic adaptation was obtained, at least in part, by hypoinsulinaemia that resulted in increased insulin sensitivity favouring enhanced fat deposition, hyperleptinaemia and hypophagia. Topics: Animal Nutritional Physiological Phenomena; Animals; Body Composition; Body Weight; Diet, Protein-Restricted; Energy Intake; Energy Metabolism; Female; Insulin; Lactation; Leptin; Obesity; Pregnancy; Rats; Rats, Wistar | 2007 |
Neonatal hyperleptinaemia programmes adrenal medullary function in adult rats: effects on cardiovascular parameters.
Epidemiological studies have shown a strong correlation between stressful events (nutritional, hormonal or environmental) in early life and development of adult diseases such as obesity, diabetes and cardiovascular failure. It is known that gestation and lactation are crucial periods for healthy growth in mammals and that the sympathoadrenal system is markedly influenced by environmental conditions during these periods. We previously demonstrated that neonatal hyperleptinaemia in rats programmes higher body weight, higher food intake and hypothalamic leptin resistance in adulthood. Using this model of programming, we investigated adrenal medullary function and effects on cardiovascular parameters in male rats in adulthood. Leptin treatment during the first 10 days of lactation (8 microg 100 g(-1) day(-1), s.c.) resulted in lower body weight (6.5%, P < 0.05), hyperleptinaemia (10-fold, P < 0.05) and higher catecholamine content in adrenal glands (18.5%, P < 0.05) on the last day of treatment. In adulthood (150 days), the rats presented higher body weight (5%, P < 0.05), adrenal catecholamine content (3-fold, P < 0.05), tyrosine hydroxylase expression (35%, P < 0.05) and basal and caffeine-stimulated catecholamine release (53% and 100%, respectively, P < 0.05). Systolic blood pressure and heart rate were also higher in adult rats (7% and 6%, respectively, P < 0.05). Our results show that hyperleptinaemia in early life increases adrenal medullary function in adulthood and that this may alter cardiovascular parameters. Thus, we suggest that imprinting factors which increase leptin and catecholamine levels during the neonatal period could be involved in development of adult chronic diseases. Topics: Adrenal Medulla; Animals; Animals, Newborn; Blood Pressure; Body Weight; Female; Heart Rate; Leptin; Male; Rats; Rats, Wistar | 2007 |
Longitudinal study of the simultaneous secretion of melatonin and leptin during normal puberty.
Pubertal changes are a consequence of the activation of the hypothalamic-pituitary-gonadal axis due to an increase in the frequency and magnitude of pulses of gonadotropin-releasing hormone (GnRH), which may depend on the intrinsic properties of the neurons of the hypothalamic arcuatus nucleus, or on the influence of neurotransmitters and/or neuromodulators. We evaluated the serum concentrations of melatonin and leptin in healthy prepubertal and adolescent subjects of both sexes, to define their participation at the initial stages and during the progression of pubertal development.. 80 pediatric subjects (47 females and 33 males), aged 6-18 years, were divided into 2 groups, prepubertal (n = 25) and adolescent (n = 55), according to the absence or presence, respectively, of physical signs of pubertal development. The subjects were assessed on two occasions: at the time of their inclusion in the study, and 12-18 months later when the subject had advanced one pubertal stage according to the Tanner classification. Blood was obtained in fasting for clinical purposes and for the hormonal study. Melatonin and leptin were measured by radioimmunoanalysis.. As described previously, melatonin decreases at the onset of puberty and during pubertal development. Both the absolute melatonin value and the decrease between evaluations tended to be greater in females; the variations were correlated with neither an increase in body weight nor with the degree of pubertal development. The concentration of leptin increased in both sexes with the progression of puberty, this value being 40% greater in women, and correlated with the indicators of an increase in body volume and fat accumulation. Although its concentration remained stable between evaluations for both sexes, among the males the association between leptin and pubertal development took place at the start of the process, while for the females we observed a significant overall association between pubertal stage and leptin concentration, this association being stronger at more advanced Tanner stages. Neither at the onset of puberty nor during its course did we observe any significant relation between melatonin concentration and any of the Tanner stages, whether for males or for females. Neither was there any correlation between the absolute values or rates of modification of melatonin and leptin.. According to the evolutionary dynamics of their respective concentrations, both initially and during pubertal progress, melatonin and leptin do not interact in the initiation or progression of human pubertal development, and do not seem to play a key role in this process. Topics: Adipose Tissue; Adolescent; Adolescent Development; Body Weight; Child; Female; Gonadotropin-Releasing Hormone; Humans; Leptin; Longitudinal Studies; Male; Melatonin; Puberty; Sex Factors | 2007 |
Knocking down the diencephalic thyrotropin-releasing hormone precursor gene normalizes obesity-induced hypertension in the rat.
We recently showed that diencephalic TRH may mediate the central leptin-induced pressor effect. Here, to study the role of TRH in obesity-induced hypertension (OIH), we used a model of OIH produced by a high-fat diet (HFD, 45 days) in male Wistar rats. After 4 wk, body weight and systolic arterial blood pressure (SABP) increased in HFD animals. Plasma leptin was correlated with peritoneal adipose tissue. Then, we treated OIH animals with an antisense oligodeoxynucleotide and small interfering (si)RNA against the prepro-TRH. Antisense significantly decreased diencephalic TRH content and SABP at 24 and 48 h posttreatment. Similar effects were observed with siRNA against prepro-TRH but for up to 4 wk. Conversely, vehicle, an inverted antisense sequence and siRNA against green fluorescence protein, produced no changes. SABP decrease seems to be owing to an inhibition of the obesity-enhanced sympathetic outflow but not to an alteration in thyroid status. Using a simple OIH model we demonstrated, for the first time, that central TRH participates in the hypertension induced by body weight gain probably through its well-known action on sympathetic activity. Thus the TRH-leptin interaction may contribute to the strong association between hypertension and obesity. Topics: Animals; Blood Pressure; Body Weight; Hypertension; Leptin; Male; Metanephrine; Normetanephrine; Obesity; Oligodeoxyribonucleotides, Antisense; Prolactin; Protein Precursors; Random Allocation; Rats; Rats, Wistar; RNA, Small Interfering; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine | 2007 |
Neuronal SH2B1 is essential for controlling energy and glucose homeostasis.
SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (alpha, beta, gamma, and/or delta) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1beta was specifically expressed in neural tissue in SH2B1-transgenic (SH2B1(Tg)) mice. SH2B1(Tg) mice were crossed with SH2B1-knockout (SH2B1(KO)) mice to generate SH2B1(TgKO) mice expressing SH2B1 only in neural tissue but not in other tissues. Systemic deletion of the SH2B1 gene resulted in metabolic disorders in SH2B1(KO) mice, including hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of SH2B1beta not only corrected the metabolic disorders in SH2B1(TgKO) mice, but also improved JAK2-mediated leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Moreover, neuron-specific overexpression of SH2B1 dose-dependently protected against high-fat diet-induced leptin resistance and obesity. These observations suggest that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity. Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue; Animals; Base Sequence; Body Weight; DNA Primers; Energy Metabolism; Glucose; Homeostasis; Hyperlipidemias; Hypothalamus; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neurons; Obesity | 2007 |
Antidepressant-like effect of leptin in streptozotocin-induced diabetic mice.
We previously reported that streptozotocin (STZ)-induced diabetic mice showed the depressive-like behavior in the tail suspension test. It has also been reported that leptin-deficient obese mice demonstrate the depressive-like behavior. Since STZ-induced diabetes causes a marked decrease in plasma leptin levels, it is possible that decrease in leptin levels and the depressive-like behavior may somehow be related. Therefore, we examined the effect of leptin on the depressive-like behavior of STZ-induced diabetic mice in the tail suspension test. The prolonged duration of immobility in diabetic mice was dose-dependently and significantly suppressed by single treatment with leptin (0.1-1 mg/kg, i.p.) without affecting on the locomotor activity. Leptin did not affect either the duration of immobility or the locomotor activity in non-diabetic mice. The anti-immobility effect of leptin (1 mg/kg, i.p.) in diabetic mice was significantly antagonized by the selective serotonin2 (5-HT2) receptor antagonist LY53,857 (0.03 mg/kg, s.c.), but not by the selective 5-HT1A receptor antagonist WAY-100635 (0.03 mg/kg, s.c.). Antagonists administered alone did not affect either the duration of immobility or the locomotor activity in diabetic mice. In conclusion, we suggest that leptin exerts the antidepressant-like effect in diabetic mice mediated by, at least in part, 5-HT2 receptors. Topics: Animals; Antidepressive Agents; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Ergolines; Hindlimb Suspension; Insulin; Leptin; Male; Mice; Mice, Inbred ICR; Motor Activity; Piperazines; Pyridines; Receptor, Serotonin, 5-HT1A; Receptors, Leptin; Receptors, Serotonin, 5-HT2; Serotonin Antagonists | 2007 |
Adiposity profile in the dwarf rat: an unusually lean model of profound growth hormone deficiency.
This study describes the previously uncharacterized ontogeny and regulation of truncal adipose reserves in the profoundly GH-deficient dwarf (dw/dw) rat. We show that, despite normal proportionate food intake, dw/dw rats develop abdominal leanness and hypoleptinemia (circulating leptin halved in dw/dw males, P < 0.05) during puberty. This contrasts with the hyperleptinemia seen in moderately GH-deficient Tgr rats (circulating leptin doubled at 6 wk of age, P < 0.05) and in GH receptor-binding protein (GHR/BP)-null mice (circulating leptin doubled; P < 0.05). This lean/hypoleptinemic phenotype was not completely normalized by GH treatment, but dw/dw rats developed abdominal obesity in response to neonatal MSG treatment or maintenance on a high-fat diet. Unlike Tgr rats, dw/dw rats did not become obese with age; plasma leptin levels and fat pad weights became similar to those in wild-type rats. In contrast with truncal leanness, tibial marrow adiposity was normal in male and doubled in female dwarves (P < 0.01), this increase being attributable to increased adipocyte number (P < 0.01). Neonatal MSG treatment and high-fat feeding elevated marrow adiposity in dw/dw rats by inducing adipocyte enlargement (P < 0.05). These results demonstrate that, despite lipolytic influence of GH, severe GH deficiency in dw/dw rats is accompanied by a paradoxical leanness. This lean/hypoleptinemic phenotype is not solely attributable to reduced GH signaling and does not appear to result from a reduction in nutrient intake or the ability of dw/dw adipocytes to accumulate lipid. Disruption of preadipocyte differentiation or adipocyte proliferation in the dw/dw rat may lead to the development of this unusually lean/hypoleptinemic phenotype. Topics: Abdominal Fat; Animals; Animals, Genetically Modified; Body Weight; Cohort Studies; Dwarfism, Pituitary; Eating; Female; Food Additives; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Rats; Sodium Glutamate; Tibia | 2007 |
Differential effects of undernourishment and nutritional rehabilitation on serum leptin levels in male and female rats.
Leptin, a peptide hormone, is secreted by adipose tissue and is crucial to the regulation of feeding behaviour. The present study has shown that both male and female rats which have been undernourished since day six of gestation, show significantly decreased serum leptin levels on postnatal day 12; but when undernourishment continues into adulthood, only males continue to show decreased leptin levels. If nutritional rehabilitation is implemented early enough in males, serum leptin levels recover and nearly reach levels found in control adult males. Undernutrition also has a long term effect on body weight in both sexes, but nutritional rehabilitation leads to some degree of body weight recovery varying with sex and the age at which rehabilitation was implemented. Undernutrition seems to affect different developmental processes in males than in females, with males being more vulnerable than females in so far as long-term effects on serum leptin levels. Topics: Adipose Tissue; Animals; Body Weight; Estrone; Female; Leptin; Male; Malnutrition; Nutritional Status; Rats; Rats, Wistar; Sex Characteristics; Testosterone | 2007 |
Neuropeptide W exerts a potent suppressive effect on blood leptin and insulin concentrations in the rat.
Neuropeptide B/W receptor 1 (NPBWR1) and neuropeptide B/W receptor 2 (NPBWR2) are two structurally related orphan receptors linked to protein G. In rodents NPBWR2 is absent, and its counterpart is described as being similar to neuropeptide B/W receptor 2. Endogenous ligands of these receptors have been identified. One of them is 29 amino acid residues long, uniquely modified with bromine and, thus, termed neuropeptide B (NPB). The other, neuropeptide W (NPW), has been identified in two molecular forms of 23 and 30 amino acids (NPW23 and NPW30), respectively. Both NPB and NPW affect food intake and energy expenditure. Since leptin, a potent anti-obesity hormone, and insulin are involved in the control of energy homeostasis, the present study aimed to investigate whether NPB and NPW affect leptin and insulin secretion in the rat. RT-PCR technique revealed the presence of ppNPB, ppNPW, NPBWR1 and NPBWR2-like mRNAs in isolated pancreatic islets of the rat. NPB and NPW immunoreactivities were observed in all of the cells of the pancreatic islets. Only when a higher dose was administered (3 nmol/100 g body weight) did NPW transiently lower blood insulin levels whereas NPB injection did not alter insulinaemia in the studied rats. At 30 min, but not 60, of the experiment, NPW notably lowered blood leptin concentrations at both tested doses. On the contrary, NPB injections had no effect on blood leptin and insulin concentrations. Thus, the results suggest that NPW but not NPB exerts a potent suppressive effect on blood leptin concentrations in the rat, and this mechanism may be involved in NPW regulation of energy homeostasis. Topics: Animals; Blood Glucose; Body Weight; Female; Gene Expression Regulation; Injections, Subcutaneous; Insulin; Leptin; Neuropeptides; Pancreas; Rats; Rats, Wistar; Receptors, Neuropeptide; RNA, Messenger | 2007 |
Prolactin inhibition in dams during lactation programs for overweight and leptin resistance in adult offspring.
Maternal malnutrition during lactation reduces prolactin (PRL) and milk production, alters milk composition, and programs the body weight of the offspring. Our study aimed to evaluate the long-term effects of maternal hypoprolactinemia at the end of lactation on food ingestion, body weight, amount of retroperitoneal white adipose tissue (RPWAT), leptinemia, and anorectic leptin effect in the adult offspring. Lactating rats were treated with bromocriptine (BRO), a PRL inhibitor, 1 mg twice a day, or saline (C - control) for the last 3 days of lactation. The body weight and food intake were monitored, and after sacrifice at 180 days, the RPWAT was weighted. In a second experiment, the anorectic leptin effect was tested on 180-day-old animals. Adult offspring whose mothers were BRO-treated showed higher body weight (10%), higher amount of RPWAT (2 x 3 times), higher total body fat (+39%), and hyperleptinemia (2 x 9 times) when compared with C, although food intake did not alter. After injection of leptin, the food ingestion at 2, 4 and 6 h was unaffected in BRO animals, confirming a resistance to the anorectic effect of leptin. Since the maternal PRL inhibition during lactation programs, a higher body weight with no alteration of food ingestion, we suggest a hypometabolic state. The leptin anorectic resistance can be due to the hyperleptinemia. We suggest that PRL changes during lactation can regulate body weight during adulthood. Topics: Adipose Tissue; Animals; Body Weight; Bromocriptine; Eating; Female; Lactation; Leptin; Maternal Nutritional Physiological Phenomena; Nutritional Status; Overweight; Prolactin; Rats; Rats, Wistar; Weaning | 2007 |
Alteration of glucose homeostasis in V1a vasopressin receptor-deficient mice.
Arginine-vasopressin (AVP) is known to be involved in maintaining glucose homeostasis, and AVP-resistance is observed in poorly controlled non-insulin-dependent diabetes mellitus subjects, resulting in a lowered plasma volume. Recently we reported that V1a vasopressin receptor-deficient (V1aR(-/-)) mice exhibited a decreased circulating blood volume and hypermetabolism of fat accompanied with impaired insulin-signaling. Here we further investigated the roles of the AVP/V1a receptor in regulating glucose homeostasis and plasma volume using V1aR(-/-) mice. The plasma glucose levels at the baseline or during a glucose tolerance test were higher in V1aR(-/-) than wild-type (WT) mice. Moreover, a hyperinsulinemic-euglycemic clamp revealed that the glucose infusion rate was significantly lower in V1aR(-/-) mice than in WT mice and that hepatic glucose production was higher in V1aR(-/-) mice than WT mice. In contrast to the increased hepatic glucose production, the liver glycogen content was decreased in the mutant mice. These results indicated that the mutant mice had impaired glucose tolerance. Furthermore, feeding V1aR(-/-) mice a high-fat diet accompanied by increased calorie intake resulted in significantly overt obesity in comparison with WT mice. In addition, we found that the circulating plasma volume and aldosterone level were decreased in V1aR(-/-) mice, although the plasma AVP level was increased. These results suggested that the effect of AVP on water recruitment was disturbed in V1aR(-/-) mice. Thus, we demonstrated that one of the AVP-resistance conditions resulting from deficiency of the V1a receptor leads to decreased plasma volume as well as impaired glucose homeostasis, which can progress to obesity under conditions of increased calorie intake. Topics: Animals; Arginine Vasopressin; Blood Glucose; Body Weight; Dietary Fats; Energy Intake; Feeding Behavior; Glycogen; Homeostasis; Insulin; Leptin; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Plasma Volume; Receptors, Vasopressin | 2007 |
Night eating and obesity in the EP3R-deficient mouse.
Adult mice carrying a null mutation of the prostanoid receptor EP3R (EP3R(-/-) mice) exhibit increased frequency of feeding during the light cycle of the day and develop an obese phenotype under a normal fat diet fed ad libitum. EP3R(-/-) mice show increased motor activity, which is not sufficient to offset the increased feeding leading to increased body weight. Altered "nocturnal" activity and feeding behavior is present from a very early age and does not seem to require age-dependent factors for the development of obesity. Obesity in EP3R(-/-) mice is characterized by elevated leptin and insulin levels and >20% higher body weight compared with WT littermates. Abdominal and subcutaneous fat and increased liver weight account for the weight increase in EP3R(-/-) mice. These observations expand the roles of prostaglandin E(2) signaling in metabolic regulation beyond the reported stimulation of leptin release from adipose tissue to involve actions mediated by EP3R in the regulation of sleep architecture and feeding behavior. The findings add to the growing literature on links between inflammatory signaling and obesity. Topics: Adipose Tissue; Aging; Animals; Body Temperature; Body Weight; Circadian Rhythm; Feeding Behavior; Food; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Male; Mice; Motor Activity; Obesity; Phenotype; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP3 Subtype | 2007 |
Polymorphism of the porcine leptin gene promoter and analysis of its association with gene expression and fatness traits.
We describe for the first time a 245 bp fragment of the porcine leptin gene promoter in the proximity of the transcription start site. Altogether, 720 pigs were screened with the PCR-SSCP technique for polymorphism in this region. Four SNPs, segregating as two haplotypes, have been identified, one of them (C113G) in the putative consensus site for the AP-2 transcription factor. This polymorphism was evenly distributed in the Duroc breed (n=21) and was absent in the Polish Landrace (n=248) and Pietrain breed (n=12). In the Polish Large White (n=191) and synthetic line 990 (n=243), allele G occurred with a very low frequency. The investigation was performed to test if the C113G SNP affects leptin mRNA level in subcutaneous fat and leptin protein concentration in serum. Additionally, the effect of this polymorphism on fatness traits was statistically analyzed. Although there was a trend toward decreased expression in GG animals, the differences were not significant between genotypes. We also found no evidence for an association of the LEP promoter genotype with the analyzed fatness traits. Topics: Adipose Tissue; Animals; Base Sequence; Body Weight; Gene Expression Regulation; Gene Frequency; Haplotypes; Leptin; Molecular Sequence Data; Phenotype; Polymorphism, Genetic; Promoter Regions, Genetic; Quantitative Trait, Heritable; Swine | 2007 |
Central interleukin-1 (IL1) signaling is required for pharmacological, but not physiological, effects of leptin on energy balance.
Hypothalamic IL1 is suggested to be a critical mediator of the central effects of the adipocyte hormone leptin on energy balance. We hypothesized that IL1 receptor signaling is required for exogenously administered leptin to cause anorexia and weight loss, but not for physiological effects of endogenous leptin signaling on energy balance. To test this hypothesis, we investigated whether chronic hypothalamic over-expression of an IL1 receptor antagonist (AdV-IL1ra) alters food intake and weight gain in normal rats. Our findings demonstrate that impaired IL1 signaling in the CNS did not cause excess weight gain over a period of 11 days (AdV-IL1ra +38.1+/-4.1 g vs. VEH +42.2+/-5.6g; p=0.6) and caused a slightly reduced daily food intake (AdV-IL1ra 29.0+/-1.1 g/day vs. VEH 33.0+/-1.6 g/day; p<0.05). Blocking central IL1 signaling also did not alter the re-feeding response to a prolonged fast, yet was entirely effective in preventing the anorexic effect of exogenously administered leptin (2 mg/kg ip, cumulative food intake at 18 h AdV-IL1ra 30.5+/-1.1 g vs. VEH 26.4+/-1.7 g, p<0.05) and prevented leptin-induced weight loss (AdV-IL1ra -0.1+/-1.3 g vs. VEH -2.7+/-1.9 g, p<0.05). Together these findings suggest that hypothalamic IL1 signaling is required for the pharmacological effects of leptin administration, but that impaired hypothalamic IL1 signaling does not alter the physiological regulation of energy balance. Topics: Adenoviridae; Analysis of Variance; Animals; Behavior, Animal; Body Weight; Central Nervous System; Eating; Energy Metabolism; Fasting; Interleukin-1; Leptin; Male; Rats; Rats, Wistar; Signal Transduction; Time Factors | 2007 |
Combined effects of rosiglitazone and conjugated linoleic acid on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed mice.
Dysfunctional cross talk between adipose tissue and liver tissue results in metabolic and inflammatory disorders. As an insulin sensitizer, rosiglitazone (Rosi) improves insulin resistance yet causes increased adipose mass and weight gain in mice and humans. Conjugated linoleic acid (CLA) reduces adipose mass and body weight gain but induces hepatic steatosis in mice. We examined the combined effects of Rosi and CLA on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed male C57Bl/6 mice. CLA alone suppressed weight gain and adipose mass but caused hepatic steatosis. Addition of Rosi attenuated CLA-induced insulin resistance and dysregulation of adipocytokines. In adipose, CLA significantly suppressed lipoprotein lipase and fatty acid translocase (FAT/CD36) mRNA, suggesting inhibition of fatty acid uptake into adipose; addition of Rosi completely rescued this effect. In addition, CLA alone increased markers of macrophage infiltration, F4/80, and CD68 mRNA levels, without inducing TNF-alpha in epididymal adipose tissue. The ratio of Bax to Bcl2, a marker of apoptosis, was significantly increased in adipose of the CLA-alone group and was partially prevented by treatment of Rosi. Immunohistochemistry of F4/80 demonstrates a proinflammatory response induced by CLA in epididymal adipose. In the liver, CLA alone induced microsteatotic liver but surprisingly increased the rate of very-low-density lipoprotein-triglyceride production without inducing inflammatory mediator-TNF-alpha and markers of macrophage infiltration. These changes were accompanied by significantly increased mRNA levels of stearoyl-CoA desaturase, FAT/CD36, and fatty acid synthase. The combined administration of CLA and Rosi reduced hepatic liver triglyceride content as well as lipogenic gene expression compared with CLA alone. In summary, dietary CLA prevented weight gain in Rosi-treated mice without attenuating the beneficial effects of Rosi on insulin sensitivity. Rosi ameliorated CLA-induced lipodystrophic disorders that occurred in parallel with rescued expression of adipocytokine and adipocytes-abundant genes. Topics: Adipocytes; Adiponectin; Adipose Tissue; Adiposity; Animals; Apoptosis; Body Weight; Dietary Fats; Disease Models, Animal; Drug Therapy, Combination; Fatty Liver; Hypoglycemic Agents; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Leptin; Linoleic Acids, Conjugated; Lipid Metabolism; Lipoproteins, VLDL; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Obesity; RNA, Messenger; Rosiglitazone; Thiazolidinediones; Time Factors; Triglycerides | 2007 |
Modulation of adiponectin and leptin during refeeding of female anorexia nervosa patients.
Several studies assessed adiponectin levels in anorexia nervosa (AN) patients, however, data regarding the dynamics of changes in adiponectin levels during refeeding of these patients is limited and contradicting.. Our objective was to assess adiponectin levels and the distribution of its different isoforms in AN patients before and after long-term refeeding, and to relate them to alterations in body mass index, leptin, insulin sensitivity, and additional endocrine parameters.. We conducted a longitudinal controlled study of 38 female adolescent malnourished AN inpatients, with 13 young, lean, healthy women serving as controls. Blood samples were obtained upon admission and thereafter at 1, 3, and 5 months (at target weight).. Changes in body mass index, leptin, adiponectin, insulin sensitivity, and adiponectin multimeric forms were measured.. At admission, leptin levels of AN patients were significantly lower, whereas insulin sensitivity (assessed by homeostasis model assessment-insulin resistance), adiponectin levels, and the ratio of high molecular weight (HMW) adiponectin to total adiponectin were significantly higher compared with controls. During weight recovery, leptin levels and homeostasis model assessment-insulin resistance increased significantly, whereas adiponectin and HMW adiponectin/total adiponectin ratio decreased significantly, to levels similar to controls. An initial increase in adiponectin levels was observed after 1 month of refeeding. There was no correlation between adiponectin and either T(4) or cortisol levels.. Our study demonstrates hyperadiponectinemia, increased adiponectin HMW isoform, and increased insulin sensitivity in adolescent AN female patients and reversal of these findings with weight rehabilitation. We hypothesize that increased adiponectin levels may have a protective role in maintaining energy homeostasis during extreme malnourishment. Topics: Adiponectin; Adolescent; Adult; Anorexia Nervosa; Blood Glucose; Body Height; Body Mass Index; Body Weight; Female; Hormones; Humans; Insulin Resistance; Isomerism; Leptin; Weight Gain | 2007 |
Okara, soybean residue, prevents obesity in a diet-induced murine obesity model.
We examined the effect of okara on the prevention of obesity in mice. A modified AIN-76 diet with a high fat content (14.1% of crude fat) was used as a basal diet. Male ICR mice were fed ad libitum with the basal diet or a dried okara-supplemented basal diet (10, 20, or 40%) for 10 weeks. The okara intake dose-dependently suppressed the development of body weight and epididymal white adipose tissue (EWAT), and prevented an increase of plasma lipids, including total cholesterol, LDL cholesterol, and non-esterified fatty acid. The okara intake also prevented steatosis in the liver. Real-time RT-PCR revealed that the okara intake induced down-regulation of the fatty acid synthetase gene and up-regulation of the cholesterol 7 alpha-hydroxylase (CYP7A1) gene in the liver. We also found that the okara intake caused a marked reduction in the expression of leptin and TNF-alpha genes in EWAT. Our results suggest that okara is beneficial in preventing obesity. Topics: Adipose Tissue, White; Animals; Body Weight; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cholesterol, LDL; Diet; Fatty Acid Synthases; Fatty Acids, Nonesterified; Fatty Liver; Gene Expression Regulation; Glycine max; Leptin; Liver; Male; Mice; Mice, Inbred ICR; Mice, Obese; Obesity; Plant Proteins; Polysaccharides; Soy Foods | 2007 |
Altered postprandial glucose, insulin, leptin, and ghrelin in liver cirrhosis: correlations with energy intake and resting energy expenditure.
Liver cirrhosis is associated with reduced energy intake and increased resting energy expenditure.. We aimed to investigate the possible role of glucose, insulin, leptin, and ghrelin in the pathogenesis of these alterations.. Nutritional status, energy intake, resting energy expenditure, and fasting glucose, insulin, and leptin were assessed in 31 patients with cirrhosis. Postprandial glucose, insulin, C-peptide, leptin, and ghrelin responses were studied in a subgroup of patients after a standard meal. Ten healthy subjects served as controls.. Patients with cirrhosis had a lower energy intake (P < 0.05), higher resting energy expenditure (P < 0.05), higher fasting leptin (P < 0.05), and higher insulin resistance (P < 0.001) than did the healthy control subjects. In the patients with cirrhosis, fasting leptin was negatively correlated with resting energy expenditure (r = -0.38, P < 0.05) but not with energy intake. In control subjects, leptin was negatively correlated with energy intake (r = -0.72, P < 0.05) but not with resting energy expenditure. The patients with cirrhosis had higher postprandial glucose (P < 0.001) and lower ghrelin (P < 0.05) concentrations at 4 h postprandially than did the control subjects. The increase in ghrelin from its minimal postmeal value to 4 h postmeal was negatively correlated (r = -0.66, P = 0.014) with weight loss in the patients with cirrhosis. Energy intake was negatively correlated (r = -0.42, P < 0.01) with the postprandial increase in glucose.. In cirrhosis, altered postprandial glucose and ghrelin are associated with reduced energy intake and weight loss, respectively, and the effects of leptin on energy intake and expenditure seem to be altered. Insulin resistance might be involved in these altered postprandial responses. Topics: Basal Metabolism; Blood Glucose; Body Mass Index; Body Weight; Calorimetry, Indirect; Eating; Energy Intake; Female; Ghrelin; Humans; Insulin; Leptin; Liver Cirrhosis; Male; Middle Aged; Nutritional Status; Peptide Hormones; Postprandial Period | 2007 |
BVT.3531 reduces body weight and activates K(ATP) channels in isolated arcuate neurons in rats.
A number of hormones, including leptin, have been shown to inhibit food intake in humans and animals. Analogues of 3-guanidinopropionic acid have also been found to reduce total food intake, but their mechanisms of action have not been well studied. The present study investigated the effects of intracerebroventricular infusion of the analogue BVT.3531 on food intake, meal pattern, and body weight in rats during 7 days. Single channel recordings from arcuate neurons and insulinoma cells were used to determine the effects of BVT.3531 on K(ATP) activity. Data analysis showed that BVT.3531 significantly decreased body weight and food intake, primarily by reducing meal size. BVT.3531 activated K(ATP) channels in cell-attached recordings from insulin-secreting cells and rat arcuate neurons but had no effect on K(ATP) channel activity in inside-out membrane patches from either cell type. BVT.3531 did not alter the firing rate or K(+) channel activity of arcuate neurons devoid of K(ATP). The study suggests that small molecules capable of mimicking the effects of leptin on food intake and body weight may utilize output mechanisms similar to those of leptin to elicit changes in arcuate neuron excitability. Topics: Acetates; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Cell Line; Dose-Response Relationship, Drug; Eating; Electrophysiology; Guanidines; Leptin; Male; Molecular Structure; Neurons; Potassium Channels, Inwardly Rectifying; Propionates; Rats; Rats, Sprague-Dawley | 2007 |
Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice.
Skeletal growth is tightly coupled to energy balance via complex and incompletely understood mechanisms. Leptin-deficient ob/ob mice are obese and develop multiple pathologies associated with the metabolic syndrome. Additionally, ob/ob mice have skeletal abnormalities. The objective of this study was to evaluate the effects of leptin deficiency and long duration selective central leptin repletion via recombinant adeno-associated virus-leptin (rAAV-lep) gene therapy on bone in growing ob/ob mice. The ob/ob mice were injected in the hypothalamus with either rAAV-lep or rAAV-GFP (control vector). Treated ob/ob and untreated wild-type (WT) mice were then maintained on a normal diet for 15 weeks. In a second experiment, similarly treated mice along with a group of pair-fed mice were maintained for 30 weeks. Leptin was not detected in blood of either rAAV-lep- or rAAV-GFP-treated mice although rAAV-lep-treated mice displayed leptin transgene expression in the hypothalamus. As expected, rAAV-lep normalized body weight and food intake. Compared to WT mice, rAAV-GFP-treated ob/ob mice had decreased femoral length (by 1.6 mm or 10%, P<0.001), decreased total femur bone volume (by 3.3 mm(3) or 19%, P<0.001), but increased cancellous bone volume in the distal femur (by 0.04 mm(3) or 60%, P<0.09) and lumbar vertebrae (by 0.26 mm(3) or 118%, P<0.001). Treatment with rAAV-lep rescued the ob/ob skeletal phenotype by increasing femoral length and total bone volume, and decreasing femoral and vertebral cancellous bone volume, so that at 15 weeks post-rAAV-lep injection the ob/ob mice no longer differed from WT mice. No further skeletal changes in either the femur or lumbar vertebra were observed at 30 weeks post-rAAV-lep administration. The results suggest that hypothalamic leptin functions as an essential permissive factor for normal bone growth. Topics: Animals; Body Weight; Bone and Bones; Bone Diseases, Metabolic; Dependovirus; Femur; Genetic Therapy; Genetic Vectors; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Treatment Outcome | 2007 |
Apelin, an APJ receptor ligand, regulates body adiposity and favors the messenger ribonucleic acid expression of uncoupling proteins in mice.
Apelin, the endogenous ligand of the APJ receptor, has been identified in a variety of tissues, including stomach, heart, skeletal muscle, and white adipose tissue. We sought to clarify the effects of apelin on body adiposity and the expression of uncoupling proteins (UCPs) in C57BL/6 mice. Treatment with ip apelin at a dose of 0.1 mumol/kg.d for 14 d decreased the weight of white adipose tissue and serum levels of insulin and triglycerides, compared with controls, without influencing food intake. Apelin treatment also decreased body adiposity and serum levels of insulin and triglycerides in obese mice fed a high-fat diet. Apelin increased the serum adiponectin level and decreased that of leptin. Additionally, apelin treatment increased mRNA expression of UCP1, a marker of peripheral energy expenditure, in brown adipose tissue (BAT) and of UCP3, a regulator of fatty acid export, in skeletal muscle. In addition, immunoblot bands and relative densities of UCP1 content in BAT were also higher in the apelin group than controls. Furthermore, apelin treatment increased body temperature and O(2) consumption and decreased the respiratory quotient. In conclusion, apelin appears to regulate adiposity and lipid metabolism in both lean and obese mice. In addition, apelin regulates insulin resistance by influencing the circulating adiponectin level, the expression of BAT UCP1, and energy expenditure in mice. Topics: Adiponectin; Adipose Tissue, White; Adiposity; Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Gene Expression Regulation; Glucose Tolerance Test; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Organ Size; RNA, Messenger; Time Factors; Triglycerides; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3 | 2007 |
Maternal leptin treatment during lactation programs the thyroid function of adult rats.
Recently, we showed that both maternal malnutrition during lactation and leptin treatment during the neonatal period program thyroid function. In this study we evaluate whether maternal leptin treatment during lactation programs thyroid function of the offspring in the adulthood. The dams were divided into 2 groups: Lep-daily sc single injected with 8 microg/100 g of body weight with recombinant rat leptin during the last 3 days of lactation and control group (C) that received the same volume of saline. The 180 day-old animals received a single i.p. injection of (125)I (2.22x10(4) Bq) and they were killed 2 h after the injection. Triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH) and leptin concentrations were measured by radioimmunoassay. The milk of leptin-treated mothers on the last day of treatment had higher leptin (p<0.05) concentration. The pups of the leptin-treated mothers had at 21 days an unchanged T3, T4 and leptin serum concentrations with higher TSH (p<0.05). The offspring of Lep mothers had at 180 days a higher T3 (p<0.05) with normal thyroid (125)I uptake, T4 and TSH serum concentrations compared to the controls. So, the mother's hyperleptinaemia during lactation programs to a higher T3 serum concentration on the offspring, probably by a higher leptin transfer through the milk. Topics: Animals; Body Weight; Female; Iodine Radioisotopes; Lactation; Leptin; Radioimmunoassay; Rats; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine | 2007 |
Nuclear translocation of the transcription factor STAT5 in the rat brain after systemic leptin administration.
Leptin binding to its functional receptor stimulates JAK-STAT-signaling pathway, which finally results in activation and nuclear translocation of transcription factors of the signal transducer and activator of transcription (STAT) family, namely of STAT3. Here we report for the first time that systemic treatment with leptin (5 mg/kg; intraperitoneal injection) also increased the number of nuclear STAT5 signals in the hypothalamus. In particular, the entire arcuate nucleus (ARC), the ventral premammilary nucleus (PMV), and the supraoptic nucleus (SO) showed an enhanced nuclear STAT5 translocation in response to leptin when compared to saline, 120 min after the respective injection. Co-localization studies revealed that a high percentage of those STAT5-responsive cells proved to be neurons. In addition, some astrocytes within the ARC showed nuclear STAT5 signals. The functional relevance of leptin-induced nuclear STAT5 activation in hypothalamic cells still has to be determined. Topics: Active Transport, Cell Nucleus; Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Astrocytes; Body Weight; Cell Nucleus; Hypothalamus; Injections, Intraperitoneal; Leptin; Male; Neurons; Rats; Rats, Wistar; Signal Transduction; STAT5 Transcription Factor; Supraoptic Nucleus | 2007 |
The intake of physiological doses of leptin during lactation in rats prevents obesity in later life.
There is epidemiological evidence that perinatal nutritional factors may have long-term effects on obesity. Which nutrients or food components are involved in this programming mechanism are unknown. Breast milk contains leptin, a hormone that regulates food intake and energy expenditure, and previous studies in rats have shown that leptin orally administered during lactation exerts anorexigenic effects.. To evaluate whether supplementation with physiological doses of oral leptin during lactation has long-term effects on body weight regulation.. A daily oral dose of leptin (equivalent to five times the amount of leptin ingested normally from maternal milk during the suckling period) or the vehicle was given to suckling male rats during lactation. Animals were fed after weaning with a normal fat (NF) or a high-fat (HF) diet. We followed body weight and food intake of animals until the age of 6 months, and measured the size of adipose tissue depots, the thermogenic capacity, the expression of leptin in the stomach and adipose tissues and the expression of two appetite-related peptides (neuropeptide Y (NPY) and proopiomelanocortin (POMC)), leptin receptor (OB-Rb) and suppressor of cytokine signalling 3 (SOCS-3) in the hypothalamus at the age of 6 months.. Leptin-treated animals had, in adulthood, lower body weight and fat content and ate fewer calories than their untreated controls. Unlike adipocitary leptin production, adult animals that were leptin-treated during lactation displayed higher gastric leptin production without changes in OB-Rb mRNA levels. In addition, in response to HF diet, leptin-treated animals (contrary to controls) showed lower hypothalamic NPY/POMC mRNA ratio. Hypothalamic OB-Rb mRNA levels decreased in control animals as an effect of HF diet feeding, but remained unchanged in leptin-treated animals; SOCS-3 mRNA levels were lower in leptin-treated animals than in their controls, both under normal or HF diet.. The animals that received leptin during lactation become more protected against fat accumulation in adult life and seem to be more sensitive to the short- and long-term regulation of food intake by leptin. Thus, leptin plays an important role in the earlier stages of neonatal life, as a component of breast milk, in the prevention of later obesity. Topics: Adipose Tissue; Administration, Oral; Aging; Animals; Animals, Newborn; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gastric Mucosa; Lactation; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Wistar; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins | 2007 |
Leptin analog antagonizes leptin effects on food intake and body weight but mimics leptin-induced vagal afferent activation.
A recombinantly produced murine leptin analog (MLA) antagonizes leptin-induced signaling in cell lines that express the long form of the leptin receptor. However, the effects of MLA on the activity of leptin-sensitive neurons and on central neural controls of food intake have not been reported. Here we report effects of MLA on food intake and body weight in adult rats and on the activity of cultured rat vagal afferent neurons. Daily intracerebroventricular coinjection of MLA with exogenous leptin significantly attenuated leptin-induced reduction of 48-h food intake and body weight. Coinjection of MLA with leptin also reduced leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in the hypothalamus. In addition, chronic intracerebroventricular MLA infusion over 14 d via osmotic minipumps significantly increased daily food intake, rate of body weight gain, fat-pad mass, and circulating plasma leptin concentrations. Surprisingly, however, MLA did not antagonize leptin-evoked increases in cytosolic calcium concentrations in vagal afferent neurons in primary culture. Rather, MLA itself produced acute activation selectively in leptin-responsive vagal afferent neurons. These data suggest that MLA is an antagonist for the central effects of leptin on food intake and body weight but an agonist at sites where leptin induces acute neuronal activation. This mixed antagonist/agonist action suggests either 1) that the coupling of a single leptin receptor (ObRb) to acute activation of neurons occurs by a signaling mechanism different from those that mediate centrally evoked reductions in food intake and body weight or 2) that acute neuronal activation and centrally induced reductions of food intake and body weight are mediated by different leptin receptor subtypes. Topics: Animals; Body Weight; Cells, Cultured; Eating; Infusion Pumps; Leptin; Male; Molecular Mimicry; Neurons, Afferent; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Vagus Nerve | 2007 |
Regulation of adiponutrin expression by feeding conditions in rats is altered in the obese state.
To characterize the effect of feeding conditions on the expression behavior of adiponutrin, a non-secreted adipose-specific protein proposed to be involved in energy homeostasis maintenance, and its relation with leptin expression in different rat adipose tissue depots under normal and obese conditions.. Two rat models were used, Wistar (lean and overweight) and Zucker (lean and obese), submitted to fasting/refeeding. Adiponutrin and leptin expression was determined in different white adipose tissue depots (epididymal, inguinal, mesenteric, and retroperitoneal) and in interscapular brown adipose tissue by reverse transcription-polymerase chain reaction.. We have found site-specific differences in adiponutrin expression in different adipose depots, being the expression pattern close to that of leptin in white adipose tissue. The depot-specific adiponutrin expression is similar in lean and obese animals, except in the inguinal depot, where adiponutrin is overexpressed in obese Zucker. Independently of the degree of expression in the tissue, adiponutrin is an acute sensor of feeding conditions compared with other diet-regulated adipokines, as is leptin. In lean rats, 14-hour fasting greatly decreases adiponutrin mRNA levels in all of the depots studied, whereas 3-hour refeeding allows the recovery of the levels found in control animals. In both overweight Wistar and obese Zucker rats, the decreased mRNA expression observed after fasting in lean rats is not as evident; moreover, in the obese Zucker, there is no recovery after refeeding.. Adiponutrin expression is highly regulated by feeding conditions in the different adipose tissue depots, but this regulation is impaired in obese rats. Topics: Adipose Tissue, White; Animals; Body Weight; Feeding Behavior; Gene Expression Regulation; Insulin; Leptin; Male; Membrane Proteins; Obesity; Rats; Rats, Wistar; Rats, Zucker; Thinness | 2007 |
Increased insulin sensitivity and reduced micro and macro vascular disease induced by 2-deoxy-D-glucose during metabolic syndrome in obese JCR: LA-cp rats.
The metabolic syndrome, characterized by obesity, insulin resistance and dyslipidemia, is a major cause of cardiovascular disease. The origins of the syndrome have been hypothesized to lie in continuous availability of energy dense foods in modern societies. In contrast, human physiology has evolved in an environment of sporadic food supply and frequent food deprivation. Intermittent food restriction in rats has previously been shown to lead to reduction of cardiovascular risk and a greater life span. The non-metabolizable glucose analogue, 2-deoxy-D-glucose (2-DG) is taken up by cells and induces pharmacological inhibition of metabolism of glucose. We hypothesized that intermittent inhibition of glucose metabolism, a metabolic deprivation, may mimic intermittent food deprivation and ameliorate metabolic and pathophysiological aspects of the metabolic syndrome.. Insulin resistant, atherosclerosis-prone JCR:LA-cp rats were treated with 2-DG (0.3% w/w in chow) on an intermittent schedule (2 days treated, one day non-treated, two days treated and two days non-treated) or continuously at a dose to give an equivalent averaged intake.. Intermittent 2-DG-treatment improved insulin sensitivity, which correlated with increased adiponectin concentrations. Further, intermittent treatment (but not continuous treatment) reduced plasma levels of leptin and the inflammatory cytokine IL-1 beta. Both 2-DG treatments reduced micro-vascular glomerular sclerosis, but only the intermittent schedule improved macro-vascular dysfunction.. Our findings are consistent with reduction in severity of the metabolic syndrome and protection against end stage micro- and macro-vascular disease through intermittent metabolic deprivation at a cellular level by inhibition of glucose oxidation with 2-DG. Topics: Acetylcholine; Adiponectin; Animals; Blood Glucose; Body Weight; Deoxyglucose; Dose-Response Relationship, Drug; Eating; Female; In Vitro Techniques; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Nitroprusside; Obesity; Phenylephrine; Rats; Rats, Inbred Strains; Rats, Mutant Strains; Renal Circulation; Time Factors; Vascular Diseases; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents | 2007 |
Severe hypoinsulinaemic hypoglycaemia in a premature infant associated with poor weight gain and reduced adipose tissue.
Hypoglycaemia is common in preterm and intrauterine growth retarded (IUGR) newborns. Although preterm and IUGR infants have limited adipose tissue stores, the role of adipose tissue and the associated adipocytokines in glucose physiology is not known.. We report the case of a premature intrauterine growth retarded infant who had poor weight gain for the first 6 weeks of life and then developed severe hypoinsulinaemic hypoketotic hypoglycaemia.. There was markedly reduced adiposity with low serum leptin and adiponectin levels. Total energy expenditure and body composition measurements showed that body fat as a percentage of weight averaged 7% at 20 weeks and 28% at 28 weeks. At 20 weeks of age, the patient was equivalent to a deficit of >2 SD scores of body fat, but average fatness by 28 weeks. The hypoglycaemia completely resolved when the patient started gaining weight with an increase in fat mass and a concomitant increase in serum leptin and adiponectin level.. Although the precise mechanism of this patient's severe hypoglycaemia is unclear, further studies are required to understand the role of adipose tissue and adipocytokines in glucose homeostasis in preterm and IUGR infants. Topics: Adiponectin; Adipose Tissue; Blood Glucose; Body Composition; Body Weight; Fetal Growth Retardation; Humans; Hypoglycemia; Infant, Newborn; Infant, Premature; Infant, Small for Gestational Age; Insulin; Leptin; Male; Weight Gain | 2007 |
The effect of short-term exercise on plasma leptin levels in patients with anorexia nervosa.
Plasma leptin concentrations are markedly reduced in malnourished patients with anorexia nervosa (AN). Whether the long-term underweight and low-fat stores affect the leptin response to exercise remains unknown. We investigated the effect of 45-minute cycle ergometer exercise (2 W kg-1 of lean body mass [LBM]) on plasma leptin, norepinephrine (NE), glycerol, and insulin levels in 10 patients with AN and in 15 healthy age-matched women (C). Plasma leptin levels immediately and 90 minutes after the exercise bout were significantly reduced compared with basal leptin levels in both AN and C groups (P<.05). Compared with the control trial, leptin levels were significantly lower immediately and 90 minutes after exercise in the AN group (P<.05) but not in the C group. Basal and exercise-induced plasma glycerol and NE levels did not differ significantly between the groups. Basal and exercise-induced plasma insulin levels were significantly lower in the AN group compared with the C group (P<.05). In conclusion, we demonstrated that a single bout of low-intensity exercise significantly reduces plasma leptin levels in patients with AN. In healthy women, exercise had no effect on lowering leptin concentrations beyond the diurnal decrease that occurs in the absence of exercise. Neither NE nor insulin are responsible for the different response of leptin to exercise in AN. Topics: Adult; Anorexia Nervosa; Body Weight; Exercise; Glycerol; Humans; Insulin; Leptin; Norepinephrine; Radioimmunoassay | 2007 |
Effects of hypoxia on glucose, insulin, glucagon, and modulation by corticotropin-releasing factor receptor type 1 in the rat.
To determine the influence of continuous hypoxia on body weight, food intake, hepatic glycogen, circulatory glucose, insulin, glucagon, leptin, and corticosterone, and the involvement of the corticotropin-releasing factor receptor type 1 (CRFR1) in modulation of these hormones, rats were exposed to a simulated altitude of 5 km (approximately 10.8% O2) in a hypobaric chamber for 1, 2, 5, 10, and 15 d. Potential involvement of CRFR1 was assessed through five daily sc injections of a CRFR1 antagonist (CP-154,526) prior to hypoxia. Results showed that the levels of body weight, food intake, blood glucose, and plasma insulin were significantly reduced; the content of hepatic glycogen initially and transiently declined, whereas the early plasma glucagon and leptin remarkably increased; plasma corticosterone was markedly increased throughout the hypoxic exposure of 1-15 d. Compared with hypoxia alone, CRFR1 antagonist pretreatment in the hypoxic groups prevented the rise in corticosterone, whereas the levels of body weight and food intake were unchanged. At the same time, the reduction in blood glucose was greater and the pancreatic glucose was increased, plasma insulin reverted toward control, and plasma glucagon decreased. In summary, prolonged hypoxia reduced body weight, food intake, blood glucose, and plasma insulin but transiently enhanced plasma glucagon and leptin. In conclusion, CRFR1 is potentially involved in the plasma insulin reduction and transient glucagon increase in hypoxic rats. Topics: Altitude; Animals; Blood Glucose; Body Weight; Corticosterone; Eating; Glucagon; Hypoxia; Insulin; Leptin; Liver Glycogen; Male; Pyrimidines; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone | 2007 |
Effects of trans-10, cis-12 conjugated linoleic acid on the expression of uncoupling proteins in hamsters fed an atherogenic diet.
It is known that conjugated linoleic acid (CLA) feeding decreases body adiposity but the mechanisms involved are not clear. The aim of this study was to analyse whether alterations in uncoupling protein (UCP) expression in white and brown adipose tissues (WAT and BAT, respectively) and in skeletal muscle may be responsible for the effect of trans-10, cis-12 CLA on the size of body fat depots in hamsters. Animals were divided into three groups and fed an atherogenic diet with different amounts of trans-10, cis-12 CLA (0 control, 0.5, or 1 g/100 g diet) for 6 weeks. CLA feeding reduced adipose depot weights, but had no effect on body weight. Leptin mRNA expression decreased in both subcutaneous and perirenal WAT depots, in accordance with lower adiposity, whereas resistin mRNA expression was not changed. Animals fed CLA had lower UCP1 mRNA levels in BAT (both doses of CLA) and in perirenal WAT (the low dose), and lower UCP3 mRNA levels in subcutaneous WAT (the high dose). UCP2 mRNA expression in WAT was not significantly affected by CLA feeding. Animals fed the high dose of CLA showed increased UCP3 and carnitine palmitoyl transferase-I (CPT-I) mRNA expression levels in skeletal muscle. In summary, induction of UCP1 or UCP2 in WAT and BAT is not likely to be responsible for the fat-reduction action of CLA, but the increased expression of UCP3 in skeletal muscle, together with a higher expression of CPT-I, may explain the previously reported effects of dietary CLA in lowering adiposity and increasing fatty acid oxidation by skeletal muscle. Topics: Adipose Tissue; Animals; Blotting, Northern; Body Weight; Cricetinae; Diet, Atherogenic; Dietary Supplements; Dose-Response Relationship, Drug; Eating; Gene Expression Regulation; Ion Channels; Leptin; Linoleic Acids, Conjugated; Male; Mesocricetus; Mitochondrial Proteins; Muscle, Skeletal; Resistin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uncoupling Protein 1 | 2007 |
Increased caloric intake after a high-fat preload: relation to circulating triglycerides and orexigenic peptides.
To investigate mechanisms that mediate the greater food intake induced by a fat-rich diet, the present study tested an acute "preload-to-test meal" paradigm in normal-weight rats. In this paradigm, the rats were given a small high-fat (HF) compared to low-fat (LF) preload and, after an intermeal interval, allowed to consume freely on a subsequent test meal. Modified versions of this paradigm were tested to determine the robustness of the greater caloric intake induced by the HF preload while standardizing the test protocol. A HF preload of 10-15 kcals, compared to an equicaloric LF preload, significantly increased food intake by 40-50% in the subsequent test meal. This effect, a 4-6 kcal increase, was observed with HF preloads equal in energy density and palatability to the LF preloads. It was evident with preloads or test meals that were liquid or solid, preloads that were injected, test meals that had variable fat content, and natural intermeal intervals of 60-120 min. This overeating after a HF preload was invariably associated with a 2- to 3-fold increase in circulating levels of triglycerides (TG), with no change in leptin or insulin. It was also accompanied by increased expression of the orexigenic peptides, galanin in the paraventricular nucleus and orexin in the perifornical lateral hypothalamus. Moreover, if given repeatedly over several days, the HF compared to equicaloric LF preload significantly increased 24-h food intake. These results establish a protocol for studying the phenomenon of increased feeding on a HF diet under controlled conditions and suggest possible underlying mechanisms involving circulating lipids and orexigenic peptides. Topics: Animals; Body Weight; Brain Chemistry; Diet; Dietary Fats; Eating; Energy Intake; Food Preferences; Galanin; Hyperphagia; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptides; Orexins; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Triglycerides; Weight Gain | 2007 |
Rosuvastatin restores superoxide dismutase expression and inhibits accumulation of oxidized LDL in the aortic arch of obese dyslipidemic mice.
Our goal was to elucidate mechanisms of the inhibitory effect of rosuvastatin on the accumulation of plaque oxidized low density lipoproteins (oxLDL) and on plaque volume, without lowering cholesterol, in mice with combined leptin and LDL-receptor deficiency (DKO).. Twelve-week old DKO mice were treated with rosuvastatin (10 mg kg(-1) day(-1), s.c.) or placebo or no treatment for 12 weeks. The effect on blood variables, aortic plaque volume and composition and gene expression in the aorta and in THP-1 cells was assessed.. Rosuvastatin lowered free fatty acids (FFA), triglycerides, and increased insulin sensitivity, without affecting cholesterol. Rosuvastatin lowered the plaque volume, inhibited macrophage, lipid and oxLDL accumulation, and decreased the oxLDL-to-LDL ratio of plaques in the aortic arch. It increased superoxide dismutase 1 (SOD1), CD36, LXR-alpha, ABCA-1 and PPAR-gamma RNA expression in aortic extracts. SOD1 was the strongest inverse correlate of oxLDL. In THP-1 macrophages and foam cells, expression of SOD1 was lower than in THP-1 monocytes. Rosuvastatin restored expression of SOD1 in THP-1 macrophages and foam cells.. Rosuvastatin restored SOD1 expression in THP-1 macrophages and foam cells in vitro and in the aorta of DKO mice. The latter was associated with less oxLDL accumulation within atherosclerotic plaques and inhibition of plaque progression. This effect was obtained at a dose not affecting cholesterol levels but improving insulin sensitivity. SOD1 is a potentially important mediator of the prevention of oxLDL accumulation within atherosclerotic plaques. Topics: Animals; Aorta; Atherosclerosis; Blood Glucose; Body Weight; Cell Line; Dyslipidemias; Fluorobenzenes; Gene Expression; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin; Leptin; Lipids; Lipoproteins, LDL; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; PPAR gamma; Pyrimidines; Receptors, LDL; Reverse Transcriptase Polymerase Chain Reaction; Rosuvastatin Calcium; Sulfonamides; Superoxide Dismutase | 2007 |
Melanocortin activation of nucleus of the solitary tract avoids anorectic tachyphylaxis and induces prolonged weight loss.
To examine the role of the brain stem melanocortin system in long-term energy regulation, we assessed the effects of overproduction of proopiomelanocortin (POMC) in the caudal brain stem of F344xBN rats with adult-onset obesity. Recombinant adeno-associated viral vector encoding POMC gene was delivered to the nucleus of solitary tract (NTS) in the hindbrain, and food intake, body weight, glucose and fat metabolism, brown adipose tissue thermogenesis, and mRNA levels of neuropeptides and melanocortin receptors were assessed. POMC delivery resulted in sustained reduction in food intake and body weight over 42 days and improved insulin sensitivity. At death, in recombinant adeno-associated viral vector-POMC-treated rats vs. control rats, alpha-melanocyte-stimulating hormone in NTS increased nearly 21-fold, whereas hypothalamic alpha-melanocyte-stimulating hormone remained unchanged. Visceral adiposity decreased by 37%; tissue triglyceride content diminished by 26% and 47% in liver and muscle, respectively; serum triglyceride and nonesterified fatty acids were reduced by 35% and 34%, respectively; phosphorylation of acetyl-CoA carboxylase was elevated by 63% in soleus muscle; brown adipose tissue uncoupling protein 1 increased by 30%; and melanocortin 3 receptor expression declined by 60%, whereas neuropeptide Y, agouti-related protein, and MC4 receptor mRNA levels were unchanged in the NTS. In conclusion, POMC overexpression in the NTS produces a characteristic unabated hypophagia that is uniquely different from the anorexic tachyphylaxis following POMC overexpression in the hypothalamus. The sustained anorectic response may result from absence of compensatory elements in the NTS, such as increased agouti-related protein expression, suggesting melanocortin activation of the brain stem may be a viable strategy to alleviate obesity. Topics: Adiposity; alpha-MSH; Animals; Animals, Genetically Modified; Anorexia; Appetite Regulation; Body Weight; Energy Metabolism; Gene Expression Regulation; Gene Transfer Techniques; Genetic Therapy; Leptin; Male; Melanocortins; Obesity; Pro-Opiomelanocortin; Rats; Rats, Inbred F344; Solitary Nucleus; Tachyphylaxis; Time Factors; Weight Loss | 2007 |
Differential body weight and feeding responses to high-fat diets in rats and mice lacking cholecystokinin 1 receptors.
Prior data demonstrated differential roles for cholecystokinin (CCK)1 receptors in maintaining energy balance in rats and mice. CCK1 receptor deficiency results in hyperphagia and obesity of Otsuka Long-Evans Tokushima Fatty (OLETF) rats but not in mice. To ascertain the role of CCK1 receptors in high-fat-diet (HFD)-induced obesity, we compared alterations in food intake, body weight, fat mass, plasma glucose, and leptin levels, and patterns of hypothalamic gene expression in OLETF rats and mice lacking CCK1 receptors in response to a 10-wk exposure to HFD. Compared with Long-Evans Tokushima Otsuka (LETO) control rats, OLETF rats on HFD had sustained overconsumption over the 10-wk period. High fat feeding resulted in greater increases in body weight and plasma leptin levels in OLETF than in LETO rats. In situ hybridization determinations revealed that, while HFD reduced neuropeptide Y (NPY) mRNA expression in both the arcuate nucleus (Arc) and the dorsomedial hypothalamus (DMH) of LETO rats, HFD resulted in decreased NPY expression in the Arc but not in the DMH of OLETF rats. In contrast to these results in OLETF rats, HFD increased food intake and induced obesity to an equal degree in both wild-type and CCK1 receptor(-/-) mice. NPY gene expression was decreased in the Arc in response to HFD, but was not detectable in the DMH in both wild-type and CCK1 receptor(-/-) mice. Together, these data provide further evidence for differential roles of CCK1 receptors in the controls of food intake and body weight in rats and mice. Topics: Adipose Tissue; Adiposity; Animals; Blood Glucose; Body Weight; Corticotropin-Releasing Hormone; Diet; Dietary Fats; Eating; Energy Intake; Gene Expression; Hypothalamus; In Situ Hybridization; Leptin; Male; Mice; Mice, Knockout; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Inbred OLETF; Receptor, Cholecystokinin A; RNA Probes | 2007 |
Various dietary fats differentially change the gene expression of neuropeptides involved in body weight regulation in rats.
Various high-fat diets are obesogenic but not to the same extent. The aim of the present study was to investigate the effects of saturated fat n-6 and n-3 polyunsaturated fatty acids (PUFAs) on the central neuropeptidergic system in adult rats. Using reverse transcriptase-polymerase chain reaction and in situ hybridisation, we evaluated the net effect of feeding in these fats, comparing the effects of a high- to low-fat diet, and the diversity of the effects of these fats in the same amount within the diet. We also determined plasma lipids, glucose, insulin and leptin concentrations. Six-week feeding with high-saturated fat evoked hyperpahagia and the largest weight gain compared to both high-PUFA diets. Rats fed high-saturated fat were found to have decreased neuropeptide Y (NPY) mRNA expression in the arcuate nucleus (ARC) and the compact zone of the dorsomedial nucleus (DMHc), unchanged pro-opiomelanocortin (POMC), galanin-like peptide (GALP) mRNA expression in the ARC, as well as melanin-concentrating hormone (MCH) and prepro-orexin (preORX) mRNA expression in the lateral hypothalamus, compared to low-saturated fed rats. By contrast, feeding with both high-PUFA diets increased POMC and GALP mRNA expression in the ARC compared to the corresponding low-fat diet and the high-saturated fat diet. Furthermore, feeding with both low-PUFA diets reduced NPY mRNA expression compared to the low-saturated fat diet exclusively in the DMHc. Uniquely, the high n-3 PUFA feeding halved MCH and preORX mRNA expression in the lateral hypothalamus compared to the other high-fat and low n-3 PUFA diets. In rats fed three high-fat diets, plasma insulin and leptin concentrations were significantly increased and the type of fat had no effect on these hormone levels. Rats fed high-saturated fat had both hyperglycaemia and hypertriacylglycerolemia and rats fed high n-3 PUFA only had hyperglycaemia. The present study demonstrates that various forms of dietary fat differentially change the expression of neuropeptide genes involved in energy homeostasis. Topics: Animals; Appetite Regulation; Blood Glucose; Body Weight; Dietary Fats; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Feeding Behavior; Galanin-Like Peptide; Gene Expression Profiling; Gene Expression Regulation; Hypothalamic Hormones; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Lipids; Male; Melanins; Neuropeptide Y; Neuropeptides; Orexins; Pituitary Hormones; Pro-Opiomelanocortin; Rats; Rats, Wistar; RNA, Messenger; Statistics, Nonparametric | 2007 |
Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway.
Published data describing leptin effects on bone are at variance with both positive and negative consequences reported. These findings are consistent with a bimodal threshold response to serum leptin levels. To test this theory, two groups of female rats (tail-suspended and unsuspended) were treated with ip leptin at two different doses or vehicle for 14 d. In tail-suspended rats, low-dose leptin compensated the decrease in serum leptin levels observed with suspension and was able to prevent the induced bone loss at both the trabecular and cortical level (assessed by three-dimensional microtomography). In contrast, high-dose leptin inhibited femoral bone growth and reduced bone mass by decreasing bone formation rate and increasing bone resorption in both tail-suspended and unsuspended groups. High- and low-dose leptin administration resulted in a reduced medullar adipocytic volume in all groups. High-dose leptin (but not low) induced a decrease in body-weight abdominal fat mass and serum IGF-I levels. Thus, the observed bone changes at high-dose leptin are at least partly mediated by a leptin-induced energy imbalance. In conclusion, a balance between negative and positive leptin effects on bone is dependent on a bimodal threshold that is triggered by leptin serum concentration. Also, the negative effects of high leptin levels are likely induced by reduced energy intake and related hormonal changes. The respective part of each pathway will be unraveled by additional studies. Topics: Adipocytes; Animals; Body Weight; Bone and Bones; Bone Density; Dose-Response Relationship, Drug; Energy Intake; Female; Femur; Insulin-Like Growth Factor I; Leptin; Osteogenesis; Rats; Rats, Wistar; Signal Transduction; Tibia; Tomography, X-Ray Computed | 2007 |
Endocrine profiles of periparturient mares and their foals.
The aim of this study was to characterize concentrations of leptin, IGF-I, and thyroid stimulating hormone (TSH) in the blood serum of mares pre-and postpartum, in the milk serum of mares postpartum, and in the blood serum of their foals. Nine pregnant Quarter Horse mares and their offspring were used in this study. Once weekly between 1000 and 1200 h for 2 wk before their predicted parturition date, mares were weighed, assigned a BCS, and blood was sampled via jugular venipuncture. Within 2 h of parturition and before the foals nursed (d 0), blood samples were obtained from the mares and foals, and a milk sample was collected from the mares. Blood from the foals and blood and milk from the mares were collected again at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 12, 19, 26, 33, and 61 d postpartum. Mares and foals also were weighed and assigned a BCS on d 0, 5, 12, 19, 26, 33, and 61. Additionally, on d 5, 33, and 61, ultrasound images of fat depth and area of the LM immediately cranial to and parallel with the last rib on the left side of the foals were measured to characterize changes in fat depth and LM area over time. There were no changes in mare blood concentrations TSH (P = 0.15), nor were there any changes in foal blood concentrations of leptin (P = 0.54) or TSH (P = 0.10) during the trial period. Mare blood concentrations of IGF-I tended to change over time (P = 0.07), whereas leptin changed over time (P < 0.001), initially decreasing and then remaining relatively stable after d 5. Foal blood concentrations of IGF-I increased initially, peaked at d 19, and stabilized thereafter (P < 0.001). Milk concentrations of leptin and TSH were greatest on d 0 and decreased over time (P < 0.007), reaching nadir concentrations at d 61. Milk concentrations of IGF-I also changed over time (P = 0.02), being greatest on d 0 and undetectable by d 12. There was no difference in BCS (P = 0.94) in mares over time, but there was a difference between pre- and postpartum BW (P < 0.001) due to foaling. However, no differences were detected in pre- (P = 0.70) or postpartum BW (P = 0.76) of mares over time. Mean ultrasonic fat depth and LM area increased (P < 0.04) as the foals aged, as did BCS and BW (P < 0.001). Recognizing changes in metabolic hormones surrounding the time of parturition in the mare and foal provides a basis for further determination of the role, if any, these hormones play in the milk, as well as in the neonate. Topics: Animals; Animals, Suckling; Body Composition; Body Constitution; Body Weight; Female; Horses; Insulin-Like Growth Factor I; Leptin; Milk; Postpartum Period; Pregnancy; Pregnancy, Animal; Radioimmunoassay; Thyrotropin; Time Factors | 2007 |
Association of single nucleotide polymorphisms in the leptin gene with body weight and backfat growth curve parameters for beef cattle.
Previous research has identified differences in carcass characteristics across SNP in the bovine leptin gene at slaughter, but before feedlot operators implement selection and sorting strategies, more information is needed to determine how carcass characteristics change over time. The objective of this study was to investigate the effect of 2 leptin SNP on growth curve parameters for BW and backfat. Two SNP (UASMS2 and R25C) were genotyped on 1,653 cross-bred steers and heifers in a commercial feedlot. Up to 4 serial measures of BW and ultrasound estimates of backfat thickness were taken for each animal from the time of placement on feed to slaughter. The measures were used to estimate growth models that describe changes in BW and backfat thickness as a function of days on feed. Data analysis was carried out by estimating nonlinear mixed models to determine the individual and joint effect of each SNP on growth curve parameters. Brody growth curves were fit to the BW data. Variations in the R25C SNP did not significantly affect growth parameters individually or in combination with the UASMS2 SNP. Variations in the UASMS2 SNP were significant in Brody growth curve parameters for BW growth (P < 0.001). The genotype UASMS2-CC was the heaviest at the beginning of the feeding period and exhibited the largest asymptotic mature BW, but UASMS2-TT cattle exhibited the fastest rate of BW growth. A modified power function was fit to the serial ultrasound backfat measures. Models that included the combined effect of the R25C and UASMS2 SNP provided the best fit to the data. Genotypes differed significantly in power function parameters for backfat growth (P < 0.001). The R25C-CC/UASMS2-TT cattle had the smallest backfat thickness at placement. The genotype R25C-CC/UASMS2-TT exhibited the fastest backfat growth rate, whereas backfat in R25C-CC/UASMS2-CC cattle grew at the slowest rate. The association between leptin genotype and growth in BW and backfat presents opportunities to identify genetically distinct cattle and to differentially optimize feeding times accordingly. Topics: Adipose Tissue; Animals; Body Weight; Cattle; Female; Genotype; Leptin; Likelihood Functions; Male; Models, Biological; Polymorphism, Single Nucleotide | 2007 |
A high oxidised frying oil content diet is less adipogenic, but induces glucose intolerance in rodents.
Oxidised frying oil (OFO) and fish oil have been shown to be peroxisome proliferator-activated receptor (PPAR)alpha activators and their ingestion results in pleotropic peroxisome proliferator responses in rats. To examine the effect of dietary OFO on adiposity, four groups of weanling Sprague-Dawley rats were fed isoenergetically with, respectively, a low fat basal diet containing 5 g/100 g of fresh soybean oil (LSB) or a high fat diet containing 20 g/100 g of fresh soybean oil (HSB), OFO (HO) or fish oil (HF). The tissue mass, cell size and lipid/DNA ratio in the retroperitoneal fat pad and serum leptin levels were lowest in the HO group (P < 0.05), indicating that dietary OFO has a greater anti-adipogenic action than dietary fish oil. However, a tendency to hyperglycaemia was observed in the HO group (P = 0.0528). To examine the effect of dietary OFO on glucose tolerance, three groups of rats and three groups of mice were fed, respectively, the LSB, HSB or HO diet, and an oral glucose tolerance test was performed. After oral glucose load, the area under the curve for blood glucose (AUCglu) over 2 h was significantly higher, and that for serum insulin (AUCins) over 90 min was significantly lower, in the HO group than in the other two groups (P < 0.05). These results demonstrate that, in rats and mice, a high OFO diet is less adipogenic, but induces glucose intolerance. Topics: Adipocytes; Adipose Tissue; Animals; Blood Glucose; Body Weight; Cell Size; Cooking; Dietary Fats; DNA; Fish Oils; Glucose Intolerance; Glucose Tolerance Test; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Rats; Rats, Sprague-Dawley; Soybean Oil | 2007 |
Prenatal exposure to lipopolysaccharide results in increases in blood pressure and body weight in rats.
To investigate the effects of prenatal exposure to lipopolysaccharide (LPS) on blood pressure and body weight of offspring in rats.. Sixteen healthy, pregnant rats were randomly divided into 2 groups. The rats in the LPS group were injected intraperitoneally with LPS (0.79 mg/kg) on the d 8, d 10, and d 12 of gestation. Those in the control group were only treated with normal saline. After delivery, all offspring were weighed and blood pressure was measured by the tailcuff method once every 2 weeks from the 6th to the 24th week. In the 15th week, their food intake was weighed every day. At the end of the 24th week, the rats were killed by decapitation. Abdominal adipose tissues were weighed, and the serum level of leptin was detected by radioimmunoassay.. The offspring with prenatal LPS exposure showed increased systemic arterial pressure, heavier body weight, elevated food intake, increased adipose tissue weight, and increased circulating leptin compared with the controls.. Prenatal exposure to LPS leads to increases in blood pressure and body weight in rats. Topics: Adipose Tissue; Animals; Blood Pressure; Body Weight; Eating; Female; Fetus; Humans; Hypertension; Leptin; Lipopolysaccharides; Male; Pregnancy; Prenatal Exposure Delayed Effects; Random Allocation; Rats; Rats, Sprague-Dawley | 2007 |
Changes in environmental temperature influence leptin responsiveness in low- and high-fat-fed mice.
Loss of body fat in leptin-treated animals has been attributed to reduced energy intake, increased thermogenesis, and preferential fatty acid oxidation. Leptin does not decrease food intake or body fat in leptin-resistant high-fat (HF)-fed mice, possibly due to a failure of leptin to activate hypothalamic receptors. We measured energy expenditure of male C57BL/6 mice adapted to low-fat (LF) or HF diet and infused them for 13 days with PBS or 10 mug leptin/day from an intraperitoneal mini-osmotic pump to test whether leptin resistance prevented leptin-induced increases in energy expenditure and fatty acid oxidation. There was no effect of low-dose leptin infusions on either of these measures in LF-fed or HF-fed mice, even though LF-fed mice lost body fat. Experiment 2 tested leptin responsiveness in LF-fed and HF-fed mice housed at different temperatures (18 degrees C, 23 degrees C, 27 degrees C), assuming that the cold would increase and the hot environment would inhibit food intake and thermogenesis, which could potentially interfere with leptin action. LF-fed mice housed at 23 degrees C were the only mice that lost body fat during leptin infusion, suggesting that an ability to modify energy expenditure is essential to the maintenance of leptin responsiveness. HF-fed mice in cold or warm environments did not respond to leptin. HF-fed mice in the hot environment were fatter than other HF-fed mice, and, surprisingly, leptin caused a further increase in body fat, demonstrating that the mice were not totally leptin resistant and that partial leptin resistance in a hot environment favors positive energy balance and fat deposition. Topics: Adiponectin; Adipose Tissue; Adiposity; Animals; Body Weight; Calorimetry; Diet; Dietary Fats; Energy Intake; Energy Metabolism; Leptin; Male; Mice; Mice, Inbred C57BL; Temperature; Thermogenesis | 2007 |
Nicotine regulates mRNA expression of feeding peptides in the arcuate nucleus in neonatal rat pups.
Maternal smoking results in low birth weight. Using a neonatal gastric intubation model corresponding to the third trimester in humans, nicotine, the major psychoactive ingredient in tobacco, causes growth retardation in rat pups. Here, we wanted to determine the underlying mechanisms of nicotine's anorexic effects. In adults, body weight and energy expenditure are regulated by the adiposity hormone leptin and the orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP) and anorexic peptides proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) expressed in the hypothalamic arcuate (Arc) nucleus. Activation of nicotinic acetylcholine receptors (nAChRs) could regulate leptin release and/or peptide expression in the Arc. Neonatal rat pups were treated twice daily with nicotine (0.25, 1.5, and 3 mg/kg) from postnatal day 1 to 8 (P1-8). This resulted in an upregulation of heteromeric nAChR binding sites in the ventromedial nucleus of the hypothalamus and Arc. Nicotine at all three doses significantly reduced body weight gain and increased mRNA expression of NPY, AgRP, and POMC effects, which were blocked by dihydro-beta-erythroidine (DHbetaE), an alpha4beta2* nAChR antagonist, but CART expression was unaffected. In contrast, serum leptin levels were significantly increased only by 3 and 1.5 mg/kg, and the increase was only partially blocked by DHbetaE. These data suggest that in neonates chronic nicotine regulates body weight gain independent from serum leptin levels by a central mechanism involving alpha4beta2* heteromeric nAChRs and stimulated increased expression of the anorexic peptide POMC. Whereas, increased NPY and AgRP expression could be a secondary response to reduction in weight gain. Topics: Age Factors; Agouti-Related Protein; Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Autoradiography; Body Weight; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Leptin; Neuropeptide Y; Nicotine; Nicotinic Agonists; Pregnancy; Pro-Opiomelanocortin; Protein Binding; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2007 |
Overexpression of apolipoprotein CIII increases and CETP reverses diet-induced obesity in transgenic mice.
We recently described that hypertriglyceridemic apolipoprotein (apo) CIII transgenic mice show increased whole body metabolic rate. In this study, we used these apo CIII-expressing mice, combined or not with the expression of the natural promoter-driven CETP gene, to test the hypothesis that both proteins modulate diet-induced obesity.. Mice expressing apo CIII, CIII/CETP, CETP and nontransgenic (NonTg) mice were maintained on a high-fat diet (14% fat by weight) during 20 weeks after weaning. At the end of this period, all groups exhibited the expected lipemic phenotype. Fasting glucose levels were neither affected by the high-fat diet nor by the distinct genotypes. However, apo CIII mice showed significantly higher glycemia ( approximately 35%) and lower insulin levels ( approximately 45%) in the fed state, compared with the NonTg mice. The apo CIII mice presented significantly increased body weight, lipid content of the carcass ( approximately 25%), visceral adipose tissue mass (about twofold) and adipocyte size ( approximately 25%) compared with the CETP and NonTg mice. The CETP expression in the apo CIII background normalized the subcutaneous adipose depot and visceral adipocyte size to the levels of NonTg mice. Plasma leptin levels were lower in CETP groups (25-50%) and higher in the apo CIII mice. Similar core body temperature in all groups and similar liver mitochondrial resting respiration rates in CIII and NonTg mice indicate no differences in basal energy expenditure rates among these mice fed a high-fat diet.. The elevation of plasma apo CIII levels aggravates diet-induced obesity and the expression of physiological levels of circulating CETP reverses this adipogenic effect, indicating a novel role for CETP in modulating adiposity. Topics: Animals; Apolipoprotein C-III; Body Composition; Body Weight; Cholesterol Ester Transfer Proteins; Fasting; Hypertriglyceridemia; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity | 2007 |
Nitrosative stress and peripheral diabetic neuropathy in leptin-deficient (ob/ob) mice.
Nitrosative stress contributes to nerve conduction slowing, thermal hypoalgesia, and impaired nitrergic innervation in animal models of Type 1 diabetes. The role for reactive nitrogen species in Type 2 diabetes-associated neuropathy remains unexplored. This study evaluated the role for nitrosative stress in functional and structural neuropathic changes in ob/ob mice, a model of Type 2 diabetes with mild hyperglycemia and obesity. Two structurally diverse peroxynitrite decomposition catalysts, Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)-pyridyl porphyrin (FP15) and Fe(III) tetra-mesitylporphyrin octasulfonate (FeTMPS), were administered to control and 8-week-old ob/ob mice for 3 weeks at the doses of 5 mg kg(-1) day(-1) (FP15) and 5 and 10 mg kg(-1) day(-1) (FeTMPS). The 11-week-old ob/ob mice developed motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable ( approximately 78%) loss of intraepidermal nerve fibers. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion neurons. Treatment with two structurally diverse peroxynitrite decomposition catalysts was associated with restoration of normal MNCV and SNCV, and alleviation of thermal hypoalgesia. Tactile response thresholds increased in response to peroxynitrite decomposition catalyst treatment, but still remained approximately 2.7- to 3.2-fold lower compared with non-diabetic controls. Intraepidermal nerve fiber loss was not alleviated by either FP15 or FeTMPS. Nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and dorsal root ganglia of peroxynitrite decomposition catalyst-treated ob/ob mice were essentially normal. In conclusion, nitrosative stress plays an important role in functional abnormalities associated with large motor, large sensory, and small sensory fiber neuropathy, but not in small sensory nerve fiber degeneration, in this animal model. Peroxynitrite decomposition catalysts alleviate Type 2 diabetes-associated sensory nerve dysfunction, likely by mechanism(s) not involving arrest of degenerative changes or enhanced regeneration of small sensory nerve fibers. Topics: Anesthesia; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Immunohistochemistry; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Motor Neurons; Nerve Fibers; Neural Conduction; Neurons, Afferent; Nitrites; Pain; Pain Measurement; Peroxynitrous Acid; Poly Adenosine Diphosphate Ribose; Touch | 2007 |
Predicting maximum Roux-en-Y gastric bypass-induced weight reduction--preoperative plasma leptin or body weight?
Weight loss after bariatric surgery varies between patients, and predicting the extent thereof is often inaccurate. The aim of this study was to assess the potential of preoperative plasma leptin and body weight in predicting the maximum weight loss within 2 years after Roux-en-Y gastric bypass (RYGBP).. The study comprised 68 subjects (39 women, 29 men; mean age 36.4 +/- 10.2 years, body weight 130.3 +/- 24.8 kg, BMI 44.4 +/-6.8 kg/m2) undergoing RYGBP who were followed for 2 years. Baseline and maximum follow-up plasma leptin and weight were assessed.. Mean maximum weight reduction of 50.5 +/- 19.1 kg (38.0 +/- 9.0%, range 24-100 kg) was noted at 15 +/- 4 months after RYGBP. Baseline plasma leptin was 37.9 +/- 14.5 ng/ml, and decreased to 17.4 +/- 8.1 ng/ml (P < 0.001) at maximum weight reduction. No significant correlation between baseline plasma leptin and absolute or relative weight reduction or minimum body weight achieved was noted. No significant plasma leptin threshold which would be predictive for any consistent extent of weight loss was found. However, baseline body weight was a strong determinant of minimum body weight attained (r = 0.67; P < 0.01) and of maximum absolute weight reduction (r = 0.81; P < 0.01).. Preoperative plasma leptin concentration cannot be used as a predictor of weight reduction following RYGBP. Preoperative body weight is a reliable predictor of post-RYGBP weight loss. Topics: Adult; Body Weight; Female; Follow-Up Studies; Gastric Bypass; Humans; Leptin; Male; Middle Aged; Obesity, Morbid; Predictive Value of Tests; Time Factors; Treatment Outcome; Weight Loss | 2007 |
Effects of diet quality on energy budgets and thermogenesis in Brandt's voles.
Food quality and availability play an important role in an animal's life history. The aim of this study was to examine the effect of diet quality [high-fiber diet (HF) or low-fiber diet (LF)] on energy budgets and thermogenesis in Brandt's voles (Lasiopodomys (Microtus) brandtii). Dry matter intake and gross energy intake increased and digestibility decreased in HF voles compared with LF voles, while the digestible energy intake was similar for both HF and LF voles. Nonshivering thermogenesis (NST) decreased in HF voles, while LF voles kept stable; no significant differences were detected in basal metabolic rate (BMR), BAT uncoupling protein 1 (UCP1) content and the levels of serum thyroid hormones (T3 and T4) between HF and LF voles. Although there were no differences in body fat content and serum leptin concentrations between HF and LF voles, serum leptin concentrations in HF voles were reduced to nearly half as those seen in LF voles after 4-weeks acclimation. These results support the hypothesis that Brandt's voles can compensate the poor quality diet physiologically by the means of increasing food intake and decreasing thermogenesis. Topics: Animals; Arvicolinae; Body Composition; Body Temperature Regulation; Body Weight; Energy Metabolism; Leptin | 2007 |
Improvement of obesity and glucose tolerance by acetate in Type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats.
Acetate has been found to have an inhibitory effect on the activity of carbohydrate-responsive element-binding protein (ChREBP) in cultured hepatocytes, this being a transcription factor that regulates several genes required for the conversion of glucose to fatty acids in the liver. The aim of this study was to investigate whether an oral administration of acetate would contribute to reducing lypogenic genes and protecting against obesity. We orally injected 5.2 mg/kg BW of acetate to obesity-linked type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. The treatment with acetate showed a marked reduction in lipid accumulation in the adipose tissue, protection against accumulation of fat in the liver, and improved glucose tolerance. An analysis by Northern blotting revealed that the transcripts of several lipogenic genes in the liver of OLETF rats were decreased by the acetate treatment. On the basis of those results, it was indicated that acetate was a potential compound to improve obesity and obesity-linked type 2 diabetes. Topics: Acetates; Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Insulin; Leptin; Lipids; Male; Models, Biological; Obesity; Random Allocation; Rats; Rats, Inbred OLETF; RNA, Messenger; Time Factors; Triglycerides | 2007 |
Successful long-term weight maintenance: a 2-year follow-up.
To find factors associated with successful weight maintenance (WM) in overweight and obese subjects after a very low-calorie diet (VLCD).. Subjects (133) followed a VLCD (2.1 MJ/d) for 6 weeks in a free-living situation. Of these, 103 subjects (age, 49.6 +/- 9.7 years; BMI, 30.9 +/- 3.8 kg/m(2)) completed the following 2-year WM period. Body weight (BW), body composition, leptin concentration, attitude toward eating, and physical activity were determined right before (t0) and after (t1) the VLCD, after 3 months (t2), after 1 year (t3), after 1.5 years (t4), and after 2 years (t5).. BW loss during VLCD was 7.2 +/- 3.1 kg. After 2 years, follow-up BW regain was 69.0 +/- 98.4%. After 2 years of WM, 13 subjects were successful (<10% BW regain), and 90 were unsuccessful (>10% BW regain). At baseline, these groups were significantly different in BMI (33.7 +/- 4.7 vs. 30.5 +/- 3.5 kg/m(2), respectively; p < 0.05) and fat mass (38.3 +/- 9.8 vs. 32.1 +/- 8.3 kg, p < 0.05). Successful subjects increased their dietary restraint significantly more during the whole study period (dietary restraint score, -4.9 +/- 4.4 vs. -2.1 +/- 3.8). Furthermore, %BW regain was associated with the amount of percentage body fat lost during VLCD, which indicates that the more fat lost, the better the WM, suggesting a fat free mass-sparing effect.. Characteristics such as the ability to increase dietary restraint and maintain this high level of restraint, fat free mass sparing, and a relatively high baseline BMI and fat mass were associated with successful long-term WM (<10% regain after 2 years). Topics: Adult; Attitude; Body Composition; Body Weight; Diet; Eating; Exercise; Follow-Up Studies; Humans; Leptin; Middle Aged; Netherlands; Surveys and Questionnaires; Time Factors; Weight Loss | 2007 |
Neonatal immune challenge does not affect body weight regulation in rats.
The perinatal environment plays a crucial role in programming many aspects of adult physiology. Myriad stressors during pregnancy, from maternal immune challenge to nutritional deficiency, can alter long-term body weight set points of the offspring. In light of the increasing concern over body weight issues, such as obesity and anorexia, in modern societies and accumulating evidence that developmental stressors have long-lasting effects on other aspects of physiology (e.g., fever, pain), we explored the role of immune system activation during neonatal development and its impact on body weight regulation in adulthood. Here we present a thorough evaluation of the effects of immune system activation (LPS, 100 microg/kg ip) at postnatal days 3, 7, or 14 on long-term body weight, adiposity, and body weight regulation after a further LPS injection (50 microg/kg ip) or fasting and basal and LPS-induced circulating levels of the appetite-regulating proinflammatory cytokine leptin. We show that neonatal exposure to LPS at various times during the neonatal period has no long-term effects on growth, body weight, or adiposity. We also observed no effects on body weight regulation in response to a short fasting period or a further exposure to LPS. Despite reductions in circulating leptin levels in response to LPS during the neonatal period, no long-term effects on leptin were seen. These results convincingly demonstrate that adult body weight and weight regulation are, unlike many other aspects of adult physiology, resistant to programming by a febrile-dose neonatal immune challenge. Topics: Acute Disease; Adipose Tissue; Age Factors; Animals; Animals, Newborn; Anorexia; Body Weight; Critical Period, Psychological; Fasting; Female; Inflammation; Leptin; Lipopolysaccharides; Male; Obesity; Pregnancy; Rats; Rats, Sprague-Dawley; Satiation; Sodium Chloride | 2007 |
Energy balance and hypothalamic effects of a high-protein/low-carbohydrate diet.
Diets high in fat or protein and extremely low in carbohydrate are frequently reported to result in weight loss in humans. We previously reported that rats maintained on a low-carbohydrate-high fat diet (LC-HF) consumed similar kcals/day as chow (CH)-fed rats and did not differ in body weight after 7 weeks. LC-HF rats had a 45% decrease in POMC expression in the ARC, decreased plasma insulin, and increased plasma leptin and ghrelin. In the present study we assessed the effects of a low-carbohydrate-high-protein diet (HP: 30% fat, 65% protein, and 5% CHO) on body weight, caloric intake, plasma hormone levels and hypothalamic gene expression. Male rats (n=16) were maintained on CH or HP for 4 weeks. HP rats gained significantly less weight than CH rats (73.4+/-9.4 and 125.0+/-8.2 g) and consumed significantly less kcals/day (94.8+/-1.5 and 123.6+/-1.1). Insulin was significantly reduced in HP rats (HP: 1.8+/-0.6 vs. CH: 4.12+/-0.8 ng/ml), there were no differences between groups in plasma leptin and plasma ghrelin was significantly elevated in HP rats (HP: 127.5+/-45 vs. CH: 76.9+/-8 pg/ml). Maintenance on HP resulted in significantly increased ARC POMC (HP: 121+/-10.0 vs. 100+/-5.9) and DMH NPY (HP: 297+/-82.1 vs. CH: 100+/-37.7) expression compared to CH controls. These data suggest that the macronutrient content of diets differentially influences hypothalamic gene expression in ways that can affect overall intake. Topics: 3-Hydroxybutyric Acid; Animals; Behavior, Animal; Body Weight; Dietary Carbohydrates; Dietary Proteins; Eating; Energy Metabolism; Food Preferences; Gene Expression Regulation; Ghrelin; Hypothalamus; Insulin; Leptin; Male; Neuropeptide Y; Pro-Opiomelanocortin; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Time Factors | 2007 |
Loss of sex-specific difference in femoral bone parameters in male leptin knockout mice.
Sex-dependent differences were identified in the femoral bone parameters of male and female ob/ob (leptin knockout) mice compared with their C57BL/6 wild-type background strain. Total fat, lean weight and body weight were not different between adult male and female leptin knockout mice. However, leptin knockout males exhibited lower lean weights than C57BL/6 males. Peripheral quantitative computerized tomographic measurements at the femoral midshaft revealed that the normal differences in the periosteal circumference, endosteal circumference, total bone mineral content, and polar moment of inertia normally observed between adult male and female wild-type mice were lost between adult male and female ob/ob mice. Significant reductions in these bone parameters were seen in male ob/ob mice compared to male wild-type mice but not in female ob/ob mice compared to female wild-type mice. In prepubertal mice, there were no differences in phenotype and femoral bone parameters between males and females within any strain, suggesting sex hormone functions. Serum free testosterone levels were 5.6-fold higher in adult male ob/ob mice than in adult male C57BL/6 wild-type mice, and serum estradiol levels were 1.8- and 1.3-fold greater in adult male and female ob/ob mice, respectively, than in their wild-type counterparts. Androgen receptor gene expression was not different in femur-derived bone cells of male ob/ob mice compared with wild-type mice. The loss of sex-related differences in these bone parameters in adult male ob/ob mice might result from deficient signaling in the androgen signaling pathway and the fact that leptin functions are permissive for androgen effects on bone development. Topics: Androgens; Animals; Body Weight; Bone and Bones; Bone Density; Female; Femur; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Androgen; Sex Factors; Tomography, X-Ray Computed | 2007 |
Effect of leptin on peroxidation and antioxidant defense in ethanol-supplemented Mus musculus heart.
The aim of the study was to evaluate the effect of exogenous mouse leptin on ethanol-induced cardiac toxicity in mice. Administering ethanol (6.32 g/kg body weight p.o.) to 4-week-old healthy mice for 45 days resulted in significantly elevated plasma levels of leptin, lactate dehydrogenase (LDH), cardiac lipid hydroperoxides (LOOH) and thiobarbituric acid reactive substances (TBARS) and significantly decreased cardiac superoxide dismutase, catalase, vitamin C, vitamin E, reduced glutathione and glutathione-dependent enzyme levels (glutathione peroxidase and glutathione S-transferase). Subsequent to the experimental induction of toxicity (i.e., after the initial period of 30 days) exogenous leptin was administered (230 microg/kg body weight i.p.) every alternate day for 15 days along with the daily dose of ethanol. Leptin administration to ethanol-treated mice significantly elevated the levels of plasma leptin, LDH and cardiac LOOH, TBARS, whereas the activity of antioxidant enzymes and the concentrations of vitamins C and E were further decreased significantly. These findings were consistent with our histological observations, confirming that leptin enhances cardiac toxicity in ethanol-supplemented mice. Topics: Animals; Antioxidants; Ascorbic Acid; Body Weight; Catalase; Central Nervous System Depressants; Ethanol; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Heart; L-Lactate Dehydrogenase; Leptin; Lipid Peroxidation; Male; Mice; Myocardium; Organ Size; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Vitamin E | 2007 |
Body fat content and feeding level interact strongly in the short- and medium-term regulation of plasma leptin during underfeeding and re-feeding in adult sheep.
Circulating leptin is regulated by food intake in the long, medium and short term; however, little is known about putative remnant effects of these successive regulations at any given time. To clarify this, two experiments were conducted in adult sheep, during which body condition parameters and plasma leptin were measured. During experiment 1, twenty ewes with normal body condition were either well fed (101 % of maintenance energy requirements (MER)) or underfed (41 % MER) for 166 d, then rapidly re-fed (at a mean of 208 % MER) for 3 d. Leptinaemia decreased after 14 d of underfeeding, remained depressed until day 166 and did not increase after 3 d re-feeding, whereas it was increased (+153 %; P < 0.05) by re-feeding the previously well-fed ewes. During experiment 2, twenty-four fat or lean ewes were either well fed (114 % MER) or underfed (52 % MER) for 94 d, and gradually re-fed for 2 d and maintained at a high feeding level (235 % MER) for 9 d. Underfeeding decreased leptinaemia in fat (from 4.19 to 2.63 ng/ml) but not lean ewes, and re-feeding increased leptinaemia after 5 d in lean previously well-fed (+123 %; P < 0.05) but not underfed ewes. In fat ewes, the impact of re-feeding was rapid (+144 %; P < 0.001 at 5 d) in previously well-fed ewes, whereas it was more gradual with a maximum at 11 d (+162 %; P < 0.01) in previously underfed ewes. In conclusion, leptinaemia is modulated by short-term energy intake level in interaction with long-term regulations involving nutritional history and body fatness, suggesting that a biological threshold of adiposity (about 20 %) is necessary to allow short- and medium-term leptin regulation. Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Weight; Circadian Rhythm; Eating; Energy Intake; Fatty Acids, Nonesterified; Female; Homeostasis; Insulin; Leptin; Lipids; Random Allocation; Sheep; Time Factors | 2007 |
Sympathetic and renin-angiotensin systems contribute to increased blood pressure in sucrose-fed rats.
This study evaluated the effect of chronic sucrose feeding on hemodynamic parameters and renal sympathetic nervous activity. In addition, angiotensin I, II, and 1-7 levels were determined in plasma, heart, kidney, and the epididymal adipose tissue.. Male Wistar rats were treated for 30 days with 20% sucrose solution (n = 21) or tap water (n = 19) and food ad libitum. Blood pressure, cardiac output, and total peripheral resistance were recorded at the end of the 30-day treatment period. Sympathetic and angiotensinergic systems were evaluated by acute hexamethonium and captopril administration; plasma and tissue (heart, kidney, and epididymal adipose tissue) angiotensins were measured by high-performance liquid chromatography; and angiotensin-converting enzyme activity was determined by continuous fluorescent assay. Plasma renin activity and plasma levels of insulin and leptin were evaluated by radioimmunoassay.. Chronic sucrose feeding was associated with increased blood pressure (BP) (129 +/- 1 v 102 +/- 3 mm Hg) and circulating insulin (171%) and leptin (356%) levels when compared with the control group. The sucrose group also showed a 27% higher renal sympathetic nervous activity. The depressor response to hexamethonium was similar in both groups, whereas captopril caused a more pronounced decrease in BP in the sucrose group than in controls (-40 +/- 2 v -11 +/- 2 mm Hg), possibly reflecting the higher plasma renin activity and plasma content of angiotensin II and renal angiotensin II in sucrose rats.. These findings suggest a specific renal renin-angiotensin-sympathetic activation as a potential mechanism for the cardiovascular changes in response to chronic sucrose feeding. Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Blood Pressure; Body Weight; Captopril; Cardiac Output; Dietary Sucrose; Hexamethonium; Hypertension; Insulin; Kidney; Leptin; Male; Random Allocation; Rats; Rats, Wistar; Renin; Renin-Angiotensin System; Sodium; Sympathetic Nervous System; Vascular Resistance | 2007 |
Plasma adiponectin is increased in mice selectively bred for high wheel-running activity, but not by wheel running per sé.
Mice selectively bred for high wheel-running activity (S) have decreased fat content compared to mice from randomly bred control (C) lines. We explored whether this difference was associated with alterations in levels of circulating hormones involved in regulation of food intake and energy balance, and whether alterations were caused by the presence of a running wheel. Plasma levels of leptin, adiponectin, and corticosterone as well as body composition were analyzed in male S mice housed with (+) and without (-) access to running wheels at ages of 10 and 18 months. These levels were compared to those found in C+ mice. Plasma corticosterone did not differ among groups. While plasma leptin levels tended to be lower in S+ mice as compared to S- or C+ mice, these differences were largely attributable to differences in fat content. Adiponectin levels were increased in S mice (+60%) compared to C mice, irrespective of wheel access. High levels of this hormone may be a trait co-segregated in mice bred for high wheel-running activity. Topics: Adiponectin; Adipose Tissue; Animals; Body Composition; Body Weight; Corticosterone; Eating; Hormones; Leptin; Mice; Mice, Inbred ICR; Motor Activity | 2007 |
Developmental variations in plasma leptin, leptin soluble receptor and their molar ratio in healthy infants.
Leptin and its soluble receptor (sOB-R) are important to regulation of body composition but there are no data on the developmental variations in these plasma variables and their relationship with body composition measurements,. Weight, length, and body composition (bone, fat and lean mass) by dual energy absorptiometry, and plasma variables were measured in healthy infants at 2, 4, 8 and 12 months.. 15 whites and 29 African Americans (21 males and 23 females) with mean birth weight 3357 +/- 45 (SEM) g and gestation of 39.3 +/- 0.17 weeks were studied. The overall Z score for weight, length and weight for length during the study were 0.00 +/- 0.15, -0.08 +/- 0.11 and 0.12 +/- 0.14 respectively. With increasing age, plasma leptin (1.0 to 18.2, median 5.5 ng/mL) and sOB-R:leptin molar ratio (10.1 to 247.4, median 59.9) were lowered (r = -0.47, p < 0.01; and r = -0.37, p < 0.05 respectively), best predicted by weight Z score and percentage of fat mass, and higher in African American and female. Presence of body composition measurements eliminated the race and gender effect on the plasma variables. Plasma sOB-R (49.5 to 173.9, median 81.3 ng/mL) did not change significantly with age and was correlated and predicted only by body composition measurements.. In healthy growing infants, plasma leptin but not sOB-R decreases with age. Gender, race and anthropometric measurements are additional physiological determinants predictive of plasma leptin and the receptor:ligand ratio. However, body composition is the only variable that can predict plasma leptin and its soluble receptor and the receptor: ligand ratio; and body composition measurements eliminated the race and gender effect on these plasma variables. Topics: Black or African American; Body Composition; Body Height; Body Weight; Cross-Sectional Studies; Female; Humans; Infant; Leptin; Male; Receptors, Cell Surface; Receptors, Leptin; Sex Characteristics; White People | 2007 |
[Association between circulating leptin level and anthropometric parameters in girls with adolescent idiopathic scoliosis].
To investigate the correlation between the circulating leptin level and the anthropometric parameters and parameters related to pubertal growth, and to explore the role of leptin in the abnormal growth pattern in girls with adolescent idiopathic scoliosis (AIS).. One hundred and twenty AIS girls selected randomly from the out-patient and in-patient departments, divided into 2 groups: Group A1 (n = 73, aged 10 - 13) and Group A2 (n = 47, aged 14 - 17), and 80 14 - 17 year-old healthy girl students receiving physical examination underwent measurement of body height and weight. Body mass index (BMI) was calculated. Peripheral fasting blood samples were collected to detect the level of leptin. The anthropometric data, pubertal status, and circulating leptin level were compared between the AIS girls and the controls. The relationships between leptin and age, menstrual status, body weight, height, BMI and Risser sign were analyzed in the AIS girls.. Eighty-eight AIS girls (73%) and 14 healthy girls (18%) had a BMI score less than 18.0. The mean leptin level of Group A1 was 6.2 microg/L, significantly lower than of Group A2 (8.6 microg/L, P = 0.024). Compared with the healthy controls, the AIS girls had significantly greater corrected height (162.7 cm vs. 160.2 cm, P = 0.026), lower weight (44.3 kg vs. 53.6 kg, P = 0.01), lower BMI (17.5 kg/m(2) vs. 20.9 kg/m(2), P = 0.01), and lower circulating leptin (8.6 microg/L vs. 14.9 microg/L), even after the adjustment for age and menstrual status. An inverse correlation was observed between the leptin level and the age at menarche (AIS, r = -0.428, P < 0.001; controls, r = -0.280, P = 0.013). Whereas, positive correlations were found between leptin and age, menstrual status, body weight, height, BMI, and Risser sign (r = 0.234 - 0.506, P = 0.01 - < 0.001).. AIS girls have markedly decreased circulating leptin level. Circulating leptin level is associated with body weight, BMI, and other growth parameters, suggesting that leptin may play an important role in the lower body mass in AIS girls. Topics: Adolescent; Body Height; Body Mass Index; Body Weight; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Scoliosis | 2007 |
Long-term consequences of maternal high-fat feeding on hypothalamic leptin sensitivity and diet-induced obesity in the offspring.
Epidemiological and animal studies suggest that the alteration of hormonal and metabolic environment during fetal and neonatal development can contribute to development of metabolic syndrome in adulthood. In this paper, we investigated the impact of maternal high-fat (HF) diet on hypothalamic leptin sensitivity and body weight gain of offspring. Adult Wistar female rats received a HF or a control normal-fat (C) diet for 6 wk before gestation until the end of the suckling period. After weaning, pups received either C or HF diet during 6 wk. Body weight gain and metabolic and endocrine parameters were measured in the eight groups of rats formed according to a postweaning diet, maternal diet, and gender. To evaluate hypothalamic leptin sensitivity in each group, STAT-3 phosphorylation was measured in response to leptin or saline intraperitoneal bolus. Pups exhibited similar body weights at birth, but at weaning, those born to HF dams weighed significantly less (-12%) than those born to C dams. When given the HF diet, males and females born to HF dams exhibited smaller body weight and feed efficiency than those born to C dams, suggesting increased energy expenditure programmed by the maternal HF diet. Thus, maternal HF feeding could be protective against adverse effects of the HF diet as observed in male offspring of control dams: overweight (+17%) with hyperleptinemia and hyperinsulinemia. Furthermore, offspring of HF dams fed either C or HF diet exhibited an alteration in hypothalamic leptin-dependent STAT-3 phosphorylation. We conclude that maternal high-fat diet programs a hypothalamic leptin resistance in offspring, which, however, fails to increase the body weight gain until adulthood. Topics: Animals; Animals, Suckling; Blotting, Western; Body Weight; Diet; Dietary Fats; Female; Hypothalamus; Leptin; Male; Obesity; Phosphorylation; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; STAT3 Transcription Factor; Weight Gain | 2007 |
Association of polymorphisms of leptin gene with body weight and body sizes indexes in Chinese indigenous cattle.
PCR-SSCP was used to analyze the polymorphism of leptin gene in 539 samples of six cattle breeds, namely Nanyang (NY), Qinchuan (QC), Jiaxianred (JXR), Xizhen (XZ), Luxi (LX), and Holstein cow (HOL) breeds. PCR products with a 330 bp were amplified and sequenced. The results showed that the frequencies of alleles A/B of NY, QC, JXR, XZ, LX, and HOL breeds were 0.558/0.442, 0.492/0.508, 0.571/0.429, 0.658/0.342, 0.591/0.409, and 0.615/0.385, respectively. The association of variations of leptin gene with growth traits in NY, QC, JXR breeds was analyzed. Some indexes of the individuals with genotype BB were higher than that with genotype AA and AB in NY breed, such as the indexes of body length, heart length, body weight, hucklebone width, body height, and average day gain. The height at hip cross of the individuals with genotype BB was higher than that of those with genotype AA and AB in QC breed (P < 0.05). So leptin gene may be one of the candidate genes for growth traits with height at hip cross, but not for body weight, heart length, and body length trait. However, the height at hip cross and hucklebone width of the individuals with genotype AB and BB were higher than that of those with genotype AA in JXR breed (P < 0.05), but the difference was not statistically significant in body weight and body sizes (body height, body length, and heart length). And the polymorphisms in leptin gene were caused by G --> T transversion at the 66th bp position, A --> C transversion at the 67th bp position and G --> T transversion at the 299th bp position. These results may be applied to marker-assisted selection of Chinese cattle breeds. Topics: Animals; Body Size; Body Weight; Cattle; Chi-Square Distribution; China; Genetic Markers; Genotype; Leptin; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Polymorphism, Single-Stranded Conformational | 2007 |
Mice with a disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis, and insulin signaling during postnatal life.
The Grb10 adapter protein is capable of interacting with a variety of receptor tyrosine kinases, including, notably, the insulin receptor. Biochemical and cell culture experiments have indicated that Grb10 might act as an inhibitor of insulin signaling. We have used mice with a disruption of the Grb10 gene (Grb10Delta2-4 mice) to assess whether Grb10 might influence insulin signaling and glucose homeostasis in vivo. Adult Grb10Delta2-4 mice were found to have improved whole-body glucose tolerance and insulin sensitivity, as well as increased muscle mass and reduced adiposity. Tissue-specific changes in insulin receptor tyrosine phosphorylation were consistent with a model in which Grb10, like the closely related Grb14 adapter protein, prevents specific protein tyrosine phosphatases from accessing phosphorylated tyrosines within the kinase activation loop. Furthermore, insulin-induced IRS-1 tyrosine phosphorylation was enhanced in Grb10Delta2-4 mutant animals, supporting a role for Grb10 in attenuation of signal transmission from the insulin receptor to IRS-1. We have previously shown that Grb10 strongly influences growth of the fetus and placenta. Thus, Grb10 forms a link between fetal growth and glucose-regulated metabolism in postnatal life and is a candidate for involvement in the process of fetal programming of adult metabolic health. Topics: Adipose Tissue, White; Adiposity; Animals; Animals, Newborn; Body Composition; Body Weight; Enzyme Activation; Feeding Behavior; Genomic Imprinting; Glucose; GRB10 Adaptor Protein; Homeostasis; Insulin; Leptin; Male; Mice; Muscle, Skeletal; Mutation; Phosphotyrosine; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; Receptor, Insulin; Signal Transduction | 2007 |
Central insulin-like growth factor 1 receptors play distinct roles in the control of reproduction, food intake, and body weight in female rats.
Estradiol and progesterone induction of the LH surge in ovariectomized female rats requires concurrent activation of brain insulin-like growth factor 1 (IGF1) receptors. The present study determined whether brain IGF1 receptor signaling is required for estrous cyclicity in gonadally intact female rats. A selective IGF1 receptor antagonist (JB-1) or vehicle was continuously administered into the third ventricle by osmotic minipumps. Following surgical placement of the minipumps, all rats temporarily reduced food intake, lost weight, and suspended estrous cycles. Control rats resumed cycles within a few days and exhibited compensatory hyperphagia until they returned to presurgical body weight. Animals receiving JB-1 had severely delayed or absent estrous cycles, failed to show rebound feeding, and regained body weight more slowly. Vehicle-infused animals pair fed to JB-1-treated rats had even lower body weights but resumed estrous cycles sooner than those given drug alone. Chronic infusion of IGF1 alone had no effect on any of these parameters, but coinfusion of IGF1 with the antagonist completely reversed JB-1 effects on food intake and estrous cyclicity and partially reversed the effects on body weight. There were no significant differences in the expression of galanin-like peptide (Galp) or Kiss1 mRNA in the arcuate or periventricular hypothalamic area of control and JB-1-treated animals at a time point when food intake and estrous cycles were different between controls and JB-1-treated rats. These data suggest that brain IGF1 signaling is necessary for normal estrous cycles as well as compensatory hyperphagia and that IGF1 modulation of the reproductive axis is not secondary to reduced food intake. Topics: Animals; Blood Glucose; Body Weight; Brain; Eating; Estrous Cycle; Female; Galanin-Like Peptide; Hyperphagia; In Situ Hybridization; Insulin; Kisspeptins; Leptin; Proteins; Rats; Rats, Sprague-Dawley; Receptor, IGF Type 1; RNA, Messenger; Signal Transduction | 2007 |
[Effect of intermittent hypoxia on leptin and leptin receptor expression in obesity mice].
In order to explore the effect and underlying mechanism of hypoxia on body weight, the effect of intermittent moderate hypoxia on high-fat diet-induced obesity was observed in mice, and the role of leptin in hypoxic effect was identified. Healthy Kunming mice were divided randomly into 4 groups (n=20 in each group). The control group: the mice were fed normally under the normal oxygen pressure. Hypoxia group: the mice were fed normally, and given intermittent moderate hypoxia training. Obesity group: the mice were fed diet rich in fat and sugar under the normal oxygen pressure. Hypoxia + obesity group: the mice were fed diet rich in fat and sugar, and given intermittent moderate hypoxia training. After 40 d of feeding and training, the body weight of mice was determined, and the average increasing rate of body weight in each group was calculated and normalized with food intake. Meanwhile, plasma leptin level was measured with ELISA method, and fatty degeneration and leptin receptor expression in liver were observed by Sudan III staining and immunohistochemistry, respectively. The obesity mouse model was successfully established with increases in body weight, plasma leptin level and distribution of adipocytes in the liver. The average body weight and density of adipocytes in the liver in hypoxia and hypoxia + obesity groups decreased obviously, while plasma leptin level and leptin receptor expression in the liver were increased. It is suggested that intermittent moderate hypoxia reduces body weight through elevating plasma leptin level and/or enhancing leptin receptor expression in the liver. Topics: Adipocytes; Animals; Body Weight; Female; Hypoxia; Immunohistochemistry; Leptin; Liver; Mice; Mice, Obese; Obesity; Receptors, Leptin | 2007 |
The distinct effects of subchronic antipsychotic drug treatment on macronutrient selection, body weight, adiposity, and metabolism in female rats.
Treatment with some antipsychotic drugs may result in excessive body weight gain which can have detrimental effects on patient compliance, morbidity and mortality. The aim of the present study was to investigate the effect of atypical antipsychotic drugs on dietary macronutrient selection, body weight, body composition and biochemical parameters related to obesity in female rats.. Forty pair-housed, adult female hooded-Lister rats (250 +/- 5 g) were habituated to three diets containing principally protein, fat, or carbohydrate in a home cage self-selection paradigm. Olanzapine (2 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg), or vehicle was injected intraperitoneally once daily for 22 days; food selection, water intake, and body weight were recorded daily, while body composition and plasma hormones (insulin, glucose, nonesterified free fatty acid, total cholesterol, glycerol, triacylglycerol, leptin, and prolactin) were analyzed at the end of the study.. Only olanzapine significantly increased body weight and food intake. Macronutrient selection was significantly altered after olanzapine and risperidone treatment (increased protein and decreased fat preference). Only olanzapine increased carcass fat content. Locomotor activity was significantly reduced in all treatment groups. Both olanzapine and risperidone significantly increased plasma prolactin. Olanzapine was without effect on any other biochemical parameter measured. Ziprasidone significantly reduced plasma leptin and nonsignificantly reduced NEFA, while risperidone significantly reduced fasting plasma glucose.. This study supports our previous work demonstrating weight gain and increased feeding behavior induced by olanzapine and could have important implications for enhancing our understanding of the mechanisms by which olanzapine and other atypical antipsychotics induce weight gain in the clinic. Topics: Adiposity; Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Composition; Body Weight; Cholesterol; Drinking; Eating; Energy Metabolism; Fatty Acids, Nonesterified; Female; Food Preferences; Glycerol; Insulin; Leptin; Motor Activity; Olanzapine; Piperazines; Prolactin; Rats; Risperidone; Thiazoles; Triglycerides | 2007 |
Effects of 11beta-hydroxysteroid dehydrogenase inhibitor on body weight and glucose tolerance in Sprague-Dawley rats fed with a high-fat diet.
Many studies have shown that glucocorticoids play a crucial role in the development of obesity and insulin resistance. This study investigated the therapeutic effects of long-term inhibition of glucocorticoid activity on obesity and insulin resistance.. Four-week-old male Sprague-Dawley (SD) rats were randomly fed with a high-fat diet (fat content accounting for 20% of total calorie) (control group, n=8) or with a high-fat diet along with glycyrrhetic acid (GE, 800 mg/L), an inhibitor of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) for 24 weeks (GE-treated group, n=9). The body weights and the amount of food intake were monitored weekly and daily, respectively. After 24 weeks of GE treatment, oral glucose tolerance tests were performed. Blood glucose was measured by glucose oxidase method. The levels of plasma glucocorticoids, insulin and leptin were measured with radioimmunoassay. The levels of serum cholesterol and triglyceride were determined with an automatic measuring analyzer.. The food intake amount decreased significantly in the GE-treated group from 6 weeks and body weight gain was markedly less from 8 weeks after GE administration compared with the control group. After 24 weeks of treatment, the plasma levels of leptin and insulin in GE-treated rats were significantly reduced compared with the control group. The serum levels of cholesterol and triglyceride decreased markedly compared with the control group and the levels of blood glucose were significantly lower 15, 30, 60 and 120 minutes after oral glucose load in the GE-treated group compared with the control group.. Long-term GE treatment may contribute to resisting diet-induced obesity and insulin resistance. Topics: 11-beta-Hydroxysteroid Dehydrogenases; Animals; Body Weight; Dietary Fats; Enzyme Inhibitors; Glucocorticoids; Glucose Tolerance Test; Glycyrrhetinic Acid; Insulin; Insulin Resistance; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley | 2007 |
[Effects of topiramate and valproate acid on serum insulin and leptin levels in young and adult rats].
To study the effects of topiramate (TPM) and valproate acid (VPA) on serum insulin and leptin levels in young and adult rats.. Thirty healthy female young rats (21 days old) and thirty healthy female adult rats (2 months old) were randomly administered with TPM (50 mg/kg daily), VPA (200 mg/kg daily) or normal saline (control group) by intragastric administration for 5 weeks. After 5 weeks, serum leptin and insulin levels were detected by radioimmunoassay (RIA).. Serum leptin and insulin levels in both the young and adult TPM groups were remarkably lower than those of the corresponding control group (P < 0.05). The adult TPM group had significantly lower serum leptin and insulin levels than the young TPM group (P < 0.05). In contrast, serum leptin and insulin levels in both the young and adult VPA groups were remarkably higher than those of the corresponding control group (P < 0.05). The young TPM group had significantly higher serum leptin and insulin levels than the adult TPM group (P < 0.05).. TPM decreases serum leptin and insulin levels in young and adult rats, especially in adult rats. VPA increases serum levels of both in young and adult rats, especially in young rats. Topics: Age Factors; Animals; Anticonvulsants; Body Weight; Female; Fructose; Insulin; Leptin; Rats; Rats, Sprague-Dawley; Topiramate; Valproic Acid | 2007 |
Sex-dependent regulation of hypothalamic neuropeptide Y-Y1 receptor gene expression in moderate/high fat, high-energy diet-fed mice.
In this study we investigated whether long-term consumption of a moderate/high fat (MHF), high-energy diet can affect the gene expression of the Y(1) receptor (Y(1)R) for neuropeptide Y (NPY) in the dorsomedial (DMH), ventromedial (VMH), arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei of male and female Y(1)R/LacZ transgenic mice, carrying the murine Y(1)R promoter linked to the LacZ gene. MHF diet-fed male mice showed an increased consumption of metabolizable energy that was associated with a significant increase in body weight as compared with chow-fed controls. In parallel, consumption of a MHF diet for 8 weeks significantly decreased Y(1)R/LacZ transgene expression in the DMH and VMH of male mice whereas no changes were found in the ARC and PVN. Leptin treatment reduced body weight of both MHF diet- and chow-fed male mice but failed to prevent the decrease in Y(1)R/LacZ transgene expression apparent in the DMH and VMH of male mice after 8 weeks of MHF diet intake. Conversely, no significant changes of metabolizable energy intake, body weight or hypothalamic beta-galactosidase expression were found in MHF diet-fed female Y(1)R/LacZ transgenic mice. A gender-related difference of Y(1)R/LacZ transgenic mice was also observed in response to leptin treatment that failed to decrease body weight of both MHF diet- and chow-fed female mice. Results herein demonstrate that Y(1)R/LacZ FVB mice show a sexual dimorphism both on energy intake and on nucleus-specific regulation of the NPY Y(1)R system in the hypothalamus. Overall, these results provide new insights into the mechanism by which diet composition affects the hypothalamic circuit that controls energy homeostasis. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Dietary Fats; Disease Models, Animal; Dorsomedial Hypothalamic Nucleus; Energy Intake; Female; Genes, Reporter; Homeostasis; Hypothalamus; Lac Operon; Leptin; Male; Mice; Mice, Transgenic; Obesity; Paraventricular Hypothalamic Nucleus; Promoter Regions, Genetic; Receptors, Neuropeptide Y; Sex Factors; Time Factors; Ventromedial Hypothalamic Nucleus | 2007 |
Afferent signalling through the common hepatic branch of the vagus inhibits voluntary lard intake and modifies plasma metabolite levels in rats.
The common hepatic branch of the vagus nerve is a two-way highway of communication between the brain and the liver, duodenum, stomach and pancreas that regulates many aspects of food intake and metabolism. In this study, we utilized the afferent-specific neurotoxin capsaicin to examine if common hepatic vagal sensory afferents regulate lard intake. Rats implanted with a corticosterone pellet were made diabetic using streptozotocin (STZ) and a subset received steady-state exogenous insulin replacement into the superior mesenteric vein. These were compared with non-diabetic counterparts. Each group was then subdivided into those whose common hepatic branch of the vagus was treated with vehicle or capsaicin. Five days after surgery, the rats were offered the choice of chow and lard to consume for a further 5 days. The STZ-diabetic rats ate significantly less lard than the non-diabetic rats. Capsaicin treatment restored lard intake to that of the insulin-replaced, STZ-diabetic rats, but modified neither chow nor total caloric intake. This increased lard intake led to selective fat deposition into the mesenteric white adipose tissue depot, as opposed to an increase in all visceral fat pad depots evident after insulin replacement-induced lard intake. Capsaicin treatment also increased the levels of circulating glucose and triglycerides and negated the actions of insulin on these and free fatty acids and ketone bodies. Collectively, these data suggest that afferent signalling through the common hepatic branch of the vagus inhibits lard, but not chow, intake, directs fat deposition and regulates plasma metabolite levels. Topics: Adipose Tissue, White; Adrenal Glands; Afferent Pathways; Animals; Biomarkers; Blood Glucose; Body Weight; Capsaicin; Corticosterone; Diabetes Mellitus, Experimental; Dietary Fats; Feeding Behavior; Food Preferences; Glucagon; Glycogen; Hypoglycemic Agents; Insulin; Leptin; Lipids; Liver; Male; Organ Size; Rats; Rats, Sprague-Dawley; Spleen; Thymus Gland; Time Factors; Vagus Nerve | 2007 |
Seasonal changes in thermogenesis and body mass in wild Mongolian gerbils (Meriones unguiculatus).
Seasonal adjustments in body mass (BM), nonshivering thermogenesis (NST) and several physiological, hormonal, and biochemical markers were measured in wild-trapped Mongolian gerbils (Meriones unguiculatus) from Inner Mongolia, China. Sexual differences were detected in BM, NST, brown adipose tissue (BAT) mass, and mitochondrial protein content. BM and NST in males were higher in winter (January) and spring (May) than in summer (August), and BM of females was also the highest in winter, but NST remained relatively constant throughout the year. Cytochrome c oxidase activity and mitochondrial uncoupling protein 1 (UCP1) content in BAT were enhanced in winter in males or females, respectively. Serum leptin concentration was the lowest in winter and positively correlated with BM and body fat mass but was negatively correlated with BAT UCP1 content. These data suggest that wild Mongolian gerbils do not depend on a decrease in BM, but instead increase their thermogenic capacity to cope with cold stress. Leptin may be involved in the seasonal regulation in energy balance and thermogenesis in field Mongolian gerbils. Topics: Acclimatization; Adipose Tissue, Brown; Animals; Basal Metabolism; Body Weight; China; Electron Transport Complex IV; Female; Gerbillinae; Ion Channels; Leptin; Male; Mitochondria; Mitochondrial Proteins; Organ Size; Seasons; Thermogenesis; Uncoupling Protein 1 | 2007 |
Hypothalamic neuropeptide gene expression during recovery from food restriction superimposed on short-day photoperiod-induced weight loss in the Siberian hamster.
Previously, 40% food restriction of male Siberian hamsters over 21 days in short-day (SD) photoperiod induced characteristic changes in expression of hypothalamic arcuate nucleus energy balance genes; mRNAs for neuropeptide Y, agouti-related peptide, and leptin receptor were upregulated, and those of proopiomelanocortin and cocaine- and amphetamine-regulated transcript were depressed. The present study examined the effect of refeeding hamsters for 6 days (approximately 50% recovery of weight differential) or 19 days (resumption of appropriate weight trajectory). Hyperphagia continued throughout refeeding, but differences in fat pad weights and leptin levels had disappeared after 19 days. Cocaine- and amphetamine-regulated transcript gene expression was depressed by prior restriction in both refed groups. The depressive effect of prior restriction on proopiomelanocortin gene expression had disappeared after 19 days of refeeding. There was no effect of prior food restriction on neuropeptide Y or agouti-related peptide gene expression. Expression of the anorexigenic brain-derived neurotrophic factor was downregulated in the ventromedial nucleus after SD exposure for 12 wk. In the SD food restriction study, there were effects of photoperiod on brain-derived neurotrophic factor gene expression but not of prior food restriction. Hypothalamic energy balance genes in the hamster respond asynchronously to return to a seasonally appropriate body weight. The achievement of this weight rather than the weight at which caloric restriction was imposed is the critical factor. The differential responses of hypothalamic energy balance genes to food restriction and refeeding are poorly characterized in any species, a critical issue given their potential relevance to human weight loss strategies that involve caloric restriction. Topics: Animals; Body Weight; Brain-Derived Neurotrophic Factor; Caloric Restriction; Cricetinae; Eating; Gene Expression; Hypothalamus; Leptin; Male; Neuropeptides; Organ Size; Phodopus; Photoperiod; Radioimmunoassay; Weight Loss | 2007 |
Wheel running affects seasonal acclimatization of physiological and morphological traits in the Djungarian hamster (Phodopus sungorus).
Wheel running was previously shown to influence body mass and torpor in short-day-acclimatized Djungarian hamsters (Phodopus sungorus). To determine whether the exercise-induced effect on body mass depends on the annual phase, hamsters were exposed to the natural change in photoperiod and given access to a running wheel (RW), either before, in the middle of, or at the end of the descending body mass trajectory during seasonal acclimatization. Due to wheel running, the seasonal weight cycle was prevented or aborted by abruptly rising body mass, resulting in a weight appropriate for summer, despite exposure to short days. Torpor was inhibited, and testicular recrudescence was advanced, compared with controls. In contrast, the change into winter fur remained unaltered. Analysis of body composition and plasma leptin revealed a low body fat mass in RW hamsters, not only in winter but also in summer, suggesting a lack of seasonal adiposity. Chronic leptin infusion in winter only decreased body mass in RW individuals, although their relative body fat mass probably was even lower than in sedentary hamsters. A constantly low body fat mass is conceivably reflecting an exercise-dependent change in metabolism, consistent with increased bone mineral content and density in RW hamsters. Additionally, bone area was increased, again supported by elongated vertebral columns. Together, the results show a striking effect of wheel running on body composition and the seasonal pattern of body mass, and they suggest that the photoperiodic regulation of body mass is regulated differently than the reproductive and pelage responses. Topics: Absorptiometry, Photon; Acclimatization; Adiposity; Animals; Body Composition; Body Weight; Color; Cricetinae; Female; Hair; Hibernation; Leptin; Male; Motor Activity; Phodopus; Photoperiod; Physical Conditioning, Animal; Seasons; Temperature; Testis | 2007 |
Alterations in the autonomic control of heart rate variability in patients with anorexia or bulimia nervosa: correlations between sympathovagal activity, clinical features, and leptin levels.
Changes in body composition, hormone secretions, and heart function with increased risk of sudden death occur in eating disorders. In this observational clinical study, we evaluated sympathovagal modulation of heart rate variability (HRV) and cardiovascular changes in response to lying-to-standing in patients with anorexia (AN) or bulimia nervosa (BN) to analyze: a) differences in autonomic activity between AN, BN, and healthy subjects; b) relationships between autonomic and cardiovascular parameters, clinical data and leptin levels in patients with eating disorders. HRV, assessed by power spectral analysis of R-R intervals, blood pressure (BP) and heart rate (HR) were studied by tilt-table test in 34 patients with AN, 16 with BN and 30 healthy controls. Autonomic and cardiovascular findings were correlated with clinical data, and serum leptin levels. Leptin levels were lowered in AN vs BN and healthy subjects (p<0.0001), but both AN and BN patients showed unbalanced sympathovagal control of HRV due to relative sympathetic failure, prevalent vagal activity, impaired sympathetic activation after tilting, independently from their actual body weight and leptin levels. No significant correlations were obtained between HRV data vs clinical data, BP and HR findings, and leptin levels in eating disorders. Body mass indices (BMI) (p<0.02), and leptin levels (p<0.04) correlated directly with BP values. Our data showed alterations of sympathovagal control of HRV in eating disorders. These changes were unrelated to body weight and BMI, diagnosis of AN or BN, and leptin levels despite the reported effects of leptin on the sympathetic activity. Topics: Adult; Anorexia Nervosa; Autonomic Nervous System Diseases; Blood Pressure; Body Mass Index; Body Weight; Bulimia Nervosa; Female; Heart Rate; Humans; Leptin; Posture; Tilt-Table Test; Vagus Nerve | 2007 |
Neuroprotective effects of leptin against ischemic injury induced by oxygen-glucose deprivation and transient cerebral ischemia.
Leptin is the major adipose hormone that regulates body weight and energy expenditure by activating leptin receptors in the hypothalamus. Leptin receptors are also present in other cell types, and a potent antiapoptotic effect for leptin has recently been reported. We investigated whether leptin was neuroprotective against ischemic brain injury.. In vitro ischemic injury was induced in rat primary neuronal culture by oxygen-glucose deprivation for 90 minutes. In vivo ischemic brain injury was induced by middle cerebral artery occlusion in mice for 60 minutes.. Leptin receptors were detected in cultured rat cortical neurons, as well as in the mouse cortex, striatum, and hippocampus. In vitro results showed that leptin, 50 to 100 mug/mL, protected primary cortical neurons against death induced by oxygen-glucose deprivation in a concentration-dependent manner. In vivo studies in the mouse brain demonstrated that the intraperitoneal administration of leptin, 2 to 8 mg/kg, dose-dependently reduced infarct volume induced by middle cerebral artery occlusion. Leptin was effective when injected 5 minutes before or 30 to 90 minutes after reperfusion, but not 2 hours after reperfusion. Leptin improved animal body weight recovery and behavioral parameters after cerebral ischemia. Leptin enhanced the phosphorylation of extracellular signal-related kinase 1/2. Both extracellular signal-related kinase 1/2 activation and neuroprotection were abolished by the administration of PD98059 in vitro and in vivo.. Leptin is neuroprotective against ischemic neuronal injury. Our findings suggest that leptin is a legitimate candidate for the treatment of ischemic stroke. Topics: Animals; Apoptosis; Body Weight; Brain; Brain Infarction; Cells, Cultured; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Glucose; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Leptin; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Phosphorylation; Rats; Receptors, Cell Surface; Receptors, Leptin; Recovery of Function; Reperfusion Injury; Treatment Outcome | 2007 |
Effects of intranasal administration of a leptin-secreting Lactococcus lactis recombinant on food intake, body weight, and immune response of mice.
Leptin is an adipocyte-derived pleiotropic hormone that modulates a large number of physiological functions, including control of body weight and regulation of the immune system. In this work, we show that a recombinant strain of the food-grade lactic acid bacterium Lactococcus lactis (LL-lep) can produce and efficiently secrete human leptin. The secreted leptin is a fully biologically active hormone, as demonstrated by its capacity to stimulate a STAT3 reporter gene in HEK293 cells transfected with the Ob-Rb leptin receptor. The immunomodulatory activity of leptin-secreting L. lactis was evaluated in vivo by coexpression with the human papillomavirus type 16 E7 protein. In C57BL/6 mice immunized intranasally with a recombinant L. lactis strain coproducing leptin and E7 antigen, the adaptive immune response was significantly higher than in mice immunized with recombinant L. lactis producing only E7 antigen, demonstrating adjuvanticity of leptin. We then analyzed the effects of intranasally administered LL-lep in obese ob/ob mice. We observed that daily administration of LL-lep to these mice significantly reduced body weight gain and food intake. These results demonstrate that leptin can be produced and secreted in an active form by L. lactis and that leptin-producing L. lactis regulates in vivo antigen-specific immune responses, as well as body weight and food consumption. Topics: Administration, Intranasal; Animals; Body Weight; Cell Line; Eating; Genetic Vectors; Humans; Immunization; Lactococcus lactis; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; Th1 Cells | 2007 |
Linking hepatic transcriptional changes to high-fat diet induced physiology for diabetes-prone and obese-resistant mice.
Insulin resistance is characterized by high insulin levels and decreased responsiveness of tissues to the clearance of glucose from the bloodstream. This study maintained the diabetes-prone C57BL/6J and obese-resistant A/J mice strains on a high-fat diet for twelve weeks to transcriptionally profile the liver for changes caused by high fat diet. In the eighth week of the experiment, the C57BL/6J mice began exhibiting signs of insulin resistance, while the A/J mice did not show any such indications during the course of the experiment. A regression model of partial least squares between serum insulin measurements and the liver gene expression profile for the C57BL/6J mice on a high-fat diet was constructed in an effort to quantitatively link the physiological measurement with the gene expressions. A series of discriminating genes between high fat and chow fed mice was generated for both the C57BL/6J and A/J strains. These discriminatory genes contain information about the mechanisms responsible for the development of insulin resistance, and the compensation for a high fat diet, respectively. The results identified several genes involved in the development of insulin resistance and serve as a framework for other studies involving other organs affected by this systemic disease. Topics: Abdominal Fat; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet, Atherogenic; Dietary Fats; Gene Expression Profiling; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Oligonucleotide Array Sequence Analysis; Transcription, Genetic | 2007 |
Obesity reduced the gene expressions of leptin receptors in hypothalamus and liver.
The expression of leptin receptor (OB-R) is downregulated by leptin in some cell lines. This study investigated the expressions of leptin receptors at central nerve system and peripheral site in a dietary model of obesity. Rats in the 8 week high-diet and control group were classified based on body weight gain into obese and control groups. Serum leptin and insulin concentrations were measured and gene expressions of short form of leptin receptor (OB-Ra) and long form (OB-Rb) in hypothalamus and liver were detected by RT-PCR. The levels of serum leptin in obese rats were increased compared with control rats (p<0.05). The levels of OB-Ra and OB-Rb gene expressions in both hypothalamus and liver in obese rats were reduced significantly (p<0.01). Serum leptin concentrations of obese rats had a significant negative relationship with both of OB-Ra or OB-Rb gene expression levels in hypothalamus and liver (p<0.01). On the other hand, serum insulin levels had no relationship with OB-Ra or OB-Rb gene expression levels in neither liver nor hypothalamus. Rats with diet-induced obesity have hyperleptinemia and reduced expressions of leptin receptors in hypothalamus and liver. The results suggest that a leptin downregulated OB-R expression is one of leptin resistant mechanisms for maintaining obesity. Topics: Animals; Body Weight; Gene Expression Regulation; Hypothalamus; Insulin; Leptin; Lipids; Liver; Male; Obesity; Protein Isoforms; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Weight Gain | 2007 |
Dissociation between adipose tissue expression and serum levels of adiponectin during and after diet-induced weight loss in obese subjects with and without the metabolic syndrome.
The study aimed to examine if dysmetabolic subjects (MetS+) have lower adiponectin gene expression and lower circulating adiponectin levels than non-dysmetabolic obese subjects (MetS-) at baseline, if adiponectin expression and adiponectin concentration rise more in the dysmetabolic group during weight loss, and if v-SNARE Vti1a (vesicle transport soluble NSF attachment protein receptor vps10p tail interacting 1a) expression increases during the weight loss, as a mechanism for increased adiponectin secretion. Twenty-one obese MetS+ and 19 obese MetS- subjects underwent a very low-energy diet for 16 weeks followed by 2 weeks of refeeding. Abdominal subcutaneous adipose tissue biopsies and blood samples were taken before, during, and after dieting for DNA microarray, reverse transcriptase-polymerase chain reaction, and biochemical analyses. Serum adiponectin was also assessed in a sex- and age-matched healthy, nonobese reference group. Weight decreased by 26.3+/-9.8 kg in the MetS+ group and 28.2+/-8.4 kg in the MetS- group with concomitant reductions in insulin, hemoglobin A1c, and triglycerides that were more pronounced in the MetS+ group. Initially, the MetS+ subjects had lower serum adiponectin, but the differences disappeared at week 8, with a continuous increase in serum adiponectin throughout the study in both groups to a level that was higher than in the reference group. The expression of adiponectin and v-SNARE Vti1a did not differ between the groups or over time. In conclusion, obese subjects with the metabolic syndrome had lower circulating adiponectin than subjects without the syndrome. Weight loss increased serum levels of adiponectin without a parallel increase in adiponectin gene expression. The mechanisms involved in the regulation of adiponectin levels merits further investigation. Topics: Adiponectin; Adipose Tissue; Adult; Body Weight; Diet, Reducing; Energy Intake; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Glycated Hemoglobin; Humans; Insulin; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA; SNARE Proteins; Triglycerides; Weight Loss | 2007 |
Recurrent intermittent restraint delays fed and fasting hyperglycemia and improves glucose return to baseline levels during glucose tolerance tests in the Zucker diabetic fatty rat--role of food intake and corticosterone.
Short-term elevations of stress hormones cause an increase in glycemia. However, the effect of intermittent stress on development of type 2 diabetes mellitus is unclear. We hypothesized that recurrent intermittent restraint stress would deteriorate glycemia. Male, prediabetic Zucker diabetic fatty (ZDF) rats were restrained 1 hour per day, 5 days per week for 13 weeks and compared with unstressed, age-matched diabetic controls and lean nondiabetic rats. To differentiate the effects of recurrent restraint stress per se vs restraint-induced inhibition of food intake, a pair-fed group of rats was included. Surprisingly, recurrent restraint and pair feeding delayed fed and fasting hyperglycemia, such that they were lowered 50% by restraint and 30% by pair feeding after 13 weeks. Rats that were previously restrained or pair fed had lower glucose levels during a glucose tolerance test, but restraint further improved the return of glucose to baseline compared to pair feeding (P<.05). This was despite pair-fed rats having slightly lowered food intake and body weights compared with restrained rats. Restraint and pair feeding did not alter insulin responses to an intraperitoneal glucose tolerance test (IPGTT) or fasting insulin, and did not lower plasma lipids. Interestingly, restraint normalized basal corticosterone to one third that in control and pair-fed rats, prevented increases in pretreatment corticosterone seen with pair feeding, and led to habituation of restraint-induced corticosterone responses. After 13 weeks of treatment, multiple regression analysis showed that elevations in basal corticosterone could explain approximately 20% of the variance in fed glucose levels. In summary, intermittent restraint and its adaptations delayed hyperglycemia and improved glucose control in Zucker diabetic fatty rats. These benefits can be partially explained by restraint-induced lowering of food intake, but additional improvements compared to pair feeding may involve lower overall corticosterone exposure with repeated restraint. Paradoxically, these novel investigations suggest some types of occasional stress may limit development of diabetes. Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Type 2; Eating; Glucagon; Glucose Tolerance Test; Hormones; Hyperglycemia; Insulin; Leptin; Lipids; Male; Organ Size; Rats; Rats, Zucker; Regression Analysis; Restraint, Physical; Stress, Psychological | 2007 |
Effects of chronic spinal cord injury on body weight and body composition in rats fed a standard chow diet.
The inability to maintain body weight within prescribed ranges occurs in a significant portion of the human spinal cord injury (SCI) population. Using a rodent model of long-term high thoracic (spinal level T3) spinal cord transection (TX), we aimed to identify derangements in body weight, body composition, plasma insulin, glucose tolerance, and metabolic function, as measured by uncoupling protein 1 (UCP1) expression in interscapular brown adipose tissue (IBAT). Sixteen weeks after SCI, body weights of injured female rats stabilized and were significantly lower than surgical control animals. At the same time point, SCI rats had a significantly lower whole body fat:lean tissue mass ratio than controls, as measured indirectly by NMR. Despite lower body weight and fat mass, the cumulative consumption of standard laboratory chow (4.0 kcal/g) and mean energy intake (kcal.day(-1).100 g body wt(-1)) of chronic SCI rats was significantly more than controls. Glucose tolerance tests indicated a significant enhancement in glucose handling in 16-wk SCI rats, which were coupled with lower serum insulin levels. The post mortem weight of gonadal and retroperitoneal fat pads was significantly reduced after SCI and IBAT displayed significantly lower real-time PCR expression of UCP1 mRNA. The reduced fat mass and IBAT UCP1 mRNA expression are contraindicative of the cumulative caloric intake by the SCI rats. The prolonged postinjury loss of body weight, including fat mass, is not due to hypophagia but possibly to permanent changes in gastrointestinal transit and absorption, as well as whole body homeostatic mechanisms. Topics: Adipose Tissue; Animals; Biomarkers; Body Composition; Body Weight; Chronic Disease; Diet; Energy Intake; Female; Glucose; Glucose Tolerance Test; Insulin; Ion Channels; Leptin; Mitochondrial Proteins; Motor Activity; Organ Size; Rats; Rats, Wistar; RNA; Spinal Cord Injuries; Thermogenesis; Uncoupling Protein 1 | 2007 |
Social isolation affects the development of obesity and type 2 diabetes in mice.
Social isolation is associated with increased risks of mortality and morbidity. In this study, we show that chronic individual housing accelerated body weight gain and adiposity in KK mice but not C57BL6J mice, and fully developed diabetes in KKA(y) mice. Individually housed KK and KKA(y) mice increased body weight gain over the initial 2 wk without increased daily average food consumption compared with group-housed animals. The individually housed KK and KKA(y) mice then gradually increased food consumption for the next 1 wk. The chronic social isolation-induced obesity (SIO) was associated with hyperleptinemia and lower plasma corticosterone and active ghrelin levels but not hyperinsulinemia. Elevated plasma leptin in the SIO suppressed expression of 5-HT2C receptor in white adipose tissue. The SIO was also associated with decreased expression of beta3-adrenergic receptors in white adipose tissue and hypothalamic leptin receptor, which might be secondary to the enhanced adiposity. Interestingly, social isolation acutely reduced food consumption and body weight gain compared with group-housed obese db/db mice with leptin receptor deficiency. Social isolation-induced hyperglycemia in KKA(y) mice was associated with increased expression of hepatic gluconeogenetic genes independent of insulin. These findings suggest that social isolation promotes obesity due to primary decreased energy expenditure and secondary increased food consumption, which are independent of the disturbed leptin signaling, in KK mice, and develops into insulin-independent diabetes associated with increased expression of hepatic gluconeogenetic genes in KKA(y) mice. Thus, social isolation can be included in the environmental factors that contribute to the development of obesity and type 2 diabetes. Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus, Type 2; Disease Progression; Eating; Energy Metabolism; Gene Expression; Homeostasis; Ion Channels; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mitochondrial Proteins; Muscle, Skeletal; Obesity; Organ Size; Peroxisome Proliferator-Activated Receptors; Receptor, Serotonin, 5-HT2C; RNA, Messenger; Social Isolation; Uncoupling Protein 1; Uncoupling Protein 2 | 2007 |
Antiobesity effects of Isaria sinclairii by repeated oral treatment in obese Zucker rats over a 4-month period.
In the present study, the antiobesity effects of Isaria sinclairii (I. sinclairii, a fungus cultured on silkworms) powder were investigated in obese (fa/fa) Zucker rats over 4 mo. Rats were given 5 or 10% (w/w) I. sinclairii powder (I. S.), 10% mulberry leaf powder, or 10% silkworm powder mixed with standard diet; a fifth (control) group was given standard diet alone. Dose-dependent decreases in rate of body weight gain were observed in the IS-treated groups after 2 wk of treatment. Interestingly, weights of abdominal adipose tissues surrounding the epididymides were markedly reduced by I. S., in parallel with an attenuated body weight gain. However, no significant differences were observed versus the control group in terms of urinalysis or ocular or histopathological examinations. In the serum, total cholesterol, triglyceride, bilirubin, and low-density lipoprotein (LDL) were significantly lower in the 10% I. S. group than control after 17 wk of treatment. The mulberry leaf diet (10%) significantly reduced serum bilirubin levels. Obese (fa/fa) Zucker rats displayed markedly elevated serum leptin levels (>24.6%) in the I. S. 5 and 10% groups compared with nontreated controls. Data suggest that I. sinclairii exerts an antiobesity effect in Zucker obese rats. Topics: Adipose Tissue; Animals; Ascomycota; Body Weight; Cholesterol; Dose-Response Relationship, Drug; Leptin; Male; Morus; Obesity; Plant Leaves; Rats; Rats, Zucker; Triglycerides; Weight Gain | 2007 |
Metabolic and hormonal changes during the refeeding period of prolonged fasting.
The discovery of leptin, a hormone primarily involved in adaptation to fasting, led to an increased interest in appetite regulation and appetite-modulating hormones. Here, we present unique data from a case of extreme starvation and refeeding, showing changes in plasma concentrations of appetite-modulating and metabolic hormones as well as biochemical changes, and draw attention to the dangers of the refeeding syndrome.. We studied the refeeding period of a 44-day voluntary fast uncomplicated by underlying disease. Biochemical and hormonal variables were compared with 16 matched subjects such that the BMI range of the controls covered the entire spectrum for the index subject's recovering BMI.. Lack of calorie intake with free access to water resulted in 25% loss of body weight. Haemoconcentration was observed and feeding was started with a low sodium, hypocaloric liquid formulation. During early refeeding, marked hypophosphataemia, haemodilution and slight oedema developed. Vitamins B1, B12 and B6 were depleted while serum free fatty acids, ketone bodies and zinc levels were abnormally high; abnormal liver function developed over the first week. The hormonal profile showed low IGF-I and insulin levels, and elevated IGF-binding protein-1 concentrations. Appetite-regulating hormones were either very low (leptin and ghrelin) or showed no marked difference from the control group (peptide YY, agouti-related peptide, alpha-melanocyte-stimulating hormone, neuropeptide Y and pro-opiomelanocortin). Appetite was low at the beginning of refeeding and a transient increase in orexin and resistin was observed coincidently with an increase in subjective hunger.. Our study illustrates the potential dangers of refeeding and provides a comprehensive insight into the endocrinology of prolonged fasting and the refeeding process. Topics: Adult; Blood Glucose; Body Composition; Body Weight; Eating; Fasting; Food, Formulated; Hormones; Humans; Hypophosphatemia; Leptin; Male; Metabolism; Peptide Hormones; Peptides; Vitamins; Water-Electrolyte Balance | 2007 |
Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice.
Chronic inflammation and reduced adiponectin are widely observed in the white adipose tissue in obesity. However, the cause of the changes remains to be identified. In this study, we provide experimental evidence that hypoxia occurs in adipose tissue in obese mice and that adipose hypoxia may contribute to the endocrine alterations. The adipose hypoxia was demonstrated by a reduction in the interstitial partial oxygen pressure (Po(2)), an increase in the hypoxia probe signal, and an elevation in expression of the hypoxia response genes in ob/ob mice. The adipose hypoxia was confirmed in dietary obese mice by expression of hypoxia response genes. In the adipose tissue, hypoxia was associated with an increased expression of inflammatory genes and decreased expression of adiponectin. In dietary obese mice, reduction in body weight by calorie restriction was associated with an improvement of oxygenation and a reduction in inflammation. In cell culture, inflammatory cytokines were induced by hypoxia in primary adipocytes and primary macrophages of lean mice. The transcription factor NF-kappaB and the TNF-alpha gene promoter were activated by hypoxia in 3T3-L1 adipocytes and NIH3T3 fibroblasts. In addition, adiponectin expression was reduced by hypoxia, and the reduction was observed in the gene promoter in adipocytes. These data suggest a potential role of hypoxia in the induction of chronic inflammation and inhibition of adiponectin in the adipose tissue in obesity. Topics: 3T3-L1 Cells; Adipocytes, White; Adiponectin; Adipose Tissue; Animals; Body Weight; Cell Hypoxia; Diet, Atherogenic; Down-Regulation; Inflammation; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; NIH 3T3 Cells; Obesity; Risk Factors | 2007 |
Comparison of hydrogenated vegetable shortening and nutritionally complete high-fat diet on limited access-binge behavior in rats.
Previous studies have suggested that intermittent exposure to hydrogenated vegetable shortening yields a binge/compensate pattern of feeding in rats. The present study was designed to assess whether rats would exhibit similar patterns of intake when given intermittent access to a nutritionally complete high-fat diet. Four groups of rats received varying exposure to either hydrogenated vegetable shortening or high-fat diet for 8 consecutive weeks. Animals were given daily and intermittent access to determine if the binge/compensate pattern of feeding was frequency dependent. At the conclusion of the study, body composition and plasma leptin levels were assessed to determine effects of diet and binge/compensate intake on endocrine alterations. As predicted, animals receiving intermittent access to high-fat diet displayed the binge/compensate pattern of feeding and appeared to compensate as a result of the caloric overload accompanying a particular binge episode. In addition, exposure to either shortening or high-fat diet led to alterations in body composition, while only exposure to shortening altered plasma leptin levels. These results suggest that binge-intake behavior occurs on a nutritionally complete high-fat diet and that this regimen is capable of altering both body composition and endocrine profile. Topics: Analysis of Variance; Animals; Behavior, Animal; Body Composition; Body Weight; Bulimia; Dietary Fats; Eating; Energy Intake; Feeding Behavior; Leptin; Male; Rats; Rats, Long-Evans | 2007 |
Modified activity-stress paradigm in an animal model of the female athlete triad.
The exercising woman with nutritional deficits and related menstrual irregularities is at risk of compromising long-term bone health, i.e., the female athlete triad. There is no animal model of the female athlete triad. The purpose of this study was to examine long-term energy restriction in voluntary wheel-running female rats on estrous cycling, bone mineral content, and leptin levels. Twelve female Sprague-Dawley rats (age 34 days) were fed ad libitum and given access to running wheels during an initial 14-wk period, providing baseline and age-related data. Daily collection included dietary intake, body weight, estrous cycling, and voluntary running distance. At 4 mo, rats were randomized into two groups, six restrict-fed rats (70% of ad libitum intake) and six rats continuing as ad libitum-fed controls. Energy intake, energy expenditure, and energy availability (energy intake - energy expenditure) were calculated for each animal. Serum estradiol and leptin concentrations were measured by RIA. Femoral and tibial bone mineral density and bone mineral content (BMC) were determined by dual-energy X-ray absorptiometry. Restrict-fed rats exhibited a decrease in energy availability during Weight Loss and Anestrous phases (P = 0.002). Compared with controls after 12 wk, restrict-fed rats showed reduced concentrations of serum estradiol (P = 0.002) and leptin (P = 0.002), lower ovarian weight (P = 0.002), and decreased femoral (P = 0.041) and tibial (P = 0.05) BMC. Decreased energy availability resulted in anestrus and significant decreases in BMC, estrogen and leptin levels, and body weight. Finally, there is a critical level of energy availability to maintain estrous cycling. Topics: Aging; Animals; Body Weight; Bone Density; Caloric Restriction; Disease Models, Animal; Energy Metabolism; Estradiol; Estrous Cycle; Female; Female Athlete Triad Syndrome; Humans; Leptin; Organ Size; Ovary; Physical Exertion; Rats; Rats, Sprague-Dawley; Stress, Physiological | 2007 |
Exercise before or after refeeding prevents refeeding-induced recovery of cell size after fasting with a different pattern of metabolic gene expressions in rat epididymal adipocytes.
We investigated the effect of exercise before or after refeeding on cell size and on the expression of several messenger RNAs (mRNAs) involved in lipolysis and lipogenesis in fasted rat epididymal adipocytes. Fasting for 65 hours reduced the diameter of adipocytes to 72.0 microm from 78.4 microm in fed control rats, whereas refeeding for 1 or 2 days restored adipocyte size to 74.0 or 75.8 microm, respectively. Exercise before or after refeeding blocked refeeding-induced restoration of adipocyte size and led to adipocyte size similar to that observed after fasting. Fasting dramatically reduced expression of the fatty acid synthase mRNA, although expression of this gene returned to the control level after refeeding. However, exercise after but not before refeeding inhibited recovery of the expression of fatty acid synthase mRNA resulting from refeeding. In contrast, exercise before but not after refeeding led to enhanced expression of mRNAs encoding the hormone-sensitive lipase and beta(3)-aderenoceptor. Thus, exercise before or after refeeding prevents refeeding-induced restoration of adipocyte size after fasting via different pathways. Exercise before and after refeeding enhanced the expression of lipolytic mRNAs or inhibited the expression of lipogenic mRNAs, respectively. Topics: Adipocytes, White; Animals; Body Weight; Cell Size; Eating; Epididymis; Fasting; Feeding Behavior; Gene Expression Regulation; Insulin; Leptin; Lipogenesis; Lipolysis; Male; Metabolic Networks and Pathways; Physical Conditioning, Animal; Rats; Rats, Wistar | 2007 |
Effects of prior or concurrent food restriction on amylin-induced changes in body weight and body composition in high-fat-fed female rats.
Amylin infusion reduces food intake and slows body weight gain in rodents. In obese male rats, amylin (but not pair feeding) caused a preferential reduction of fat mass with protein preservation despite equal body weight loss in amylin-treated (fed ad libitum) and pair-fed rats. In the present study, the effect of prior or concurrent food restriction on the ability of amylin to cause weight loss was evaluated. Retired female breeder rats were maintained on a high-fat diet (40% fat) for 9 wk. Prior to drug treatment, rats were either fed ad libitum or food restricted for 10 days to lose 5% of their starting body weight. They were then subdivided into treatment groups that received either vehicle or amylin (100 microgxkg(-1)xday(-1) via subcutaneous minipump) and placed under either a restricted or ad libitum feeding schedule (for a total of 8 treatment arms). Amylin 1) significantly reduced body weight compared with vehicle under all treatment conditions, except in always restricted animals, 2) significantly decreased percent body fat in all groups, and 3) preserved lean mass in all groups. These results indicate that amylin's anorexigenic and fat-specific weight loss properties can be extended to a variety of nutritive states in female rats. Topics: Algorithms; Amyloid; Animals; Body Composition; Body Weight; Caloric Restriction; Diet, Atherogenic; Dietary Fats; Eating; Female; Gene Expression Profiling; Islet Amyloid Polypeptide; Leptin; Liver; Rats; Rats, Sprague-Dawley; Time Factors | 2007 |
Nutritional influences on reproductive neuroendocrine output: insulin, leptin, and orexigenic neuropeptide signaling in the ovine hypothalamus.
This study investigated how changing nutritional status may alter reproductive neuroendocrine (LH) output via circulating leptin and insulin signaling through orexigenic hypothalamic pathways. Thin sheep were given an increasing nutritional plane (INP), sheep with intermediate adiposity a static nutritional plane (SNP), and fat sheep a decreasing nutritional plane (DNP) for 6 wk. Mean group adiposities converged by wk 6, LH output increased in INP, remained unchanged in SNP, and decreased in DNP sheep. Plasma and cerebrospinal fluid (CSF) insulin and plasma leptin concentrations increased in INP but did not change in the SNP and DNP groups. In INP sheep, LH output correlated positively with adiposity and plasma and CSF insulin concentrations and negatively with orexigenic neuropeptide Y gene expression in the hypothalamic arcuate nucleus (ARC). In DNP sheep, LH output correlated positively with adiposity, CSF leptin concentrations, and ARC proopiomelanocortin gene expression and negatively with leptin receptor (OB-Rb) and agouti-related peptide gene expression in the ARC. These data are consistent with the feedback response to an increasing nutritional plane being mediated by increasing circulating insulin entering the brain and stimulating LH via inhibition of hypothalamic neuropeptide Y and the response to a decreasing nutritional plane being mediated by altered hypothalamic leptin signaling brought about by increased OB-Rb expression and decreased melanocortin signaling. Because end point adiposity was similar yet LH output was different, the hypothalamus apparently retains a nutritional memory, based on changes in orexigenic neuropeptide expression, that influences contemporary neuroendocrine responses. Topics: Animals; Blood Glucose; Body Weight; Eating; Gene Expression; Glucose; Hypothalamus; Insulin; Leptin; Luteinizing Hormone; Male; Neuropeptide Y; Nutritional Physiological Phenomena; Reproduction; Sheep; Signal Transduction | 2007 |
Melatonin and estradiol effects on food intake, body weight, and leptin in ovariectomized rats.
The study in ovariectomized (Ovx) rats, as a model of menopausal status, of the effects of melatonin (M) and/or estradiol (E), associated or not with food restriction, on body weight (BW) and serum leptin levels.. Female SD rats (200-250 g) were Ovx and treated with E, M, E+M or its diluents. Control sham-Ovx rats were treated with E-M diluents. After 7 weeks being fed ad libitum, the animals were exposed for 7 more weeks to a 30% food restriction. We measured: food intake, BW, nocturnal and diurnal urinary excretion of sulphatoxymelatonin (aMT6s), leptin in midday and midnight blood samples, glucose, total cholesterol, LDL, HDL and triglycerides.. Day/night rhythm of aMT6s excretion was preserved in all cases. The increase of aMT6s excretion in M-treated animals basically affected the nocturnal period. In animals fed ad libitum, E fully prevented Ovx-induced increase of BW, leptin and cholesterol. Melatonin reduced food intake and partially prevented the increase of BW and cholesterol, without changing leptin levels. Under food restriction, M was the most effective treatment in reducing BW and cholesterol. Leptin levels were similar in M, E or E+M treated rats, and lower than in untreated Ovx rats.. Our result gives a preliminary experimental basis for a post-menopausal co-treatment with estradiol and melatonin. It could combine the effectiveness of estradiol (not modified by melatonin) with the positive effects of melatonin (improvement of sleep quality, prevention of breast cancer, etc.). The possible beneficial effects of melatonin which could justify its use, need to be demonstrated in clinical trials. Topics: Analysis of Variance; Animals; Body Weight; Cholesterol; Disease Models, Animal; Eating; Estradiol Congeners; Female; Leptin; Melatonin; Obesity; Ovariectomy; Random Allocation; Rats; Rats, Sprague-Dawley | 2007 |
Androgens and glucuronidated androgen metabolites are associated with metabolic risk factors in men.
Androgens are associated with metabolic risk factors in men. However, the independent impact of androgens and androgen metabolites on metabolic risk factors in men is unclear.. Our objective was to determine the predictive value of serum levels of androgens and glucuronidated androgen metabolites for metabolic risk factors.. We conducted a population-based study of two Swedish cohorts (1,068 young adult and 1,001 elderly men).. We measured correlation of serum dihydrotestosterone (DHT), testosterone (T), and glucuronidated androgen metabolites with fat mass, fat distribution, serum lipids, and insulin resistance.. Both DHT and T were negatively associated with different measures of fat mass in both cohorts (P < 0.001). Further statistical analysis indicated that DHT, but not T, was independently negatively associated with different measures of fat mass and insulin resistance (P < 0.001). The glucuronidated androgen metabolite androstane-3alpha,17beta-diol-17glucuronide (17G) was independently positively associated with fat mass (P < 0.001). Most importantly, the 17G to DHT ratio was strongly correlated, not only with fat mass but also with central fat distribution, intrahepatic fat, disturbed lipid profile, insulin resistance, and diabetes, explaining a substantial part of the total variance in total body fat (12% in young adult men, 15% in elderly men), the homeostasis model assessment index (10%), and high-density lipoprotein cholesterol (7%).. Our findings demonstrate that 17-glucuronidation of the DHT metabolite androstane-3alpha,17beta-diol is strongly associated with several metabolic risk factors in men. Future longitudinal studies are required to determine the possible impact of the 17G to DHT ratio as a metabolic risk factor in men. Topics: Abdomen; Absorptiometry, Photon; Adult; Aged; Aging; Androgens; Arm; Blood Glucose; Body Mass Index; Body Weight; Cohort Studies; Glucuronates; Gonadal Steroid Hormones; Humans; Insulin; Leg; Leptin; Lipids; Male; Middle Aged; Risk Factors; Sweden; Tomography, X-Ray Computed | 2007 |
Adipokine and insulin profiles distinguish diabetogenic and non-diabetogenic obesities in mice.
To use longitudinal profiling of plasma adipokines to distinguish diabetogenic vs. non-diabetogenic obesity syndrome in two new mouse models of polygenic obesity.. Male mice of the NONcNZO5 strain develop a polygenic obesity syndrome uncomplicated by diabetes, whereas NONcNZO10 males develop a comparable polygenic obesity that precipitates type 2 diabetes. A multiplex immunoassay for simultaneous measurement of insulin and a panel of mouse adipokines (leptin, resistin, adiponectin, interleukin-6, tumor necrosis factor alpha, macrophage chemoattractant protein-1, plasminogen activator inhibitor-1) were used to profile longitudinal changes in these strains between 4 and 16 weeks of age that might distinguish the non-diabetogenic vs. diabetogenic obesity (diabesity).. Both strains became adipose, with NONcNZO5 males attaining a higher mean body weight with a higher percentage fat content. Weight gain in NONcNZO5 was accompanied by a transient peak in plasma insulin (PI) at 8 weeks followed by a decline into normal range, with normoglycemia maintained throughout. In contrast, NONcNZO10 showed no early PI secretory response because both body weight and plasma glucose increased between 4 and 8 weeks. Only after 12 weeks, with hyperglycemia established, was a delayed PI secretory response observed. Neither plasma leptin nor adiponectin concentrations significantly differentiated the two syndromes over time. However, repeated measures ANOVA showed that NONcNZO10 males maintained significantly higher plasma concentrations of two adipokines, resistin and plasminogen activator inhibitor-1, and the pro-inflammatory cytokine/adipokine macrophage chemoattractant protein-1.. Longitudinal profiling of PI and adipokines in two new mouse models developing moderate obesity demonstrated that specific marker signatures differentiated a non-diabetogenic obesity from a diabetogenic obesity. Topics: Adiponectin; Animals; Blood Glucose; Body Composition; Body Weight; Chemokine CCL2; Diabetes Mellitus, Type 2; Disease Models, Animal; Genetic Predisposition to Disease; Insulin; Leptin; Longitudinal Studies; Male; Mice; Mice, Obese; Obesity; Peptide Hormones; Plasminogen Activator Inhibitor 1; Resistin | 2007 |
Extreme obesity reduces bone mineral density: complementary evidence from mice and women.
To evaluate the effects of body adiposity on bone mineral density in the presence and absence of ovarian hormones in female mice and postmenopausal women.. We assessed percentage body fat, serum leptin levels, and bone mineral density in ovariectomized and non-ovariectomized C57BL/6 female mice that had been fed various calorically dense diets to induce body weight profiles ranging from lean to very obese. Additionally, we assessed percentage body fat and whole body bone mineral density in 37 overweight and extremely obese postmenopausal women from the Women's Contraceptive and Reproductive Experiences study.. In mice, higher levels of body adiposity (>40% body fat) were associated with lower bone mineral density in ovariectomized C57BL/6 female mice. A similar trend was observed in a small sample of postmenopausal women.. The complementary studies in mice and women suggest that extreme obesity in postmenopausal women may be associated with reduced bone mineral density. Thus, extreme obesity (BMI > 40 kg/m2) may increase the risk for osteopenia and osteoporosis. Given the obesity epidemic in the U.S. and in many other countries, and, in particular, the rising number of extremely obese adult women, increased attention should be drawn to the significant and interrelated public health issues of obesity and osteoporosis. Topics: Adult; Animals; Body Composition; Body Weight; Bone Density; Female; Humans; Leptin; Linear Models; Mice; Mice, Inbred C57BL; Middle Aged; Obesity; Osteoporosis; Ovariectomy; Random Allocation | 2007 |
C57BL/6J and A/J mice fed a high-fat diet delineate components of metabolic syndrome.
The aim of this study was to assess the suitability of A/J and C57BL/6J mice of both sexes as models of some components of the human metabolic syndrome (MetS) under nutritional conditions more comparable with the actual worldwide diet responsible for the increased incidence of the MetS.. We fed large cohorts (n = 515) of two strains of mice, A/J and the C57BL/6J, and of both sexes a high-fat diet (HFD; 60% fat) that, in contrast with most previous reports using saturated fats, was enriched in mono- and polyunsaturated fatty acids, thus more closely mimicking most Western diets, or a control diet (10% fat), for 20 weeks.. In sharp contrast to previous reports, weight gain and hyperleptinemia were similar in both strains and sexes. Hyperinsulinemia, glucose tolerance, insulin resistance, and hypercholesterolemia were observed, although with important differences between strains and sexes. A/J males displayed severely impaired glucose tolerance and insulin resistance. However, in contrast with C57BL6/J mice, which displayed overt type 2 diabetes, A/J mice of both sexes remained normoglycemic.. With important differences in magnitude and time course, the phenotypic and metabolic characteristics of both strains and both sexes on this HFD demonstrate that these models are very useful for identifying the mechanisms underlying progression or resistance to subsequent type 2 diabetes. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Cholesterol; Cohort Studies; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Eating; Fatty Acids, Monounsaturated; Female; Glucose Tolerance Test; Insulin; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; Pregnancy; Specific Pathogen-Free Organisms; Triglycerides | 2007 |
Serum leptin correlates in infertile oligozoospermic males.
Leptin is an adipocyte-secreted protein that participates in the regulation of energy homeostasis. Eighty men were investigated; fertile normozoospermia as a control (n = 30) and infertile oligozoospermia (n = 50). The patients underwent estimation of body weight (kg), height (cm), calculation of body mass index (BMI), semen analysis, serum leptin and testosterone hormones. Mean body weight was significantly higher in infertile oligozoospermia compared with controls. Mean height, BMI and serum testosterone levels showed nonsignificant differences between the two groups. Infertile oligozoospermia had significantly higher mean serum leptin level than controls (mean +/- SD; 6.88 +/- 8.65, 16.3 +/- 13.98 ng ml(-1), P < 0.01). Serum leptin demonstrated significant positive correlation with age, body weight, BMI and significant inverse correlation with serum testosterone. It had nonsignificant correlation with the height and sperm concentration. These results are suggestive of a link between the adipocyte derived hormone, leptin and male reproduction. Topics: Adult; Age Factors; Body Mass Index; Body Weight; Case-Control Studies; Humans; Infertility, Male; Leptin; Male; Middle Aged; Oligospermia; Prospective Studies; Testosterone | 2007 |
Age-associated loss in adiponectin-activation by caloric restriction: lack of compensation by enhanced inducibility of adiponectin paralogs CTRP2 and CTRP7.
Hormonal signals from adipose tissue regulate energy homeostasis but may also be involved in the anti-aging effects of caloric restriction. The purpose of the current study was the investigation of age-dependent effects of caloric restriction on the release of adiponectin, on the expression and activation of adiponectin-related signaling and on parameters of altered insulin sensitivity. In young and in senescent rats, 2 months moderate caloric restriction reduces serum leptin and insulin (young: -50%; old: -30%) suggesting increased insulin sensitivity. However, the same diet enhances serum adiponectin in young (+60%) but not in senescent (+2%, n=NS) rats. Similarly, adiponectin expression (visceral fat) and muscular AdipoR1/2 expression are induced in young rats but not in senescent rats. The locally produced adiponectin paralogs CTRP2/7 are elevated in muscular tissues of old animals (CTRP2 protein: +40%; CTRP7 protein: +50%) and further induced by caloric restriction but this does not result in an increased activation of their downstream target AMPK. Thus, aging is associated with a partial loss of adiponectin inducibility following moderate caloric restriction. This loss is not sufficiently compensated by the locally induced adiponectin paralogs CTRP2/7, although caloric restriction results in increased insulin sensitivity in young and in senescent animals. Thus, the improvement in insulin sensitivity appears to be independent of adiponectin induction by caloric restriction in this model. Topics: Adiponectin; Aging; AMP-Activated Protein Kinases; Animals; Body Weight; Caloric Restriction; Enzyme Activation; Gene Expression Regulation; Leptin; Male; Membrane Proteins; Multienzyme Complexes; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Receptors, Adiponectin; RNA, Messenger; Sequence Homology, Amino Acid | 2007 |
New animal model opens opportunities for research on the female athlete triad.
Topics: Aging; Animals; Body Weight; Bone Density; Caloric Restriction; Disease Models, Animal; Energy Metabolism; Estradiol; Estrous Cycle; Female; Female Athlete Triad Syndrome; Humans; Leptin; Organ Size; Ovary; Physical Exertion; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Research Design; Stress, Physiological | 2007 |
Effects of altered food intake during pubertal development in male and female wistar rats.
The U.S. Environmental Protection Agency is currently validating assays that will be used in a Tier I Screening Battery to detect endocrine disrupting chemicals. A primary concern with the Protocols for the Assessment of Pubertal Development and Thyroid Function in Juvenile Male and Female Rats is that a nonspecific reduction in body weight (BWT) during the exposure period may potentially confound the interpretation of effects on the endocrine endpoints. Wistar rats were underfed 10, 20, 30, or 40% less than the ad libitum food consumed by controls from postnatal days (PNDs) 22 to 42 (females) or PNDs 23 to 53 (males). Terminal BWT of females and males were 2, 4, 12, and 19% and 2, 6, 9, and 19% lower than controls, respectively. In the females, neither the age of pubertal onset nor any of the thyroid hormone endpoints were affected by food restriction (FR) that led to a 12% decrease in BWT. Similarly, none of the male reproductive endpoints examined were altered by FR that led to a 9% BWT decrease. However, decreased triiodothyronine and thyroxin was observed in FR males with a 9% reduced BWT. While these data support the use of the maximum tolerated dose for BWT (10%) for the female protocol, effects on the male thyroid endpoints indicate that a slightly lower limit ( Topics: Adrenal Glands; Animals; Blood Glucose; Body Weight; Endocrine Disruptors; Female; Food Deprivation; Genitalia, Female; Genitalia, Male; Kidney; Leptin; Liver; Male; Organ Size; Pituitary Gland; Rats; Rats, Wistar; Reproducibility of Results; Sexual Maturation; Thyroid Gland; Thyroid Hormones; Toxicity Tests; Vagina; Weight Loss | 2007 |
A moderately high fat diet promotes salt-sensitive hypertension in obese zucker rats by impairing nitric oxide production.
The objective of this research was to examine the contribution of a moderately high fat (MHF) diet to the development of salt-sensitive hypertension in obese Zucker rats. Lean and obese Zucker rats were fed either a MHF diet or a diet of standard rat chow (control diet) for 10 weeks. From week 4 through week 10, the drinking water was supplemented with 1% NaCl. Blood pressure was measured weekly, and urinary excretion of nitric oxide metabolites (NO(x)) was determined at weeks 4 and 10. At week 10, renal nitric oxide synthase (NOS) activity was assessed in kidney homogenates. Blood pressures of obese, but not lean, rats on the MHF fat diet were significantly increased by salt-supplementation, whereas blood pressures of rats on the control diet were not appreciably affected. NO(x) excretion was increased in response to salt-supplementation in rats on the control diet, with the effect being particularly dramatic in obese rats. After salt-supplementation, NO(x) excretion by rats on the MHF diet was lower than rats on the control diet. In obese rats on the MHF diet, this decrease in NO production was accompanied by a reduction in renal NOS activity. These results indicate that obese rats are more inclined than lean rats to develop diet-induced hypertension in response to a moderately high fat, salt-supplemented diet. Furthermore, they suggest that MHF diet-induced defects in NO production may promote the salt-sensitivity of blood pressure in obese Zucker rats, which appear to require more NO to maintain blood pressure during a salt challenge. Topics: Animals; Body Weight; Diet; Dietary Fats; Disease Models, Animal; Feedback, Physiological; Female; Hypertension; Insulin; Leptin; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Nutrition Disorders; Obesity; Rats; Rats, Zucker; Sodium Chloride, Dietary | 2007 |
Neonatal dietary supplementation of arachidonic acid increases prostaglandin levels in adipose tissue but does not promote fat mass development in guinea pigs.
The role of arachidonic acid (AA) on the development of adipose tissue is still controversial since its metabolites, i.e., prostaglandins, can either stimulate or inhibit preadipocyte differentiation in vitro. In the present study, we evaluated the effects of early postnatal supplementation of AA on body weight and adipose tissue development in guinea pigs. Male newborn guinea pigs were fed for 21 days (day 21) with diets (milk and pellet) supplemented (+AA) or not (-AA) with 1.2% (total fatty acids) AA. From day 21 to day 105 both groups were fed a chow diet. The 21-days-old +AA pups showed a twofold higher AA accretion in phospholipids associated with a two- to sixfold increase in several prostaglandins, such as 6-keto PGF(1alpha) (the stable hydrolysis product of PGI(2)), PGF(2alpha), PGE(2), and PGD(2) in adipose tissue, compared with the -AA group. No difference in fat pad and body weight, aP2, and leptin gene expression in adipose tissue, fasting plasma glucose, free-fatty acids, and triglyceride concentration was observed between groups at day 21 or day 105. These results show that dietary supplementation of AA during the suckling/weaning period increases prostaglandin levels in adipose tissue but does not influence early fat mass development in the guinea pig. Topics: Adipose Tissue; Adiposity; Animals; Animals, Newborn; Animals, Suckling; Arachidonic Acid; Body Weight; Diet; Eicosanoids; Energy Intake; Fatty Acids; Female; Gene Expression; Guinea Pigs; Leptin; Muscle, Skeletal; Prostaglandins | 2007 |
What fuels fat.
Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Body Weight; Diet, Reducing; Energy Metabolism; Environment; Exercise; Gastric Bypass; Gastroplasty; Genetic Predisposition to Disease; Homeostasis; Humans; Hypothalamus; Leptin; Obesity; Signal Transduction; Stomach | 2007 |
Prolactin/Leptin interactions in the control of food intake in rats.
Recent evidence suggests that the peptide hormone prolactin (PRL) modulates energy balance through a number of mechanisms, including acting in the brain to increase food intake. In the current studies, we first demonstrated that chronic infusions of PRL into the lateral ventricles increased food intake in cycling rats without disrupting estrous cyclicity. In subsequent experiments the hypothesis that at least part of PRL's ability to increase food intake resulted from PRL-induced leptin resistance was tested. Female rats given chronic infusions of PRL (5 microg/h) into the cerebral ventricles for 10 d did not show a reduction in food intake or body weight after a central injection of 4 microg murine leptin, whereas the expected reduction in both of these parameters was seen in vehicle-infused rats. Leptin injections were without effect on these parameters, whether they were administered to free feeding PRL-infused rats or after 24-h food deprivation. This lack of a behavioral response to leptin was accompanied by an attenuation in Fos induction and phosphorylation of signal transducer and activator of transcription 3 after leptin administration in PRL-infused rats in both the ventromedial hypothalamus and paraventricular hypothalamic nucleus. Topics: Animals; Body Weight; Brain; Dose-Response Relationship, Drug; Drug Interactions; Eating; Female; Immunohistochemistry; Leptin; Prolactin; Rats; Rats, Wistar; STAT3 Transcription Factor | 2007 |
Dmbx1 is essential in agouti-related protein action.
Dmbx1 is a paired-class homeodomain transcription factor. We show here that mice deficient in Dmbx1 exhibit severe leanness associated with hypophagia and hyperactivity and that isolation of a Dmbx1(-/-) mouse from its cohabitants induces self-starvation, sometimes leading to death, features similar to those of anorexia nervosa in humans. Interestingly, overexpression of agouti in Dmbx1(-/-) mice failed to induce aspects of the A(y)/a phenotype, including hyperphagia, obesity, and diabetes mellitus. In Dmbx1(-/-) mice, administration of agouti-related protein increased cumulative food intake for the initial 6 h but significantly decreased it over 24- and 48-h periods. In addition, Dmbx1 was shown to be expressed at embryonic day 15.5 in the lateral parabrachial nucleus, the rostral nucleus of the tractus solitarius, the dorsal motor nucleus of the vagus, and the reticular nucleus in the brainstem, all of which receive melanocortin signaling, indicating involvement of Dmbx1 in the development of the neural network for the signaling. Thus, Dmbx1 is essential for various actions of agouti-related protein and plays a role in normal regulation of energy homeostasis and behavior. Topics: Agouti-Related Protein; Animals; Body Weight; Brain; Feeding Behavior; Gene Expression Regulation, Developmental; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Transgenic; Models, Biological; Nerve Tissue Proteins; Neuropeptides; Otx Transcription Factors; Phenotype; Time Factors | 2007 |
Comparison of leptin levels, body composition and insulin sensitivity and secretion by OGTT in healthy, early pubertal girls born at either appropriate- or small-for-gestational age.
Small for gestational age (SGA) has been associated with decreased insulin sensitivity (IS). A possible mechanism is the postnatal development of a metabolically disadvantageous body composition (BC).. To determine whether there are differences between IS and BC in girls in early puberty who were SGA (birth weight < 10th percentile) or appropriate for gestational age (AGA, 10th-90th percentile).. Age-matched (SGA/AGA) early pubertal girls (Tanner II) were recruited from local schools. We determined waist circumference (WC), the sum of four skinfolds (S4S), and per cent fat mass (fat %) by impedanciometry. Leptin and OGTT assays were performed. The insulinogenic index (I-In), HOMA-IR (homeostasis model assessment of insulin resistance) and WBISI (whole body insulin sensitivity) were calculated.. Median age (interquartile range) for 30 SGA and 35 AGA girls was 10.2 (1.1) vs. 9.8 (0.9), respectively (P = NS). BMI percentiles were 62.6 (56) vs. 67.4 (39); WC 60.5 (9.5) vs. 62.2 (6.5) cm; S4S 52 (30) vs. 52.2 (29.5) cm, and fat %[26.2 (6.7) vs. 28.5 (6.3)] was similar in both groups. SGA girls had higher leptin levels [15.4 (9.7) vs. 9.6 (11) ng/ml; P = 0.01] and I-In [2.05 (1.86) vs. 1.47 (1.27) microU/ml* mg/dl; P = 0.02]. No differences between HOMA-IR [2.07 (1.26) vs. 2.04 (1.4)] and WBISI [5.3 (3.3) vs. 5.1 (3.1)] were found between groups.. The higher leptin level and I-In in girls born SGA at the beginning of puberty may be early indicators of an underlying subtle degree of insulin resistance, despite similar BMI and BC to AGA girls. Topics: Blood Glucose; Body Composition; Body Weight; Case-Control Studies; Child; Female; Glucose Tolerance Test; Humans; Infant, Newborn; Infant, Small for Gestational Age; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Prospective Studies; Statistics, Nonparametric | 2007 |
Adrenocortical insufficiency in Otsuka Long-Evans Tokushima Fatty rats, a type 2 diabetes mellitus model.
In diabetes, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis causes effects such as elevation of corticotropin (ACTH) and glucocorticoids. Cholecystokinin and its receptors are involved in the HPA axis and influence the regulation of the HPA axis. We examined adrenocortical function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, that lack the cholecystokinin A receptor. We measured adrenal weight, plasma ACTH, serum and urinary corticosterone, and serum leptin in OLETF rats at 5 to 36 weeks of age. Messenger RNA (mRNA) expression of 11beta-hydroxysteroid dehydrogenase and 5alpha-reductase type 1 in adrenal glands of the rats were examined. Long-Evans Tokushima Otsuka (LETO) rats were used as controls. In OLETF rats at 32 to 36 weeks of age, plasma ACTH was significantly higher (P < .001); serum corticosterone and 24-hour urinary corticosterone were significantly lower (P < .005); and adrenal weight was significantly lower (P < .005) than those in LETO rats. At the same ages, serum leptin in OLETF rats was significantly higher (P < .001) than that in LETO rats. In the younger OLETF rats, these changes were not observed. Overall, there was an inverse correlation between serum corticosterone and serum leptin (r = -0.374, P < .0005), whereas there was a positive correlation between plasma ACTH and serum leptin (r = 0.654, P < .0001). At 5 and 36 weeks of age, mRNA expression of 5alpha-reductase type 1 in the adrenal gland of OLETF rats was significantly higher (P < .05) than that of LETO rats, whereas there was no significant difference in mRNA expressions of 11beta-hydroxysteroid dehydrogenase types 1 and 2. We showed that adrenocortical insufficiency and adrenal atrophy were acquired in OLETF rats, and the possibility of elevated serum leptin relates to this phenomenon. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Adrenal Cortex; Adrenal Cortex Function Tests; Adrenal Glands; Adrenal Insufficiency; Adrenocorticotropic Hormone; Aging; Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Type 2; DNA Primers; Insulin; Leptin; Organ Size; Rats; Rats, Inbred OLETF; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2007 |
Association between diencephalic thyroliberin and arterial blood pressure in agouti-yellow and ob/ob mice may be mediated by leptin.
Leptin, a hormone secreted by the adipose tissue, stimulates anorexigenic peptides and also inhibits orexigenic peptides in hypothalamic arcuate nuclei-located neurons. It also counteracts the starvation-induced suppression of thyroid hormones by up-regulating the expression of preproTRH gene. On the other hand, in addition to its role as a modulator of the thyroid-hypothalamic-hypophysial axis, thyrotropin-releasing hormone (TRH) acts as a modulator of the cardiovascular system. In fact, we reported that overexpression of diencephalic TRH (dTRH) induces hypertension. We have recently shown that, in rats with obesity-induced hypertension, hyperleptinemia may produce an increase of dTRH together with an elevation of arterial blood pressure (ABP) through an increase of sympathetic activity and that these alterations were reversed by antisense oligonucleotide and small interfering RNA against preproTRH treatments. Here we explore the possible role of dTRH as a mediator involved in leptin-induced hypertension in 2 obesity mouse models: agouti-yellow mice, which are hyperleptinemic and hypertensive, and ob/ob mice, which lack functional circulating leptin. These 2 models share some characteristics, but ob/ob mice show lower ABP and plasma catecholamines levels. Then, for the first time, we report that there is a clear association between ABP and dTRH levels in both mouse models, as we have found that dTRH content was elevated in agouti-yellow mice and diminished in ob/ob mice compared with their controls. We also show that, after 3 days of subcutaneous leptin injections (10 microg/12 hours), ABP and dTRH increased significantly in ob/ob mice with no alterations of thyroid hormone levels. These results add evidence to the putative molecular mechanisms for the strong association between obesity and hypertension. Topics: Animals; Blood Pressure; Body Weight; Diencephalon; Eating; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine | 2007 |
High dietary sodium intake increases white adipose tissue mass and plasma leptin in rats.
Salt restriction has been reported to increase white adipose tissue (WAT) mass in rodents. The objective of this study was to investigate the effect of different sodium content diets on the lipogenic and lipolytic activities of WAT.. Male Wistar rats were fed on normal-sodium (NS; 0.5% Na(+)), high-sodium (HS; 3.12% Na(+)), or low-sodium (LS; 0.06% Na(+)) diets for 3, 6, and 9 weeks after weaning. Blood pressure (BP) was measured using a computerized tail-cuff system. At the end of each period, rats were killed and blood samples were collected for leptin determinations. The WAT from abdominal and inguinal subcutaneous (SC), periepididymal (PE) and retroperitoneal (RP) depots was weighed and processed for adipocyte isolation, rate measurement of lipolysis and d-[U-(14)C]-glucose incorporation into lipids, glucose-6-phosphate dehydrogenase (G6PDH) and malic enzyme activity evaluation, and determination of G6PDH and leptin mRNA expression.. After 6 weeks, HS diet significantly increased BP; SC, PE, and RP WAT masses; PE adipocyte size; plasma leptin concentration; G6PDH activity in SC WAT; and PE depots and malic activity only in SC WAT. The leptin levels correlated positively with WAT masses and adipocyte size. An increase in the basal and isoproterenol-stimulated lipolysis and in the ability to incorporate glucose into lipids was observed in isolated adipocytes from HS rats.. HS diet induced higher adiposity characterized by high plasma leptin concentration and adipocyte hypertrophy, probably due to an increased lipogenic capacity of WAT. Topics: Adipocytes; Adipose Tissue, White; Animal Feed; Animals; Blood Pressure; Body Weight; Glucose; Glucosephosphate Dehydrogenase; Leptin; Lipids; Lipogenesis; Lipolysis; Male; Obesity; Rats; Rats, Wistar; Sodium, Dietary | 2007 |
Obesity and the beta cell: lessons from leptin.
In this issue of the JCI, Morioka et al. report on mice with a whole-pancreas knockout of the leptin receptor that exhibit improved glucose tolerance due to enhanced insulin secretion . At first glance, their findings are very different from those reported in another recent study in which beta cell-specific and hypothalamic knockout of the same gene caused obesity and impaired beta cell function. The differences, which are understandable when one considers the body weights of the animals studied, provide new insight into the links among insulin, leptin action, and beta cell function. Topics: Adiposity; Animals; Body Weight; Glucose; Homeostasis; Humans; Insulin-Secreting Cells; Leptin; Mice; Mice, Knockout; Obesity; Receptors, Leptin | 2007 |
Disruption of leptin receptor expression in the pancreas directly affects beta cell growth and function in mice.
Obesity is characterized by hyperinsulinemia, hyperleptinemia, and an increase in islet volume. While the mechanisms that hasten the onset of diabetes in obese individuals are not known, it is possible that the adipose-derived hormone leptin plays a role. In addition to its central actions, leptin exerts biological effects by acting in peripheral tissues including the endocrine pancreas. To explore the impact of disrupting leptin signaling in the pancreas on beta cell growth and/or function, we created pancreas-specific leptin receptor (ObR) KOs using mice expressing Cre recombinase under the control of the pancreatic and duodenal homeobox 1 (Pdx1) promoter. The KOs exhibited improved glucose tolerance due to enhanced early-phase insulin secretion, and a greater beta cell mass secondary to increased beta cell size and enhanced expression and phosphorylation of p70S6K. Similar effects on p70S6K were observed in MIN6 beta cells with knockdown of the ObR gene, suggesting crosstalk between leptin and insulin signaling pathways. Surprisingly, challenging the KOs with a high-fat diet led to attenuated acute insulin secretory response to glucose, poor compensatory islet growth, and glucose intolerance. Together, these data provide direct genetic evidence, from a unique mouse model lacking ObRs only in the pancreas, for a critical role for leptin signaling in islet biology and suggest that altered leptin action in islets is one factor that contributes to obesity-associated diabetes. Topics: Animals; Body Weight; Cell Size; Diabetes Mellitus; Female; Glucose; Glucose Tolerance Test; Hyperplasia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Leptin; Male; Mice; Mice, Knockout; Obesity; Pancreas; Phosphorylation; Receptors, Leptin; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction | 2007 |
The A y allele at the agouti locus enhances sensitivity to endotoxin-induced lethality in mice.
In the course of investigations on anorexia during infection, I found that B6-A(y) mice had significantly increased sensitivity to lipopolysaccharide (LPS)-induced lethality as compared with isogenic B6 mice. I also found that the sensitivity to the lethal effect of LPS dramatically increased in aged mice (age effect), both B6 and B6-A(y). However, the A(y) effect of enhancing sensitivity to LPS-induced lethality was still significant, suggesting that the A(y) effect is independent of age. In the absence of tumor necrosis factor alpha (TNFalpha), the A(y) effect was still significant, suggesting that the A(y) effect is independent of TNFalpha toxicity. A dose of LPS of 100 mug per mouse caused 15% lethality in B6, 65% in B6-A(y) (significantly higher than B6), and 100 % in leptin-deficient B6-ob/ob (significantly higher than B6 and B6-A(y)). The results support the hypothesis that endogenous leptin has a protective role against infection, and that a part of this leptin effect is mediated by alpha-melanocyte-stimulating hormone (alphaMSH). In contrast to the results of simple blockade at the melanocortin 4 receptor (MC4R), B6-A(y) suffered more severe LPS-induced anorexia than did B6; therefore, the pathway involving MC4R is not absolutely required for the LPS-induced anorexia, and the presence of pathways involving other melanocortin receptor types was suggested. Because alphaMSH is suggested to be an endogenous anti-inflammatory peptide, and because melanocortin 1 receptor (MC1R) is expressed in various cutaneous cell types, the A(y) effect might be caused via the pathway involving MC1R. Physiologic significance of alphaMSH-MC1R interaction in host defense against infection is discussed. Topics: Age Factors; Agouti Signaling Protein; Alleles; alpha-MSH; Animals; Anorexia; Body Weight; Crosses, Genetic; Eating; Female; Intercellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Leptin; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Receptor, Melanocortin, Type 1; Specific Pathogen-Free Organisms | 2007 |
Leptin resistance in obese Indian girls?
Topics: Body Mass Index; Body Weight; Child; Female; Humans; India; Leptin; Male; Obesity; Radioimmunoassay; Sampling Studies; Sex Factors | 2007 |
Viral mediated neuropeptide Y expression in the rat paraventricular nucleus results in obesity.
Chronic central administration of neuropeptide Y (NPY) has dramatic effects on energy balance; however, the exact role of the hypothalamic paraventricular nucleus (PVN) in this is unknown. The aim of this study was to further unravel the contribution of NPY signaling in the PVN to energy balance.. Recombinant adeno-associated viral particles containing NPY (rAAV-NPY) were injected in the rat brain with coordinates targeted at the PVN. For three weeks, body weight, food intake, endocrine parameters, body temperature, and locomotor activity were measured. Furthermore, effects on insulin sensitivity and expression of NPY, agouti-related protein (AgRP), and pro-opiomelanocortin in the arcuate nucleus were studied.. Food intake was increased specifically in the light period, and dark phase body temperature and locomotor activity were reduced. This resulted in obesity characterized by increased fat mass; elevated plasma insulin, leptin, and adiponectin; decreased AgRP expression in the arcuate nucleus; and decreased insulin sensitivity; whereas plasma corticosterone was unaffected.. These data suggest that increased NPY expression targeted at the PVN is sufficient to induce obesity. Interestingly, plasma concentrations of leptin and insulin were elevated before a rise in food intake, which suggests that NPY in the PVN influences leptin and insulin secretion independently from food intake. This strengthens the role of the PVN in regulation of energy balance by NPY. Topics: Adenoviridae; Adiponectin; Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Body Temperature; Body Weight; Glucose Tolerance Test; Insulin; Leptin; Male; Motor Activity; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Wistar; Transfection | 2007 |
Effects of calorie-restricted low-carbohydrate diet on glucose and lipid metabolism in Otsuka Long Evans Tokushima Fatty rats.
We investigated the effects of a calorie-restricted low-carbohydrate diet on glucose and lipid metabolism, and body fat distribution, especially on the secretion of leptin and lipoprotein lipase from adipose tissue in Otsuka Long Evans Tokushima Fatty (OLETF) rats.. Forty-three week-old male OLETF rats were randomized into three groups (n=6 per group): the HC group (HC) was fed a diet with 60% carbohydrate; the LC group (LC) with 30% carbohydrate; and the P-HC group (P-HC) with 60% carbohydrate and pioglitazone (0.1%). The total calorie intake was restricted to 70% of the average intake from each diet (60 kcal/day). The diets were continued for 8 weeks.. Similar decreases in body weight and serum glucose were observed in the three groups. Serum insulin concentration was significantly decreased in LC and P-HC compared to HC. Serum total cholesterol and triglycerides decreased significantly (p<0.05) in LC and P-HC compared to HC. The decrease of visceral fat area measured by computed tomography was greatest in LC among the three groups. At the end of the diet, leptin secretion from visceral adipose tissue and lipoprotein lipase (LPL) activity in subcutaneous adipose tissue were significantly higher in LC and P-HC compared to HC (p<0.05).. These results indicate that under calorie-restricted conditions, low carbohydrates are much more effective than high carbohydrates in improving insulin sensitivity. Topics: Animals; Body Weight; Caloric Restriction; Diet, Carbohydrate-Restricted; Glucose; Insulin Resistance; Leptin; Lipid Metabolism; Lipoprotein Lipase; Male; Rats; Rats, Inbred OLETF | 2007 |
Perinatal and postnatal exposure to bisphenol a increases adipose tissue mass and serum cholesterol level in mice.
To investigate whether the perinatal and postnatal exposure of mice to bisphenol A (BPA) caused the development of obesity and/or hyperlipidemia.. Pregnant mice were exposed to BPA in drinking water at concentrations of either 1 microg/mL (LD group) or 10 microg/mL (HD group) from gestation day 10 and throughout the lactating period. After weaning, the pups were allowed free access to drinking water containing the appropriate concentrations of BPA. The body weight, adipose tissue weight, and serum lipid levels were measured in the offspring at postnatal day 31.. In females, the mean body weight increased by 13% in the LD group (p<0.05) and 11% in the HD group (p<0.05) compared with the control group. The mean adipose tissue weight increased by 132% in the LD group (p<0.01). The mean total cholesterol level increased by 33% in the LD group (p<0.01) and 17% in the HD group (p<0.05). In males, the mean body weight and mean adipose tissue weight increased by 22% (p<0.01) and 59% (p<0.01), respectively, in the HD group compared with the control group. The mean triacylglycerol level increased by 34% in the LD group (p<0.05).. The continuous exposure of mice to BPA during the perinatal and postnatal periods caused the development of obesity and hyperlipidemia. Topics: Adipose Tissue; Animals; Benzhydryl Compounds; Blood Glucose; Body Weight; Cholesterol; Estrogens, Non-Steroidal; Female; Hyperlipidemias; Leptin; Male; Mice; Obesity; Phenols; Pregnancy; Prenatal Exposure Delayed Effects; Sex Factors | 2007 |
Detrimental metabolic effects of combining long-term cigarette smoke exposure and high-fat diet in mice.
Obesity and cigarette smoking are both important risk factors for insulin resistance, cardiovascular disease, and cancer. Smoking reduces appetite, which makes many people reluctant to quit. Few studies have documented the metabolic impact of combined smoke exposure (se) and high-fat-diet (HFD). Neuropeptide Y (NPY) is a powerful hypothalamic feeding stimulator that promotes obesity. We investigated how chronic se affects caloric intake, adiposity, plasma hormones, inflammatory mediators, and hypothalamic NPY peptide in animals fed a palatable HFD. Balb/c mice (5 wk old, male) were exposed to smoke (2 cigarettes, twice/day, 6 days/wk, for 7 wk) with or without HFD. Sham-exposed mice were handled similarly without se. Plasma leptin, hypothalamic NPY, and adipose triglyceride lipase (ATGL) mRNA were measured. HFD induced a 2.3-fold increase in caloric intake, increased adiposity, and glucose in both sham and se cohorts. Smoke exposure decreased caloric intake by 23%, with reduced body weight in both dietary groups. Fat mass and glucose were reduced only by se in the chow-fed animals. ATGL mRNA was reduced by HFD in se animals. Total hypothalamic NPY was reduced by HFD, but only in sham-exposed animals; se increased arcuate NPY. We conclude that although se ameliorated hyperphagia and reversed the weight gain associated with HFD, it failed to reverse fat accumulation and hyperglycemia. The reduced ATGL mRNA expression induced by combined HFD and se may contribute to fat retention. Our data support a powerful health message that smoking in the presence of an unhealthy Western diet increases metabolic disorders and fat accumulation. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Brain; Carboxyhemoglobin; Carboxylic Ester Hydrolases; Corticosterone; Cytokines; Dietary Fats; Energy Intake; Gene Expression; Insulin; Ion Channels; Leptin; Lipase; Liver; Male; Mice; Mice, Inbred BALB C; Mitochondrial Proteins; Neuropeptide Y; RNA, Messenger; Tobacco Smoke Pollution; Triglycerides; Uncoupling Protein 1 | 2007 |
Gene expression of mineralocorticoid and glucocorticoid receptors in the limbic system is related to type-2 like diabetes in leptin-resistant rats.
Diabetes is often accompanied by a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis which is regulated centrally via glucocorticoid (GR) and mineralocorticoid receptors (MR). Here, we compared the expression of both receptor subtypes in the brain of Zucker fatty and Zucker diabetic fatty (ZDF) rats together with their respective control rats. Both strains are primarily leptin resistant due to a mutated leptin receptor; ZDF rats, however, develop type-2 like diabetes. Using quantitative real-time PCR (qPCR) we found increased hypothalamic corticotrophin releasing hormone (CRH) levels in rats with the genetic ZDF background independently from leptin resistance. This was accompanied by elevated plasma corticosterone levels and by a higher reactivity of the HPA axis in response to CRH. Rats with the genetic ZDF background showed increased mRNA levels of GR in the amygdala and hypothalamus and increased mRNA levels of MR in the hippocampus and hypothalamus compared to rats with the Zucker fatty background. In leptin resistant ZDF rats but not in Zucker fatty rats, the mRNA levels of MR were selectively increased in the amygdala compared to nondiabetic control rats. No differences in the GR mRNA levels were found between leptin resistant Zucker fatty rats and lean control rats. Thus, an increased drive of the HPA axis in rats with ZDF background is associated with a differential expression of GR and MR in the limbic system. This dysregulation of the HPA axis may eventually lead, in combination with leptin resistance, to the development of diabetes in ZDF rats. Topics: Analysis of Variance; Animals; Area Under Curve; Blood Glucose; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression; Insulin; Leptin; Limbic System; Male; Rats; Rats, Zucker; Receptors, Glucocorticoid; Receptors, Mineralocorticoid | 2007 |
Cold exposure restores the decrease in leptin receptors (OB-Rb) caused by neonatal leptin treatment in 30-day-old rats.
We had previously shown that neonatal leptin treatment programs thyroid function in adulthood. As both thyroid hormones (TH) and leptin increased thermogenesis, it was interesting to evaluate the effect of cold exposure on the thyroid function of neonate rats treated with leptin. Pups were divided into two groups: Lep, injected with leptin (8 mug/100 g/BW, s.c.) for the first 10 days of lactation and control (C), injected with saline. When they were 30 days old, the groups were subdivided into two subgroups: LepC and CC, which were exposed to 8 degrees C for 12 h and compared with C and Lep groups, maintained at 25 +/- 1 degrees C. Serum leptin, TH, and TSH were measured by RIA. Type I liver deiodinase (D1) and mitochondrial alpha-glycerol-3-phosphate dehydrogenase (mGPD) activities were assayed by the release of (125)I from (125)I-reverse and colorimetric method respectively. Leptin receptor (OB-Rb) was evaluated by western blot. Lep group had hyperleptinemia (+22%) and lower free tri-iodothyronine (FT(3); -33%). Cold exposure increased TH both in LepC and CC groups compared with respective controls free thyroxine (FT(4):+63 and +39%; FT(3):+75 and +40%). Liver D1 activity was lower in Lep (-22%) and increased with cold exposure (LepC +51% and CC +22%). The mGPD activity was lower in Lep (-34%) and increased (fourfold) when this group is cold exposed. Hypothalamic and thyroidal OB-Rb receptors were lower in Lep group (-47 and -36% respectively) and they were restored to normal levels after cold exposure. Leptin-programmed rats had higher TH response after cold exposure. OB-Rb had a fast response to cold exposure normalizing the lower levels observed in the leptin-programmed animals and may contribute to the higher TH cold responses. Topics: Aging; Animals; Animals, Newborn; Blotting, Western; Body Temperature; Body Weight; Cold Temperature; Drug Administration Schedule; Eating; Glycerolphosphate Dehydrogenase; Hormones; Hypothalamus; Iodide Peroxidase; Isoenzymes; Leptin; Liver; Mitochondria, Liver; Osmolar Concentration; Rats; Rats, Wistar; Receptors, Leptin; Thyroid Gland; Thyroxine; Triiodothyronine | 2007 |
Possible implications of leptin, adiponectin and ghrelin in the regulation of energy homeostasis by thyroid hormone.
Thyroid hormone plays a critical role in energy homeostasis through mechanisms, which are not fully understood. In the present study, we investigated possible alterations of important energy regulators such as leptin, adiponectin, and ghrelin in relation to changes in thyroid hormones. Thyroid hormone (250 microg/kg) was administered in male Wistar rats for 2 weeks (THYR), while hypothyroidism (HYPO) was induced by propylthiouracil administration (0.05% in drinking water) for 3 weeks. Untreated animals served as controls (NORM). Leptin and adiponectin were measured in plasma by ELISA, while total ghrelin was measured with RIA. Body weight was significantly reduced both in THYR and HYPO rats, while food intake was significantly increased in THYR and decreased in HYPO. This response was associated with various changes in leptin, adiponectin, and ghrelin in plasma. In fact, in THYR rats, leptin levels (mean +/- SEM) were 240 +/- 55 pg/ml as compared to 819 +/- 70 pg/ml in untreated rats (P < 0.05), while no changes were observed in ghrelin and adiponectin. In HYPO rats, leptin levels were 1400 +/- 200 pg/ml vs. 819 +/- 70 pg/ml in untreated rats (P < 0.05), while ghrelin and adiponectin were significantly increased in HYPO rats as compared to untreated rats (P < 0.05). Furthermore, T(3) and T(4) levels were inversely correlated to leptin (P = 0.014), while ghrelin and adiponectin were inversely correlated to weight changes (P = 0.05 and P = 0.03, respectively). In conclusion, leptin seems mainly to be involved in the thyroid hormone effects on energy homeostasis. Ghrelin and adiponectin may serve a compensatory physiological role in hypothyroidism. Topics: Adiponectin; Animals; Body Weight; Eating; Energy Metabolism; Ghrelin; Homeostasis; Leptin; Male; Rats; Rats, Wistar; Thyroid Hormones | 2007 |
High-fat, high-sucrose, and high-cholesterol diets accelerate tumor growth and metastasis in tumor-bearing mice.
Epidemiological studies indicate that the risk factors for the development of various cancers are closely associated with metabolic symptoms such as obesity, hyperlipidemia, and insulin resistance caused by the excess consumption of high-calorie diets. However, the mechanisms of tumor growth and metastasis caused by feeding a high-calorie diet have not been clarified yet in tumor-bearing mice. In this study, we examined the effects of a high-fat (HF), a high-sucrose (HS), a high-cholesterol (HC) or a low-fat/low-sucrose (LF/LS) diet on tumor growth and metastasis in tumor-bearing mice. Angiogenic factors such as plasma leptin and monocyte chemoattractant protein-1 (MCP-1) were increased after the implantation of tumors, whereas conversely, an antiangiogenic factor, adiponectin, was reduced after the implantation of tumors in mice fed the HF, the HS, or the HC diet compared to LF/LS diet. Furthermore, we found that vascular endothelial growth factor, hypoxia inducible factor-1alpha and MCP-1 expression levels in tumors of mice fed the HF, the HS, or the HC diet were increased compared to those of mice fed the LF/LS diet. These findings suggest that the acceleration of tumor growth and metastasis by feeding the 3 diets may be due to the increase of angiogenic factors and the reduction of antiangiogenic factors. Topics: Adiponectin; Animals; Body Weight; Carcinoma, Lewis Lung; Chemokine CCL2; Cholesterol, Dietary; Diet; Dietary Fats; Dietary Sucrose; Disease Progression; Dose-Response Relationship, Drug; Glucose Intolerance; Glucose Tolerance Test; Hyperinsulinism; Hyperlipidemias; Immunohistochemistry; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Obesity; Random Allocation | 2007 |
Sucrose access differentially modifies 11beta-hydroxysteroid dehydrogenase-1 and hexose-6-phosphate dehydrogenase message in liver and adipose tissue in rats.
11Beta-hydroxysteroid dehydrogenase-1 (11beta-HSD-1) plays a key role in the regulation of intracellular glucocorticoid concentrations. Increased message and/or activity of adipose 11beta-HSD-1 are characteristics of human and animal models of obesity. Hexose-6-phosphate dehydrogenase (H6PDH) is colocalized with 11beta-HSD-1 and may be a critical factor in determining the oxo-reductase activity of 11beta-HSD-1. This study examined the effects of sucrose solution access on body weight, body composition, and message of 11beta-HSD-1 and H6PDH in mesenteric adipose and liver. Rats were assigned to 3 groups: 1) control (ad libitum intake of nonpurified diet and water only); 2) ad libitum intake of 16% sucrose solution (S16); or 3) ad libitum intake of 32% sucrose solution (S32) in addition to ad libitum intake of diet and water. The S32 group consumed more energy daily than the S16 and control groups, yet body weight did not differ among groups. Percentages of body fat did not differ between the S16 and S32 groups but were higher than in controls. Hepatic 11beta-HSD-1 message was suppressed by 46% in the S16 group and by 47% in the S32 group, whereas the H6PDH message nearly doubled in the S16 group compared to the control group. In mesenteric fat, 11beta-HSD-1 message increased 23-fold in the S16 group and 32-fold in the S32 group and the H6PDH message increased 3.5-fold in the S16 group compared to the control group. These data demonstrate that sucrose can promote increased 11beta-HSD-1 and H6PDH message in mesenteric fat while concomitantly decreasing 11beta-HSD-1 message and increasing H6PDH message in liver. These observations support the hypothesis that sucrose access causes obesity via its ability to increase adipose 11beta-HSD-1. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Weight; Carbohydrate Dehydrogenases; Energy Metabolism; Feeding Behavior; Food Deprivation; Insulin; Leptin; Liver; Male; Rats; Rats, Sprague-Dawley; Signal Transduction; Sucrose; Time Factors | 2007 |
Increase in ghrelin levels after weight loss in obese Zucker rats is prevented by gastric banding.
Gastric banding is thought to decrease appetite in addition to the mechanical effects of food restriction, although this has been difficult to demonstrate in human studies. Our aim was to investigate the changes in orexigenic signals in the obese Zucker rat after gastric banding.. Obese Zucker rats (fa/fa) were submitted to gastric banding (GBP), sham gastric banding fed ad libitum (sham), or sham operation with food restriction, pair-fed to the gastric banding group (sham-PF). Lean Zucker rats (fa/+) were used as additional controls. Body weight and food intake were daily recorded for 21 days after surgery when epididymal fat was weighed and fasting ghrelin and hypothalamic NPY mRNA expression were measured.. Gastric banding in obese Zucker rats resulted in a significant decrease of cumulative body weight gain and food intake. Furthermore, gastric banded rats were leaner than Sham-PF, as expressed by a significantly lower epididymal fat weight. Ghrelin levels of gastric banded rats were not increased when compared to sham-operated animals fed ad libitum and were significantly lower than the levels of weight matched sham-PF rats (1116.9 +/- 103.3 g GBP vs 963.2 +/- 54.3 g sham, 3,079.5 +/- 221.6 sham-PF and 2,969.9 +/- 150.9 g lean rats, p < 0.001); hypothalamic NPY mRNA expression was not increased in GBP when compared to sham-operated rats.. In obese Zucker rats, GBP prevents the increase in orexigenic signals that occur during caloric deprivation. Our data support the hypothesis that sustained weight loss observed after gastric banding does not depend solely on food restriction. Topics: Adiposity; Animals; Blood Glucose; Body Weight; Caloric Restriction; Feeding Behavior; Gastrointestinal Hormones; Gastroplasty; Gene Expression; Ghrelin; Hypothalamus; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Radioimmunoassay; Random Allocation; Rats; Rats, Zucker; RNA, Messenger; Triglycerides | 2007 |
Endocrine and metabolic responses to extreme altitude and physical exercise in climbers.
Chronic hypoxia induces complex metabolic and endocrine adaptations. High-altitude (HA) exposure is a physiological model of hypoxia.. To further investigate the endocrine and metabolic responses to extreme HA.. We studied nine male elite climbers at sea level and at 5200 m after climbing Mt. Everest.. After 7 weeks at HA, body weight was reduced (P<0.05); regarding endocrine variables we observed: a) an increase of 2-h mean GH concentration (P<0.05) as well as of total IGF-I and IGF binding protein-3 levels (P<0.05 for both); b) a prolactin increase (P<0.05) coupled with testosterone decrease (P<0.01) and progesterone increase (P<0.05) without any change in estradiol levels: c) no change in cortisol, ACTH, and dehydroepiandrosterone sulfate (DHEAS) levels; d) an increase in free thyroxine (P<0.05) and free tri-iodothyronine (T(3)) decrease (P<0.05) but no change in TSH levels; e) a plasma glucose decrease (P<0.05) without any change in insulin levels; f) an increase in mean free fatty acid levels (P<0.05); g) despite body weight loss, leptin levels showed non-significant trend toward decrease, while ghrelin levels did not change at all.. The results of the present study in a unique experimental human model of maximal exposure to altitude and physical exercise demonstrate that extreme HA and strenuous physical exercise are coupled with specific endocrine adaptations. These include increased activity of the GH/IGF-I axis and a low T(3) syndrome but no change in ghrelin and leptin that was expected taking into account body weight decrease. These findings would contribute to better understanding human endocrine and metabolic physiology in hypoxic conditions. Topics: Adult; Altitude; Body Weight; Estradiol; Exercise; Human Growth Hormone; Humans; Hypoxia; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Pituitary Hormones; Progesterone; Prolactin; Testosterone; Thyroxine; Triiodothyronine | 2007 |
Ghrelin enhances in vivo skeletal muscle but not liver AKT signaling in rats.
Ghrelin administration can induce fat weight gain and hyperglycemia (potentially through ghrelin-induced hepatic glucose production), but plasma ghrelin is positively associated with whole-body insulin sensitivity (mainly reflecting muscle insulin action) being increased in lean individuals or after diet-induced weight loss and reduced in obesity or after diet-induced weight gain. To investigate potential mechanisms, we measured in vivo effects of sustained ghrelin administration at a non-orexigenic dose on skeletal muscle and liver insulin signaling at the AKT level and adipokine expression changes.. Young-adult male rats received 4-day, twice daily subcutaneous ghrelin (200 mug/injection) or saline. We measured skeletal muscle (mixed, gastrocnemius; oxidative, soleus) and liver protein levels of activated [phosphorylated (P)] and total (T) AKT and glycogen synthase kinase (GSK; reflecting AKT-dependent GSK inactivation) and epididymal adipose tissue adipokine mRNA.. Ghrelin increased body weight (+1.4%) and blood glucose (both p < 0.05 vs. saline) but not food intake, plasma insulin, or free fatty acids. Ghrelin, however, enhanced P/T/AKT and P/T/GSK ratios and glucose transporter-4 mRNA in soleus (p < 0.05), but not in gastrocnemius, muscle. In contrast, ghrelin reduced hepatic P/T-AKT and P/T-GSK. No alterations occurred in adiponectin, leptin, or resistin transcripts or plasma adiponectin.. Despite moderate weight gain and in the absence of insulin-free fatty acid changes, sustained ghrelin administration enhanced oxidative muscle AKT activation. Reduced liver AKT signaling could potentially contribute to concomitant blood glucose increments. These findings support ghrelin as a novel tissue-specific modulator of lean tissue AKT signaling with insulin-sensitizing effects in skeletal muscle but not in liver in vivo. Topics: Adiponectin; Animals; Body Weight; Dose-Response Relationship, Drug; Energy Metabolism; Ghrelin; Glucose; Glucose Transporter Type 4; Glycogen Synthase Kinases; Leptin; Liver; Male; Muscle, Skeletal; Oncogene Protein v-akt; Rats; Rats, Wistar; Resistin; Signal Transduction | 2007 |
Effects of subcutaneous leptin injections on hypothalamic gene profiles in lean and ob/ob mice.
Leptin-deficient ob/ob mice are more sensitive to exogenous leptin than lean mice and leptin treatment normalizes many of the phenotypic characteristics of ob/ob mice. The primary objective of this experiment was to investigate whether this altered leptin sensitivity in ob/ob mice was reflected in the hypothalamic mRNA profile.. Fifteen-week-old female ob/ob and lean mice were treated with 14 days of subcutaneous (sc) infusion of phosphate-buffered saline (PBS) or leptin (10 mug/d) using osmotic pumps. Real-time Taqman reverse transcription polymerase chain reaction (RT-PCR) (ABI Microfluidic cards) was used to quantitatively compare the mRNA levels of selected hypothalamic genes in these groups.. Hypothalamic mRNA levels for ob/ob control mice were higher for agouti-related protein (AGRP), neuropeptide Y (NPY), and arginine vasopressin (AVP), and lower for cocaine- and amphetamine-regulated transcript (CART), cAMP response element binding protein (CREB)-1, proopiomelanocortin (POMC)-1, and urocortin (UCN)-3 compared with lean controls. In leptin-treated ob/ob mice, hypothalamic mRNA levels were reduced for NPY, AGRP, AVP, and increased for suppressor of cytokine signaling 3 (SOCS3) compared with ob/ob controls. Leptin treatment dramatically up-regulated hypothalamic mRNA level of POMC1 in both lean and ob/ob mice. Strong correlations were observed between hypothalamic Janus kinase 2 (JAK2) and CREB1, STAT3 and CREB1, JAK2 and STAT3, NPY and AVP in all samples.. ob/ob and lean mice have different hypothalamic mRNA expression patterns (particularly those of feeding-related genes), and selected genes in ob/ob mice are more sensitive to exogenous leptin stimulation compared with lean mice. Topics: Animals; Arginine Vasopressin; Body Weight; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Eating; Female; Gene Expression Profiling; Hypothalamus; Injections, Subcutaneous; Janus Kinase 2; Leptin; Mice; Mice, Obese; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Thinness; Urocortins | 2007 |
Prolonged decrease of adipocyte size after rosiglitazone treatment in high- and low-fat-fed rats.
The anti-diabetic thiazolidinediones (TZDs) stimulate adipocyte differentiation and decrease mean adipocyte size. However, whether these smaller, more insulin-sensitive adipocytes maintain their size after TZD therapy is discontinued has not been studied.. Adult female Sprague-Dawley rats were fed a low-fat (10% fat) diet or, to elevate body weight (BW), a high-fat (HF) diet (45% fat) for 6 weeks. Rats were initially randomized to groups (n = 12) fed either low-fat or HF diets, with or without the TZD rosiglitazone (ROSI; 5 mg/kg per day), for 6 weeks. ROSI was then discontinued, and all animals were fed HF for another 6 weeks before sacrifice. Retroperitoneal (RP) adipose tissue morphology was determined from tissue collected by serial biopsies before and after 6 weeks of ROSI treatment and at sacrifice.. Measures of BW and adiposity did not differ among groups 6 weeks after stopping ROSI treatment. However, during treatment, ROSI in both diets significantly decreased RP adipocyte size and increased RP DNA content, and these effects continued to be observed after discontinuing treatment. ROSI administration also decreased circulating insulin, leptin, and triglycerides and increased circulating adiponectin levels; however, these effects were reversed on stopping treatment.. These results demonstrated that TZD-induced effects on adipocyte size and number were maintained after discontinuing treatment, even with consumption of an obesigenic diet. However, additional studies are needed to determine whether TZD-treated animals eventually achieve an adipocyte size similar to that of untreated animals at the expense of a higher BW. Topics: Adipocytes; Adiponectin; Adipose Tissue; Adiposity; Animals; Biopsy; Body Weight; Cell Size; Dietary Fats; Eating; Female; Hypoglycemic Agents; Insulin; Leptin; Random Allocation; Rats; Rats, Sprague-Dawley; Rosiglitazone; Thiazolidinediones; Triglycerides | 2007 |
Effects of high-fat diet and/or body weight on mammary tumor leptin and apoptosis signaling pathways in MMTV-TGF-alpha mice.
Obesity is a risk factor for postmenopausal breast cancer and is associated with shortened mammary tumor (MT) latency in MMTV-TGF-alpha mice with dietary-induced obesity. One link between obesity and breast cancer is the adipokine, leptin. Here, the focus is on diet-induced obesity and MT and mammary fat pad (MFP) leptin and apoptotic signaling proteins.. MMTV-TGF-alpha mice were fed low-fat or high-fat diets from 10 to 85 weeks of age. High-Fat mice were divided into Obesity-Prone and Obesity-Resistant groups based on final body weights. Mice were followed to assess MT development and obtain serum, MFP, and MT.. Incidence of palpable MTs was significantly different: Obesity-Prone > Obesity-Resistant > Low-Fat. Serum leptin was significantly higher in Obesity-Prone compared with Obesity-Resistant and Low-Fat mice. Low-Fat mice had higher MFP and MT ObRb (leptin receptor) protein and Jak2 (Janus kinase 2) protein and mRNA levels in comparison with High-Fat mice regardless of body weight. Leptin (mRNA) and pSTAT3 (phosphorylated signal transducer and activator of transcription 3) (mRNA and protein) also were higher in MTs from Low-Fat versus High-Fat mice. Expression of MT and MFP pro-apoptotic proteins was higher in Low-Fat versus High-Fat mice.. These results confirm a connection between body weight and MT development and between body weight and serum leptin levels. However, diet impacts MT and MFP leptin and apoptosis signaling proteins independently of body weight. Topics: Animals; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Blotting, Western; Body Weight; Densitometry; Dietary Fats; Female; Janus Kinase 2; Leptin; Mammary Neoplasms, Experimental; Mice; Obesity; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transforming Growth Factor alpha | 2007 |
Pinealectomy and melatonin administration in rats: their effects on plasma leptin levels and relationship with zinc.
The aim of this study was to examine effects of pinealectomy and melatonin administration plasma leptin levels and its relationship with zinc in rats. The study was conducted on 40 adult male Sprague-Dawley rats. They were divided into four groups each containing 10 animals. Group 1 served as control. Group 2 was pinealectomized group. Animals in Group 3 were pinealectomized and injected with melatonin (3 mg/kg/day, ip). Group 4 received melatonin alone (3 mg/kg/day, ip). At the end of the experiments, all animals were decapitated and trunk blood collected. Plasma leptin and zinc levels were determined by radioimmunoassay and Atomic Absorption Spectrophotometer methods, respectively. Although mean weights of the animals at the beginning were not significantly different among the groups, the mean weight of the pinealectomized group was found to be significantly lower than all other groups at the end of a six-month period (p < 0.01). Plasma leptin and zinc levels were the highest in melatonin-administered group (group 4; p < 0.01). The lowest plasma leptin and zinc levels were obtained in the pinealectomized group (group 2; p < 0.01). Changes in these two parameters were not statistically significant in groups 1 and 3. Our findings indicate that pinealectomy results in a decrease in leptin and zinc levels in rats, and that melatonin administration to pinealectomized rats prevents the decrease in the these parameters. In addition, long-term administration of melatonin to rats leads to an increase in both leptin and zinc concentrations. Topics: Analysis of Variance; Animals; Body Weight; Leptin; Male; Melatonin; Pineal Gland; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Spectrophotometry, Atomic; Zinc | 2007 |
[Leptin levels in school age children associated with anthropometric measurements and lipid profiles].
Leptins are proteins that regulate body weight. Their concentrations are modified depending on several factors including metabolic status, diabetes mellitus type 2 and cardiovascular diseases.. The leptin concentrations were measured in Colombian children and related to age, sex, body mass index, triceps skinfold and lipid profile.. School age children from 5 provinces of central-eastern Colombia were examined. Measurements included body mass index, body fat reserves, leptin concentrations and lipid profile.. The overall leptin concentrations were 8.3+/-8.9 ng/ml. The concentrations varied by differences in the age and sex, but were equal in children with higher body weight and greater fat deposition. A positive relationship was observed between high leptin levels and high total cholesterol in males, and in females, an association of high leptin levels with high levels of triglycerides.. The leptin concentrations followed a trend similar to those of other population groups with differences according to the age, sex and deposits of fat mass. However, the values seem to be influenced by hormonal differences and food habits. In addition, overweight or obese school children probably have hyperleptinemia, correlated to metabolic syndrome, diabetes mellitus type 2 and cardiovascular diseases. The sex specific association between total cholesterol, triglycerides and leptin suggests a complex relationship that depends on biological and hormonal differences, as well as environmental and life style differences. Each of these associations requires additional focused study for verification. Topics: Adolescent; Anthropometry; Body Composition; Body Mass Index; Body Weight; Child; Child, Preschool; Colombia; Female; Humans; Leptin; Lipids; Male; Skinfold Thickness | 2007 |
Adiponectin and leptin are related to fat mass in horses.
Plasma concentrations of adiponectin and leptin were measured in 23 mature Standardbred mares (age: 10+/-3 years) and 12 weanling fillies (10 Quarter Horse/Belgian crossbreds and two Quarter Horses; aged: 4+/-3 months) to test the hypothesis that adipocytokines are proportional to adiposity in horses. Rump fat thickness was measured using B-mode ultrasound and percent body fat (% fat) calculated using a published formula for the estimation of fatness in horses. Plasma adiponectin and leptin were determined using radioimmunoassay. In the absence of purified equine adiponectin or leptin, results were expressed as human equivalents (HE) of immunoreactive (ir) adipocytokines. Plasma ir-leptin HE concentration was positively correlated (r=0.543; P<0.001) with percent body fat and (r=0.556; P<0.001) to fat mass in all horses. The plasma ir-leptin HE concentration was lower (P=0.03) in weanlings (1.90+/-0.34 ng/mL HE) than in mature mares (3.47+/-0.50 ng/mL HE). The ratio of ir-adiponectin HE to ir-leptin HE was negatively correlated (r=-0.621; P<0.001) to percent fat and (r=-631; P<0.001) to fat mass in all horses. The ratio of ir-adiponectin HE to ir-leptin HE was higher (P<0.001) in weanlings (3.04+/-0.51) than mature mares (1.03+/-0.13). These data suggest that leptin is proportional while adiponectin is inversely proportional to adiposity in horses. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Female; Horses; Leptin; Linear Models | 2006 |
Hepatic insulin gene therapy prevents deterioration of vascular function and improves adipocytokine profile in STZ-diabetic rats.
Hepatic insulin gene therapy (HIGT) ameliorates hyperglycemia in diabetic rodents, suggesting that similar approaches may eventually provide a means to improve treatment of diabetes mellitus. However, whether the metabolic and hormonal changes produced by HIGT benefit vascular function remains unclear. The impact of HIGT on endothelium-dependent vasodilation, nitrosyl-hemoglobin content (NO-Hb), and insulin sensitivity were studied using aortic ring preparations, electron spin resonance spectroscopy (ESR), homeostasis assessment of insulin resistance (HOMA-IR) calculations, and insulin tolerance testing (ITT). Data were correlated with selected hormone and adipocytokine concentrations. Rats made diabetic with streptozotocin were treated with subcutaneous insulin pellets dosed to sustain body weights and hyperglycemia or with HIGT; nondiabetic rats served as controls. Hyperglycemic rats demonstrated impaired endothelium-dependent vasodilation, reduced levels of NO-Hb, and diminished insulin, leptin, and adiponectin concentrations compared with controls. In contrast, HIGT treatment significantly reduced blood sugars and sustained both endothelium-mediated vasodilation and NO-Hb at control levels. HOMA-IR calculations and ITT indicated enhanced insulin sensitivity among HIGT-treated rats. HIGT partially restored suppressed leptin levels in hyperglycemic rats and increased adiponectin concentrations to supranormal levels, consistent with indicators of insulin sensitivity. Our findings indicate that the metabolic milieu produced by HIGT is sufficient to preserve vascular function in diabetic rodents. These data suggest that improved glycemia, induction of a beneficial adipocytokine profile, and enhanced insulin sensitivity combine to preserve endothelium-dependent vascular function in HIGT-treated diabetic rats. Consequently, HIGT may represent a novel and efficacious approach to reduce diabetes-associated vascular dysfunction. Topics: Acetylcholine; Adenoviridae; Adiponectin; Animals; Aorta; Blood Glucose; Body Weight; Cardiovascular Physiological Phenomena; Diabetes Mellitus, Experimental; Erythrocytes; Genetic Therapy; Glucagon; Hemoglobins; Humans; In Vitro Techniques; Injections, Intravenous; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Nitric Oxide Synthase; Nitroprusside; Peptide Hormones; Rats; Rats, Sprague-Dawley; Vasodilation | 2006 |
Abnormalities of the somatotrophic axis in the obese agouti mouse.
Abnormalities of the melanocortin system produce obesity and increased linear growth. While the obesity phenotype is well characterised, the mechanism responsible for increased linear growth is unclear. The somatotrophic axis was studied in the obese agouti (A(y)/a) mouse as a model of a perturbed melanocortin system.. Adult obese A(y)/a mice were compared to age- and sex-matched wild-type (WT) controls. Weight and body length (nose-anus) were recorded. Plasma growth hormone (GH), insulin-like growth factor-I (IGFI), insulin and leptin were measured using radioimmunoassay. Since ghrelin is a potent GH secretagogue, plasma ghrelin, stomach ghrelin peptide and stomach ghrelin mRNA expression were studied. Hypothalamic periventricular (PeVN) somatostatin neurones and arcuate (Arc) neuropeptide Y (NPY) neurones inhibit the growth axis, whereas Arc growth hormone-releasing hormone (GHRH) neurones are stimulatory. Therefore, specific hypothalamic expression of somatostatin, NPY and GHRH was measured using quantitative in situ hybridisation.. Obese A(y)/a mice were significantly heavier and longer than WT controls. Plasma IGFI concentrations were 30% greater in obese A(y)/a mice. Obese A(y) /a mice were hyperinsulinaemic and hyperleptinaemic, yet plasma ghrelin, and stomach ghrelin peptide and mRNA were significantly reduced. In obese A(y)/a mice, PeVN somatostatin and Arc NPY mRNA expression were reduced by 50% compared to WT controls, whereas Arc GHRH mRNA expression was unchanged.. Increased body length in adult obese A(y)/a mice may result from reduced Arc NPY and PeVN somatostatin mRNA expression, which in turn, may increase plasma IGFI concentrations and upregulate the somatotrophic axis. Topics: Agouti Signaling Protein; Animals; Biometry; Body Weight; Gastric Mucosa; Gene Expression; Ghrelin; Growth Disorders; Growth Hormone; Hypothalamus; Insulin; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Leptin; Male; Melanocyte-Stimulating Hormones; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptide Hormones; Pituitary Gland, Anterior; RNA, Messenger; Signal Transduction; Somatostatin | 2006 |
Prevention of programmed hyperleptinemia and hypertension by postnatal dietary omega-3 fatty acids.
Fetal programming is now recognized as a key determinant of the adult phenotype, with major implications for adult-onset diseases including hypertension. Two mediators of fetal programming are maternal nutrition and fetal glucocorticoid exposure. Recent studies show that postnatal dietary manipulations can exacerbate programming effects, but whether programming effects can be attenuated by postnatal dietary manipulations, and thus provide a possible therapeutic strategy, is unknown. In this study, we tested the hypothesis that a postnatal diet enriched with long-chain omega-3 fatty acids attenuates programmed hyperleptinemia and hypertension. Pregnant rats were treated with dexamethasone (Dex) from d 13 to term, and offspring were cross-fostered to mothers on either a standard diet or a diet high in omega-3 fatty acids and remained on these diets postweaning. Maternal Dex reduced birthweight and delayed the onset of puberty in offspring. Hyperleptinemia (associated with elevated leptin mRNA expression in adipose tissue) and hypertension were evident in offspring by 6 months of age in Dex-exposed animals consuming a standard diet, but these effects were completely blocked by a high omega-3 diet. These results demonstrate for the first time that manipulation of postnatal diet can limit adverse outcomes of fetal programming, with programmed hyperleptinemia and hypertension prevented by a postnatal diet enriched with omega-3 fatty acids. This raises the possibility that dietary supplementation with omega-3 fatty acids may provide a viable therapeutic option for preventing and/or reducing adverse programming outcomes in humans. Topics: Animals; Animals, Newborn; Body Weight; Dietary Fats; Energy Intake; Fatty Acids, Omega-3; Female; Hyperlipidemias; Hypertension; Leptin; Male; Pregnancy; Pregnancy, Animal; Rats; Rats, Wistar | 2006 |
Leptin corrects host defense defects after acute starvation in murine pneumococcal pneumonia.
Leptin is an adipocyte-derived hormone that declines dramatically during fasting and plays a pivotal role in the neuroendocrine response to starvation. Previously, we employed leptin-deficient (ob/ob) mice to identify an important role for leptin in the host defense against Klebsiella pneumonia.. To assess the effects of fasting on the innate immune response against pneumococcal pneumonia and to determine the effects of maintaining circulating leptin levels on host defense in fasted mice.. C57BL/6 mice were either fed ad libitum or fasted for 48 h and given an intraperitoneal injection of saline or recombinant leptin (1 microg/g of body weight) twice daily for 48 h before bacterial challenge. Mice were challenged with 10(5) cfu of Streptococcus pneumoniae via the intranasal route.. Lung homogenate S. pneumoniae burden was nearly 20-fold greater in the fasted as compared with fed mice. The impairment in bacterial clearance observed in fasted animals was associated with reduced bronchoalveolar lavage neutrophil counts and interleukin-6 and macrophage inflammatory protein-2 levels. Alveolar macrophages from fasted animals also exhibited defective phagocytosis and killing of S. pneumoniae and reduced calcium-ionophore-stimulated leukotriene B(4) synthesis in vitro. In contrast, the provision of exogenous leptin to fasted animals restored bacterial clearance, bronchoalveolar lavage levels of neutrophils and cytokines, alveolar macrophage bacterial killing, and leukotriene B(4) synthesis.. These results suggest that reduced leptin levels substantially contribute to the suppression of pulmonary antibacterial host defense during starvation and that administration of this adipokine may be of therapeutic benefit clinically. Topics: Acute Disease; Animals; Blood Glucose; Body Weight; Bronchoalveolar Lavage; Corticosterone; Disease Models, Animal; Fasting; Interleukin-6; Leptin; Leukocytes; Leukotriene B4; Lung; Mice; Mice, Inbred C57BL; Neutrophils; Phagocytosis; Pneumonia, Pneumococcal; Sodium Chloride; Starvation; Streptococcus pneumoniae | 2006 |
Antecedent intake of traditional Asian-style diets exacerbates pancreatic beta-cell function, growth and survival after Western-style diet feeding in weaning male rats.
The prevalence of type 2 diabetes has been rapidly increasing in conjunction with the westernization of diet patterns in Asia. We determined whether the antecedent consumption of traditional Asian-style diets (ADs) deteriorates insulin action, insulin secretion and pancreatic beta-cell mass after subsequent imposition of the diabetogenic challenge of Western-style diets (WDs) in weaning male Sprague-Dawley rats. Rats were provided AD (a low-fat and plant protein diet), WD (a high-fat and animal protein diet) or a control diet (CD) (a low-fat and animal protein diet) for 12 weeks. After 12 weeks, the groups were divided into two subsets; one set of the groups continued to consume their previous diets of WD, AD and CD for another 12 weeks, and the second set was divided into three groups represented by a switch in their designated diets from WD to AD, AD to WD and CD to WD. Whole-body glucose disposal rates and GLUT4 contents in soleus muscles were lower in WD regardless of the antecedent protein sources. The first-phase insulin secretion was higher in the CD group than in the other groups, whereas the second phase was lowered with AD consumption as antecedent and/or present diets. Asian-style diet and AD-WD intake did not compensate for insulin resistance due to the failure of beta-cell expansion via decreased proliferation. These findings suggest that the antecedent consumption of AD possibly accelerates and augments the development of glucose dysregulation via decreased insulin secretion capacity and pancreatic beta-cell mass when the diets switch to WD. Topics: Animals; Asia; Blood Glucose; Body Weight; Diet; Diet, Fat-Restricted; Dietary Fats; Dietary Proteins; Energy Intake; Fasting; Glucose Clamp Technique; Glucose Intolerance; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Male; Plant Proteins; Rats; Rats, Sprague-Dawley; Weaning | 2006 |
Leptin receptor-deficient obese Zucker rats reduce their food intake in response to hypobaric hypoxia.
Exposure to hypoxia induces anorexia in humans and rodents, but the role of leptin remains under discussion and that of orexigenic and anorexigenic hypothalamic neuropeptides remains unknown. The present study was designed to address this issue by using obese (Lepr(fa)/Lepr(fa)) Zucker rats, a rat model of genetic leptin receptor deficiency. Homozygous lean (Lepr(FA)/Lepr(FA)) and obese (Lepr(fa)/Lepr(fa)) rats were randomly assigned to two groups, either kept at ambient pressure or exposed to hypobaric hypoxia for 1, 2, or 4 days (barometric pressure, 505 hPa). Food intake and body weight were recorded throughout the experiment. The expression of leptin and vascular endothelial growth factor (VEGF) genes was studied in adipose tissue with real-time quantitative PCR and that of selected orexigenic and anorexigenic neuropeptides was measured in the hypothalamus. Lean and obese rats exhibited a similar hypophagia (38 and 67% of initial values at day 1, respectively, P < 0.01) and initial decrease in body weight during hypoxia exposure. Hypoxia led to increased plasma leptin levels only in obese rats. This resulted from increased leptin gene expression in adipose tissue in response to hypoxia, in association with enhanced VEGF gene expression. Increased hypothalamic neuropeptide Y levels in lean rats 2 days after hypoxia exposure contributed to accounting for the enhanced food consumption. No significant changes occurred in the expression of other hypothalamic neuropeptides involved in the control of food intake. This study demonstrates unequivocally that altitude-induced anorexia cannot be ascribed to anorectic signals triggered by enhanced leptin production or alterations of hypothalamic neuropeptides involved in anabolic or catabolic pathways. Topics: Adipose Tissue; Animals; Body Weight; Eating; Gene Expression; Hematocrit; Hypoxia; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A | 2006 |
Effect of leptin on insulin resistance of muscle--direct or indirect?
We examined the effect of leptin on the insulin resistance in skeletal muscles by measuring glucose transport. Male Wistar rats were fed rat chow or high-fat diets for 30 days. Before sacrifice, rats fed high-fat diet were subcutaneously injected with leptin (1 mg/kg b.w.) for 3 days. The glucose transport in epitrochlearis and soleus muscles did not differ in the experimental groups under basal conditions, however these values decreased significantly in the rats fed high-fat diet under insulin stimulation (p<0.01). Leptin treatment recovered the decreased glucose transport in epitrochlearis (p<0.05) and soleus muscles (p=0.08). Triglyceride concentrations in soleus muscles were increased significantly in the rats fed high-fat diet as compared to rats fed chow diet (p<0.01), and were decreased significantly by leptin treatment (p<0.01). The glucose transport was measured under basal conditions and after 60 microU/ml of insulin treatment with or without 50 ng/ml of leptin. Leptin had no direct stimulatory effect on glucose transport under both basal and insulin-stimulated conditions in vitro. These results demonstrate that leptin injection to rats fed high-fat diet recovered impaired insulin responsiveness of skeletal muscles and muscle triglyceride concentrations. However, there was no direct stimulatory effect of leptin on insulin sensitivity of skeletal muscles in vitro. Topics: Abdominal Fat; Animals; Appetite; Blood Glucose; Body Weight; Deoxyglucose; Dietary Fats; Eating; Insulin Resistance; Leptin; Male; Muscle, Skeletal; Rats; Rats, Wistar; Triglycerides | 2006 |
Reduction of diet-induced obesity by a combination of tea-catechin intake and regular swimming.
Obesity is a metabolic disorder resulting from imbalance between metabolizable energy intake and energy expenditure. It is known to be a strong risk factor for lifestyle-related diseases. Here, we investigated the effects of long-term intake of tea catechins (Cat) in combination with regular exercise (Ex) on the development of obesity in C57BL/6 mice.. We compared body weight, adipose tissue mass, plasma parameters and beta-oxidation activity in mice fed a low-fat diet (5% triglyceride (TG); LF), a high-fat diet (30% TG; HF), a HF diet supplemented with 0.5% (w/w) tea Cat, a HF diet in addition to swimming Ex or a HF diet plus 0.5% tea Cat in addition to swimming Ex (Cat+Ex) for 15 weeks. Oxygen consumption and respiratory quotients were measured using indirect calorimetry.. Tea-Cat intake in combination with swimming Ex suppressed HF diet-induced body-weight gain by 18 and 22%, respectively, compared to Ex and tea-Cat intake on their own. Visceral fat accumulation and the development of hyperinsulinemia and hyperleptinemia were also reduced in the HF+Cat+Ex group. Muscular beta-oxidation activity in this group was 69 and 52% higher, respectively, than that in the HF and HF+Cat groups. Lipid oxidation, determined using indirect calorimetry, was higher in the HF+Cat+Ex group, suggesting increased lipid utilization at the individual level.. These results indicate that intake of tea Cat, together with regular Ex helps to reduce diet-induced obesity. This effect might be attributed, at least in part, to the activation of whole-body energy metabolism. Topics: Adipose Tissue; Animals; Body Weight; Catechin; Combined Modality Therapy; Diet; Energy Intake; Energy Metabolism; Fatty Acids; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Oxidation-Reduction; Phytotherapy; Plant Extracts; Swimming; Tea | 2006 |
Defending body mass during food restriction in Acomys russatus: a desert rodent that does not store food.
Golden spiny mice, which inhabit rocky deserts and do not store food, must therefore employ physiological means to cope with periods of food shortage. Here we studied the physiological means used by golden spiny mice for conserving energy during food restriction and refeeding and the mechanism by which food consumption may influence thermoregulatory mechanisms and metabolic rate. As comparison, we studied the response to food restriction of another rocky desert rodent, Wagner's gerbil, which accumulates large seed caches. Ten out of 12 food-restricted spiny mice (resistant) were able to defend their body mass after an initial decrease, as opposed to Wagner's gerbils (n = 6). Two of the spiny mice (nonresistant) kept losing weight, and their food restriction was halted. In four resistant and two nonresistant spiny mice, we measured heart rate, body temperature, and oxygen consumption during food restriction. The resistant spiny mice significantly (P < 0.05) reduced energy expenditure and entered daily torpor. The nonresistant spiny mice did not reduce their energy expenditure. The gerbils' response to food restriction was similar to that of the nonresistant spiny mice. Resistant spiny mice leptin levels dropped significantly (n = 6, P < 0.05) after 24 h of food restriction, and continued to decrease throughout food restriction, as did body fat. During refeeding, although the golden spiny mice gained fat, leptin levels were not correlated with body mass (r(2) = 0.014). It is possible that this low correlation allows them to continue eating and accumulate fat when food is plentiful. Topics: Activity Cycles; Adaptation, Physiological; Animals; Basal Metabolism; Body Temperature; Body Temperature Regulation; Body Weight; Desert Climate; Energy Intake; Energy Metabolism; Feeding Behavior; Food Deprivation; Heart Rate; Leptin; Mice; Murinae; Nutritional Status; Oxygen Consumption | 2006 |
Effect of social isolation on 24-h pattern of stress hormones and leptin in rats.
This work analyzes the effect of social isolation of growing male rats on 24-h changes of plasma prolactin, growth hormone, ACTH and leptin, and on plasma and adrenal corticosterone concentrations. At 35 days of life, rats were either individually caged or kept in groups (6-8 animals per cage) under a 12:12 h light/dark schedule (lights on at 08:00 h). A significant arrest of body weight gain regardless of unchanged daily food intake was found in isolated rats after 2 weeks of isolation. On the 4th week, rats were killed at 6 time intervals during a 24-h cycle, beginning at 09:00 h. In isolated rats the 24-h pattern of all parameters tested became distorted, as assessed by Cosinor analysis. When analyzed as a main factor in a factorial analysis of variance, isolation decreased plasma prolactin and growth hormone, increased plasma leptin and corticosterone while decreased adrenal corticosterone. Plasma corticosterone levels correlated significantly with plasma ACTH and with adrenal corticosterone levels in group-caged rats only. These changes can be attributed to an effect of mild stress on the endogenous clock that modulates the circadian hormone release. Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; Biological Clocks; Body Weight; Circadian Rhythm; Corticosterone; Eating; Growth Hormone; Leptin; Male; Prolactin; Rats; Rats, Wistar; Social Isolation; Weight Gain | 2006 |
Histological analyses of normally grown, fertile Apaf1-deficient mice.
Topics: Animals; Apoptotic Protease-Activating Factor 1; Body Weight; Fertility; Growth Hormone; Intracellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Proteins | 2006 |
Exogenous leptin advances puberty in domestic hen.
The present study was undertaken to examine the effect of recombinant chicken leptin administered to fed ad libitum and feed-restricted immature chickens of a layer strain on ovarian development and the timing of sexual maturity. In the first experiment 11-week-old pullets (77 days of age) fed ad libitum were injected daily with leptin at four dose levels (4, 16, 64 and 256 microg/kg body weight) until sexual maturity (lay of the first egg). Leptin treatment at the highest dose significantly (P<0.05) advanced the onset of puberty (day 116.3+/-1.0) in comparison to controls (day 121.3+/-1.2). The rises of luteinizing hormone, estradiol and progesterone in blood plasma were also advanced by leptin treatment. In the second experiment, both full-fed and feed-restricted pullets (79 days of age) were injected daily with leptin (256 microg/kg body weight). In birds fed ad libitum, exogenous leptin again significantly (P<0.05) advanced first ovipostion (day 118.4+/-1.4 versus day 124.4+/-1.7), while abolishing the significant (P<0.05) delay caused by feed restriction (day 131.5+/-1.6) and restoring the normal onset of sexual maturity (day 125.7+/-1.6). Analysis of the ovaries in 106-day-old pullets revealed that leptin injections advanced follicular development, particularly in birds fed ad libitum, and significantly (P<0.01) reduced follicular apoptosis both in full-fed and feed-restricted birds. In conclusion, we have shown that in female chickens exogenous leptin advances the onset of puberty by attenuation of ovarian apoptosis and enhancement of folliculogenesis. Topics: Animals; Apoptosis; Body Weight; Chickens; Estradiol; Female; Food Deprivation; In Situ Nick-End Labeling; Leptin; Luteinizing Hormone; Ovary; Progesterone; Sexual Maturation | 2006 |
Different skeletal regional response to continuous brain infusion of leptin in the rat.
This study was designed to evaluate whether or not continuous intracerebroventricular infusion of leptin (1.5 microg/rat/24 h, for 28 days) produced different regional response on the skeleton of growing rats. Leptin reduce the accretion of total femoral bone mineral content (BMC) and density (BMD). This effect was related to a reduction of metaphyseal femur as no changes were detected in the diaphysis. Despite the reduced accretion in the volumetric of both femur and tibia compared to controls, leptin had no significant effects on the lumbar vertebrae. Urine deoxypyrydinoline and serum osteocalcin remained more elevated in the leptin-treated group as compared to controls. The results demonstrate that long-term central infusion of leptin activates bone remodeling with a negative balance. Leptin induces distinct responses in the different structure of bone and in the axial and appendicular skeleton. Topics: Animals; Body Weight; Bone and Bones; Bone Density; Brain; Leptin; Male; Osteocalcin; Peptides; Rats; Rats, Sprague-Dawley; Time Factors; Tomography, X-Ray Computed | 2006 |
Hyperhomocysteinemia correlates with insulin resistance and low-grade systemic inflammation in obese prepubertal children.
Obesity is an independent risk factor for the development of cardiovascular disease frequently associated with hypertension, dyslipemia, diabetes, and insulin resistance. Higher homocysteine (Hcy) levels are observed in the hyperinsulinemic obese adults and suggest that Hcy could play a role in the higher risk of cardiovascular disease in obesity. We analyzed total Hcy levels in obese prepubertal children and their possible association with both metabolic syndrome and various inflammatory biomarkers and leptin. We studied 43 obese children (aged 6-9 years) and an equal number of nonobese children, paired by age and sex. The obese subjects presented significantly elevated values for insulin (P = .003), C-reactive protein (P = .033), and leptin (P < .001). No significant differences were found in Hcy levels between the obese and nonobese children. However, Hcy concentration was significantly higher in the hyperinsulinemic obese children than in the normoinsulinemic group (P = .002). Using multivariant regression analysis, in the obese group, corrected for age and sex, the homeostasis model assessment for insulin resistance (P partial = .001) and leptin (P partial = .02) are independent predictive factors for Hcy. In the control group, corrected for age and sex, the homeostasis model assessment for insulin resistance (P partial = .005) and leptin (P partial = .031) also are independent predictive factor for Hcy. Increased plasma Hcy, particularly in hyperinsulinemic obese children, may be causally involved in the pathogenesis of atherosclerosis and/or cardiovascular disease, both of which are common in obesity. Topics: Anthropometry; Biomarkers; Body Weight; Case-Control Studies; Child; Female; Fluorescence Polarization Immunoassay; Homocysteine; Humans; Inflammation; Inflammation Mediators; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Puberty | 2006 |
A low maternal protein diet during pregnancy and lactation has sex- and window of exposure-specific effects on offspring growth and food intake, glucose metabolism and serum leptin in the rat.
Extensive epidemiological and experimental evidence indicates that a sub-optimal environment during fetal and neonatal development in both humans and animals may programme offspring susceptibility to later development of chronic diseases including obesity and diabetes that are the result of altered carbohydrate metabolism. We determined the effects of protein restriction during pregnancy and/or lactation on growth, serum leptin, and glucose and insulin responses to a glucose tolerance test in male and female offspring at 110 days postnatal life. We fed Wistar rats a normal control 20% casein diet (C) or a restricted diet (R) of 10% casein during pregnancy. Female but not male R pups weighed less than C at birth. After delivery, mothers received the C or R diet during lactation to provide four offspring groups: CC (first letter maternal pregnancy diet and second maternal lactation diet), RR, CR and RC. All offspring were fed ad libitum with C diet after weaning. Relative food intake correlated inversely with weight. Offspring serum leptin correlated with body weight and relative, but not absolute, food intake in both male and female pups. Serum leptin was reduced in RR female pups compared with CC and increased in RC males compared with CC at 110 days of age. Offspring underwent a glucose tolerance test (GTT) at 110 days postnatal life. Female RR and CR offspring showed a lower insulin to glucose ratio than CC. At 110 days of age male RR and CR also showed some evidence of increased insulin sensitivity. Male but not female RC offspring showed evidence of insulin resistance compared with CC. Cholesterol was similar and triglycerides (TG) higher in male compared with female CC. Cholesterol and TG were higher in males than females in RR, CR and RC (P < 0.05). Cholesterol and TG did not differ between groups in females. Cholesterol and TG were elevated in RC compared with CC males. Nutrient restriction in lactation increased relative whole protein and decreased whole lipid in both males and females. RC females showed decreased relative levels of protein and increased fat. We conclude that maternal protein restriction during either pregnancy and/or lactation alters postnatal growth, appetitive behaviour, leptin physiology, TG and cholesterol concentrations and modifies glucose metabolism and insulin resistance in a sex- and time window of exposure-specific manner. Topics: Animals; Animals, Newborn; Blood Glucose; Body Weight; Cholesterol; Diet, Protein-Restricted; Eating; Female; Insulin; Lactation; Leptin; Male; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Sex Characteristics; Triglycerides | 2006 |
Energy expenditure and body composition of chronically maintained decerebrate rats in the fed and fasted condition.
The contribution of the caudal brainstem to adaptation to starvation was tested using chronically maintained decerebrate (CD) and neurologically intact controls. All rats were gavage fed an amount of diet that maintained weight gain in controls. CD rats were subjected to a two-stage surgery to produce a complete transection of the neuroaxis at the mesodiencephalic juncture. One week later, the rats were housed in an indirect calorimeter, and 24 h energy expenditure was measured for 4 d. One half of each of the CD and control groups was then starved for 48 h. Fed CD rats maintained a lower body temperature (35 C), a similar energy expenditure per unit fat-free mass but an elevated respiratory quotient compared with controls. They gained less weight, had 20% less lean tissue, and had 60% more fat than controls. Circulating leptin, adiponectin, and insulin were elevated, glucose was normal, but testosterone was dramatically reduced. Responses to starvation were similar in CD and controls; they reduced energy expenditure, decreased respiratory quotient, indicating lipid utilization, defended body temperature, mobilized fat, decreased serum leptin and insulin, and regulated plasma glucose. These data clearly demonstrate that the isolated caudal brainstem is sufficient to mediate many aspects of the energetic response to starvation. In intact animals, these responses may be refined by a contribution by more rostral brain areas or by communication between fore- and hind-brain. In the absence of communication from the forebrain, the caudal brainstem is inadequate for maintenance of testosterone levels or lean tissue in fed or fasted animals. Topics: Adiponectin; Adipose Tissue; Animal Feed; Animals; Blood Glucose; Body Composition; Body Temperature; Body Weight; Brain; Energy Intake; Energy Metabolism; Fasting; Food Deprivation; Insulin; Leptin; Lipid Metabolism; Lipids; Male; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Temperature; Testosterone; Time Factors; Weight Gain | 2006 |
Chronic administration of leptin in Asian Blue Quail.
It is well known that leptin has the capacity to reduce food intake, cause body weight loss, and increase energy expenditure in several vertebrate species. In this study, we investigated the effects of chronically elevated leptin levels on behavior and physiology of Asian Blue Quail (Coturnix chinensis). Fifteen male quail were treated with chicken leptin dissolved in phosphate-buffered saline (PBS) via subcutaneously inserted osmotic pumps that released approximately 1 microg/g body weight/day during a 14-day period. Another 15 males acted as controls and their pumps released PBS only. All males were housed together with two females. We observed a decrease in body weight and feeding behavior in leptin-treated birds, but not in control birds, after 2 days of treatment. Thereafter, all birds increased in weight. Males treated with leptin were more active and more likely to preen the day after the beginning of the treatment. Plasma cholesterol levels in leptin birds decreased during the first week of treatment and plasma triglycerides tended to remain lower compared to the controls during the whole 2-week period of treatment. Glucose levels appeared stable during the observation period. Leptin-treated males remained closer to accompanying females than did control males, and females together with leptin males took longer to lay their first egg compared to females together with control males. This is the first article showing the effect of leptin on cholesterol and triglyceride levels in birds. We also observed a change in the activity and male-female interaction pattern in tested quail. Topics: Analysis of Variance; Animals; Appetite Regulation; Blood Glucose; Body Weight; Cholesterol; Coturnix; Drug Administration Schedule; Feeding Behavior; Female; Infusion Pumps, Implantable; Leptin; Male; Motor Activity; Pair Bond; Sexual Behavior, Animal; Triglycerides | 2006 |
Social defeat increases food intake, body mass, and adiposity in Syrian hamsters.
Overeating and increases in body and fat mass are the most common responses to day-to-day stress in humans, whereas stressed laboratory rats and mice respond oppositely. Group housing of Syrian hamsters increases body mass, adiposity, and food intake, perhaps due to social confrontation-induced stress. In experiment 1 we asked, Does repeated social defeat increase food intake, body mass, and white adipose tissue (WAT) mass in Syrian hamsters? Male hamsters subjected to the resident-intruder social interaction model and defeated intermittently 15 times over 34 days for 7-min sessions significantly increased their food intake, body mass, and most WAT masses compared with nondefeated controls. Defeat significantly increased terminal adrenal norepinephrine, but not epinephrine, content. In experiment 2 we asked, Are 15 intermittent resident-intruder interactions necessary to increase body mass and food intake? Body mass and food intake of subordinate hamsters defeated only once were similar to those of nondefeated controls, but four or eight defeats similarly and significantly increased these responses. In experiment 3 we asked, Do intermittent defeats increase adiposity and food intake more than consecutive defeats? Four intermittent or consecutive defeats similarly and significantly increased food intake and body mass compared with nondefeated controls, but only intermittent defeats significantly increased all WAT masses. Consecutive defeats significantly increased mesenteric and inguinal WAT masses. Plasma leptin, but not insulin, concentrations were similarly and significantly increased compared with nondefeated controls. Collectively, social defeat, a natural stressor, significantly increased food intake, body mass, and adiposity in Syrian hamsters and may prove useful in determining mechanisms underlying human stress-induced obesity. Topics: Adipose Tissue; Adrenal Glands; Animals; Body Weight; Catecholamines; Cricetinae; Eating; Hydrocortisone; Leptin; Male; Mesocricetus; Organ Size; Radioimmunoassay; Social Dominance; Spleen; Testis; Thymus Gland | 2006 |
Racial differences in adiponectin in youth: relationship to visceral fat and insulin sensitivity.
The purpose of this study was to investigate 1) whether adiponectin is associated with insulin sensitivity independent of visceral adipose tissue in African-American and Caucasian youth and 2) whether adiponectin is associated with racial differences in insulin sensitivity.. Total body fat was measured by dual-energy X-ray absorptiometry and abdominal adipose tissue with computed tomography. Insulin sensitivity was measured by a 3-h hyperinsulinemic-euglycemic clamp.. Adiponectin was inversely associated (P < 0.01) with visceral adipose tissue, fasting insulin, and proinsulin and was positively related (P < 0.01) to insulin sensitivity after controlling for Tanner stage and sex independent of race. Stepwise multiple regression revealed that adiponectin was a strong independent predictor of insulin sensitivity, explaining 27% of the variance in insulin sensitivity. When subjects were categorized into tertiles of visceral adipose tissue and further low (< or = 50th) and high (>50th) adiponectin groups, insulin sensitivity was significantly different across the visceral adipose tissue groups (main effect, P < 0.01) in both races. However, within each visceral adipose tissue group, subjects with high adiponectin had higher insulin sensitivity (main effect, P < 0.05) than subjects with low adiponectin, independent of race. Racial differences in insulin sensitivity remained significant (P < 0.01) after controlling for leptin and visceral adipose tissue but not (P > 0.05) after additional adjustment for adiponectin.. Adiponectin is associated with insulin sensitivity independent of visceral adipose tissue in both African-American and Caucasian youth. Low adiponectin in African-American youth may be a biological marker that predisposes them to a greater risk of insulin resistance. Topics: Adiponectin; Adipose Tissue; Adolescent; Black People; Blood Glucose; Body Mass Index; Body Weight; Child; Glucose Clamp Technique; Humans; Infusions, Intravenous; Insulin; Leptin; Racial Groups; Regression Analysis; United States; Viscera; White People | 2006 |
Ciliary neurotrophic factor restores gallbladder contractility in leptin-resistant obese diabetic mice.
Obesity and diabetes are major risk factors for cholesterol gallstones, and the majority of obese people are leptin-resistant. Our previous work has shown that both leptin-deficient (Lepob) and leptin-resistant (Lepdb) obese diabetic mice have decreased in vitro gallbladder motility. Leptin administration to leptin-deficient (Lepob) animals restores gallbladder motility and reverses obesity and hyperinsulinemia. However, additional leptin in leptin-resistant obesity would not be expected to improve obesity-related parameters. Recent studies demonstrate that ciliary neurotrophic factor (CNTF) reduces weight and hyperinsulinemia in leptin-resistant obesity. Our hypothesis is that CNFT would cause weight loss, lower blood sugars, and restore gallbladder contractility in leptin-resistant (Lepdb) mice.. 20 C57b/6J and 20 Lepdb 8-week-old female mice were injected daily with either intraperitoneal saline or 0.3 microg/g CNTFAx15 for 17 days. Gallbladders were mounted in muscle baths and stimulated with acetylcholine, neuropeptide Y, and cholecystokinin. Gallbladder volume, serum glucose, insulin, liver weight, liver fat, and gallbladder responses were measured. Data were analyzed by ANOVA.. Saline treated obese mice had greater body weight and obesity parameters, but decreased gallbladder contractility to neurotransmitters compared to saline treated lean mice. CNTF administration to obese mice decreased body weight and obesity parameters, and restored gallbladder contractility. CNTF treated lean animals had weight loss and decreased gallbladder contraction to acetylcholine and cholecystokinin compared to saline treated lean animals.. Ciliary neurotrophic factor (CNTF) causes 1) weight loss, 2) improvement of diabetes, and 3) alterations in gallbladder motility that is improved in obese mice but decreased in lean mice. We conclude that CNTF may improve gallbladder contractility in leptin-resistant obesity with diabetes. Topics: Animals; Blood Glucose; Body Weight; Ciliary Neurotrophic Factor; Diabetes Mellitus, Type 2; Female; Gallbladder; Gallbladder Emptying; Insulin; Leptin; Liver; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Obese; Muscle Contraction; Obesity; Organ Size; Vacuoles | 2006 |
Photoperiod regulates leptin sensitivity in field voles, Microtus agrestis.
We have previously shown that cold-acclimated (8 degrees C) male field voles (Microtus agrestis) transferred from short (SD, 8:16 h L:D) to long photoperiod (LD, 16:8 h L:D) exhibit increases in body mass, adiposity and food intake. To assess whether these increases were associated with decreased leptin sensitivity, we infused LD and SD voles with physiological doses of murine leptin (or saline) delivered peripherally for 7 days via mini-osmotic pumps. Measurements were made of body mass (weight-reducing effect of leptin), food intake (anorectic effect of leptin) and gene expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) (thermogenic effect of leptin). The SD animals were sensitive to the weight-reducing effects of leptin (mean body mass decrease of 1.2 g over 7 days) and appetite-reducing effect of leptin (mean food intake decrease of 2.5 g over 7 days), whereas LD voles were resistant to the hormone treatment. The switch from a leptin-sensitive to leptin-resistant state appears to act as a desensitisation mechanism that allows voles transferred from SD to LD to ignore elevated leptin levels generated by increased body fat and accumulate adipose tissue without stimulating compensatory changes opposing the weight gain. Neither SD nor LD voles responded to infusion of leptin by changes in BAT UCP1 gene expression, suggesting dissociation of anorectic and thermogenic effects of leptin, possibly related to chronic cold exposure. Our results indicate that cold-acclimated voles show photoperiod-regulated changes in leptin sensitivity and may provide an attractive model for elucidating molecular mechanisms of leptin resistance. Topics: Acclimatization; Animals; Arvicolinae; Body Composition; Body Weight; Carrier Proteins; Eating; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Photoperiod; Uncoupling Protein 1 | 2006 |
Leptin secretion after a high-fat meal in normal-weight rats: strong predictor of long-term body fat accrual on a high-fat diet.
The objective of this study was to investigate meal-related endocrine changes that permit one to identify Sprague-Dawley rats at normal weight that are prone (OP) vs. resistant (OR) to obesity. In blood collected via chronic cardiac catheters, a 2-h high-fat meal (HFM, 50% fat, 40 kcal) at dark onset caused a significant increase in leptin, insulin, and triglycerides compared with premeal levels. Similar to patterns in already obese compared with lean rats on a high-fat diet, these meal-induced endocrine changes in normal-weight rats on lab chow were almost twofold larger in OP rats that, compared with OR rats, subsequently accumulated 100% more fat mass on a chronic high-fat diet. These exaggerated endocrine changes were similarly observed in blood collected using a simpler tail vein puncture procedure. In three separate experiments, the HFM-induced rise in leptin was found to be the strongest, positive correlate (r = +0.58, +0.62 and +0.64) of long-term body fat accrual. The lowest (2-5 ng/ml) vs. highest (6-9 ng/ml) scores for this post-HFM leptin measurement identified distinct OR and OP subgroups, respectively, when they were similar in body weight (340-350 g), premeal leptin (2.6-3.4 ng/ml), and meal size (40 kcal). Subsequent tests in these normal-weight OP rats revealed a distinct characteristic compared with OR rats, namely, exaggerated HFM-induced rise in expression of the orexigenic peptide galanin in the paraventricular nucleus. Thus, with this HFM-induced leptin measurement, OP rats can be identified while still at normal weight and then investigated for mechanisms that contribute to their excessive body fat accrual on a high-fat diet. Topics: Animals; Body Weight; Dietary Fats; Disease Susceptibility; Immunity, Innate; Insulin; Leptin; Male; Obesity; Postprandial Period; Prognosis; Rats; Rats, Sprague-Dawley; Reference Values; Time Factors; Triglycerides | 2006 |
Regulation of dietary energy level and oil source on leptin and its long form receptor mRNA expression of the adipose tissues in growing pigs.
Two experiments were conducted to evaluate the effects of dietary energy level and source of oil on leptin mRNA and long form leptin receptor (Ob-Rl) mRNA expression in dorsal, abdominal and visceral adipose tissues in young growing pigs. In experiment one, 15 barrows (initial body weight 15.0 kg) were used to examine the effects of dietary energy levels on leptin mRNA and Ob-Rl mRNA expression. The pigs were randomly allotted to one of three dietary treatments (n=5 per treatment) containing 13.4, 15.1 or 16.7 MJ DE/kg diet for 28 days. Based on the results of experiment one, experiment two was designed to examine the effects of oil sources including soybean oil (rich in n-6 polyunsaturated fatty acids) or fish oil (rich in n-3 polyunsaturated fatty acids) on leptin mRNA and Ob-Rl mRNA expression in the same adipose tissues examined in experiment one. The energy content of these diets was 15.1 MJ/kg. Fourteen barrows (initial weight 20.5 kg) were allocated to either of the two dietary treatments (n=7 per treatment), which was supplemented with either soybean or fish oil (both 5.73% of the diet) and fed to the pigs for 21 days. At the end of both experiments, blood samples were collected to determine plasma leptin and insulin concentrations. Adipose tissues were sampled to determine leptin and Ob-Rl mRNA expression using real-time fluorescence quantification PCR. In experiment one, plasma leptin concentrations were enhanced (P=0.02), and insulin concentrations were decreased (P<0.01) in pigs fed the high-energy diet (16.7 MJ DE/kg). Dorsal adipose tissue leptin mRNA expression was increased by feeding the diet containing 15.1 MJ/kg DE compared with the diets containing 13.4 and 16.7 MJ/kg DE. There was no difference in leptin mRNA expression in abdominal and visceral adipose tissue. In experiment two, there were no differences in plasma leptin and insulin concentrations between pigs fed with either fish oil or soybean oil diets. Nevertheless, fish oil decreased both leptin mRNA and Ob-Rl mRNA expression in dorsal adipose tissues compared with soybean oil (P<0.01). These experiments indicate that the source of oil plays a more potent role in regulation of leptin mRNA expression relative to dietary energy levels by an insulin-independent mechanism. Plasma leptin concentrations may also be regulated by a post-transcriptional mechanism. Topics: Adipose Tissue; Animals; Body Weight; Dietary Fats, Unsaturated; Energy Intake; Fish Oils; Insulin; Leptin; Male; Random Allocation; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Soybean Oil; Swine | 2006 |
Diacylglycerol-enriched structured lipids containing CLA and capric acid alter body fat mass and lipid metabolism in rats.
The present study compared the effect of corn oil, diacylglycerol (DG) oil, and DG-enriched structured lipids (SL-DG) produced from corn oil, capric and conjugated linoleic acid on adiposity in rats fed an AIN-76 diet (5% fat) for 6 weeks.. The plasma and hepatic lipids, adipose tissue weight, and enzyme activities related to fatty acid metabolism were determined.. The weights of the epididymal white adipose tissue (WAT), perirenal WAT, and interscapular WAT were significantly lower in the SL-DG group than in the DG group. Reduction of fat mass in the SL-DG group was related to suppressing fatty acid synthase activities and enhancing beta-oxidation activity in perirenal WAT. The plasma leptin was lower in the SL-DG group than in the DG group, plus a lower plasma TG level was accompanied by an increase in adipocyte LPL activity. Meanwhile the SL-DG supplement lowered the plasma and hepatic cholesterol level. In addition, the hepatic HMG-CoA reductase and ACAT activities were significantly lower in the SL-DG group than in the other groups.. The DG-enriched SL used in this study was effective in enhancing triglyceride metabolism in adipose tissue, especially as regards reducing the abdominal fat mass and cholesterol metabolism in the liver. Topics: Adipose Tissue; Animals; Body Weight; Corn Oil; Decanoic Acids; Diglycerides; Fatty Acid Synthases; Leptin; Linoleic Acids, Conjugated; Lipid Metabolism; Lipoprotein Lipase; Male; Oxidation-Reduction; Random Allocation; Rats; Rats, Sprague-Dawley; Triglycerides | 2006 |
Effect of ovariectomy and ad libitum feeding on body composition, thyroid status, ghrelin and leptin plasma concentrations in female dogs.
The objective of this study was to evaluate the effects of ovariectomy (i) and ad libitum feeding (ii) on energy intake, body weight (BW), body composition, thyroid status, leptin and ghrelin plasma concentrations. Four young adult female Beagle dogs were fed a maintenance diet for 6 weeks prior to ovariectomy, then 6 months after. Food allowance was adjusted in order to maintain optimal BW. Then, a diet slightly higher in energy concentration was fed ad libitum for 4 months. The maintenance diet was then fed ad libitum for one additional month. The maintenance of optimal BW after ovariectomy required a significant decrease in energy allowance. No increase in fat mass was observed. Ghrelin concentration remained unchanged. During the first month of ad libitum feeding, plasma ghrelin concentration and energy intake increased, then they decreased. Mean BW, plasma leptin, thyrotropin (TSH), total triiodothyronine (TT3) and total thyroxine (TT4) concentrations significantly increased over the study. The BW increase was exclusively due to an increase in body fat. In conclusion, energy allowance should be strictly controlled in spayed female dogs. The results suggest that in dogs, thyroid hormones, leptin and ghrelin concentrations change in response to a positive energy balance in an attempt to limit weight gain. However, the significant weight gain shows that this goal was not achieved. Topics: Adipose Tissue; Animal Feed; Animals; Body Composition; Body Weight; Dogs; Energy Intake; Female; Ghrelin; Leptin; Ovariectomy; Peptide Hormones; Thyroid Hormones | 2006 |
NO-1886 (ibrolipim), a lipoprotein lipase-promoting agent, accelerates the expression of UCP3 messenger RNA and ameliorates obesity in ovariectomized rats.
The synthetic compound NO-1886 (ibrolipim, [4-(4-bromo-2-cyano-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester, CAS 133208-93-2) is a lipoprotein lipase (LPL)-promoting agent that decreases plasma triglycerides, increases high-density lipoprotein cholesterol levels, and prevents fat accumulation in high fat-fed rats. However, the effect of NO-1886 on body weight, fat accumulation, and energy expenditure in ovariectomized (OVX) rats is not clear. The primary aim of this study was to ascertain whether NO-1886 ameliorated obesity in OVX rats and to examine the effects on fatty acid oxidation-related enzymes. NO-1886 decreased accumulation of visceral fat and suppressed the increase in body weight resulting from the ovariectomy. NO-1886 decreased the respiratory quotient and increased expression of the fatty acid translocase messenger RNA (mRNA) in the liver, soleus muscle, and mesenteric fat. NO-1886 also increased the expression of fatty acid-binding protein mRNA in the liver and soleus muscle and the expression of the uncoupling protein 3 (UCP3) mRNA in the heart, soleus muscle, and mesenteric fat, but not in the brown adipose tissue. Furthermore, NO-1886 did not affect UCP1 and UCP2 in brown adipose tissue. Therefore, amelioration of obesity by NO-1886 in OVX rats is possibly because of an the increased expression of fatty acid oxidation-related enzymes and UCP3, both of which are related to fatty acid transfer and fat use. Our study indicates that the LPL-promoting agent NO-1886 may be potentially beneficial in the treatment of obesity and obesity-linked health problems in postmenopausal women. Topics: Adipose Tissue, Brown; Animals; Benzamides; Blood Glucose; Body Weight; Carrier Proteins; Eating; Fatty Acid Transport Proteins; Fatty Acid-Binding Proteins; Female; Gene Expression; Hypolipidemic Agents; Insulin; Ion Channels; Leptin; Mitochondrial Proteins; Muscle, Skeletal; Myocardium; Obesity; Organophosphorus Compounds; Ovariectomy; Oxygen Consumption; Proton-Translocating ATPases; Random Allocation; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uncoupling Protein 3 | 2006 |
The effects of a new soluble dietary fiber on weight gain and selected blood parameters in rats.
This study was designed to investigate a new dietary fiber, alpha-cyclodextrin, marketed under the trade name FBCx (Wacker Biochem, Adrian, MI), for beneficial effects on weight reduction and the improvement of certain blood parameters in rats. Male Wistar rats were divided into 4 groups and fed ad libitum for a period of 6 weeks: (1) a normal low-fat diet (LF; 4% fat wt/wt); (2) an LF diet with FBCx added; (3) a high-fat diet (HF, 40% fat wt/wt); and (4) an HF diet with FBCx. The FBCx was added at the rate of 10% (wt/wt) of the fat in the diet. Body weight and food intake were recorded 3 times per week. Plasma constituent levels and liver and fecal lipid contents, as well as body composition were determined at sacrifice. Adding FBCx to the diet significantly reduced weight gain in rats fed with an HF diet relative to rats fed with the HF control diet (P < .05). FBCx also elicited a reduction in plasma triglyceride levels of 30%, total cholesterol of 9%, and increased the fat content of the feces in the rats fed with the HF diet with FBCx. In addition, the serum leptin levels were normalized, and the calculated insulin sensitivity was improved. No adverse effects were observed in the rats consuming FBCx. It would appear that FBCx might be effective in reducing body weight gain and improving metabolic syndrome. Topics: alpha-Cyclodextrins; Animals; Blood Glucose; Body Composition; Body Weight; Cholesterol; Dietary Fats; Dietary Fiber; Eating; Feces; Insulin; Leptin; Liver; Male; Obesity; Rats; Rats, Wistar; Triglycerides | 2006 |
Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis.
Leptin, an adipocyte-derived hormone, acts directly on the brain to control food intake and energy expenditure. An important question is the identity of first-order neurons initiating leptin's anti-obesity effects. A widely held view is that most, if not all, of leptin's effects are mediated by neurons located in the arcuate nucleus of the hypothalamus. However, leptin receptors (LEPRs) are expressed in other sites as well, including the ventromedial hypothalamus (VMH). The possible role of leptin acting in "nonarcuate" sites has largely been ignored. In the present study, we show that leptin depolarizes and increases the firing rate of steroidogenic factor-1 (SF1)-positive neurons in the VMH. We also show, by generating mice that lack LEPRs on SF1-positive neurons, that leptin action at this site plays an important role in reducing body weight and, of note, in resisting diet-induced obesity. These results reveal a critical role for leptin action on VMH neurons. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Diet; Electrophysiology; Energy Metabolism; Green Fluorescent Proteins; Homeodomain Proteins; Homeostasis; Immunohistochemistry; In Vitro Techniques; Leptin; Male; Mice; Mice, Transgenic; Neurons; Obesity; Patch-Clamp Techniques; Phenotype; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; RNA Probes; Signal Transduction; STAT3 Transcription Factor; Steroidogenic Factor 1; Transcription Factors; Ventromedial Hypothalamic Nucleus | 2006 |
Leptin: a potential novel antidepressant.
Leptin, a hormone secreted from adipose tissue, was originally discovered to regulate body weight. The localization of the leptin receptor in limbic structures suggests a potential role for leptin in emotional processes. Here, we show that rats exposed to chronic unpredictable stress and chronic social defeat exhibit low leptin levels in plasma. Systemic leptin treatment reversed the hedonic-like deficit induced by chronic unpredictable stress and improved behavioral despair dose-dependently in the forced swim test (FST), a model widely used for screening potential antidepressant efficacy. The behavioral effects of leptin in the FST were accompanied by increased neuronal activation in limbic structures, particularly in the hippocampus. Intrahippocampal infusion of leptin produced a similar antidepressant-like effect in the FST as its systemic administration. By contrast, infusion of leptin into the hypothalamus decreased body weight but had no effect on FST behavior. These findings suggest that: (i) impaired leptin production and secretion may contribute to chronic stress-induced depression-like phenotypes, (ii) the hippocampus is a brain site mediating leptin's antidepressant-like activity, and (iii) elevating leptin signaling in brain may represent a novel approach for the treatment of depressive disorders. Topics: Adipose Tissue; Animals; Anti-Anxiety Agents; Antidepressive Agents; Behavior, Animal; Body Weight; Dose-Response Relationship, Drug; Hippocampus; Hypothalamus; In Situ Hybridization; Leptin; Male; Models, Statistical; Motor Activity; Neurons; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Stress, Psychological; Sucrose; Swimming; Time Factors | 2006 |
Direct and indirect effects of leptin on preadipocyte proliferation and differentiation.
Leptin has been shown to reduce body fat in vivo. Adipocytes express the leptin receptor; therefore, it is realistic to expect a direct effect of leptin on adipocyte growth and metabolism. In vitro studies examining the effect of leptin on adipocyte metabolism require supraphysiological doses of the protein to see a decrease in lipogenesis or stimulation of lipolysis, implying an indirect action of leptin. It also is possible that leptin reduces adipose mass by inhibiting preadipocyte proliferation (increase in cell number) and/or differentiation (lipid filling). Thus we determined direct and indirect effects of leptin on preadipocyte proliferation and differentiation in vitro. We tested the effect of leptin (0-500 ng/ml), serum from leptin-infused rats (0.25% by volume), and adipose tissue-conditioned medium from leptin-infused rats (0-30% by volume) on preadipocyte proliferation and differentiation in a primary culture of cells from male Sprague-Dawley rat adipose tissue. Leptin (50 ng/ml) stimulated proliferation of preadipocytes (P<0.05), but 250 and 500 ng leptin/ml inhibited proliferation of both preadipocyte and stromal vascular cell fractions (P<0.01), as measured by [3H]thymidine incorporation. Serum from leptin-infused rats inhibited proliferation of the adipose and stromal vascular fractions (P=0.01), but adipose tissue-conditioned medium had no effect on proliferation of either cell fraction. None of the treatments changed preadipocyte differentiation as measured by sn-glycerophosphate dehydrogenase activity. These results suggest that leptin could inhibit preadipocyte proliferation by modifying release of a factor from tissue other than adipose tissue. Topics: Adipocytes; Adipogenesis; Animals; Body Composition; Body Weight; Cell Proliferation; Cell Survival; Culture Media, Conditioned; Dose-Response Relationship, Drug; Eating; Glucosephosphate Dehydrogenase; Insulin-Like Growth Factor I; Leptin; Male; Rats; Rats, Sprague-Dawley; Stromal Cells | 2006 |
Effect of alterations in the quantity and composition of the pre-mating diet on embryo survival and foetal growth in the pig.
This trial examined the effects of feeding six diets, which varied in either amount or composition, during the oestrous cycle prior to insemination on embryo survival and foetal development on day 27+/-2 of pregnancy in gilts. Ten or 11 gilts per group received either a maintenance (M) diet, 1.8 x M, 2.6 x M or nutritionally balanced diets in which the content of fibre, protein or starch was increased. Of the six diets tested, only the high fibre diet significantly increased embryo survival when compared to its 1.8 x M isoenergetic control (88.20+/-1.96% versus 81.25+/-2.67%; P<0.05). More litters from gilts fed the 1.8 x M and the starch diets had foetuses defined as intra-uterine growth retarded (IUGR; 50% and 62.5 of litters, respectively), compared to the other four groups in which 0-12.5% of litters contained IUGR foetuses (P<0.05). There was no effect of dietary treatment on foetal or placental size or on the within-litter variability in foetal and placental size. Plasma concentrations of oestradiol and progesterone on days 4-8 of the oestrous cycle and on day 27+/-2 of pregnancy were unaffected by treatment. Feed intake was positively related to mean plasma IGF-1 concentrations on days 4-8 of the cycle (P<0.01) and to mean leptin concentrations on days 4 and 5 (P<0.001). Leptin concentrations were unaffected by alterations in the composition of the diet, whereas IGF-1 concentrations were higher in gilts fed the starch diet compared to the M control (159+/-9.52 versus 127+/-7.65 ng/ml; P<0.05). These data demonstrate that alteration to the composition of the feed consumed during the cycle before insemination can affect both embryo survival and the distribution of foetal size within the litter. The underlying mechanism(s) remain to be determined, but probably involve dietary-induced changes in concentrations of reproductive hormones and/or intermediary metabolites that in turn affect ovarian follicular and oocyte development. Topics: Adipose Tissue; Animal Nutritional Physiological Phenomena; Animals; Body Composition; Body Weight; Diet; Dietary Fiber; Dietary Proteins; Embryo, Mammalian; Estradiol; Female; Fetal Development; Fetal Growth Retardation; Fetal Weight; Insulin-Like Growth Factor I; Leptin; Organ Size; Placenta; Pregnancy; Progesterone; Starch; Swine; Swine Diseases | 2006 |
Characterization of obesity in Japanese monkeys (Macaca fuscata) in a pedigreed colony.
Japanese monkey, Macaca fuscata, is recognized as the monkey species inhabiting the northernmost area in the world, and thus likely to possess unique fat-depositing mechanisms to resist cold weather in winter. We report that obese females are present in the Wakasa group of Japanese monkey reared in an open enclosure of the Primate Research Institute, Kyoto University.. Eight of 12 females were categorized as obese, showing percentage body fat of over 22%. The levels of serum leptin (mean +/- SD, 4.9 +/- 2.3 ng/ml) measured in these obese monkeys were significantly higher than those of non-obese peers of the same group (n = 4; 1.2 +/- 0.5 ng/ml) and another Japanese monkey group (Takahama, n = 14; 0.8 +/- 0.25 ng/ml); however, serum levels of adiponectin, insulin, glucose, hemoglobin A1c, and fructosamine did not differ between obese and non-obese monkeys. Few serum lipid parameters such as triglyceride and cholesterol showed lower levels in obese monkeys than their non-obese peers.. These results show that these obese monkeys in the Wakasa group have not developed obesity-related diseases/disorders such as diabetes. In the Wakasa group, the frequency of obese individuals was high in some maternal lineages, suggesting that genetic factors responsible for obesity may have been inherited in these lineages. Topics: Adiposity; Aging; Animals; Blood Glucose; Body Weight; Cytokines; Female; Insulin; Leptin; Lipids; Macaca; Male; Obesity; Organ Size; Pedigree | 2006 |
Differential effects of saturated and unsaturated fatty acid diets on cardiomyocyte apoptosis, adipose distribution, and serum leptin.
Fatty acids are the primary fuel for the heart and are ligands for peroxisome proliferator-activated receptors (PPARs), which regulate the expression of genes encoding proteins involved in fatty acid metabolism. Saturated fatty acids, particularly palmitate, can be converted to the proapoptotic lipid intermediate ceramide. This study assessed cardiac function, expression of PPAR-regulated genes, and cardiomyocyte apoptosis in rats after 8 wk on either a low-fat diet [normal chow control (NC); 10% fat calories] or high-fat diets composed mainly of either saturated (Sat) or unsaturated fatty acids (Unsat) (60% fat calories) (n = 10/group). The Sat group had lower plasma insulin and leptin concentrations compared with the NC or Unsat groups. Cardiac function and mass and body mass were not different. Cardiac triglyceride content was increased in the Sat and Unsat groups compared with NC (P < 0.05); however, ceramide content was higher in the Sat group compared with the Unsat group (2.9 +/- 0.2 vs. 1.4 +/- 0.2 nmol/g; P < 0.05), whereas the NC group was intermediate (2.3 +/- 0.3 nmol/g). The number of apoptotic myocytes, assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, was higher in the Sat group compared with the Unsat group (0.28 +/- 0.05 vs. 0.17 +/- 0.04 apoptotic cells/1,000 nuclei; P < 0.04) and was positively correlated to ceramide content (P < 0.02). Both high-fat diets increased the myocardial mRNA expression of the PPAR-regulated genes encoding uncoupling protein-3 and pyruvate dehydrogenase kinase-4, but only the Sat diet upregulated medium-chain acyl-CoA dehydrogenase. In conclusion, dietary fatty acid composition affects cardiac ceramide accumulation, cardiomyocyte apoptosis, and expression of PPAR-regulated genes independent of cardiac mass or function. Topics: Adipose Tissue; Animals; Apoptosis; Body Constitution; Body Weight; Cells, Cultured; Dietary Fats; Dietary Fats, Unsaturated; Fatty Acids; Leptin; Male; Myocytes, Cardiac; Rats; Rats, Wistar | 2006 |
Fat oxidation before and after a high fat load in the obese insulin-resistant state.
Obesity may be associated with a lowered use of fat as a fuel, which may contribute to the enlarged adipose tissue stores.. The aim of the present study was to study fatty acid use in the fasting state and in response to a high fat load in a large cohort of obese subjects (n = 701) and a lean reference group (n = 113).. Subjects from eight European centers underwent a test meal challenge containing 95 en% fat [energy content 50% of estimated resting energy expenditure (EE)]. Fasting and postprandial fat oxidation and circulating metabolites and hormones were determined over a 3-h period.. Postprandial fat oxidation (as percent of postprandial EE, adjusted for fat mass, age, gender, center, and energy content of the meal) decreased with increasing body mass index (BMI) category (P < 0.01), an effect present only in those obese subjects with a relatively low fasting fat oxidation (below median, interaction BMI category x fasting fat oxidation, P < 0.001). Fasting fat oxidation increased with increasing BMI category (P < 0.001), which was normalized after adjustment for fat-free mass and fat mass. Furthermore, insulin resistance was positively associated with postprandial fat oxidation (P < 0.05) and negatively associated with fasting fat oxidation (expressed as percent of EE), independent of body composition.. The present data indicate an impaired capacity to regulate fat oxidation in the obese insulin-resistant state, which is hypothesized to play a role in the etiology of both obesity and insulin resistance. Topics: Adult; Area Under Curve; Body Composition; Body Mass Index; Body Weight; Dietary Fats; Female; Humans; Hydrocortisone; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Obesity; Oxidation-Reduction; Sex Characteristics | 2006 |
Leukemia inhibitory factor reduces body fat mass in ovariectomized mice.
Ovariectomized (OVX) mice are known to gain body fat while exposure to estrogens decreases fat mass. We have previously shown that estrogen replacement therapy enhances the expression of receptors for the cytokine, leukemia inhibitory factor (LIF). LIF and other cytokines acting via the gp130 signal transducing receptor have been reported to decrease obesity. In the present study, we investigated whether LIF treatment can reduce obesity in OVX mice.. Eight-week-old female C57Bl/6 mice were OVX or sham-operated. The mice were treated with LIF, 30 microg/kg or PBS via daily i.p. injections for 15 days (n = 9-10).. Dual X-ray absorptiometry and computerized tomography.. We found that LIF treatment of OVX mice caused a significant reduction in the weight of white fat depots (P = 0.017) and serum leptin levels (P = 0.011). LIF also caused a significant decrease in brown fat mass (P = 0.036). Treatment with LIF decreased thymus weight but did not affect crown-rump length, femur length, trabecular bone mineral density or the weight of several non-fat organs including the uterus.. The cytokine, LIF, decreases body fat mass in OVX mice, suggesting that estrogen signaling is not required for this effect. Topics: Absorptiometry, Photon; Adipose Tissue; Adipose Tissue, Brown; Animals; Body Composition; Body Weight; Female; Interleukin-6; Leptin; Leukemia Inhibitory Factor; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Ovariectomy; Tomography, X-Ray Computed | 2006 |
Role of nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) in the regulation of blood pressure by leptin in lean and obese rats.
We investigated the role of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in hemodynamic action of leptin. The effect of leptin (1 mg/kg i.p.) on systolic blood pressure (SBP) was examined in lean rats and in rats made obese by feeding highly palatable diet for either 1 or 3 months. Separate groups received NO synthase inhibitor, L-NAME, or EDHF inhibitors, the mixture of apamin+charybdotoxin or sulfaphenazole, before leptin administration. Leptin increased NO production, as evidenced by increase in plasma and urinary NO metabolites and cyclic GMP. This effect was impaired in both obese groups. In lean rats either leptin or EDHF inhibitors had no effect on blood pressure. L-NAME increased blood pressure in lean animals and this effect was prevented by leptin. However, when leptin was administered to animals pretreated with both L-NAME and EDHF inhibitors, blood pressure increased even more than after L-NAME alone. In the 1-month obese group leptin had no effect on SBP, however, pressor effect of leptin was observed in animals pretreated with EDHF inhibitors. In the 3-month obese group leptin alone increased SBP, and EDHF inhibitors did not augment its pressor effect. The results suggest that leptin may stimulate EDHF when NO becomes deficient, e.g. after NOS blockade or in short-term obesity. Although the effect of leptin on NO production is impaired in the 1-month obese group, BP does not increase, probably because EDHF compensates for NO deficiency. In contrast, leptin increases BP in 3-month obesity because its effect on EDHF is also attenuated. Topics: 6-Ketoprostaglandin F1 alpha; Animals; Biological Factors; Blood Pressure; Body Weight; Cyclic GMP; Diet; Indicators and Reagents; Isoprostanes; Leptin; Male; Nitric Oxide; Obesity; Rats; Rats, Wistar | 2006 |
Does vagal nerve stimulation affect body composition and metabolism? Experimental study of a new potential technique in bariatric surgery.
It has been shown that vagal nerve stimulation (VNS) can affect body mass. The aim of this study was to evaluate effect of VNS on body mass, body composition, metabolic rate, and plasma leptin and IGF-I levels.. Eight female pigs were included in the study. Under general anesthesia, a bipolar electrode was implanted on the anterior vagal nerve by laparoscopy. Group A was treated by VNS, and group B was the control. After 4 weeks, stimulation was discontinued in group A and started in group B. The following parameters were evaluated: body mass, body composition, metabolic rate, plasma leptin and IGF-1 levels and intramuscular fat content (IMF).. VNS attenuated body weight gain (2.28 +/- 3.47 kg vs 14.04 +/- 6.75 kg; P = .0112, for stimulation and nonstimulation periods, respectively), backfat gain (0.04 +/- 0.26 mm vs 2.31 +/- 1.12 mm) and IMF gain (-3.76 +/- 6.06 mg/g MS vs 7.24 +/- 12.90 mg/g MS; P = .0281). VNS resulted in lower backfat depth/loin muscle area ratio (0.33 +/- 0.017 vs 0.38 +/- 0.35; P = .0476). Lower plasma IGF-I concentration was found after VNS (-3.67 +/- -11.55 ng/mL vs 9.86 +/- 10.74 ng/mL; P = .0312). No significant changes in other parameters were observed.. VNS affects body weight mainly at the expense of body fat resources; however, metabolic rate is not affected. Topics: Animals; Bariatric Surgery; Body Composition; Body Mass Index; Body Weight; Electric Stimulation Therapy; Female; Insulin-Like Growth Factor I; Leptin; Obesity; Swine; Vagus Nerve | 2006 |
Peripheral metabolic responses to prolonged weight reduction that promote rapid, efficient regain in obesity-prone rats.
Weight regain after weight loss is the most significant impediment to long-term weight reduction. We have developed a rodent paradigm that models the process of regain after weight loss, and we have employed both prospective and cross-sectional analyses to characterize the compensatory adaptations to weight reduction that may contribute to the propensity to regain lost weight. Obese rats were fed an energy-restricted (50-60% kcal) low-fat diet that reduced body weight by 14%. This reduced weight was maintained for up to 16 wk with limited provisions of the low-fat diet. Intake restriction was then removed, and the rats were followed for 56 days as they relapsed to the obese state. Prolonged weight reduction was accompanied by 1) a persistent energy gap resulting from an increased drive to eat and a reduced expenditure of energy, 2) a higher caloric efficiency of regain that may be linked with suppressed lipid utilization early in the relapse process, 3) preferential lipid accumulation in adipose tissue accompanied by adipocyte hyperplasia, and 4) humoral adiposity signals that underestimate the level of peripheral adiposity and likely influence the neural pathways controlling energy balance. Taken together, long-term weight reduction in this rodent paradigm is accompanied by a number of interrelated compensatory adjustments in the periphery that work together to promote rapid and efficient weight regain. These metabolic adjustments to weight reduction are discussed in the context of a homeostatic feedback system that controls body weight. Topics: Adipose Tissue; Animals; Body Weight; Carbohydrate Metabolism; Circadian Rhythm; Diet, Fat-Restricted; Energy Intake; Energy Metabolism; Insulin; Leptin; Lipid Metabolism; Male; Models, Biological; Obesity; Proteins; Rats; Rats, Wistar; Weight Gain; Weight Loss | 2006 |
Differential role of SH2-B and APS in regulating energy and glucose homeostasis.
SH2-B and APS, two members of a pleckstrin homology and SH2 domain-containing adaptor family, promote both insulin and leptin signaling in a similar fashion in cultured cells. In addition, APS mediates insulin-stimulated activation of the c-Cbl/CAP/TC10 pathway in cultured adipocytes. Here we characterized genetically modified mice lacking SH2-B, APS, or both to determine the physiological roles of these two proteins in animals. Disruption of the SH2-B gene resulted in obesity, hyperglycemia, hyperinsulinemia, and glucose intolerance. Conversely, deletion of the APS gene did not alter adiposity, energy balance, and glucose metabolism. Energy intake, energy expenditure, fat content, body weight, and plasma insulin, leptin, glucose, and lipid levels were similar between APS(-/-) and WT littermates fed either normal chow or a high-fat diet. Moreover, deletion of APS failed to alter insulin and glucose tolerance. APS(-/-)/SH2-B(-/-) double knockout mice also developed energy imbalance, obesity, hyperleptinemia, hyperinsulinemia, hyperglycemia, and glucose intolerance; however, plasma leptin and insulin levels were significantly lower in APS(-/-)/SH2-B(-/-) than in SH2-B(-/-) mice. These results suggest that SH2-B, but not APS, is a key positive regulator of energy and glucose metabolism in mice. Topics: Adaptor Proteins, Signal Transducing; Adipocytes; Adipose Tissue; Animals; Body Composition; Body Weight; Crosses, Genetic; Gene Deletion; Gene Expression Regulation, Neoplastic; Glucose; Glucose Tolerance Test; Homeostasis; Immunoblotting; Immunoprecipitation; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Recombination, Genetic; Signal Transduction; Time Factors | 2006 |
Chronic leptin infusion advances, and immunoneutralization of leptin postpones puberty onset in normally fed and feed restricted female rats.
Does leptin play a vital role in initiating puberty in female rats and can it overrule a nutrionally imposed (i.e. a 30% feed restriction, FR) delay in puberty onset? Prepubertal female rats were chronically infused for 14 days with leptin (icv or sc) or leptin-antiserum (icv) while puberty onset was monitored by means of scoring the moment of vaginal opening (VO). Median VO age was higher (35 days versus 27 days) in FR animals but leptin levels at VO were significantly decreased (1.44 +/- 0.17 ng/ml versus 2.79 +/- 0.31 ng/ml). Centrally (icv) and peripherally (sc) infused leptin (1 microg/day) advanced VO age compared to FR controls (30 days versus 35 days and 31 days versus 41 days, respectively). Congruently, centrally (icv) administered leptin-antiserum (0.6 microg/day) delayed puberty onset. In normally fed rats median VO age was only marginally advanced (26 days versus 27 days) but only if leptin was applied centrally. The effects of FR on puberty onset are counteracted or even normalized by the infusion of leptin, whereas immunoneutralization of central leptin postpones puberty onset. We therefore conclude that central leptin is crucial for initiating puberty in female rats. Topics: Animals; Behavior, Animal; Body Weight; Cerebral Ventricles; Feeding Behavior; Female; Food Deprivation; Injections, Subcutaneous; Leptin; Peptides; Rats; Rats, Wistar; Sexual Maturation; Time Factors | 2006 |
Central and/or peripheral immunoreactivity of orexin-A in pregnant rats and women.
Orexins (A and B) have been implicated in feeding behavior, energy balance and state of vigilance. During pregnancy, their involvement in feeding regulation and reproduction are poorly understood. In this study, we investigated orexin-A immunoreactivity in the hypothalamus and serum in pregnant rats and women by immunofluorescence staining, image analysis and radioimmunoassay, examined the correlation of serum orexin-A and leptin with gestational age in pregnant women by regression analysis, and explored the effect of leptin injected intracerebroventricularly (i.c.v.) on orexin-A immunoreactivity in the hypothalamus of normal rats by immunohistochemistry. The results showed that pregnant rats had significantly greater daily food intake on days 15 and 20 of pregnancy than virgin ones (+27.3%, P< 0.01 and +38.6%, P< 0.001 respectively), with significantly fewer number and lower mean staining intensity of orexin-A-immunoreactive (ir) neurons on days 16 (both P< 0.05) and 21 (both P< 0.01) of pregnancy. Moreover, serum levels of orexin-A exhibited 2.0-fold and 2.2-fold increases (both P< 0.001) in rats on days 16 and 21 of pregnancy compared with those in virgin rats, and 1.9-fold and 2.0-fold increases (both P< 0.001) in mid (13-26 weeks) and late pregnant women (27-40 weeks) compared with those in non-pregnant women. Simultaneously, serum levels of leptin showed a 2.3-fold and 2.2-fold increase (both P< 0.001) in rats on days 16 and 21 of pregnancy, and a 3.3-fold and 4.3-fold increase (both P< 0.001) in mid and late pregnant women. Serum levels of both orexin-A and leptin correlated positively with gestational age in pregnant women. Leptin injected i.c.v. significantly decreased the number (P< 0.01) and mean staining intensity (P< 0.01) of orexin-A-ir neurons in the hypothalamus, food intake (P< 0.01) and body weight gain (P< 0.001) compared with vehicle injection in normal rats. These results suggested that central and serum orexin-A might be involved in the regulation of feeding and energy metabolism during pregnancy. The change in central orexin-A immunoreactivity might be related to the increased serum leptin concentrations. Topics: Animals; Body Weight; Feeding Behavior; Female; Fluorescent Antibody Technique; Hypothalamus; Injections, Intraventricular; Intracellular Signaling Peptides and Proteins; Leptin; Neuropeptides; Orexins; Pregnancy; Rats | 2006 |
Leptin is required for uncoupling protein-1-independent thermogenesis during cold stress.
We investigated the role of leptin in regulating energy metabolism through induction of uncoupling protein (UCP)-1-based brown fat thermogenesis by comparing phenotypes of energy balance in ob/ob and double-mutant ob/ob.Ucp1(-/-) mice. Measurements of adiposity and lean body mass (nuclear magnetic resonance), energy expenditure (indirect calorimetry), body weight, food intake, and core body temperature were determined in the two mutant stocks of 3-month-old mice maintained at an initial ambient temperature of 28 C for 21 d and then at 21 C for 16 d, and finally with leptin administration for 8 d at 21 C. No phenotypic differences between ob/ob and ob/ob.Ucp1(-/-) mice were detected, suggesting that UCP1-based thermogenesis is not essential for the regulation of adiposity in ob/ob mice at temperatures between 21 and 28 C. Although both Ucp1(-/-) and ob/ob mice can survive in extreme cold at 4 C, provided they are adapted to the cold by gradually lowering ambient temperature, ob/ob.Ucp1(-/-) mice could not adapt and survive at temperatures lower than 12 C unless they were administered leptin. As the ambient temperature was reduced from 20 to 16 C, ob/ob.Ucp1(-/-) mice treated with leptin have elevated levels of circulating T(3) that correlate with elevated sarcoendoplasmic reticulum Ca(2+) ATPase 2a mRNA levels in gastrocnemius muscle. Furthermore, ob/ob.Ucp1(-/-) mice, treated with T(3), were able to maintain body temperature and stimulate sarcoendoplasmic reticulum Ca(2+) ATPase 2a expression when the ambient temperature was gradually reduced to 4 C. Thus, in the absence of UCP1, leptin-induced thermogenesis protects body temperature in part through its action on the thyroid hormone axis. Topics: 3-Hydroxybutyric Acid; Adipose Tissue; Animals; Body Temperature; Body Weight; Calcium-Transporting ATPases; Calorimetry; Carrier Proteins; Cold Temperature; Female; Gene Expression Regulation; Glucose; Insulin; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondrial Proteins; Mutation; Oxygen Consumption; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Temperature; Thyroid Hormones; Time Factors; Triiodothyronine; Uncoupling Protein 1 | 2006 |
Oral administration of uridylic acid increases plasma leptin, but suppresses glucose and non-esterified fatty acid concentrations in rats.
Nucleic acids have been known to have biological effects on the digestive and immune systems, although less attention has been paid to the action on metabolism. In the present study, in order to investigate the effects of oral ingestion of uridylic acid (5'-uridine monophosphate, 5'-UMP) on hormonal and metabolic levels, we measured changes in the plasma concentrations of leptin, insulin, glucose, non-esterified fatty acids (NEFA), weights of the liver and abdominal fat and fat accumulation in the liver and M. gastrocnemius in male rats. Intragastric administration of 5'-UMP via a stomach tube at a dose of 44 mg/day for 7 days slightly (P=0.098) blunted the body weight gain without causing a significant change in food intake. The administration significantly reduced the plasma concentrations of glucose (P=0.004) and NEFA (P=0.004), whereas it significantly increased (P=0.03) plasma leptin concentration. The weights of perirenal (but not epididymal) fat (P=0.083) and the liver (P=0.061) were slightly increased. The triacylglyceride concentration in M. gastrocnemius was slightly increased (P=0.097), although the muscle weight was not significantly changed (P=0.197). In summary, acute oral administration of 5'-UMP was effective in the rat in reducing plasma concentrations of glucose and NEFA, an effect that was accompanied by an elevated plasma leptin concentration. Topics: Adipose Tissue; Administration, Oral; Animals; Blood Glucose; Body Weight; Colostrum; Fatty Acids, Nonesterified; Leptin; Liver; Male; Muscle, Skeletal; Organ Size; Rats; Rats, Wistar; Uridine Monophosphate | 2006 |
Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents.
To characterize a model of atypical antipsychotic drug-induced obesity and evaluate its mechanism.. Chronically, olanzapine or clozapine was self-administered via cookie dough to rodents (Sprague-Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance.. Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting approximately 24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted.. A model of olanzapine-induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug-induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine-induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge. Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Clozapine; Disease Models, Animal; Energy Intake; Female; Glucose Tolerance Test; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Olanzapine; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Dopamine; Sex Factors | 2006 |
The association of serum leptin with the reduction of food intake and body weight during electroacupuncture in rats.
Previous studies indicate that acupuncture or electroacupuncture (EA) treatment reduces body weight and food intake in rats by increasing the level of anoretic peptides and decreasing that of orexigenic peptides in the hypothalamus. Considering a well-established role of leptin as a major regulator for feeding behavior in the hypothalamus, we hypothesized that EA might exert its effect via increasing serum leptin levels. In this study, we tested our hypothesis by evaluating the effects of EA on food intake and body weight, as well as on serum leptin levels in rats. Rats were randomly divided into 3 groups: AL (fed ad libitum with no treatments), Holder (fed ad libitum with daily holder restraint) and EA (fed ad libitum with daily holder restraint and 100 Hz EA stimulation) groups. During the four-week experimental period, daily food intake and body weight were measured. At the end of the experiment, levels of serum leptin and corticosterone, and plasma epinephrine (Epi) and norepinephrine (NE) were determined. Here we demonstrate that EA treatment indeed led to reduction of food intake and body weight, and to an increase of serum leptin levels. The level of Epi, NE, and corticosterone increased in the Holder group, but such increase in the level of aforementioned stress hormones was not observed in the EA group. Overall, our results suggest that EA treatment reduces food intake and body weight in rats possibly through increasing leptin levels, and that this effect of EA is not due to the stress caused by the daily holder restraint. Topics: Animals; Body Weight; Catecholamines; Corticosterone; Eating; Electroacupuncture; Epinephrine; Leptin; Male; Norepinephrine; Rats; Rats, Sprague-Dawley | 2006 |
Relationships between serum leptin and bone markers during stable weight, weight reduction and weight regain in male and female judoists.
Despite a preliminary understanding of leptin-skeletal interactions, data in humans are inconsistent and the exact roles of leptin on bone metabolism have not yet been defined. The aim of this study was to examine the possible role of leptin in the regulation of bone metabolism in healthy, physically trained adults.. Body composition and bone mass (dual-energy X-ray absorptiometry), anthropometry, serum leptin, insulin, cortisol, osteocalcin, C-terminal telopeptide of type I collagen (CTx) and total plasma proteins were measured in judoists at normal body weight, after weight reduction and after weight regain. Physical training, weight cycling history, menstrual status and nutritional intake using a 7-day food record were assessed.. Precompetitive weight loss averaged 4 +/- 0.3% of bodyweight and resulted in a significant decrease in leptin levels of 64% (P < 0.001) and of 31% for insulin (P < 0.0001). CTx and cortisol concentrations rose by 33% (P < 0.0001) and 81% (P < 0.05) respectively. Osteocalcin and total plasma protein remained unaffected by weight loss. A 4 +/- 0.5% weight regain induced a 276% increase in leptin levels (P < 0.001) and an 18% increase in insulin (P < 0.001). CTx and cortisol decreased by 23% (P < 0.0001) and 27% (P < 0.05) respectively. Changes in leptin were significantly correlated with changes in bone resorption marker in response to both weight loss (r = 0.56, P < 0.01) and regain (r = 0.44, P < 0.05).. These findings suggest that leptin is involved in the regulation of bone metabolism in healthy adults and might play a potential role in the prevention of osteoporosis. Topics: Adult; Biomarkers; Body Weight; Bone and Bones; Cohort Studies; Diet; Female; Hormones; Humans; Leptin; Life Style; Male; Martial Arts; Menstrual Cycle; Motor Activity; Weight Loss | 2006 |
Melanin-concentrating hormone receptor 1 deficiency increases insulin sensitivity in obese leptin-deficient mice without affecting body weight.
The hypothalamic peptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis. Animals overexpressing MCH develop hyperphagia, obesity, and insulin resistance. In this study, mice lacking both the MCH receptor-1 (MCHr1 knockout) and leptin (ob/ob) double-null mice (MCHr1 knockout ob/ob) were generated to investigate whether the obesity and/or the insulin resistance linked to the obese phenotype of ob/ob mice was attenuated by ablation of the MCHr1 gene. In MCHr1 knockout ob/ob mice an oral glucose load resulted in a lower blood glucose response and markedly lower insulin levels compared with the ob/ob mice despite no differences in body weight, food intake, or energy expenditure. In addition, MCHr1 knockout ob/ob mice had higher locomotor activity and lean body mass, lower body fat mass, and altered body temperature regulation compared with ob/ob mice. In conclusion, MCHr1 is important for insulin sensitivity and/or secretion via a mechanism not dependent on decreased body weight. Topics: Animals; Body Composition; Body Temperature Regulation; Body Weight; Corticotropin-Releasing Hormone; Eating; Glucose; Insulin Resistance; Leptin; Mice; Mice, Obese; Motor Activity; Obesity; Receptors, Leptin; Receptors, Somatostatin; RNA, Messenger; Stearoyl-CoA Desaturase | 2006 |
Seven days' around the clock exhaustive physical exertion combined with energy depletion and sleep deprivation primes circulating leukocytes.
Both exhaustive physical exertion and starvation have been reported to induce depression of immune function. The aim of the present study was to investigate the inflammatory environment and state of activation and mediator-producing potential of circulating leukocytes during prolonged physical activity with concomitant energy and sleep deprivation. Eight well-trained males were studied during 7 days of semi-continuous physical activity. Sleep was restricted to about 1 h/24 h, energy intake to 1.5- 3.0 MJ/24 h. Blood was drawn at 07.00 A.M.: on days 0, 2, 4, and 7. Plasma levels of inflammation markers were measured. The response of circulating leukocytes to lipopolysaccharide (LPS; 1 microg mL(-1)), and the effect of added hydrocortisone (10 and 100 nmol L(-1)), were measured in the supernatant after 3 h of incubation in an ex vivo whole blood model. Activation of leukocytes steadily increased as measured by plasma matrix metalloproteinase-9, tumour necrosis factor-alpha, interleukin-1beta, and interleukin-6. Inhibitors of systemic inflammation were either unaltered (tissue inhibitor of matrix metalloproteinase-1) or elevated (plasma interleukin-1 receptor antagonist). Cortisol levels increased on days 2 and 4, but thereafter reverted to baseline values. The leukocytes responded to LPS activation with increasing release of inflammatory cytokines throughout the study period. The anti-inflammatory potency of hydrocortisone decreased. Prolonged multifactorial stress thus activated circulating immune cells and primed them for an increased response to a subsequent microbial challenge. Topics: Adult; Body Weight; C-Reactive Protein; Food Deprivation; Humans; Hydrocortisone; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-10; Interleukin-6; Leptin; Leukocyte Count; Leukocytes; Lipopolysaccharides; Male; Matrix Metalloproteinase 9; Physical Exertion; Sialoglycoproteins; Sleep Deprivation; Stress, Physiological; Time Factors; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factor-alpha | 2006 |
Model for predicting and phenotyping at normal weight the long-term propensity for obesity in Sprague-Dawley rats.
Tests were conducted to determine whether weight gain or nutrient intake measures during the first week of exposure to a macronutrient diet can accurately predict an animal's long-term propensity towards obesity. In multiple groups of normal-weight Sprague-Dawley rats (n=35-70/group), daily weight gain during the first 5 days on a high-fat diet (45-60% fat) was found to be strongly, positively correlated (r=+0.71 to r=+0.82) with accumulated body fat in 4 dissected depots after 4-6 weeks on the diet. This measure consistently identified obesity-prone (OP) rats which, relative to the obesity-resistant (OR) rats, were only slightly heavier (+15 g, 4%) and hyperphagic (+9 kcal, 8%) after 5 days but markedly heavier (+70g) with up to 2-fold greater fat mass after several weeks on the diet. Other dietary conditions and measures revealed weaker relationships to ultimate body fat accrual. The OP rats identified by their 5-day weight-gain score exhibited at this early stage clear disturbances characteristic of markedly obese rats. These included elevated leptin, insulin, triglycerides and glucose, along with increased lipoprotein lipase activity (LPL) in adipose tissue and galanin expression in the paraventricular nucleus. Most notable were significant reductions in muscle of LPL activity and ratio of beta-hydroxyacyl-CoA dehydrogenase to citrate synthase activity, indicating a decline in lipid transport and capacity of muscle to metabolize lipids. By occurring early with initial weight gain, these hypothalamic and metabolic disturbances in OP rats, favoring fat storage in adipose tissue over fat oxidation in muscle, may have causal relationships to long-term accumulation of body fat. Topics: 3-Hydroxyacyl CoA Dehydrogenases; Adiposity; Animal Feed; Animals; Body Weight; Citrate (si)-Synthase; Dietary Carbohydrates; Dietary Fats; Energy Intake; Galanin; Insulin; Leptin; Male; Models, Animal; Models, Biological; Muscle, Skeletal; Obesity; Phenotype; Predictive Value of Tests; Rats; Rats, Sprague-Dawley; Triglycerides; Weight Gain | 2006 |
Energy metabolism, thermogenesis and body mass regulation in Brandt's voles (Lasiopodomys brandtii) during cold acclimation and rewarming.
Environmental cues play important roles in the regulation of an animal's physiology and behavior. The purpose of the present study was to test the hypothesis that ambient temperature was a cue to induce adjustments in body mass, energy intake and thermogenic capacity, associated with changes in serum leptin levels in Brandt's voles (Lasiopodomys brandtii). We found that Brandt's voles increased resting metabolic rate (RMR) and energy intake and kept body mass stable when exposed to the cold while showed a significant increase in body mass after rewarming. The increase in body mass after rewarming was associated with the higher energy intake compared with control. Uncoupling protein 1 (UCP1) content in brown adipose tissue (BAT) increased in the cold and reversed after rewarming. Serum leptin levels decreased in the cold while increased after rewarming, associated with the opposite changes in energy intake. Further, serum leptin levels were positively correlated with body mass and body fat mass. Together, these data supported our hypothesis that ambient temperature was a cue to induce changes in body mass and metabolism. Serum leptin, as a starvation signal in the cold and satiety signal in rewarming, was involved in the processes of thermogenesis and body mass regulation in Brandt's voles. Topics: Acclimatization; Analysis of Variance; Animals; Arvicolinae; Body Weight; Energy Metabolism; Leptin; Male; Seasons; Temperature; Thermogenesis | 2006 |
Improvement in cardiac systolic function and reduced prevalence of metabolic syndrome after two years of growth hormone (GH) treatment in GH-deficient adult survivors of childhood-onset acute lymphoblastic leukemia.
Survivors of childhood-onset (CO) acute lymphoblastic leukemia (ALL) treated with prophylactic cranial radiotherapy often exhibit GH deficiency (GHD), which is associated with increased prevalence of cardiovascular risk factors and cardiac dysfunction.. The objective of the study was to evaluate the effect of GH replacement on cardiovascular risk factors and cardiac function in former CO ALL patients.. Eighteen former CO ALL patients (aged 19-32 yr) treated with cranial radiotherapy (18-24 Gy) and chemotherapy and with confirmed GHD were studied at baseline and after 12 (n = 18) and 24 months (n = 13) of GH treatment (median 0.5 mg/d). A group of 18 age- and sex-matched subjects served as controls.. After 12 months of GH treatment, a significant decrease in serum leptin (P = 0.002), leptin per kilogram fat mass (FM) (P = 0.01), plasma glucose (P = 0.004), FM (P = 0.002), and hip (P = 0.04) and waist (P = 0.02) circumference and increased muscle mass (P = 0.004) were recorded in the patients. Before GH treatment six patients had a metabolic syndrome, but after 12 months only one had it and after 24 months none. After 24 months of GH treatment, an increase in left ventricular mass index (P = 0.06) and significant improvements in cardiac systolic function, measured as fractional shortening (P = 0.03) and ejection fraction (P = 0.03), were recorded.. Improvement in cardiac systolic function and reduced prevalence of metabolic syndrome were recorded after 2 yr of GH replacement in former CO ALL patients with GHD. Long-term follow-up is highly warranted. Topics: Absorptiometry, Photon; Adult; Body Composition; Body Mass Index; Body Weight; Child; Echocardiography, Doppler; Exercise; Female; Growth Hormone; Heart; Heart Function Tests; Heart Rate; Human Growth Hormone; Humans; Leptin; Lipoproteins; Male; Metabolic Syndrome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Survivors; Waist-Hip Ratio | 2006 |
Acute and chronic leptin reduces food intake and body weight in goldfish (Carassius auratus).
The purpose of the present study was to elucidate the possible role of leptin in food intake and body weight regulation in goldfish. We examined the effects of i.c.v. or i.p. acute leptin administration on food intake in food-deprived goldfish at different time intervals post-injection (0-2, 2-8 and 0-8 h). Food intake was reduced by i.p. administered leptin (1 microg) at 8 h post-injection, without statistically significant differences after i.c.v. treatment. The present study shows for the first time in a teleost that chronic (10 days) leptin treatment (i.p.) reduces food intake, body weight gain, specific growth rate and food efficiency ratio. Moreover, lipid and carbohydrate metabolism seems to be regulated by leptin in fish. Chronic leptin treatment increased lipid mobilization and carbohydrate storage as hepatic and muscle glycogen. Finally, leptin could mediate its actions on energy homeostasis in fish, at least in part, through interactions with hypothalamic catecholamines, since chronic leptin treatment reduced both hypothalamic noradrenergic and dopaminergic turnover without significant modifications in hypothalamic serotoninergic and neuropeptide Y (NPY) systems. In summary, our results suggest that leptin can regulate feeding behaviour and body weight homeostasis in fish. Topics: Animals; Body Weight; Carbohydrate Metabolism; Catecholamines; Eating; Energy Metabolism; Glycogen; Goldfish; Hypothalamus; Injections, Intraperitoneal; Injections, Intravenous; Leptin; Lipid Metabolism; Liver; Muscles; Neuropeptide Y; Serotonin; Starvation; Time Factors | 2006 |
Cigarette smoke exposure reprograms the hypothalamic neuropeptide Y axis to promote weight loss.
Despite irrefutable epidemiologic evidence, cigarette smoking remains the major preventable cause of lung disease morbidity worldwide. The appetite-suppressing effect of tobacco is a major behavioral determinant of smoking, but the underlying molecular and neuronal mechanisms are not understood. Neuropeptide Y (NPY) is an orexigenic neuropeptide, whose activity in the hypothalamic paraventricular nucleus governs appetite.. To compare the effects of smoke exposure and equivalent food restriction on body weight, organ mass, cytokines, and brain NPY in Balb/c mice.. A pair-feeding study design compared smoke exposure (4 wk; 1 cigarette, 3 x /d, 5 d/wk) to equivalent food restriction (pair-fed) and sham-exposed control mice.. Smoke exposure rapidly induced mild anorexia. After 4 wk, smoke-exposed and pair-fed groups were lighter than control mice (22.0 +/- 0.2, 23.2 +/- 0.5, 24.9 +/- 0.4 g, respectively; p < 0.05). Brown and white fat masses were only reduced by smoke exposure, relative to control mice. NPY concentration in the paraventricular nucleus was significantly and paradoxically reduced by smoke exposure, despite lower plasma leptin concentrations; this was not observed in the pair-fed group experiencing 19% food restriction. Adipose mRNA expression of uncoupling proteins, inflammatory cytokines interleukin 6 and tumor necrosis factor alpha, and adipose triglyceride lipase was decreased by smoke exposure, and even lower in pair-fed mice.. In contrast to food restriction, smoke exposure caused a reduction in hypothalamic NPY and fat mass, and regulated adipose cytokines. These findings may contribute to understanding weight loss in smoking-related lung disease and in the design of more effective smoking cessation strategies. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Anorexia; Appetite Regulation; Body Weight; Carrier Proteins; Hypothalamus; Interleukin-6; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mitochondrial Proteins; Neuropeptide Y; RNA, Messenger; Smoking; Tumor Necrosis Factor-alpha; Uncoupling Protein 1; Uncoupling Protein 3; Weight Loss | 2006 |
Effects of a selective melanin-concentrating hormone 1 receptor antagonist on food intake and energy homeostasis in diet-induced obese mice.
Melanin concentrating hormone (MCH) is a cyclic neuropeptide expressed in the lateral hypothalamus that plays an important role in energy homeostasis. To investigate the pharmacological consequences of inhibiting MCH signaling in murine obesity models, we examined the effect of acute and chronic administration of a selective MCH1 receptor antagonist (SCH-A) in diet-induced obese (DIO) and Lep(ob/ob) mice. Oral administration of SCH-A for 5 consecutive days (30 mg/kg q.d.) produced hypophagia, a loss of body weight and adiposity, and decreased plasma leptin levels in DIO mice, and hypophagia and reduced weight gain in Lep(ob/ob) mice. Chronic administration of SCH-A to DIO mice decreased food intake, body weight and adiposity, and plasma leptin and free fatty acids. These effects were accompanied by increases in several hypothalamic neuropeptides. Acute administration of SCH-A (30 mg/kg) prevented the decrease in energy expenditure associated with food restriction. These results indicate that MCH1 receptor antagonists may be effective in the treatment of obesity. Topics: Adipose Tissue; Administration, Oral; Animals; Binding, Competitive; Body Weight; Brain; CHO Cells; Cricetinae; Cricetulus; Dietary Fats; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Fatty Acids, Nonesterified; Female; Galanin; Gene Expression; Homeostasis; Hypothalamic Hormones; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins; Iodine Radioisotopes; Leptin; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Neuropeptides; Nitriles; Obesity; Oligopeptides; Orexin Receptors; Orexins; Piperazines; Pituitary Hormones; Protein Binding; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; Triglycerides; Urea | 2006 |
GABAA receptor antagonists prevent abnormalities in leptin, insulin and amylin actions on paraventricular hypothalamic neurons of overweight rats.
The hypothalamic regulatory system of body weight which develops in rats during critical periods of early postnatal life seems to express plastic changes depending on nutrition at that time. Adult rats previously exposed to early postnatal overnutrition by raising them in small litters become persistently predisposed to overweight, hyperphagia and hyperleptinaemia. The hypothesis was raised that feeding-related peptides could be involved through altered effects on neuronal activity of the regulatory systems of such rats. This was studied on brain slices of small-litter rats and normal-weight controls between days 60 and 120 of life. Neurons of the medial parvocellular part of the paraventricular nucleus were significantly activated by the adiposity signals leptin, insulin and amylin in controls. This is a kind of negative feedback, because activation of these neurons is known to be followed in vivo by increased energy expenditure. GABAergic mechanisms seem to affect these neuronal responses because the activating effects of insulin and amylin were reduced in the presence of a GABA(A) receptor antagonist. In overweight small-litter rats, however, the neuronal responses to the adiposity signals were significantly changed; activating effects were reduced and inhibitory effects increased. By means of blockade of GABA(A) receptors, significant alterations in the neuronal responses to leptin, insulin and amylin in small-litter rats were prevented. Responses to the peptides were reversed and now resembled those of controls. In conclusion, changes in neuronal wiring with GABAergic interneurons seem to contribute to a persistently reduced negative feedback of adiposity signals in early postnatally overfed rats. Topics: Action Potentials; Amyloid; Animals; Body Weight; Female; GABA Antagonists; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Neurons; Overweight; Paraventricular Hypothalamic Nucleus; Pregnancy; Pyridazines; Random Allocation; Rats; Rats, Wistar; Receptors, GABA-A | 2006 |
Sterol regulatory element binding protein (SREBP)-1 expression in brain is affected by age but not by hormones or metabolic changes.
Sterol regulatory element binding protein (SREBP)-1 is a membrane-bound transcription factor that regulates the expression of several genes involved in cellular fatty acid synthesis in the peripheral tissues, including liver. Although SREBP-1 is expressed in brain, little is known about its function. The aim of the present study was to clarify the characteristics of SREBP-1 mRNA expression in rat brain under various nutritional and hormonal conditions. In genetically obese (fa/fa) Zucker rats, expression of SREBP-1 mRNA was greater in liver than in hypothalamus or cerebrum compared to the lean littermates of these rats. Fasting for 45 h and refeeding for 3 h did not affect expression in brains of Wistar rats of SREBP-1 mRNA or the mRNAs of lipogenic enzymes that are targets of SREBP-1, i.e., fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC). Infusion of 2.0 mIU insulin or 3.0 microg leptin into the third cerebroventricle did not affect SREBP-1 mRNA expression in either hypothalamus or cerebrum. SREBP-1 mRNA expression in brains of transgenic mice that overexpressed leptin did not differ from that of wild-type mice. However, we observed a unique age-related alteration in SREBP-1 mRNA expression in brains of Sprague-Dawley rats. Specifically, SREBP-1 mRNA expression increased between 1 and 20 months of age, while there was no such change in the expression of FAS or ACC. This raises the possibility that increased SREBP-1 expression secondary to aging-related decline of polyunsaturated fatty acid (PUFA) might compensate for the reduction of FAS expression in brain. These findings suggest that the expression of SREBP-1 and downstream lipogenic enzymes in brain is probably not regulated by peripheral nutritional conditions or humoral factors. Aging-related changes in SREBP-1 mRNA expression may be involved in developmental changes in brain lipid metabolism. Topics: Acetyl-CoA Carboxylase; Age Factors; Aging; Animals; Blotting, Northern; Body Weight; Brain; Fasting; Fatty Acids; Gene Expression; Gene Expression Regulation; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Rats; Rats, Sprague-Dawley; Rats, Wistar; Rats, Zucker; RNA, Messenger; Sterol Regulatory Element Binding Protein 1 | 2006 |
Gonadal hormones determine sensitivity to central leptin and insulin.
Males have proportionally more visceral fat and are more likely to develop complications associated with obesity than females, and the male brain is relatively more sensitive to the catabolic action of insulin and less sensitive to that of leptin than the female brain. To understand the underlying mechanism, we manipulated estrogen through ovariectomy (OVX) and estradiol administration. Rats with relatively high systemic estrogen (intact females and OVX females and males administered estrogen subcutaneously) were significantly more sensitive to leptin's anorexic action in the brain (i3vt), as well as significantly less sensitive to insulin's i3vt action, than intact males. Administering estradiol directly into the brain of our females increased i3vt leptin sensitivity while decreasing i3vt insulin sensitivity and changed the body fat distribution of our females to resemble that of intact females. These data indicate that estrogen acts within the brain to increase leptin sensitivity, decrease insulin sensitivity, and favor subcutaneous over visceral fat. Topics: Animals; Body Weight; Energy Intake; Estradiol; Female; Insulin; Leptin; Male; Orchiectomy; Ovariectomy; Rats; Rats, Long-Evans; Sex Characteristics | 2006 |
Induction of leptin resistance through direct interaction of C-reactive protein with leptin.
The mechanisms underlying leptin resistance are still being defined. We report here the presence in human blood of several serum leptin-interacting proteins (SLIPs), isolated by leptin-affinity chromatography and identified by mass spectrometry and immunochemical analysis. We confirmed that one of the major SLIPs is C-reactive protein (CRP). In vitro, human CRP directly inhibits the binding of leptin to its receptors and blocks its ability to signal in cultured cells. In vivo, infusion of human CRP into ob/ob mice blocked the effects of leptin upon satiety and weight reduction. In mice that express a transgene encoding human CRP, the actions of human leptin were completely blunted. We also found that physiological concentrations of leptin can stimulate expression of CRP in human primary hepatocytes. Recently, human CRP has been correlated with increased adiposity and plasma leptin. Thus, our results suggest a potential mechanism contributing to leptin resistance, by which circulating CRP binds to leptin and attenuates its physiological functions. Topics: Animals; Blotting, Western; Body Weight; C-Reactive Protein; Carrier Proteins; Cells, Cultured; Dose-Response Relationship, Drug; Drug Interactions; Female; Hepatocytes; Humans; Inhibitory Concentration 50; Interleukin-6; Leptin; Mice; Mice, Obese; Mice, Transgenic; Precipitin Tests; Rats; RNA-Binding Proteins; Transgenes | 2006 |
Effects of central leptin infusion on the reward-potentiating effect of D-amphetamine.
It was previously reported that chronic food restriction and maintenance of rats at 75-80% of initial body weight enhanced the reward-potentiating effect of D-amphetamine in the lateral hypothalamic self-stimulation (LHSS) paradigm. Moreover, the enhancement reversed in parallel with body weight recovery when ad libitum access to food was reinstated. The present study tested the hypothesis that hypoleptinemia during food restriction is necessary for expression of enhanced drug reward. In Experiment 1, intracerebroventricular (i.c.v.) infusion of leptin (0.5 microg/0.5 microl/hr for 8 days) in food-restricted rats did not alter the rewarding effect of D-amphetamine (0.5 mg/kg, i.p.). Considering that i.c.v. leptin may not diffuse into deep brain regions where direct effects on drug reward sensitivity may be exerted, effects of acute bilateral microinjection of leptin (0.5 microg) in ventral tegmental area and nucleus accumbens were tested in Experiment 2 and found to have no effect. In Experiment 3, chronic i.c.v. leptin infusion in ad libitum fed rats decreased food intake and body weight and enhanced the rewarding effect of D-amphetamine. Sensitivity to D-amphetamine returned to normal as body weight recovered following cessation of leptin infusion. This result suggests that weight loss, whether from hormone-induced appetite suppression or experimenter-imposed food restriction, is sufficient to enhance drug reward sensitivity. Experiment 4 tested whether food restriction in the absence of body weight loss alters drug reward sensitivity. Rats received chronic i.c.v. infusion of the orexigenic melanocortin receptor antagonist, SHU9119 (0.02 microg/0.5 microl/hr for 12 days), and a subset were pair-fed to vehicle-infused controls. Although these subjects ingested approximately 50% of the amount of food ingested by free-feeding SHU9119-infused rats, they displayed no weight loss and no change in sensitivity to D-amphetamine. Together, results of this study support the importance of weight loss, but not leptin, in the enhancement of drug reward sensitivity. Topics: Animals; Behavior, Animal; Body Weight; Central Nervous System Stimulants; Dextroamphetamine; Drug Administration Routes; Drug Administration Schedule; Drug Interactions; Eating; Food Deprivation; Leptin; Male; Melanocyte-Stimulating Hormones; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Reward; Self Stimulation; Time Factors | 2006 |
Hypothalamic huntingtin-associated protein 1 as a mediator of feeding behavior.
The hypothalamus responds to circulating leptin and insulin in the control of food intake and body weight. A number of neurotransmitters in the hypothalamus, including gamma-aminobutyric acid (GABA), also have key roles in feeding. Huntingtin-associated protein 1 (Hap1) is expressed more abundantly in the hypothalamus than in other brain regions, and lack of Hap1 in mice leads to early postnatal death. Hap1 is also involved in intracellular trafficking of the GABA(A) receptor. Here, we report that fasting upregulates the expression of Hap1 in the rodent hypothalamus, whereas intracerebroventricular administration of insulin downregulates Hap1 by increasing its degradation through ubiquitination. Decreasing the expression of mouse hypothalamic Hap1 by siRNA reduces the level and activity of hypothalamic GABA(A) receptors and causes a decrease in food intake and body weight. These findings provide evidence linking hypothalamic Hap1 to GABA in the stimulation of feeding and suggest that this mechanism is involved in the feeding-inhibitory actions of insulin in the brain. Topics: Animals; Body Weight; Eating; Electrophysiology; Fasting; Feeding Behavior; Humans; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; RNA, Small Interfering; Ubiquitin | 2006 |
[Effect of soy isoflavone on gene expression of leptin and insulin sensibility in insulin-resistant rats].
To explore the effects of soy isoflavone (SIF) on gene expression of leptin and insulin sensibility in insulin-resistant (IR) rats induced by high-fat, and to reveal the mechanisms of SIF in ameliorating insulin sensibility.. IR rats were randomly divided into four groups based on their insulin-resistant indexes (IRI): one model control group and three SIF groups that were gavaged with water solutions with SIF at doses of 0 mg/kg, 50 mg/kg, 150 mg/kg, and 450 mg/kg, respectively. After one month, fasting glucose, fasting insulin, leptin in serum, and leptin mRNA in the perirenal adipocyte were detected by enzymic method, radioimmunoassay, enzyme linked immunosorbent assay, and real time quantitative RT-PCR, respectively.. The model control group was used to compare against the other groups: (1) Insulin and IRI were lower in the 150 mg/kg and 450 mg/kg groups; (2) In the 450 mg/kg group, body weight and leptin mRNA expression were lower, serum leptin content was higher.. These results indicate that soy isoflavone might decrease body weight of rats and leptin mRNA, increase serum leptin level, and ameliorate leptin and insulin sensitivities. Topics: Animals; Blood Glucose; Body Weight; Gene Expression; Glycine max; Insulin; Insulin Resistance; Isoflavones; Leptin; Male; Rats; Rats, Sprague-Dawley | 2006 |
Leptin transgene expression in the hypothalamus enforces euglycemia in diabetic, insulin-deficient nonobese Akita mice and leptin-deficient obese ob/ob mice.
We have tested the hypothesis that sustained leptin action in the hypothalamus alone can engender and maintain euglycemia in wild type mice and in two monogenic diabetic models, the insulin-deficient nonobese Akita mice and the hyperinsulinemic leptin-deficient obese, ob/ob mice. A single intracerebroventricular injection of recombinant adeno-associated virus vector encoding leptin (rAAV-lep) enhanced leptin transgene expression in the hypothalamus without any evidence of leptin leakage to the peripheral circulation, and promptly reinstated euglycemia that persisted along with severe insulinopenia in all three genotypes through the 7-week period of observation. A comparative evaluation of known etiologic factors of hyperglycemia showed that this long-term benefit on glucose homeostasis was not due to diminished energy consumption, weight and adiposity, but was conferred by at least two mechanisms operating simultaneously, enhanced glucose metabolism to meet the demand for the rAAV-lep induced increased non-shivering thermogenesis mediated by brown adipose tissue and insulin hypersensitivity. These findings endorse the hypothesis that increased leptin action locally in the hypothalamus can impose euglycemia independent of pancreatic insulin, and central leptin reinforcement may serve as a newer adjunct therapy to treat type 1 and type 2 diabetes. Topics: Adenoviridae; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Eating; Genetic Vectors; Glucose Clamp Technique; Glucose Tolerance Test; Hypothalamus; Insulin; Ion Channels; Leptin; Male; Mice; Mice, Obese; Mice, Transgenic; Mitochondrial Proteins; Time Factors; Transgenes; Uncoupling Protein 1 | 2006 |
Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation.
The eight catalytic subunits of the mammalian phosphoinositide-3-OH kinase (PI(3)K) family form the backbone of an evolutionarily conserved signalling pathway; however, the roles of most PI(3)K isoforms in organismal physiology and disease are unknown. To delineate the role of p110alpha, a ubiquitously expressed PI(3)K involved in tyrosine kinase and Ras signalling, here we generated mice carrying a knockin mutation (D933A) that abrogates p110alpha kinase activity. Homozygosity for this kinase-dead p110alpha led to embryonic lethality. Mice heterozygous for this mutation were viable and fertile, but displayed severely blunted signalling via insulin-receptor substrate (IRS) proteins, key mediators of insulin, insulin-like growth factor-1 and leptin action. Defective responsiveness to these hormones led to reduced somatic growth, hyperinsulinaemia, glucose intolerance, hyperphagia and increased adiposity in mice heterozygous for the D933A mutation. This signalling function of p110alpha derives from its highly selective recruitment and activation to IRS signalling complexes compared to p110beta, the other broadly expressed PI(3)K isoform, which did not contribute to IRS-associated PI(3)K activity. p110alpha was the principal IRS-associated PI(3)K in cancer cell lines. These findings demonstrate a critical role for p110alpha in growth factor and metabolic signalling and also suggest an explanation for selective mutation or overexpression of p110alpha in a variety of cancers. Topics: Adiposity; Animals; Body Weight; Catalytic Domain; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Eating; Embryo Loss; Enzyme Activation; Glucose; Growth; Heterozygote; Homozygote; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Leptin; Mice; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoproteins; Receptor, Insulin; Signal Transduction | 2006 |
Phenotypic variations between a fat-preferring strain and a macronutrient non-preferring strain of mouse.
This study aims to establish a model that will allow the comparison of the phenotypic variations between a fat-preferring strain and a macronutrient non-preferring strain of mouse.. Five strains (AKR, A/J, ARC, C57Bl/6 and BALB/c) were fed a two-choice diet (high-fat/low-carbohydrate and low-fat/high-carbohydrate) for 30 days. Following completion of the 30-day feeding period, the brains of the fat-preferring and macronutrient non-preferring mice were removed for the analysis of the expression of the genes - agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC).. Upon completion of the experiment, it was found that the C57Bl/6 strain was the strongest fat preferrer consuming 72% of their calories from the high-fat diet, whereas the BALB/c was found to have no macronutrient preference. Using in situ hybridization techniques, no significant differences in the expression of POMC were found between the two strains. It was, however, showed that the BALB/c mice had a 33.7% higher expression level of AgRP than the C57Bl/6 mice.. The lower expression level of AgRP in the C57Bl/6 mice may be suggestive of a defensive response to their chronic preferential consumption of the high-fat diet. However, the wide variety of neuroregulatory signals involved in macronutrient preference along with the possibility of the occurrence of post-transcriptional effects suggests further biological analyses need to be performed using this model. Topics: Agouti-Related Protein; Animals; Body Weight; Dietary Carbohydrates; Dietary Fats; Energy Intake; Food Preferences; Gene Expression; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred Strains; Phenotype; Pro-Opiomelanocortin; RNA, Messenger; Species Specificity; Weight Gain | 2006 |
The mahoganoid mutation (Mgrn1md) improves insulin sensitivity in mice with mutations in the melanocortin signaling pathway independently of effects on adiposity.
Mahoganoid (Mgrn1(md)) is a mutation of the mahogunin (Mgrn1) gene. The hypomorphic allele suppresses the yellow pigmentation and obesity of the A(y) mouse that ubiquitously overexpresses agouti signaling protein (ASP). To assess the physiological effects of MGRN1 on energy and glucose homeostasis, we generated animals doubly mutant for Mgrn1(md) and A(y), Lep(ob), or a null allele of Mc4r, and diet-induced obesity (DIO) mice segregating for Mgrn1(md). Mgrn1(md) suppressed the obesity, hyperglycemia, and hyperinsulinemia of A(y) mice. Mgrn1(md) suppressed A(y)-induced obesity by reducing food intake, and reduced adiposity in Lep(ob)/Lep(ob) females, but did not alter the body weight or body composition of mice fed a high-fat diet. There was no effect of Mgrn1(md) on weight gain, body composition, energy intake, or energy expenditure in Mc4r-null animals. Mgrn1(md) reduced circulating insulin concentrations in DIO, A(y), and Mc4r-null but not Lep(ob)/Lep(ob) mice. The effect of Mgrn1(md) on circulating insulin concentrations was not due primarily to reductions in fat mass, since the plasma insulin concentrations of Mgrn1(md) mice segregating for either A(y) or Mc4r-null alleles, adjusted for fat mass and plasma glucose, were reduced compared with A(y) and Mc4r mice, respectively. The effect of Mgrn1(md) on insulin sensitivity of Mc4r-null mice suggests that Mgrn1(md) may be increasing insulin sensitivity via the hypothalamic melanocortin-3 receptor pathway. Topics: Adiposity; Agouti Signaling Protein; Animals; Blood Glucose; Body Weight; Eating; Female; Genotype; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Mice, Mutant Strains; Mice, Obese; Mutation; Obesity; Receptor, Melanocortin, Type 4; Signal Transduction; Ubiquitin-Protein Ligases | 2006 |
Obesity and osteoporosis.
Topics: Adiponectin; Adipose Tissue; Animals; Body Composition; Body Weight; Bone Density; Female; Fractures, Bone; Humans; Insulin; Leptin; Male; Menopause; Nutritional Physiological Phenomena; Obesity; Osteoporosis; Resistin | 2006 |
Expression of purinergic receptors in the hypothalamus of the rat is modified by reduced food availability.
ATP-sensitive P2 receptors are suggested to play an important role in the cerebral signal transduction. We examined the expression of the P2Y1 receptor and the possibly downstream-related neuronal nitric oxide synthase (nNOS) in the hypothalamus of rats food-restricted for 3 or 10 days and rats refed after a restriction of 10 days. The restriction caused a reduction of the body weight and plasma triacylglyceride, an increase of non-esterified fatty acid levels correlating with a decrease of leptin levels and an enhancement of plasma corticosterone. All changes returned to basal levels after refeeding. The restriction induced an enhanced intake within 30 min after food presentation and a reduction in the latency. Interestingly, the latter was not abolished by refeeding. The daily food intake induced by refeeding was enhanced at the first day only. The expression of hypothalamic P2Y1 receptor/nNOS mRNA and protein and of leptin receptor mRNA were enhanced after restricted feeding. These changes were abolished after 3 days of refeeding. Immunofluorescence studies indicated that P2Y1 receptor and nNOS immunoreactivities are present in the dorsomedial, ventromedial and lateral hypothalamus and in the nucleus arcuatus. P2Y1 receptor-positive cells were partially also nNOS-positive. The P2Y1 receptor labeling was restricted to cell bodies of obviously non-glial cells, whereas nNOS labeling could be detected also at cellular processes of these cells. In the nucleus arcuatus, astrocytes were identified, expressing P2Y1 receptors at cell bodies and cellular processes. The data suggest that restricted feeding may enhance the sensitivity of the hypothalamus to extracellular ADP/ATP by regulation of the expression of P2Y1 receptors and possibly of their signal transduction pathway via nitric oxide production. Topics: Adenosine Triphosphate; Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Astrocytes; Body Weight; Caloric Restriction; Corticosterone; Energy Intake; Fatty Acids; Hypothalamus; Immunohistochemistry; Leptin; Neurons; Nitric Oxide; Nitric Oxide Synthase Type I; Rats; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; RNA, Messenger; Signal Transduction; Triglycerides | 2006 |
Mature-onset obesity in interleukin-1 receptor I knockout mice.
Interleukin-1 (IL-1) is a major mediator of inflammation that exerts its biological activities through the IL-1 type I receptor (IL-1RI). The body weights of IL-1RI(-/-) mice of both sexes started to deviate from those of wild-type mice at 5-6 months of age and were 20% higher at 9 months of age. Visceral and subcutaneous fat mass, measured by dual-energy X-ray absorptiometry and magnetic resonance imaging, was markedly (1.5- to 2.5-fold) increased. Lean body mass and crown-rump length were also slightly (11 and 5%, respectively) increased, as was serum IGF-I. Obese IL-1RI(-/-) mice were insulin resistant, as evidenced by hyperinsulinemia, decreased glucose tolerance, and insulin sensitivity. To elucidate the mechanisms for the development of obesity, young pre-obese IL-1RI(-/-) mice were investigated. They showed decreased suppression of body weight and food intake in response to systemic leptin treatment. The decreased leptin responsiveness was even more pronounced in older obese animals. Moreover, spontaneous locomotor activity and fat utilization, as measured by respiratory quotient, were decreased in pre-obese IL-1RI(-/-) mice. In conclusion, lack of IL-1RI-mediated biological activity causes mature-onset obesity. This obese phenotype is preceded by decreased leptin sensitivity, fat utilization, and locomotor activity. Topics: Absorptiometry, Photon; Adipose Tissue; Aging; Animals; Body Weight; Leptin; Mice; Mice, Knockout; Obesity; Organ Size; Receptors, Interleukin-1 | 2006 |
Genistein and daidzein modulate hepatic glucose and lipid regulating enzyme activities in C57BL/KsJ-db/db mice.
This study examines whether anti-diabetic effects of genistein and daidzein are mediated by hepatic glucose and lipid regulating enzyme activities in type 2 diabetic animals. Male C57BL/KsJ-lepr(db)/lepr(db) (db/db) mice and age-matched non-diabetic littermates (db/+) were used in this study. The db/db mice were divided into control, genistein (0.02%, w/w) and daidzein (0.02%, w/w) groups. The blood glucose and HbA(1c) levels were significantly lower in the genistein and daidzein groups than in the control group, while glucose tolerance only was significantly improved in the genistein-supplemented group. The plasma insulin and C-peptide levels did not differ significantly between groups, yet the glucagon level was lower in the genistein and daidzein groups compared to that in the control db/db or db/+ group. The genistein and daidzein supplements increased the insulin/glucagon ratio in the type 2 diabetic animals. While the hepatic glucokinase activity was significantly lower in the db/db control group, the glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities were significantly higher in the control group compared to the db/+ group. Interestingly, these hepatic glucose metabolizing enzyme activities were reversed by the genistein and daidzein supplementation in db/db mice compared to the control group. The hepatic fatty acid synthase, beta-oxidation and carnitine palmitoyltransferase activities were all significantly lower in the genistein and daidzein groups than in the control group. The genistein and daidzein supplements also improved the plasma total cholesterol, triglyceride, HDL-cholesterol/total cholesterol, free fatty acid and hepatic triglyceride concentrations in the db/db mice. These results suggest that genistein and daidzein exert anti-diabetic effect in type 2 diabetic conditions by enhancing the glucose and lipid metabolism. Topics: Animals; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Diet; Eating; Genistein; Glucagon; Glucose; Glucose Tolerance Test; Glycated Hemoglobin; Insulin; Isoflavones; Leptin; Lipid Metabolism; Liver; Liver Glycogen; Mice; Mice, Inbred C57BL; Phytoestrogens; Receptors, Cell Surface; Receptors, Leptin | 2006 |
Behavioral, physiological, and molecular differences in response to dietary restriction in three inbred mouse strains.
Food restriction paradigms are widely used in animal studies to investigate systems involved in energy regulation. We have observed behavioral, physiological, and molecular differences in response to food restriction in three inbred mouse strains, C57BL/6J, A/J, and DBA/2J. These are the progenitors of chromosome substitution and recombinant inbred mouse strains used for mapping complex traits. DBA/2J and A/J mice increased their locomotor activity during food restriction, and both displayed a decrease in body temperature, but the decrease was significantly larger in DBA/2J compared with A/J mice. C57BL/6J mice did not increase their locomotor activity and displayed a large decrease in their body temperature. The large decline in body temperature during food restriction in DBA/2J and C57BL/6J strains was associated with a robust reduction in plasma leptin levels. DBA/2J mice showed a marked decrease in white and brown adipose tissue masses and an upregulation of the antithermogenic hypothalamic neuropeptide Y Y(1) receptor. In contrast, A/J mice showed a reduction in body temperature to a lesser extent that may be explained by downregulation of the thermogenic melanocortin 3 receptor and by behavioral thermoregulation as a consequence of their increased locomotor activity. These data indicate that genetic background is an important parameter in controlling an animal's adaptation strategy in response to food restriction. Therefore, mouse genetic mapping populations based on these progenitor lines are highly valuable for investigating mechanisms underlying strain-dependent differences in behavioral physiology that are seen during reduced food availability. Topics: Adipose Tissue; Animals; Behavior, Animal; Body Temperature; Body Weight; Eating; Food Deprivation; Gene Expression; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Motor Activity; Receptor, Melanocortin, Type 3; Receptors, Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction | 2006 |
Neonatal capsaicin causes compensatory adjustments to energy homeostasis in rats.
Several mechanisms involved in ingestive behavior and neuroendocrine activity rely on vagal afferent neuronal signaling. Seemingly contradictory to this idea are observations that vagal afferent neuronal ablation by neonatal capsaicin (CAP) treatment has relatively small effects on glucose homeostasis and long-term regulation of energy balance. It may be proposed that humoral endocrine factors and/or their sensitivities compensate for the loss of vagal afferent information, particularly when subjects face disturbances in ambient fuel levels. Therefore, male adult rats neonatally treated with CAP or with the vehicle (VEH) underwent intravenous glucose tolerance tests (IVGTTs) during which blood fuel levels, and circulating adipose, pancreatic, and adrenal hormones were assessed. CAP rats displayed similar hyperglycemia as VEH rats, but with markedly reduced plasma insulin and corticosterone responses. These results indicate that CAP rats have increased insulin sensitivity during hyperglycemic episodes, and lower plasma levels of corticosterone in CAP rats relative to VEH rats could underlie this effect. After the IVGTT, CAP rats had increased plasma adiponectin and reduced plasma resistin levels, and these alterations in adipose hormones might be relevant for post-ingestive metabolic processes. In a second experiment, anorexigenic efficacies of cholecystokinin and leptin were assessed. While VEH rats, but not CAP rats, responded with reduced food intake to i.p. injected cholecystokinin, only CAP rats responded to i.v. infused leptin with a reduction in food intake. It is concluded that reduced HPA axis activity and/or increased leptin signaling could underlie compensations in fuel handling and energy balance following CAP treatment. Topics: Adiponectin; Animals; Animals, Newborn; Body Weight; Capsaicin; Cholecystokinin; Corticosterone; Eating; Energy Metabolism; Fatty Acids, Nonesterified; Glucose; Glucose Tolerance Test; Homeostasis; Insulin; Leptin; Male; Rats; Rats, Wistar; Time Factors | 2006 |
Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice.
Ghrelin and leptin are suggested to regulate energy homeostasis as mutual antagonists on hypothalamic neurons that regulate feeding behavior. We employed reverse genetics to investigate the interplay between ghrelin and leptin. Leptin-deficient mice (ob/ob) are hyperphagic, obese, and hyperglycemic. Unexpectedly, ablation of ghrelin in ob/ob mice fails to rescue the obese hyperphagic phenotype, indicating that the ob/ob phenotype is not a consequence of ghrelin unopposed by leptin. Remarkably, deletion of ghrelin augments insulin secretion in response to glucose challenge and increases peripheral insulin sensitivity; indeed, the hyperglycemia exhibited by ob/ob mice is markedly reduced when ob/ob mice are bred onto the ghrelin(-/-) background. We further demonstrate that ablation of ghrelin reduces expression of Ucp2 mRNA in the pancreas, which contributes toward enhanced glucose-induced insulin secretion. Hence, chronically, ghrelin controls glucose homeostasis by regulating pancreatic Ucp2 expression and insulin sensitivity. Topics: Animals; Blood Glucose; Body Temperature Regulation; Body Weight; Diabetes Mellitus, Type 2; Down-Regulation; Ghrelin; Insulin; Ion Channels; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Mitochondrial Proteins; Obesity; Pancreas; Peptide Hormones; Phenotype; RNA, Messenger; Uncoupling Protein 2 | 2006 |
Increased maternal nutrition alters development of the appetite-regulating network in the brain.
Individuals exposed to an increased nutrient supply before birth have a high risk of becoming obese children and adults. It has been proposed that exposure of the fetus to high maternal nutrient intake results in permanent changes within the central appetite regulatory network. No studies, however, have investigated the impact of increased maternal nutrition on the appetite regulatory network in species in which this network develops before birth, as in the human. In the present study, pregnant ewes were fed a diet which provided 100% (control, n = 8) or approximately 160% (well-fed, n = 8) of metabolizable energy requirements. Ewes were allowed to lamb spontaneously, and lambs were sacrificed at 30 days of postnatal age. All fat depots were dissected and weighed, and expression of the appetite-regulating neuropeptides and the leptin receptor (OBRb) were determined by in situ hybridization. Lambs of well-fed ewes had higher glucose (Glc) concentrations during early postnatal life (F = 5.93, P<0.01) and a higher relative subcutaneous (s.c.) fat mass at 30 days of age (34.9+/-4.7 g/kg vs. 22.8+/-3.3 g/kg; P<0.05). The hypothalamic expression of pro-opiomelanocortin was higher in lambs of well-fed ewes (0.48+/-0.09 vs. 0.28+/-0.04, P<0.05). In lambs of overnourished mothers, but not in controls, the expression of OBRb was inversely related to total relative fat mass (r2 = 0.50, P = 0.05, n = 8), and the direct relationship between the expression of the central appetite inhibitor CART and fat mass was lost. The expression of neuropeptide Y and AGRP was inversely related to total relative fat mass (NPY, r2 = 0.28, P<0.05; agouti-related peptide, r2 = 0.39, P<0.01). These findings suggest that exposure to increased nutrition before birth alters the responses of the central appetite regulatory system to signals of increased adiposity after birth. Topics: Adipose Tissue; Agouti-Related Protein; Animals; Appetite Regulation; Blood Glucose; Body Weight; Eating; Fatty Acids, Nonesterified; Female; Fetal Development; Gestational Age; Hypothalamus; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Maternal Nutritional Physiological Phenomena; Milk; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Pregnancy; Pro-Opiomelanocortin; Proteins; Receptors, Cell Surface; Receptors, Leptin; Sheep | 2006 |
Adiponectin is present in human milk and is associated with maternal factors.
Previous studies have shown that human milk has a role in the gastrointestinal, neural, and immune development of neonates. If present in milk, adiponectin would be a promising candidate for influencing infant development, given its metabolic functions.. Our objectives were to determine whether adiponectin is present in human milk and to characterize maternal factors associated with potential variation in milk adiponectin concentrations.. We quantified adiponectin concentrations in human milk samples from donors to the Cincinnati Children's Research Human Milk Bank and randomly selected participants in a cohort study in Mexico City funded by the National Institutes of Health. Using cross-sectional and longitudinal data, we examined milk adiponectin concentrations in relation to lactation duration, maternal body mass index (BMI; in kg/m(2)), and ethnicity.. Adiponectin was detected in human skim milk (range: 4.2-87.9 ng/mL). In cross-sectional and longitudinal analyses, duration of lactation was negatively associated with milk adiponectin concentrations (beta = -0.059 +/- 0.024 and -0.059 +/- 0.007, respectively; P < 0.02 for both). Maternal postpregnancy BMI was positively associated with milk adiponectin concentrations (beta = 0.08 +/- 0.02, P < 0.0001; longitudinal analysis). Mexican mothers had lower median milk adiponectin concentrations at 1 mo than did the non-Hispanic white subjects from Cincinnati (11.5 and 19.8 ng/mL; P = 0.003).. Adiponectin is present in human milk and its concentrations are associated with duration of lactation, maternal adiposity, and ethnicity. Given the importance of adiponectin in inflammation, insulin sensitivity, and fatty acid metabolism, future studies should examine milk adiponectin's role in infant metabolic development. Topics: Adiponectin; Body Mass Index; Body Weight; Cohort Studies; Cross-Sectional Studies; Ethnicity; Female; Humans; Lactation; Leptin; Longitudinal Studies; Mexico; Milk, Human; Ohio; Postpartum Period; Time Factors | 2006 |
Effects of periodic intake of a high-caloric diet on body mass and leptin resistance.
The effects of continuous or intermittent access to a high-caloric (HC) diet, always offered in addition to standard chow, on body mass and leptin resistance were analyzed in female C57BL/6J mice. Susceptibility for diet-induced obesity (DIO) was apparent from the marked preference for the HC diet. Continuous HC diet feeding of mice at 4 weeks of age induced leptin resistance within 2 weeks and massive gains in body mass, although with increasing inter-individual variability in the inbred strain considered to be isogenic. In adult mice receiving HC diet for the first time, leptin treatment failed to reduce energy intake first after 11 days of HC diet feeding, but became effective again within 3 days after HC diet withdrawal. In mice with a history of several preceding periods of access to the HC diet totalling >30 days, supplementary HC diet abolished the anorectic effect of leptin treatment within only 3 days and it reappeared not earlier than 11 days after HC diet withdrawal. Thus, in the investigated DIO-prone mouse strain both, the loss of responsiveness to leptin under HC diet and its recovery after HC diet withdrawal strongly depended on the dietary history. Recovery from leptin resistance during periods of intermittent chow feeding was associated with losses of body mass that did not completely compensate for the obesity-inducing effect of the preceding HC diet. Topics: Age Factors; Animals; Behavior, Animal; Body Mass Index; Body Weight; Dietary Fats; Drug Resistance; Eating; Energy Intake; Female; Leptin; Mice; Mice, Inbred C57BL; Periodicity | 2006 |
Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle.
AMP-activated protein kinase (AMPK) is a key regulator of cellular energy balance and of the effects of leptin on food intake and fatty acid oxidation. Obesity is usually associated with resistance to the effects of leptin on food intake and body weight. To determine whether diet-induced obesity (DIO) impairs the AMPK response to leptin in muscle and/or hypothalamus, we fed FVB mice a high fat (55%) diet for 10-12 weeks. Leptin acutely decreased food intake by approximately 30% in chow-fed mice. DIO mice tended to eat less, and leptin had no effect on food intake. Leptin decreased respiratory exchange ratio in chow-fed mice indicating increased fatty acid oxidation. Respiratory exchange ratio was low basally in high fat-fed mice, and leptin had no further effect. Leptin (3 mg/kg intraperitoneally) increased alpha2-AMPK activity 2-fold in muscle in chow-fed mice but not in DIO mice. Leptin decreased acetyl-CoA carboxylase activity 40% in muscle from chow-fed mice. In muscle from DIO mice, acetyl-CoA carboxylase activity was basally low, and leptin had no further effect. In paraventricular, arcuate, and medial hypothalamus of chow-fed mice, leptin inhibited alpha2-AMPK activity but not in DIO mice. In addition, leptin increased STAT3 phosphorylation 2-fold in arcuate of chow-fed mice, but this effect was attenuated because of elevated basal STAT3 phosphorylation in DIO mice. Thus, DIO in FVB mice alters alpha2-AMPK in muscle and hypothalamus and STAT3 in hypothalamus and impairs further effects of leptin on these signaling pathways. Defective responses of AMPK to leptin may contribute to resistance to leptin action on food intake and energy expenditure in obese states. Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animal Feed; Animals; Body Weight; Energy Metabolism; Fatty Acids; Hypothalamus; Leptin; Male; Mice; Multienzyme Complexes; Muscle, Skeletal; Obesity; Oxygen; Protein Serine-Threonine Kinases | 2006 |
Late but not early gestational maternal growth hormone treatment increases fetal adiposity in overnourished adolescent sheep.
In the overnourished adolescent sheep, maternal tissue synthesis is promoted at the expense of placental growth and leads to a major decrease in lamb birth weight at term. Maternal growth hormone (GH) concentrations are attenuated in these pregnancies, and it was recently demonstrated that exogenous GH administration throughout the period of placental proliferation stimulates uteroplacental and fetal development by Day 81 of gestation. The present study aimed to determine whether these effects persist to term and to establish whether GH affects fetal growth and body composition by increasing placental size or by altering maternal metabolism. Adolescent recipient ewes were implanted with singleton embryos on Day 4 postestrus. Three groups of ewes offered a high dietary intake were injected twice daily with recombinant bovine GH from Days 35 to 65 of gestation (high intake plus early GH) or from Days 95 to 125 of gestation (high intake plus late GH) or remained untreated (high intake only). A fourth moderate-intake group acted as optimally nourished controls. Pregnancies were terminated at Day 130 of gestation (6 per group) or were allowed to progress to term (8-10 per group). GH administration elevated maternal plasma concentrations of GH, insulin, glucose, and nonesterified fatty acids during the defined treatment windows, while urea concentrations were decreased. At Day 130, GH treatment had reduced the maternal adiposity score, percentage of fat in the carcass, and internal fat depots and leptin concentrations, predominantly in the high-intake plus late GH group. Placental weight was lower in high-intake vs. control dams but independent of GH treatment. In contrast, fetal weight was elevated by late GH treatment, and these fetuses had higher relative carcass fat content, perirenal fat mass, and liver glycogen concentrations than all other groups. Expression of leptin mRNA in fetal perirenal fat and fetal plasma leptin concentrations were not significantly altered by maternal nutritional intake or GH. In pregnancies proceeding to term, the duration of gestation, fetal placental mass, and lamb birth weight were reduced in high-intake compared with control dams but were not significantly affected by GH treatment. In conclusion, exogenous GH has profound effects on maternal endocrinology, metabolism, and body composition when administered during early and late pregnancy. Treatment during late pregnancy has a modest effect on fetal growth independent of plac Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Eating; Endocrine System; Female; Fetal Development; Gestational Age; Growth Hormone; Leptin; Maternal Age; Maternal Nutritional Physiological Phenomena; Placenta; Placentation; Pregnancy; Pregnancy Outcome; Sheep | 2006 |
Neuroscience. Regulating energy balance: the substrate strikes back.
Topics: AMP-Activated Protein Kinases; Animals; Appetite; Body Weight; Diet; Eating; Energy Metabolism; Homeostasis; Hypothalamus; Leptin; Leucine; Multienzyme Complexes; Neural Pathways; Neurons; Obesity; Protein Kinases; Protein Serine-Threonine Kinases; Rats; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; Starvation; Thinness; TOR Serine-Threonine Kinases | 2006 |
[The effects of inhalation of essential oils on the body weight, food efficiency rate and serum leptin of growing SD rats].
This experimental study was designed to verify the effect of inhalation of essential oils on body weight, feed intake, food efficiency rate and serum leptin.. The subjects of this study were 90 growing SD rats (46 males and 44 females). They were allocated into one of four groups, the Fennel group, Patchouli group, Bergamot group and control group. The experimental treatment was the inhalation of aromatherapy essential oils which was applied two times a day for 10 minutes each during 8 weeks. To evaluate the effects, body weight, feed intake, food efficiency rate and serum leptin were measured before and after the treatment. The collected data was analyzed by repeated measures of Kolmogorov-smirnov test and Normal Q-Q plot for normality, Kruskal Wallis test and chi2-test for experimental effects with the SPSS program.. The food efficiency rate was significantly lower in the Patchouli group and Fennel group than in the Bergamot group and control group (P=.000). No significant group effects were found for SD rat's body weight, feeding amount and serum leptin.. In conclusion, these findings indicate that the inhalation of essential oils could be effective in lowering the food efficiency rate rather than the feed intake. Topics: Administration, Inhalation; Animals; Body Weight; Eating; Female; Leptin; Male; Oils, Volatile; Rats; Rats, Sprague-Dawley | 2006 |
Gender-specific orexigenic and anorexigenic mechanisms in rats.
Feeding dysregulation may manifest as either under-nourishment (e.g., anorexia) or excessive eating leading to obesity. Recent studies have suggested a gender-related variance in weight maintenance in response to chronic disease or obesity-related dietary regimens. However it is unclear whether these gender differences in weight management are secondary to appetite-mediated food intake or alternative mechanisms (e.g., exercise, metabolism). In this study, we explored gender-dependent feeding and hormonal responses to dietary restriction (12-h fast) or to an inflammatory stimulus (LPS, 100 microg/kg b.w.; i.p.) in rats. In response to a 12 h fast, female rats increased (p<0.05) total daily food intake above that of male rats by primarily increasing nighttime feeding by 40%, as compared to 10% in males. Consistent with the increased food intake, fasting induced a greater percent increase in female as compared to male plasma ghrelin (141 vs. 65%, p<0.001). In response to LPS, both male and female rats showed similar reductions in total daily food consumption. However LPS (6 h) induced a greater percent increase in plasma leptin in female than male rats (230 vs. 33%, p<0.01), whereas ghrelin was similarly decreased in both females and males (66 vs. 44%). These findings demonstrate sexual dimorphic responses in feeding and appetite-associated hormonal responses to fasting or LPS treatment. Our findings suggest that therapeutic interventions with ghrelin or leptin must be modified according to gender in order to optimally achieve either weight loss for obesity or weight gain/maintenance for chronic illness-associated anorexia. Topics: Animals; Anorexia; Appetite; Body Weight; Fasting; Feeding Behavior; Female; Ghrelin; Leptin; Lipopolysaccharides; Male; Peptide Hormones; Rats; Rats, Sprague-Dawley; Sex Factors | 2006 |
Precalving effects on metabolic responses and postpartum anestrus in grazing primiparous dairy cows.
The effect of increased access to pasture feeding during the last 6 wk of gestation on metabolic responses and postpartum anestrous interval was investigated. Heifers with a body condition score (BCS) of 5.0 (BC5+FF; on a 1-to-10 scale, US = 1.5 + 0.32 x New Zealand) were offered unrestricted pasture, and those with BCS 4.0 were fed either pasture unrestricted (BC4+FF) or restricted (BC4+RES) for the last 6 wk of gestation. After calving, all groups were offered unrestricted pasture. Mean BCS at calving for BC5+FF, BC4+FF, and BC4+RES were 4.7 +/- 0.1, 4.3 +/- 0.1, and 3.5 +/- 0.1, respectively. At 35 d postpartum, LH pulse frequency was lower in BC4+RES than in BC4+FF and BC5+FF, which were similar. At 77 d after calving, 8% of BC4+RES cows had ovulated compared with 75% of BC4+FF and 69% of BC5+FF cows. Metabolic hormonal differences between BC4+FF and BC4+RES were not reflected in the differences between BC4+FF and BC5+FF for LH pulse frequency or ovulation. Unrestricted access to pasture during the final 6 wk of gestation for BC4 heifers reduced the risk of prolonged postpartum anestrus. Systemic factors, tissue sensitivity, and critical developmental set points are probably involved in the integrated control of ovulation by body condition. Topics: Anestrus; Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Body Composition; Body Weight; Cattle; Diet; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Insulin; Lactation; Leptin; Luteinizing Hormone; Ovulation; Parity; Postpartum Period; Pregnancy; Time Factors | 2006 |
Leptin and prolactin, but not corticosterone, modulate body weight and thyroid function in protein-malnourished lactating rats.
To understand the role of hormonal changes in the lower food ingestion and body weight in protein-restricted lactating rats as well as the higher serum T (3), higher deiodination, iodide and T (3) milk transfer, we measured maternal serum prolactin, leptin, TSH and corticosterone, which are hormones that could influence those parameters. After birth, dams were separated into: control-fed with a 23 % protein diet (n = 12) and PR (protein-restricted)-fed with an 8 % protein diet (n = 12). At the 4 (th) and 21 (st) day of lactation, half of the animals in each group were sacrificed. PR dams presented hyperleptinemia (day 4: + 20 %; day 21: + 19 %; p < 0.05) and hypoprolactinemia (day 4: - 85 %; day 21: - 92 %; p < 0.05), which could help explain the lower food consumption and body weight in lactating PR rats since leptin is anorexigenic and prolactin is orexigenic. Also, this hyperleptinemia could contribute for the increase in serum T (3) of PR dams, since leptin stimulates T (3) production, especially acting on deiodinases. Serum corticosterone was not different between PR and C groups, and TSH was lower only at the end of lactation. Thus, we suggest that both leptin and prolactin could play an important role in the body weight and thyroid hormone changes observed in protein-malnourished lactating rats. Topics: Animals; Body Weight; Corticosterone; Dietary Proteins; Eating; Female; Leptin; Male; Prolactin; Protein Deficiency; Rats; Rats, Wistar; Thyroid Gland; Thyrotropin; Triiodothyronine | 2006 |
Relationship of ghrelin and leptin hormones with body mass index and waist circumference in a random sample of adults.
To evaluate the relationship of ghrelin and leptin hormones with body mass index (BMI) and waist circumference in a population-based random sample of adult men and women subsequently categorized from normal weight to severely obese based on BMI criteria. The relationship between total ghrelin and leptin was also evaluated.. A cross-sectional study was conducted on adults.. Two-hundred thirty-three men (n=107) and women (n=126) between the ages of 23 and 75 years were randomly selected from a database of over 600,000 adults who had previously participated in a population-based study conducted by the University of Utah Cardiovascular Genetics Program. Items collected included height, weight, waist circumference, and fasting blood samples. Blood samples were later thawed, and plasma leptin and total ghrelin levels were analyzed with radioimmunoassay kits.. Leptin levels were directly associated with BMI (r=0.72, P=0.001) and waist circumference (r=0.71, P=0.0001), whereas total ghrelin was inversely associated with BMI (r=-0.39, P=0.001) and waist circumference (r=-0.37, P=0.001). There were also statistically significant linear changes in means across the BMI categories for both hormones. After controlling for BMI and waist circumference, the highly significant correlation of leptin with ghrelin (r=-0.39) was reduced but still significant (r=-0.17, P=0.01).. Leptin increases and ghrelin decreases were linear over the five BMI categories, suggesting there is no threshold of BMI where the hormone levels change abruptly. There remain other factors beyond current BMI and waist circumference that induce a correlation of these two hormones. Further understanding of the role that each of these hormones has in influencing appetite and body weight may provide insight into mechanisms involved with obesity. Topics: Adult; Aged; Body Height; Body Mass Index; Body Weight; Body Weights and Measures; Cross-Sectional Studies; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Peptide Hormones | 2006 |
Effect of nutritional status and fat reserves on the periparturient immune response to Haemonchus contortus infection in sheep.
A study was made of the effect of body fat stored by ewes in early pregnancy on the subsequent immune response to gastrointestinal parasites around parturition. Pregnant ewes were given access to a lucerne pelleted diet either ad libitum (H) or at approximately 0.70 of their maintenance requirements (L) from the 42nd day of pregnancy in order to achieve a clearly differentiated level of body reserves by the 90th day of pregnancy. Then, all animals were put on the same plane of nutrition till 3 weeks after parturition. All ewes in both groups received 7,000 infective larvae of Haemonchus contortus per week for 7 weeks prior to lambing. The dietary treatments led to large differences between both groups of ewes in back-fat thickness that had a high correlation with mean plasma concentrations of leptin. In spite of the fact that animals were on the same plane of nutrition at infection time, host resistance, as measured by faecal egg counts, was significantly affected by the nutritional treatment established during early pregnancy. This effect produced noticeable differences in worm size and in worm burden at lambing. The response was accompanied by a marked increase in circulating eosinophils in better-fed ewes than in those maintained on a restricted diet in early pregnancy. Serum pepsinogen concentration, however, was inversely affected by the nutritional treatment till lambing, showing a maximum difference as early as 2 weeks after infection. The results support the view that higher levels of nutrition during early pregnancy enhance the expression of immunity against gastrointestinal parasites around parturition. Furthermore, the differences in the immune response appeared associated with serum leptin levels suggesting that leptin may be a key link between nutritional status and the protective immune reactivity against GI nematode infection. Topics: Adipose Tissue; Animals; Body Weight; Energy Intake; Feces; Female; Haemonchiasis; Haemonchus; Immunity, Innate; Leptin; Nutritional Status; Parasite Egg Count; Parturition; Pepsinogens; Pregnancy; Random Allocation; Sheep; Sheep Diseases | 2006 |
Multilevel regulation of leptin storage, turnover, and secretion by feeding and insulin in rat adipose tissue.
The mechanisms of the increased serum leptin in response to feeding are poorly understood. Therefore, we used metabolic labeling to directly assess leptin biosynthesis, secretion, and turnover in adipose tissue from 14 h-starved compared with fed 12-14 week old rats. Starvation decreased serum leptin (-47 +/- 7%), adipose tissue leptin content (-32 +/- 5%), and leptin secretion during 3 h of incubation (-65 +/- 12%). Starvation did not affect leptin mRNA levels but decreased rates of leptin biosynthesis by tissue fragments, as determined by [(35)S]methionine/cysteine incorporation into immunoprecipitable leptin. Insulin in vitro did not acutely increase leptin biosynthesis or rates of (125)I-leptin degradation. Pulse-chase studies showed that in adipose tissue from fed but not starved rats, insulin accelerated the secretion of [(35)S]leptin by approximately 2-fold after 30 and 60 min of chase. Degradation of newly synthesized leptin was slower in adipose tissue of starved than fed rats (half-lives of 50 and 150 min, respectively). Inhibitor experiments showed that both lysosomes and proteosomes contributed to leptin degradation. In conclusion, feeding compared with starvation influences leptin production at multiple posttranscriptional levels: synthesis, tissue storage, turnover, and secretion. The insulin-stimulated release of leptin from a preformed intracellular leptin pool may contribute to increases in serum leptin levels after meals. Topics: Adipocytes; Adipose Tissue; Animals; Blotting, Northern; Body Weight; Chloroquine; Cycloheximide; Insulin; Iodine Isotopes; Leptin; Leupeptins; Lysosomes; Male; Rats; Rats, Wistar; RNA, Messenger; Starvation; Sulfur Isotopes | 2006 |
Age-related loss of muscle mass and bone strength in mice is associated with a decline in physical activity and serum leptin.
The mechanisms underlying age-related loss of muscle and bone tissue are poorly understood but are thought to involve changes in sex hormone status, physical activity, and circulating levels of inflammatory cytokines. This study attempts to develop an animal model useful for evaluating these mechanisms in vivo. Male C57BL/6 mice were included for study at 3, 6, 12, 18, 24, and 29 months of age. Endocortical mineralizing surface, serum leptin, body weight, and percentage of body fat all increased between 6 and 12 months of age as activity level declined. Serum levels of the inflammatory marker IL-6 increased significantly after 12 months of age, following the observed increase in body weight and percent body fat. Hindlimb muscle mass declined significantly between 18 and 24 months of age, both absolutely and relative to total body mass, with a further decline ( approximately 15%) between 24 and 29 months. Loss of muscle mass after 18 months of age was accompanied by a significant increase in bone resorption, as indicated by serum pyridinoline cross-links, and a significant decrease in fat mass, serum leptin, bone strength, bone mineral density, and vertical cage activity. No significant changes in serum testosterone with aging were detected in the mice, as levels were essentially constant between 6 and 29 months. Our data show that mice lose a significant amount of muscle and bone tissue with age, and this loss of musculoskeletal tissue is accompanied by a drop in serum leptin and preceded by a significant decrease in physical activity. Topics: Age Factors; Animals; Biomechanical Phenomena; Blood Glucose; Body Composition; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Interleukin-6; Leptin; Male; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Models, Animal; Motor Activity; Muscle Contraction; Muscle, Skeletal; Osteocalcin; Tomography, X-Ray Computed | 2006 |
Melanocortin-4 receptor mediates chronic cardiovascular and metabolic actions of leptin.
This study tested whether the melanocortin 4-receptor (MC4R) is essential for the chronic cardiovascular and metabolic actions of leptin. Twenty- to 22-week-old male wild-type (WT) C57BL/6J and obese MC4R (-/-) mice (N=5 to 6 per group) were implanted with radiotelemetric transmitters and catheters for measuring mean arterial pressure (MAP) and heart rate 24 hours per day and intravenous infusions. After a 3-day stable control period, leptin was infused (2 microg/kg per minute IV) for 7 days in WT, obese ad libitum-fed MC4R (-/-), and nonobese pair-fed MC4R (-/-) mice. WT mice receiving vehicle for 7 days served as controls. MC4 (-/-) mice were 30% heavier and had 4- and 11-fold increases in plasma insulin and leptin levels, respectively, compared with WT mice. Despite obesity, MAP and heart rate tended to be lower in MC4R (-/-) mice compared with WT mice. Chronic leptin infusion in the different groups increased plasma leptin levels to 45 to 65 ng/mL. Seven-day leptin infusion in WT mice increased MAP by 12+/-3 mm Hg despite a 35% reduction in food intake and an 8% reduction in body weight. Leptin did not alter plasma glucose but reduced plasma insulin in WT mice (5.9+/-1.0 versus 3.0+/-0.5 microU/mL). These cardiovascular and metabolic actions of leptin were abolished in obese and nonobese MC4R (-/-) mice. These data suggest that MC4R deficiency, and not obesity-induced leptin resistance, abolished the cardiovascular and metabolic actions of leptin in obese MC4R (-/-) mice. Thus, a functional MC4R is essential for the chronic cardiovascular and metabolic actions of leptin. Topics: Adiposity; Analysis of Variance; Animals; Blood Glucose; Blood Pressure; Body Weight; Eating; Glomerular Filtration Rate; Heart Rate; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Receptor, Melanocortin, Type 4; Receptors, Leptin | 2006 |
The hypothalamic paraventricular nucleus is not essential for orexigenic NPY or anorexigenic melanocortin action.
Bilateral electrolytic lesions of the paraventricular nucleus of the hypothalamus (PVN) produce hyperphagia with excess weight gain. The orexigenic neuropeptide Y (NPY) system and the anorexigenic melanocortin system act in the PVN to regulate food intake, and participate in mediating the anorexic effects of leptin. We hypothesized that changes in the responsiveness of these systems may contribute to the hyperphagia observed in PVN-lesioned rats. Adult female Sprague-Dawley rats received either sham or electrolytic lesions in the PVN immediately followed by implantation of a guide cannula into the third cerebroventricle. Twenty-five days following surgery groups of sham and hyperphagic PVN-lesioned rats were injected intracerebroventricularly (i.c.v.) with either 118 pmole or 470 pmole of NPY and food intake was measured for 3 h. Food intake in response to NPY was nearly three-fold higher in PVN-lesioned rats as compared to sham rats. However, the response to 5 microg leptin i.c.v. was not different in lesioned versus sham rats. The effect of the melanocortin agonist MTII on food intake was tested in additional rats beginning either 7-14 days or 30-40 days following surgery. Doses of 0.1 nmole or 1.0 nmole of MTII were injected immediately before lights-off and food intake was measured at 2 h, 24 h and 48 h post-injection. Suppression of food intake in PVN-lesioned rats was not different from that in sham-lesioned rats. These data suggest that hyper-responsiveness to NPY may account in part for the hyperphagia observed in PVN-lesioned rats. Furthermore, based on the similarities of responses of PVN-lesioned and sham control rats to the anorexigenic agents MTII and leptin and the hypersensitivity of lesioned rats to NPY, we conclude that the PVN is not essential for NPY stimulation of food intake or for melanocortin suppression of food intake and that NPY and melanocortin receptors outside of the PVN are sufficient to produce these effects. Topics: alpha-MSH; Animals; Body Weight; Eating; Female; Leptin; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 3; Time Factors | 2006 |
Effects of acute and chronic relaxin-3 on food intake and energy expenditure in rats.
The effects of acute and repeated intraparaventricular (iPVN) administration of human relaxin-3 (H3) were examined on food intake, energy expenditure, and the hypothalamo-pituitary thyroid axis in male Wistar rats. An acute high dose iPVN injection of H3 significantly increased food intake 1 h post-administration [0.4+/-0.1 g (vehicle) vs 1.6+/-0.5 g (180 pmol H3), 2.4+/-0.5 g (540 pmol H3) and 2.2+/-0.5 g (1,620 pmol H3), p<0.05 for all doses vs vehicle]. Repeated iPVN H3 injection (180 pmol/twice a day for 7 days) significantly increased cumulative food intake in ad libitum fed animals compared with vehicle [211.8+/-7.1 g (vehicle) vs 261.6+/-6.7 g (ad libitum fed H3), p<0.05]. Plasma leptin was increased in the H3 ad libitum fed group. Plasma thyroid stimulating hormone was significantly decreased after acute and repeated administration of H3. These data suggest H3 may play a role in long-term control of food intake. Topics: Acute Disease; Adipose Tissue; Animals; Body Weight; Energy Metabolism; Humans; Ion Channels; Leptin; Male; Mitochondrial Proteins; Radioimmunoassay; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Relaxin; Thyrotropin; Uncoupling Protein 1 | 2006 |
Bone abnormalities in adolescent leptin-deficient mice.
Ob/ob and db/db mice have different aberrations in leptin signaling that both lead to abnormalities in bone mineral density (BMD), and bone histological and histomorphometric outcomes. A few studies have directly compared bone metabolism in ob/ob and db/db mice, and biomechanical strength properties that are surrogate measures of fracture risk, have not been extensively studied. This study compared bone mineral content (BMC), BMD and biomechanical strength properties of femurs and lumbar vertebrae among 10 week old male ob/ob, db/db and C57Bl/6 wildtype (WT) mice. Femurs and lumbar vertebrae were specifically studied to determine if trabecular and cortical bone are regulated by leptin in a similar manner in ob/ob and db/db mice. Femurs of ob/ob and db/db mice had lower BMC, BMD and biomechanical strength properties, including peak load, compared to WT mice. In contrast, lumbar vertebrae BMC and BMD did not differ among genotypes, nor did the peak load from compression testing of an individual lumbar vertebra differ among groups. These findings suggest that leptin deficiency in adolescent male mice first results in changes in femurs, a representative long bone, and alterations in lumbar vertebrae may occur later in life. Topics: Animals; Biomechanical Phenomena; Body Weight; Bone and Bones; Bone Density; Bone Diseases; Dose-Response Relationship, Drug; Femur; Genotype; Leptin; Lumbar Vertebrae; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Time Factors | 2006 |
Reduced fat mass in rats fed a high oleic acid-rich safflower oil diet is associated with changes in expression of hepatic PPARalpha and adipose SREBP-1c-regulated genes.
PPARs and sterol regulatory element-binding protein-1c (SREPB-1c) are fatty acid-regulated transcription factors that control lipid metabolism at the level of gene expression. This study compared a high oleic acid-rich safflower oil (ORSO) diet and a high-butter diet for their effect on adipose mass and expressions of genes regulated by PPAR and SREPB-1c in rats. Four groups of Wistar rats were fed 30S (30% ORSO), 5S (5% ORSO), 30B (29% butter + 1% ORSO), or 5B (4% butter plus 1% ORSO) diets for 15 wk. Compared with the 30B group, the 30S group had less retroperitoneal white adipose tissue (RWAT) mass and lower mRNA expressions of lipoprotein lipase, adipocyte fatty acid-binding protein, fatty acid synthase, acetyl CoA carboxylase, and SREBP-1c in the RWAT, higher mRNA expressions of acyl CoA oxidase, carnitine palmitoyl-transferase 1A, fatty acid binding protein, and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in the liver (P < 0.05). The 18:2(n-6) and 20:4(n-6) contents in the liver and RWAT of the 30S group were >2 fold those of the 30B group (P < 0.05). These results suggested that the smaller RWAT mass in rats fed the high-ORSO diet might be related to the higher tissue 18:2(n-6) and 20:4(n-6). This in turn could upregulate the expressions of fatty acid catabolic genes through the activation of PPARalpha in the liver and downregulate the expressions of lipid storage and lipogenic gene through the suppression of SREBP-1c in the RWAT. Topics: Adipose Tissue; Animals; Body Weight; Dietary Fats; Leptin; Liver; Male; Oleic Acid; Organ Size; PPAR alpha; Rats; Rats, Wistar; Safflower Oil; Sterol Regulatory Element Binding Protein 1; Triglycerides | 2006 |
Protein intake does not affect insulin sensitivity in normal weight cats.
Topics: Animals; Area Under Curve; Body Weight; Cats; Dietary Proteins; Female; Insulin; Insulin Secretion; Insulin-Like Growth Factor I; Leptin; Male | 2006 |
Chronic intracerebroventricular administration of relaxin-3 increases body weight in rats.
Bolus-administered intracerebroventricular (ICV) relaxin-3 has been reported to increase feeding. In this study, to examine the role of relaxin-3 signaling in energy homeostasis, we studied the effects of chronically administered ICV relaxin-3 on body weight gain and locomotor activity in rats. Two groups of animals received vehicle or relaxin-3 at 600 pmol/head/day, delivered with Alzet osmotic minipumps. In animals receiving relaxin-3, food consumption and weight gain were statistically significantly higher than those in the vehicle group during the 14-day infusion. During the light phase on days 2 and 7 and the dark phase on days 3 and 8, there was no difference in locomotor activity between the two groups. Plasma concentrations of leptin and insulin in rats chronically injected with relaxin-3 were significantly higher than in the vehicle-injected controls. These results indicate that relaxin-3 up-regulates food intake, leading to an increase of body weight and that relaxin-3 antagonists might be candidate antiobesity agents. Topics: Animals; Body Weight; Eating; Humans; Injections, Intraventricular; Insulin; Leptin; Male; Motor Activity; Nerve Tissue Proteins; Obesity; Rats; Rats, Wistar; Recombinant Proteins; Relaxin; Signal Transduction | 2006 |
Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis.
Insulin signaling in the hypothalamus plays a role in maintaining body weight. Studies suggest that the forkhead transcription factor Foxo1 is an important mediator of insulin signaling in peripheral tissues. Here we demonstrate that in normal mice, hypothalamic Foxo1 expression is reduced by the anorexigenic hormones insulin and leptin. These hormones' effects on feeding are inhibited when hypothalamic Foxo1 is activated, establishing a new signaling pathway through which insulin and leptin regulate food intake in hypothalamic neurons. Moreover, activation of Foxo1 in the hypothalamus increases food intake and body weight, whereas inhibition of Foxo1 decreases both. Foxo1 stimulates the transcription of the orexigenic neuropeptide Y and Agouti-related protein through the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway, but suppresses the transcription of anorexigenic proopiomelanocortin by antagonizing the activity of signal transducer-activated transcript-3 (STAT3). Our data suggest that hypothalamic Foxo1 is an important regulator of food intake and energy balance. Topics: Analysis of Variance; Animals; Blotting, Western; Body Weight; Cell Line, Tumor; Chromatin Immunoprecipitation; Eating; Electrophoretic Mobility Shift Assay; Energy Metabolism; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression; Green Fluorescent Proteins; Homeostasis; Humans; Hypothalamus; Immunohistochemistry; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Neuroblastoma; RNA, Small Interfering | 2006 |
Body composition and concentrations of leptin, neuropeptide Y, beta-endorphin, growth hormone, insulin-like growth factor-I and insulin at menarche in girls with constitutional delay of puberty.
Constitutional delay of puberty (CDP), a rare condition among girls, manifests as retarded sexual maturity past the 13th year of life. The clinical and endocrinological aspects of this interesting problem appear to have escaped attention in the literature. The purpose of the present study was to compare body composition and concentrations of leptin, neuropeptide Y (NPY), beta-endorphin, growth hormone (GH), insulin growth factor-I (IGF-I) and insulin at menarche in CDP girls and girls with normal pubertal development (NP).. We enrolled 11 girls with CDP and 40 girls with NP. All participants were studied at or within 3 months of menarche. Age, height and weight were recorded. Body composition was established with a body composition analyzer. Radioimmunoassays were performed to measure concentrations of NPY, beta-endorphin, leptin, GH, IGF-I and insulin.. The mean age at menarche in the CDP and NP groups was 16.1 and 12.5 years, respectively (p = 0.0001). CDP girls at menarche were taller (1.64 vs. 1.57 m; p = 0.012). The difference between groups in body weight (57.5 vs. 50.4 kg; p = 0.1), body mass index (BMI), fat mass, fat percentage (BF%) and lean mass was not significant, and nor was the difference in leptin, GH and insulin levels. However, CDP girls demonstrated significantly higher NPY concentrations (199.4+/-105.1 vs. 56.9+/-26.3 pg/ml; p = 0.001). NPY correlated with BF% (r = 0.60) in this group. IGF-I concentrations were significantly lower in CDP girls (524.8+/-50.6 ng/ml) than in NP girls (744.5+/-56.1 ng/ml; p = 0.024).. Girls with CDP differed from NP girls only in age at menarche and height; they did not differ significantly with respect to BMI and body composition parameters. Higher concentrations of NPY in CDP girls may be responsible for CDP and reduced levels of IGF-I. Correlation of NPY with BF% suggests an involvement of this neuropeptide in the process of fat accumulation associated with CDP. Topics: Adipose Tissue; Adolescent; beta-Endorphin; Body Composition; Body Height; Body Mass Index; Body Weight; Child; Female; Human Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Menarche; Neuropeptide Y; Puberty, Delayed | 2006 |
Seasonal regulations of energetics, serum concentrations of leptin, and uncoupling protein 1 content of brown adipose tissue in root voles (Microtus oeconomus) from the Qinghai-Tibetan plateau.
Survival of small mammals in winter requires proper adjustments in physiology, behavior and morphology. The present study was designed to examine the changes in serum leptin concentration and the molecular basis of thermogenesis in seasonally acclimatized root voles (Microtus oeconomus) from the Qinghai-Tibetan plateau. In January root voles had lower body mass and body fat mass coupled with higher nonshivering thermogenesis (NST) capacity. Consistently, cytochrome c oxidase activity and mitochondrial uncoupling protein-1 (UCP1) protein contents in brown adipose tissues were higher in January as compared to that in July. Circulating level of serum leptin was significantly lower in winter and higher in July. Correlation analysis showed that serum leptin levels were positively related with body mass and body fat mass while negatively correlated with UCP1 protein contents. Together, these data provided further evidence for our previous findings that root voles from the Qinghai-Tibetan plateau mainly depend on higher NST coupled with lower body mass to enhance winter survival. Further, fat deposition was significantly mobilized in cold winter and leptin was potentially involved in the regulation of body mass and thermogenesis in root voles. Serum leptin might act as a starvation signal in winter and satiety signal in summer. Topics: Adipose Tissue, Brown; Animals; Arvicolinae; Basal Metabolism; Body Temperature Regulation; Body Weight; Electron Transport Complex IV; Energy Metabolism; Female; Ion Channels; Leptin; Male; Mitochondrial Proteins; Seasons; Tibet; Uncoupling Protein 1 | 2006 |
Relationships of physical activity with metabolic syndrome features and low-grade inflammation in adolescents.
Physical activity has beneficial effects on symptoms of the metabolic syndrome and low-grade inflammation in adults. These associations have rarely been studied in adolescents. Moreover, it has not been established whether they depend on adiposity, fat localisation and adipokines.. We used cross-sectional data of 640 12-year-old adolescents participating in the Intervention Centred on Adolescents' Physical Activity and Sedentary Behaviour Study (ICAPS). Weight, height, body fat mass and WHR were measured. Metabolic syndrome components, two inflammatory markers (IL-6 and C-reactive protein), plasma leptin, adiponectin and soluble TNF-alpha receptor 1 (sTNF-alpha R1) were determined. Insulin resistance was estimated by homeostasis model assessment (HOMA) and energy expenditure due to organised leisure-time physical activity (PAE) assessed by questionnaire.. The metabolic syndrome was present in 5.8% of the adolescents. After adjustment for sex, sexual maturity and socio-economic status, a beneficial relationship between PAE and all metabolic syndrome features was found, but only the associations with HOMA and IL-6 were independent of body fat mass and WHR. Adjusted means from the lowest to the highest tertile of PAE were 1.99, 1.80 and 1.78 for HOMA (p=0.04), and 0.88, 0.69 and 0.70 pg/ml for IL-6 (p=0.02). PAE was inversely associated with leptin, independently of body fat mass and WHR (p<10(-2)), but not with adiponectin or sTNF-alpha R1. Further adjustment for adipokines did not change the relationships of PAE with HOMA and IL-6.. In adolescents, physical activity is inversely related to HOMA and IL-6, independently of adiposity and fat localisation. These relationships are not accounted for by adipokines. Topics: Adipocytes; Adiponectin; Adiposity; Body Weight; C-Reactive Protein; Child; Cross-Sectional Studies; Female; Humans; Inflammation; Interleukin-6; Least-Squares Analysis; Leptin; Male; Metabolic Syndrome; Motor Activity; Receptors, Tumor Necrosis Factor, Type I; Socioeconomic Factors; Surveys and Questionnaires | 2006 |
Phenotypic variation in constitutional delay of growth and puberty: relationship to specific leptin and leptin receptor gene polymorphisms.
Constitutional delay of growth and puberty (CDGP) is a variant of normal pubertal timing and progress, often with dominant inheritance. It is likely that one or more genes will be associated with CDGP. Possible candidates are the leptin (L) and the leptin receptor (LR) genes, as the leptin axis links nutritional status to pubertal development. This study has assessed whether a) L or LR gene polymorphisms were associated with CDGP and b) the CDGP phenotype was influenced by these polymorphisms.. Case-control and transmission disequilibrium tests were used to test genetic association of L and LR polymorphisms with CDGP.. We genotyped L (3'CTTT repeat) and LR polymorphisms (Gln > Arg substitution, exon 6) in 81 CDGP children and 94 controls in the UK and 88 CDGP children from the US and assessed the effect of genotype on their anthropometric characteristics.. There was no association of these L or LR gene polymorphisms with CDGP. There was no difference in height or bone age delay within L or LR genotypes. However, UK CDGP children homozygous for the L short allele were heavier than heterozygotes and long allele homozygotes, with a similar trend in the US cohort. UK CDGP children with severe pubertal delay, who were thin, had significantly greater bone age delay and an increased frequency of parental pubertal delay than other groups and were less likely to be L short allele homozygotes.. There was no association of specific L or LR polymorphisms with CDGP, but L short allele carriage influenced the phenotype within CDGP. Topics: Adolescent; Alleles; Anthropometry; Body Height; Body Mass Index; Body Weight; Bone Development; Case-Control Studies; Child; Chromatography, High Pressure Liquid; DNA; Female; Genotype; Growth; Humans; Leptin; Linkage Disequilibrium; Male; Nutritional Status; Phenotype; Polymorphism, Genetic; Puberty, Delayed; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; United Kingdom; United States | 2006 |
Blood-brain leptin transport and appetite and reproductive neuroendocrine responses to intracerebroventricular leptin injection in sheep: influence of photoperiod.
Impaired anorectic actions of leptin may be due to intrahypothalamic insensitivity and/or reduced blood-brain transport. The influence of photoperiod on leptin responses and leptin transport from blood into cerebrospinal fluid (CSF) was examined in sheep. Sheep kept on ad libitum food for 15 wk in long days (LD) had higher voluntary food intake and lower GnRH/LH output than in short days (SD). Food intake was decreased approximately 30% after intracerebroventricular (icv) (and not iv) leptin injection, but only in SD. GnRH/LH secretion was decreased after icv (but not iv) leptin in both photoperiods. Leptin concentrations in CSF were higher in LD than SD but correlated with plasma leptin only in LD. Amounts of leptin entering CSF after iv leptin injection were greater in LD than SD. In a separate experiment, plasma (but not CSF) leptin was higher in fat than thin sheep in natural summer LD and after 5 wk in SD. CSF leptin correlated with plasma leptin in LD but not SD. CSF leptin after iv leptin injection was higher in thin than fat sheep but only in LD. Endogenous CSF to plasma concentration ratios correlated negatively with plasma concentrations, indicating decreased blood-brain transport with increased leptinemia. Therefore, icv (and not iv) leptin inhibited appetite only in SD and decreased GnRH/LH output in both photoperiods, and the proportion of circulating leptin entering CSF was higher in LD and thinner animals. Photoperiod apparently modulates intrahypothalamic leptin sensitivity of appetite, but not reproductive, regulatory pathways, whereas photoperiod and leptinemia influence leptin blood-brain transport. Topics: Animals; Appetite; Biological Transport, Active; Blood-Brain Barrier; Body Weight; Brain; Estradiol; Gonadotropin-Releasing Hormone; Hypothalamus; Injections; Injections, Intraventricular; Leptin; Luteinizing Hormone; Male; Neurosecretory Systems; Orchiectomy; Photoperiod; Radioimmunoassay; Reproduction; Sheep | 2006 |
Leptin suppresses stearoyl-CoA desaturase 1 by mechanisms independent of insulin and sterol regulatory element-binding protein-1c.
Stearoyl-CoA desaturase (SCD)1 catalyzes the rate-limiting reaction of monounsaturated fatty acid (MUFA) synthesis and plays an important role in the development of obesity. SCD1 is suppressed by leptin but induced by insulin. We have used animal models to dissect the effects of these hormones on SCD1. In the first model, leptin-deficient ob/ob mice were treated with either leptin alone or with both leptin and insulin to prevent the leptin-mediated fall in insulin. In the second model, mice with a liver-specific knockout of the insulin receptor (LIRKO) and their littermate controls (LOXs) were treated with leptin. As expected, leptin decreased SCD1 transcript, protein, and activity by >60% in ob/ob and LOX mice. However, the effects of leptin were not diminished by the continued presence of hyperinsulinemia in ob/ob mice treated with both leptin and insulin or the absence of insulin signaling in LIRKO mice. Furthermore, genetic knockout of sterol regulatory element-binding protein (SREBP)-1c, the lipogenic transcription factor that mediates the effects of insulin on SCD1, also had no effect on the ability of leptin to decrease either SCD1 transcript or activity. Thus, the effect of leptin on SCD1 in liver is independent of insulin and SREBP-1c, and leptin, rather than insulin, is the major regulator of hepatic MUFA synthesis in obesity-linked diabetes. Topics: Animals; Base Sequence; Blood Glucose; Body Weight; DNA Primers; Energy Intake; Insulin; Leptin; Mice; Mice, Knockout; Mice, Obese; Polymerase Chain Reaction; Receptor, Insulin; Receptors, Leptin; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1 | 2006 |
Central application of IGF-1 postpones time of vaginal opening in normally fed, but not in food-restricted rats.
Central but also peripheral IGF-1 is suggested to play a role in the initiation of puberty as it directly affects GnRH synthesis and release. A possible intermediate in the effects of IGF-1 on puberty might be the adiposity-signaling hormone leptin, whose plasma levels are decreased in food-restricted (FR) rats.. IGF-1 was chronically centrally infused in 23-day-old prepubertal female rats which were either normally fed or 30% FR, and the effects on time of vaginal opening (VO) and plasma leptin levels were monitored.. FR treatment postponed time of VO and decreased plasma leptin levels. In normally fed rats centrally infused with IGF-1, time of VO was found to be postponed to the same extent as FR treatment did. The IGF-1 infusion did not affect plasma leptin levels in normally fed animals but increased leptin levels in the FR group compared to controls. Daily food intake was equal between all groups but body weight course was lower in FR rats. IGF-1 treatment did not significantly affect food intake or body weight course.. FR treatment delays the moment of vaginal opening to the same extent as observed in normally fed rats that were centrally infused with IGF-1. Topics: Animal Nutritional Physiological Phenomena; Animals; Body Weight; Drug Administration Routes; Female; Food Deprivation; Infusion Pumps, Implantable; Insulin-Like Growth Factor I; Leptin; Male; Rats; Rats, Wistar; Sexual Maturation; Vagina | 2006 |
Overfeeding during lactation modulates insulin and leptin signaling cascade in rats' hearts.
Insulin has been described as a potential mediator of intrinsic responses to the nutritional state in the heart due to its effects on cardiac metabolism, mainly on glucose transport. It has been demonstrated that leptin can act through some components of the insulin-signaling cascade. We investigated the association between overfeeding during lactation and alterations of insulin and leptin signaling in the heart. In summary, we analyzed a feasible cross-talk between insulin and leptin through the study of some key proteins of their cascades in the heart. In order to study the effect of overfeeding on these cascades, Wistar rats were overfed through litter size reduction to only three pups. At 10 and 21 days of life, key proteins such as insulin receptor, leptin receptor, PI3-kinase, JAK2, STAT3, and GLUT4 were measured by Western blotting. Furthermore, the pups' weight and the plasma levels of insulin, leptin and glucose were determined. Overfed animals were overweight, had high insulin and leptin plasma levels, and displayed an activation of insulin and leptin cascade, leading to an increased translocation of GLUT4. We suggest that overfeeding during lactation probably alters cardiac metabolism, through the activation of a modulated cross-talk between leptin and insulin cascades. Topics: Animals; Animals, Suckling; Body Composition; Body Weight; Female; Heart; Insulin; Insulin Secretion; Lactation; Leptin; Male; Models, Animal; Myocardium; Rats; Rats, Wistar; Signal Transduction | 2006 |
Restoration of normal glucose tolerance in severely obese patients after bilio-pancreatic diversion: role of insulin sensitivity and beta cell function.
The aim of this study was to analyse the mechanisms underlying the improvement in glucose tolerance seen in morbidly obese patients undergoing bilio-pancreatic diversion (BPD).. We evaluated glucose tolerance (by OGTT), insulin sensitivity (euglycaemic-hyperinsulinaemic clamp and the OGTT index OGIS) and beta cell function (OGTT modelling analysis) in 32 morbidly obese (BMI=52+/-7 kg/m(2), mean+/-SD) patients (12 with NGT, 9 with IGT and 11 with type 2 diabetes), before and after BPD, and in 22 lean control subjects. Patients were studied before and from 7 days to 60 months after surgery.. BPD improved glucose tolerance in all subjects, who after surgery all had normal glucose tolerance. Insulin sensitivity was restored to normal levels in all subjects (pre-BPD 341+/-79 ml min(-1) m(-2), post-BPD 511+/-57 ml min(-1) m(-2), lean 478+/-49 ml min(-1) m(-2)). The insulin sensitivity change was detectable within 10 days of BPD. At baseline, beta cell sensitivity to glucose was impaired in diabetic subjects (25 [18] pmol min(-1) m(-2) l mmol(-1), median [interquartile range]) compared with lean subjects (82 [98]; p=0.05). After BPD, beta cell glucose sensitivity showed a tendency towards improvement but remained impaired in diabetic subjects (30 [62]; p<0.01 vs lean). Total insulin output decreased in parallel with the insulin sensitivity increase in all groups. In the whole patient group, mean OGTT glucose levels were inversely related to both insulin sensitivity and beta cell glucose sensitivity (r (2)=0.67, partial r=-0.76 and -0.41, respectively). NEFAs, leptin and adiponectin were related to insulin sensitivity but could not explain the early improvement.. Following BPD, glucose tolerance was restored mainly as a result of a rapid and large improvement in insulin sensitivity. Topics: Adiponectin; Adult; Biliopancreatic Diversion; Blood Glucose; Body Mass Index; Body Weight; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Leptin; Male; Middle Aged; Obesity, Morbid; Time Factors | 2006 |
Adrenal expression of orexin receptor subtypes is differentially regulated in experimental streptozotocin induced type-1 diabetes.
Orexins (hypocretins) are involved in the regulation of energy homeostasis and sleeping behavior. Orexins were also implicated in the regulation of neuroendocrine and autonomic functions. Recent data show the expression of orexin receptors within the hypothalamic-pituitary-adrenal (HPA) axis and suggest specific actions of orexins at the pituitary and adrenal glands. To further evaluate the role of orexin in the HPA axis, we investigated the mRNA expression of prepro-orexin (PPO) and orexin receptors within the HPA axis of streptozotocin-injected (STZ) rats showing type-1 like diabetes. PPO, as well as OX(1) and OX(2) receptor levels were analyzed by quantitative real-time PCR (qPCR). STZ rats were characterized by decreased body weight, plasma insulin, and leptin levels and by increased plasma glucose. Hypothalamic PPO mRNA levels were significantly reduced in STZ compared to non-diabetic control rats. No differences were found in the mRNA levels of hypothalamic or pituitary OX(1) and OX(2) receptors between control and STZ rats. In adrenals, OX(1) receptor mRNA levels were significantly elevated in STZ rats while OX(2) receptors were significantly reduced. Our results imply distinct functions of adrenal orexin receptor subtypes during type-1 like diabetes. Topics: Adrenal Glands; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptides; Orexin Receptors; Orexins; Pituitary Gland; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; RNA, Messenger; Streptozocin | 2006 |
Impact of prenatal stress on long term body weight is dependent on timing and maternal sensitivity.
Stress experienced during pregnancy increases the risk for altered birth weights. Recent studies have revealed a link between abnormal birth weights and a future predisposition toward developing overweight or obesity. To determine the gestational time window when stress exposure produces the greatest impact on offspring body weight regulation, we have examined the birth weights and long-term body weight changes in offspring exposed to chronic variable stress (CVS) early, mid-, or late in gestation. As it is likely that the influences of prenatal stress on development stem from a complex interaction between both environmental and genetic factors, our study has included comparisons with offspring born to stress-sensitive (corticotropin-releasing factor receptor-2 deficient) mice. Stress experienced late in pregnancy significantly elevated offspring birth weights in wild type mice compared to unstressed controls. However, this weight difference diminished postnatally. In contrast, stress experienced mid- to late in pregnancy produced significant and long-term effects on body weight in offspring from stress-sensitive dams, were the male offspring were 15% heavier as adults. Adult offspring plasma glucose and leptin levels were also dependent on the timing of stress exposure, indicating that alterations in energy homeostasis may be influencing long-term body weight. Results from these studies support our hypothesis that the ultimate effect of prenatal stress on offspring long-term outcome is dependent on the timing of exposure and maternal sensitivity. Topics: Animals; Birth Weight; Blood Glucose; Body Weight; Corticosterone; Data Interpretation, Statistical; Eating; Energy Metabolism; Female; Growth; Homeostasis; Hypothalamo-Hypophyseal System; Leptin; Litter Size; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, Corticotropin-Releasing Hormone; Sex Ratio; Stress, Psychological | 2006 |
[A study of the level of serum leptin in patients with obstructive sleep apnea-hypopnea syndrome and obesity and patients with normal body mass].
To explore the level of serum leptin in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) and obesity and patients with normal body mass.. Polysomnography (PSG) was performed in 53 patients with OSAHS and in 41 simple obesity and in 62 patients with normal body mass. The level of serum leptin was detected by radioimmunoassay. The stature, weight, neck collar, hip circumference, waistline were measured.. (1) Serum leptin level in patients with OSAHS and obesity was higher than patients with normal body mass. At the same time, serum leptin level in patients with OSAHS was higher than obesity ( P < 0.05). (2) Serum leptin levels were positive significantly correlated with BMI in both OSAHS patients and simple obesity, but only the leptin level in patients with OSAHS was significantly correlated with apnea and hypopnea index (AHI) and proportion of neck circumference and waist-hip ratio (WHR).. The rise of the serum leptin level in obesity was resisted of leptin. The serum leptin level of patients with OSAHS correlated with AHI shows that OSAHS maybe one reason of arising serum leptin's rising. Leptin could stimulate aspirator centrum. Topics: Adult; Aged; Body Weight; Case-Control Studies; Female; Humans; Leptin; Male; Middle Aged; Obesity; Sleep Apnea, Obstructive | 2006 |
Effects of central or peripheral leptin administration on norepinephrine turnover in defined fat depots.
Leptin preserves lean tissue but decreases adipose tissue by increasing lipolysis and/or inhibiting lipogenesis. The sympathetic nervous system (SNS) is a primary regulator of lipolysis, but it is not known if leptin increases norepinephrine turnover (NETO) in white adipose tissue. In this study, we examined the effect of leptin administered either as a chronic physiological dose (40 microg/day for 4 days from ip miniosmotic pumps) or as an acute injection in the third ventricle (1.5 microg injected two times daily for 2 days) on NETO and the size of brown and white fat depots in male Sprague Dawley rats. NETO was determined from the decline in tissue norepinephrine (NE) during 4 h following administration of the NE synthesis inhibitor alpha-methyl-para-tryrosine. The centrally injected leptin-treated animals demonstrated more dramatic reductions in food intake, body weight, and fat pad size and an increase in NETO compared with the peripherally infused animals. Neither route of leptin administration caused a uniform increase in NETO across all fat pads tested, and in both treatment conditions leptin decreased the size of certain fat pads independent of an increase in NETO. Similar discrepancies in white fat NETO were found for rats pair fed to leptin-treated animals. These results demonstrate that leptin acting either centrally or peripherally selectively increases sympathetic outflow to white fat depots and that a leptin-induced change in fat pad weight does not require an increase in NETO. Topics: Adipose Tissue, White; Adiposity; Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Infusions, Parenteral; Injections, Intraventricular; Leptin; Male; Metabolic Clearance Rate; Norepinephrine; Rats; Rats, Sprague-Dawley | 2006 |
Neuronal PTP1B regulates body weight, adiposity and leptin action.
Obesity is a major health problem and a risk factor for type 2 diabetes. Leptin, an adipocyte-secreted hormone, acts on the hypothalamus to inhibit food intake and increase energy expenditure. Most obese individuals develop hyperleptinemia and leptin resistance, limiting the therapeutic efficacy of exogenously administered leptin. Mice lacking the tyrosine phosphatase PTP1B are protected from diet-induced obesity and are hypersensitive to leptin, but the site and mechanism for these effects remain controversial. We generated tissue-specific PTP1B knockout (Ptpn1(-/-)) mice. Neuronal Ptpn1(-/-) mice have reduced weight and adiposity, and increased activity and energy expenditure. In contrast, adipose PTP1B deficiency increases body weight, whereas PTP1B deletion in muscle or liver does not affect weight. Neuronal Ptpn1(-/-) mice are hypersensitive to leptin, despite paradoxically elevated leptin levels, and show improved glucose homeostasis. Thus, PTP1B regulates body mass and adiposity primarily through actions in the brain. Furthermore, neuronal PTP1B regulates adipocyte leptin production and probably is essential for the development of leptin resistance. Topics: Adipose Tissue; Animals; Body Weight; Drug Administration Schedule; Eating; Gene Expression Regulation, Enzymologic; Glucose; Homeostasis; Injections, Intraperitoneal; Leptin; Male; Mice; Mice, Knockout; Neurons; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Time Factors | 2006 |
Electrophysiological characterization of left ventricular myocytes from obese Sprague-Dawley rat.
Obesity is a complex multifactorial disease that is often associated with cardiac arrhythmias. Various animal models have been used extensively to study the effects of obesity on physiological functions, but, to our knowledge, no study related to ionic membrane currents has been performed on isolated cardiac myocytes. Therefore, we examined the electrophysiological characteristics of four ionic currents from isolated left ventricular myocytes of a high-energy (HE)-induced obesity rat model.. Male Sprague-Dawley rats were fed with either a control diet or a diet containing 33% kcal as fat (HE) for 14 weeks starting at 6 weeks of age. Voltage-clamp experiments were performed on ventricular myocytes. Leptin receptor (ObR) expression was measured using ObR enzyme-linked immunosorbent assay.. In the HE group, rats designated as obese did not develop a cardiac hypertrophy, either at the organ level or at the cellular level. Densities and kinetics of the L-type calcium current, the transient outward potassium current, the delayed rectifier potassium current, and the sodium-calcium exchange current (I(NCX)) were not significantly different between control and obese rats. A down-regulation of ObR expression was evidenced in the heart of obese rats compared with controls. Acute exposure (5 minutes) of leptin (100 nM) did not induce a significant modification in the current densities either in control or in obese rats, except for I(NCX) density measured in control rats.. The absence of effect of leptin on I(NCX) in obese rats could be a potential arrhythmogenic substrate in obesity. Topics: Adipose Tissue, White; Adiposity; Animals; Body Weight; Cell Size; Electrophysiology; Heart Ventricles; Leptin; Male; Membrane Potentials; Myocytes, Cardiac; Obesity; Organ Size; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin | 2006 |
Testosterone decreases adiponectin levels in female to male transsexuals.
To evaluate the effect of testosterone (T) on adiponectin serum levels in transsexual female patients.. We measured adiponectin, leptin, luteinizing hormone and follicle stimulating hormone, T, estradiol, lipid profile, biochemical parameters and body composition in 16 transsexual female patients at baseline and after 6 months of T treatment (100 mg Testoviron Depot /10 days, i.m.).. Adiponectin levels were 16.9 +/- 7.3 mg/mL at baseline and 13.5 +/- 7.4 mg/mL at month 6 of T treatment (P < 0.05). Leptin and high-density lipoprotein cholesterol decreased significantly, whereas body mass index, waist circumference and lean body mass increased significantly after 6 months of T treatment. No changes in insulin or Homeostasis Model Assessment were detected.. T can significantly reduce adiponectin serum levels in transsexual female patients. Topics: Adiponectin; Adipose Tissue; Adult; Body Mass Index; Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Female; Humans; Leptin; Sex Hormone-Binding Globulin; Testosterone; Transsexualism | 2006 |
Increased leptin expression in the dorsal vagal complex suppresses adiposity without affecting energy intake and metabolic hormones.
Increased leptin transgene expression locally in hypothalamic sites suppresses weight and energy intake, enhances thermogenic energy expenditure, and differentially modulates metabolic hormones for an extended period. We evaluated whether a similar localized expression of leptin transgene in the dorsal vagal complex (DVC) in the caudal brain stem that also displays the biologically relevant leptin receptor would reproduce these varied responses and thus demonstrate functional connectivity between the hypothalamus and DVC.. Adult female rats were microinjected with a recombinant adeno-associated virus encoding either rat leptin or green fluorescent protein gene (control) in the DVC. Food intake and body weight were monitored weekly, and metabolic variables were analyzed at the end of 10 weeks.. Increased leptin transgene expression in the DVC suppressed the time-related increase in body weight accompanied by a transient decrease in food intake at week 1 post-injection and little effect on thermogenic energy expenditure. That suppression of weight was due to decreased adiposity is shown by the markedly suppressed white adipose tissue-derived hormones, leptin and adiponectin. Circulating concentrations of pancreatic insulin, gastric ghrelin, and glucose levels were unchanged. This segregation of the varied effects of leptin expression in hypothalamic sites vs. DVC endorses the view that among the various endocrine organs under sympathetic nervous system control, only those leptin-activated neural circuits in the hypothalamus that suppress weight and adiposity on a long-term basis transverse through DVC en route to white adipose tissue. Topics: Adiponectin; Adipose Tissue, Brown; Adiposity; Animals; Animals, Genetically Modified; Blood Glucose; Body Weight; Dependovirus; Eating; Energy Intake; Female; Gene Expression; Gene Transfer Techniques; Ghrelin; Hormones; Hypothalamus; Insulin; Ion Channels; Leptin; Microinjections; Mitochondrial Proteins; Peptide Hormones; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; RNA, Messenger; Transgenes; Uncoupling Protein 1 | 2006 |
Adiponectin, adipocyte fatty acid binding protein, and epidermal fatty acid binding protein: proteins newly identified in human breast milk.
Breastfeeding may protect children from developing metabolic syndrome and other diseases later in life. We investigated novel proteins in human breast milk that might play a role in this process.. We used ELISA to measure adiponectin, adipocyte and epidermal fatty acid binding proteins (AFABP, EFABP), and leptin concentrations in human breast milk obtained from 59 mothers 48 h after initiation of lactation. Using a questionnaire and medical records, we collected information about the mothers and newborns.. Mean (SE) adiponectin concentrations in breast milk were 13.7 (0.8), range 3.9-30.4 microg/L; AFABP concentrations 26.7 (4.4), range 1.2-137.0 microg/L; EFABP concentrations 18.1 (1.4), range 0.8-47.0 microg/L; and leptin concentrations 0.50 (0.05), range 0-1.37 microg/L. We found a significant correlation between AFABP and EFABP concentrations (r = 0.593, P <0.0001). Maternal EFABP concentrations were significantly higher in mothers who delivered boys than in those who delivered girls [21.7 (2.3) vs 15.4 (1.7) microg/L, P = 0.028] and correlated with newborn birth weight (r = 0.266, P = 0.045). Maternal leptin correlated with body weight before pregnancy (r = 0.272, P = 0.043) and at delivery (r = 0.370, P = 0.005), body mass index before pregnancy (r = 0.397, P = 0.003) and at delivery (r = 0.498, P <0.0001), body weight gain during pregnancy (r = 0.267, P = 0.047), and newborn gestational age (r = 0.266, P = 0.048). Leptin was significantly lower in mothers who delivered preterm vs term babies [0.30 (0.09) vs 0.60 (0.05) ug/L, P = 0.026].. Concentrations of adiponectin, AFABP, and EFABP in human breast milk are related to nutritional variables of mothers and newborns and thus may play a role in the protective effects of breastfeeding. Topics: Adipocytes; Adiponectin; Birth Weight; Body Mass Index; Body Weight; Enzyme-Linked Immunosorbent Assay; Epidermis; Fatty Acid-Binding Proteins; Female; Humans; Infant, Newborn; Leptin; Male; Milk, Human; Pregnancy; Sex Factors | 2006 |
Satiety assessment in neonatally handled rats.
We have previously demonstrated that neonatal handling increases sweet food ingestion. In the present study, we examined whether food intake, using different kinds of food, is altered in neonatally handled animals, with or without inducing satiety using a sucrose solution. Abdominal fat, glycemia and hormones linked to appetite including leptin, ghrelin and insulin were also measured. We tested palatable food consumption in the homecage to verify whether environmental cues could influence ingestion. Nests of Wistar rats were either (1) non-handled or (2) handled (10 min/day). Handling was performed on days 1-10 after birth. When adults, rats were habituated to sweet food (Froot Loops, Kellogg's) and to palatable fiber pellets (Fiber One), Nestlé). Sweet food consumption was increased in the neonatally handled group, when tested in the homecage, and also in the satiety experiment. These rats displayed a satiety curve when compared to the control group, which ate less but constantly. Handled rats exposed to a sucrose solution decreased sweet food ingestion, which did not occur in the control group. When exposed to a food with complex carbohydrates, these differences disappeared. There were no differences in body weight, abdominal fat or in glycemia, as well as no differences in plasma levels of insulin or leptin. However, ghrelin was decreased in neonatally handled rats. Neonatally handled rats demonstrated an increased consumption of sweet food, satiety responses to sucrose, as well as decreased levels of plasma ghrelin. It is possible that signaling mechanisms related to satiety, both peripherally and/or centrally may contribute to these behavioral findings. Topics: Abdominal Fat; Analysis of Variance; Animals; Animals, Newborn; Appetite; Behavior, Animal; Blood Glucose; Body Weight; Eating; Enzyme-Linked Immunosorbent Assay; Fasting; Feeding Behavior; Female; Food; Ghrelin; Habituation, Psychophysiologic; Handling, Psychological; Insulin; Leptin; Male; Peptide Hormones; Pregnancy; Rats; Satiety Response | 2006 |
Diminished hypothalamic bdnf expression and impaired VMH function are associated with reduced SF-1 gene dosage.
In the central nervous system, steroidogenic factor 1 (SF-1) is required for terminal differentiation of neurons within the ventromedial hypothalamus (VMH). Given the importance of this brain region in regulating physiological homeostasis including energy balance, we asked how sf-1 gene dosage affects VMH function. Despite an apparent normal VMH cytoarchitecture, sf-1 heterozygous (+/-) mice exhibited diet-induced obesity when they were group housed with hyperphagia and impaired sympathetic activity. On the basis of previous findings suggesting brain-derived neurotrophic factor (bdnf) as an SF-1 target gene, we assessed the colocalization of SF-1 and BDNF expressing neurons, as well as expression of the four exon-specific bdnf promoter transcripts in the VMH. Indeed, a subset of neurons located primarily in the ventrolateral VMH coexpress SF-1 and BDNF, and in contrast to other brain regions, bdnf I, II, and IV but not III are found. Consistent with these findings, cellular assays showed that SF-1 is able to activate exon I and IV promoters. More important, levels of bdnf I and IV in the VMH were reduced in heterozygous mice similar to levels observed in fasted wild-type mice. Collectively, we propose that a reduction in the sf-1 gene dosage directly affects BDNF levels in the VMH and disrupts normal hypothalamic function. Topics: alpha-MSH; Animals; Body Weight; Brain-Derived Neurotrophic Factor; Cold Temperature; Food Deprivation; Gene Expression; Homeodomain Proteins; Immunohistochemistry; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Oxygen Consumption; Promoter Regions, Genetic; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Steroidogenic Factor 1; Stress, Physiological; Transcription Factors; Ventromedial Hypothalamic Nucleus | 2006 |
Minor gene effect of leptin receptor variant on the body weight in KK/Ta mice.
Leptin is an adipocyte-derived hormone involved in body weight regulation that acts through the leptin receptor. Previous studies exploring potential association between the leptin receptor (Lepr) variant and obesity have reported conflicting results. The objectives of the present study are to evaluate (1) whether the Lepr variant contributes to type 2 diabetes and its related disorders such as obesity and (2) whether the gene interaction between Lepr and Zn-alpha(2) glycoprotein1 (Azgp1) genes is recognized using genetically homogeneous type 2 diabetic KK/Ta mice.. The levels of leptin (Lep) and Lepr mRNA in adipose tissues and brain were measured by relative quantitative RT-PCR. The levels of leptin protein in sera were measured by enzyme-linked immunosorbent assay. Genotyping of backcross mice was performed using a mismatch primer.. Leptin protein and its mRNA levels were increased in KK/Ta mice. Lepr mRNA levels of KK/Ta mice did not differ from those of BALB/c mice. Sequence analysis revealed that the coding region of Lep in KK/Ta mice was identical to that in BALB/c mice. Six nucleotide polymorphisms were observed in the coding region of Lepr. In KK/Ta x (BALB/c x KK/Ta) F1 backcross mice, the Lepr variant of KK/Ta mice failed to alter any of the variables of obesity except for body weight at 20 weeks of age. However, it enhanced the effect of Azgp1 on body weight.. It is concluded that the Lepr variant contributes to obesity to some degree in KK/Ta mice. Topics: Adipose Tissue; Animals; Body Weight; Brain; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genotype; Leptin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Obesity; Phenotype; Polymorphism, Restriction Fragment Length; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2006 |
Time course of changes in in vitro lipolysis of intra-abdominal fat depots in relation to high-fat diet-induced hepatic steatosis in rats.
The purpose of the present study was to determine the time course of changes in in vitro lipolysis and in perilipin content (Western blot) in the mesenteric and/or the retroperitoneal fat depots in relation to the development of hepatic steatosis in high-fat diet-fed rats. Female Sprague-Dawley rats were submitted to a high-fat diet (HF diet; 42 % as kJ) or a standard diet (SD diet) for 1, 2, 3 or 8 weeks. Fat accretion in the mesenteric and retroperitoneal tissues was higher (P<0.01) in HF diet-fed than in SD diet-fed rats as soon as 1 week after the beginning of the diet. Liver triacylglycerol concentrations were significantly (P<0.01) higher in HF diet-fed than in SD diet-fed rats throughout the experiment, the highest values being reached at week 2 of the diet. Basal and stimulated lipolysis (10(-4) to 10(-7) M-isoproterienol) in the mesenteric and retroperitoneal fat depots was not changed during the first 3 weeks, regardless of the diet. Lipolysis in the mesenteric adipose tissue in the basal and stimulated states was, however, higher (P<0.01) in HF diet-fed than in SD diet-fed rats after 8 weeks of the diets. There were no significant (P>0.05) effects of diet and time on perilipin content of mesenteric tissue. In spite of a rapid fat accretion, the present results do not provide any evidence of a rapid (3 weeks) increase in in vitro lipolysis in intra-abdominal fat depots upon the undertaking of an HF diet at a time where liver lipid infiltration is the most significant. Topics: Adipocytes; Animals; Blood Glucose; Body Weight; Carrier Proteins; Cells, Cultured; Dietary Fats; Fatty Acids, Nonesterified; Fatty Liver; Female; Insulin; Intra-Abdominal Fat; Leptin; Lipolysis; Liver; Perilipin-1; Phosphoproteins; Rats; Rats, Sprague-Dawley | 2006 |
Effect of dietary supply of butters rich either in trans-10-18 : 1 or in trans-11-18 : 1 plus cis-9, trans-11-18 : 2 on rabbit adipose tissue and liver lipogenic activities.
Experimental butters with a high content of trans-18 : 1 fatty acids and/or cis-9,trans-11-18 : 2 (rumenic acid; RA) were fed to thirty-six New Zealand White rabbits to investigate their effects on adipose tissue (AT) and liver lipogenic activities. Animals received one of three atherogenic (0.2 % cholesterol) diets containing 12 % butter with either a standard fatty acid composition (rich in saturated fatty acids), rich in trans-10-18 : 1 (T10 diet) or in trans-11-18 : 1 plus RA (T11+ RA diet) for 6 or 12 weeks. The ingestion of butters rich in trans fatty acids and/or RA for 6 weeks had little or no effect on liver and AT lipogenesis. The ingestion for 12 weeks of butter rich in T11+ RA decreased perirenal AT weight, lipogenic enzyme and lipoprotein lipase activities, without affecting liver lipid concentration or lipogenic activities except for a decrease in glycerol-3-phosphate dehydrogenase activity. Similar trends, but of a lower magnitude, were observed in rabbits fed the T10 diet for 12 weeks. Ingestion of the T10 or T11+ RA diets for 6 or 12 weeks had no significant effect on plasma metabolites and hormones except for glucose which increased at 6 weeks in the T10 group. Plasma leptin concentration was positively correlated with AT weight but did not differ between the three diets. In conclusion, the supply of butters rich in either T10 or T11+ RA in an atherogenic diet for 12 weeks decreased rabbit AT lipogenesis, with a more marked effect of the T11+RA diet, but had no effect on liver lipogenesis. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Butter; Diet; Dietary Fats; Fatty Acids, Nonesterified; Glucosephosphate Dehydrogenase; Glycerolphosphate Dehydrogenase; Insulin; Leptin; Linoleic Acids, Conjugated; Lipogenesis; Lipoprotein Lipase; Liver; Male; Rabbits; Trans Fatty Acids | 2006 |
Opposing influences of prenatal and postnatal growth on the timing of menarche.
Menarche is a milestone of reproductive development, and its timing may be differentially influenced by the growth conditions before birth and those between birth and puberty. The present study explored the relationships among menarcheal timing and markers of prenatal and midchildhood growth in healthy Australian girls.. A total of 156 girls aged 8 yr from a birth cohort of full-term babies had height, weight, and waist circumference measured. One hundred three girls had dual x-ray absorptiometry performed and blood analyzed for insulin, leptin, IGF-I, estradiol, and dehydroepiandrosterone sulfate levels. Girls were followed up at age 15 yr and their age of menarche was recorded.. Measures included age of menarche; birth weight and birth length; height, weight, waist circumference, and body composition by dual x-ray absorptiometry; and plasma insulin, leptin, IGF-I, estradiol, and dehydroepiandrosterone sulfate at age 8 yr.. Girls with earlier menarche were light and long at birth and had higher total and central adiposity and IGF-I and estradiol levels in midchildhood, compared with those with later menarche. Age of menarche was best predicted by combining size at birth and body mass index z score at age 8 yr (r2 = 0.12; P < 0.001).. The timing of menarche appears to be influenced in opposing directions by pre- and postnatal growth. Menarche was found to occur earlier in girls who were long and light at birth and who had a higher fat mass and circulating IGF-I in childhood. These findings may partly explain ethnic differences and secular trends in the age of menarche. Topics: Adolescent; Birth Weight; Body Fat Distribution; Body Height; Body Mass Index; Body Size; Body Weight; Child; Estradiol; Female; Fetal Development; Follow-Up Studies; Humans; Infant, Newborn; Insulin; Insulin-Like Growth Factor I; Leptin; Menarche; Puberty, Delayed; Puberty, Precocious; Regression Analysis | 2006 |
Increased susceptibility to diet-induced obesity in histamine-deficient mice.
The neurotransmitter histamine is involved in the regulation of appetite and in the development of age-related obesity in mice. Furthermore, histamine is a mediator of the anorexigenic action of leptin. The aim of the present study was to investigate a possible role of histamine in the development of high-fat diet (HFD)-induced obesity.. Histamine-deficient histidine decarboxylase knock-out (HDC-KO) mice and C57BL/6J wild-type (WT) mice were given either a standard diet (STD) or HFD for 8 weeks. Body weight, 24-hour caloric intake, epididymal adipose tissue size, plasma leptin concentration and quantitative expression of leptin receptor (Ob-R) mRNA were measured.. Both HDC-KO and WT mice fed an HFD for 8 weeks increased their body weight significantly more than STD-fed mice. A significant difference in body weight gain between HDC-KO mice fed an HFD or an STD was seen after 2 weeks, whereas a significant difference in body weight gain was first observed after 5 weeks in WT mice. After 8 weeks 24-hour caloric intake was significantly lower in HFD- than in STD-fed WT mice. In HDC-KO mice no difference in caloric intake was observed between HFD- and STD-fed mice. After 8 weeks epididymal adipose tissue size and plasma leptin concentration had increased significantly in HFD-fed WT and HDC-KO mice compared to their STD-fed controls. Epididymal adipose tissue size was higher in HDC-KO than WT mice, both in STD- and HFD-fed mice. A significant decrease in Ob-R mRNA in HFD-fed HDC-KO mice compared to STD-fed HDC-KO mice was observed, while no such difference was observed in WT mice.. Based on our results, we conclude that histamine plays a role in the development of HFD-induced obesity. Topics: Adipose Tissue; Animals; Body Weight; Dietary Fats; Energy Intake; Histamine; Histidine Decarboxylase; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Statistics, Nonparametric | 2006 |
Conjugated linoleic acid and chromium lower body weight and visceral fat mass in high-fat-diet-fed mice.
More than half of the U.S. population has a body mass index of 25 kg/m2 or more, which classifies them as overweight or obese. Obesity is often associated with comorbidities such as diabetes, cardiovascular diseases, and cancer. CLA and chromium have emerged as major dietary supplements that reduce body weight and fat mass, and increase basal metabolic rate in animal models. However, studies show that CLA induces insulin resistance in mice and in humans, whereas Cr improves insulin sensitivity. Hence, we designed the present study to examine the combined effect of CLA and Cr on body composition and insulin sensitivity in a Balb/c mice (n = 10/group) model of high-fat-diet-induced obesity. CLA alone lowered body weight, total body fat mass, and visceral fat mass, the last of which decreased further with the combination of CLA and Cr. This effect was accompanied by decreased serum leptin levels in CLA-fed and CLA + Cr-fed mice, and by higher energy expenditure (EE) and oxygen consumption (OC) in CLA + Cr-fed mice. Serum levels of glucose, insulin, the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6), as well as insulin resistance index (IRI), decreased with CLA, whereas CLA and Cr in combination had significant effects on insulin and IL-6 concentrations and IRI. In summary, CLA + Cr decreased body weight and fat mass in high-fat-diet-fed mice, which may be associated with decreased leptin levels and higher EE and OC. Topics: Adiponectin; Analysis of Variance; Animals; Body Weight; Chromium; Dietary Fats; Energy Metabolism; Intra-Abdominal Fat; Leptin; Linoleic Acids, Conjugated; Male; Mice; Mice, Inbred BALB C | 2006 |
Diverse basal and stress-related phenotypes of Sprague Dawley rats from three vendors.
Based on observed phenotypic differences in growth and ACTH responses to stress in Sprague Dawley rats obtained from different vendors, we ran head-to-head comparisons on rats obtained from three different vendors, Harlan, Charles River, and Simonsen, with respect to baseline phenotypic differences and a metabolic feedback hypothesis of hypothalamo-pituitary-adrenal (HPA) regulation. Charles River and Harlan rats gained weight faster than Simonsen rats, but chow intake standardized for body weight was not increased, consistent with their greater caloric efficiency. Weight gain was inversely related with mean daily temperatures, without differences in activity levels. Half of the animals given lard and 32% sucrose solutions in addition to chow increased caloric intake and core temperature, decreased caloric efficiency, and increased fat depots, leptin, and in Simonsen rats, insulin. A 5-day regimen of once-daily 2-h restraint decreased feeding and caloric efficiency. Rats from two vendors with the availability of sucrose and lard, Charles River and Simonsen, showed blunted HPA responses to restraint compared to chow controls, whereas the Harlans exhibited no adrenocorticotropin (ACTH) response and an amplified adrenocortical response on the high-energy diet compared to chow controls. Substantial phenotypic differences exist between Sprague Dawley rats from different vendors with respect to metabolism and HPA function. The metabolic feedback hypothesis was supported in two of the three vendors' rats. Topics: Adrenocorticotropic Hormone; Animals; Basal Metabolism; Body Composition; Body Temperature; Body Weight; Corticosterone; Energy Intake; Feeding Behavior; Hypothalamo-Hypophyseal System; Insulin; Leptin; Male; Phenotype; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Species Specificity; Stress, Psychological | 2006 |
Hypothalamic ghrelin treatment modulates NPY-but not CRH-ergic activity in adrenalectomized rats subjected to food restriction: Evidence of a novel hypothalamic ghrelin effect.
It has been proposed that ghrelin induces food intake by a mechanism due to the stimulation of hypothalamic NPY-ergic activity. It is recognized that bilateral adrenalectomy (ADX) enhances hypothalamic CRH-ergic function and reduces appetite. Thus, the aim of the present study was to test whether, icv-administered, ghrelin modulates NPY- and CRH-ergic functions after food restriction (FR) and glucocorticoid deprivation. For this purpose, 1 microg ghrelin was administered icv to ad libitum (AL) eating and to corticosterone (B)-depleted (ADX) and -replete (sham and ADX+B) male animals habituated, for 15 d, to FR. Food intake, hypothalamic function, and peripheral ghrelin, ACTH, and B concentrations were evaluated 2 h after ghrelin administration. Results indicate that while icv ghrelin treatment stimulated 2-h food intake in AL rats, it failed to do so in sham- and ADX+B-FR animals; moreover, 2-h food intake was inhibited by icv ghrelin treatment in ADX-FR rats. Regarding peripheral hormone levels: (a) basal circulating ghrelin levels, already enhanced (vs AL rats) by FR, significantly increased 2 h after icv ghrelin treatment in AL and sham-FR rats; (b) central ghrelin treatment stimulated ACTH secretion in circulation of AL and glucocorticoid-replete-FR rats; and (c) B circulating levels remained unchanged after ghrelin treatment, although they were in relation to the food intake condition of rats. Finally, hypothalamic NPY mRNA expression was enhanced by FR and, in response to icv ghrelin treatment, it decreased in ADX-FR rats only. ADX-enhanced hypothalamic CRH mRNA levels were reduced by ghrelin icv administration only when animals received B replacement therapy. Our data indicate an inhibitory effect of hypothalamic ghrelin on NPY-ergic activity in FR rats lacking endogenous glucocorticoid. Topics: Adrenalectomy; Adrenocorticotropic Hormone; Animals; Body Weight; Corticotropin-Releasing Hormone; Drug Administration Routes; Eating; Food Deprivation; Gene Expression; Ghrelin; Glucocorticoids; Hypothalamus; Injections; Leptin; Male; Neuropeptide Y; Peptide Hormones; Rats; Rats, Wistar; RNA, Messenger | 2006 |
Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes mellitus.
Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus. Topics: Animals; Appetite; Body Weight; Diabetes Mellitus; Histamine Agonists; Imidazoles; Insulin; Leptin; Mice; Mice, Knockout; Obesity; Piperidines; Receptors, Histamine H3; Thiourea | 2006 |
Is the CCK2 receptor essential for normal regulation of body weight and adiposity?
Cholecystokinin (CCK) is a gastrointestinal satiety signal released from the duodenum to terminate feeding, via CCK1 receptors. CCK2 receptors are considered to be involved in anxiety. CCK2 receptor knockout mice have increased body weight and food intake. Little is known regarding the effects of CCK2 receptor deficiency on adipose distribution and hypothalamic feeding regulators such as neuropeptide Y (NPY), a powerful stimulator of feeding. Adult (10 week) CCK2 receptor knockout and wild-type mice were anaesthetized and killed by decapitation. Brain sections, organs and fat tissue were dissected. Plasma leptin, insulin and brain NPY content were measured by radioimmunoassay. Female CCK2 receptor knockout mice weighed more than control mice (22.0 +/- 0.2 vs. 19.9 +/- 0.4 g, P < 0.05), with this difference being less marked in male mice (26.4 +/- 0.4 vs. 25.6 +/- 0.6 g). Fat masses in all locations sampled were significantly smaller in CCK2 receptor knockout mice of both genders (P < 0.05), resulting in lower plasma leptin and insulin levels. NPY concentrations were significantly increased in arcuate nucleus and anterior hypothalamus in both male and female CCK2 receptor knockout mice, and total hypothalamic NPY content was increased by 7 and 9% in males and females, respectively (P < 0.05). CCK2 receptor deletion was associated with increased body weight and hypothalamic NPY content, but reduced fat masses and plasma leptin and insulin. Increased NPY might contribute to increased food intake in CCK2 receptor knockout mice. Further work needs to focus on the metabolic changes. Topics: Adiposity; Animals; Body Weight; Brain Chemistry; Corticosterone; Female; Insulin; Leptin; Male; Mice; Mice, Knockout; Neuropeptide Y; Radioimmunoassay; Receptor, Cholecystokinin B; Sex Factors | 2006 |
Intraventricular insulin and leptin reduce food intake and body weight in C57BL/6J mice.
As the incidence of obesity continues to increase, adequate animal models acquire increased importance for the investigation of energy homeostatic mechanisms. Understanding the central mechanism of action of the adiposity hormones, insulin and leptin, has become particularly important as researchers examine ways to treat or prevent obesity. Although the intra-3rd-ventricular (i3vt) administration of insulin reduces food intake in several species, its effects on food intake and body weight have not been previously been assessed in mice. Male C57BL/6J mice were administered insulin i3vt (0.05, 0.1 or 0.4 microU) or leptin i3vt (5 microg/1 microl) as a positive control. As it occurs in other species, i3vt insulin dose-dependently reduced 24-h food intake and body weight, and increased hypothalamic proopiomelanocortin (POMC) mRNA. Hence, genetic manipulations that influence brain insulin sensitivity in mice can now more easily be integrated with the broader literature on energy homeostasis. Topics: Animals; Behavior, Animal; Blood Glucose; Body Weight; Dose-Response Relationship, Drug; Eating; Gene Expression Regulation; Hypoglycemic Agents; Hypothalamus; Injections, Intraventricular; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Pro-Opiomelanocortin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors | 2006 |
Plasma adipokines and body composition in response to modest dietary manipulations in the mouse.
The relationship between adipokine levels and body composition has not been carefully examined. Most studies in humans are cross-sectional, and the few studies in mice have been restricted to a comparison of control animals with markedly obese, insulin-resistant mice. Our objective was to study changes in adipokine levels and body composition in response to modest dietary intervention.. Plasma resistin, adiponectin, and leptin levels were examined in mice fed ad libitum, a 75% restricted diet, or a diet supplemented with 10% sucrose. Body composition was determined by whole-body DXA.. The percentage body fat was reduced in mice subjected to the restricted diet and increased in mice supplemented with 10% dextrose. Adipokine levels were not different in either of these groups compared with the control mice. A significant inverse correlation was observed between resistin levels and total body fat, whereas there was no significant correlation between body fat and adiponectin levels. Positive correlations were observed between leptin levels and percentage body fat, total body fat, and abdominal fat. Leptin levels correlated with plasma glucose, but multivariate analysis revealed that this correlation was the result of a strong positive correlation between leptin and insulin levels. There were no correlations between glycemia and resistin or glycemia and adiponectin levels, and no correlation was observed between any of the adipokine levels and bone mineral content or density.. These data suggest that in the mouse, modest dietary perturbations have little effect on resistin and adiponectin levels despite significant effects on glycemia, insulin levels, and bone parameters. Topics: Adiponectin; Analysis of Variance; Animals; Blood Glucose; Body Composition; Body Weight; Diet, Reducing; Dietary Carbohydrates; Dietary Supplements; Insulin; Leptin; Male; Mice; Peptide Hormones; Resistin; Sucrose | 2006 |
The importance of catch-up growth after early malnutrition for the programming of obesity in male rat.
To investigate whether catch-up growth after maternal malnutrition would favor the development of obesity in adulthood.. Pregnant rats were submitted to protein or calorie restriction during the course of gestation. During lactation, pups were protein-restricted, normally fed, or overfed [reduced litter size, control (C) diet]. At weaning, rats were transferred to chow or to a hypercaloric diet (HCD) known to induce obesity. Body weight, food intake, blood parameters, glucose tolerance, adipocyte cellularity, and adipose factors contributing to cardiovascular disease development were measured.. Protein and calorie restriction during gestation led to growth retardation at birth. If malnutrition was prolonged throughout lactation, adult body weight was permanently reduced. However, growth-retarded offspring overfed during the suckling period underwent a rapid catch-up growth and became heavier than the normally fed Cs. Offspring of calorie-restricted rats gained more weight than those of dams fed protein-restricted diet. Feeding an HCD postnatally amplified the effect of calorie restriction, and offspring that underwent catch-up growth became more obese than Cs. The HCD was associated with hyperphagia, hyperglycemia, hyperinsulinemia, glucose intolerance, insulin resistance, and adipocyte hypertrophy. The magnitude of effects varied depending on the type and the timing of early malnutrition. The expression of genes encoding factors implicated in cardiovascular disease was also modulated differently by early malnutrition and adult obesity.. Catch-up growth immediately after early malnutrition should be a key point for the programming of obesity. Topics: Adipocytes; Adiponectin; Adipose Tissue; Angiotensinogen; Animals; Animals, Newborn; Body Weight; Diet; Eating; Female; Leptin; Litter Size; Male; Obesity; Plasminogen Activator Inhibitor 1; Pregnancy; Prenatal Exposure Delayed Effects; Protein-Energy Malnutrition; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Triglycerides | 2006 |
A physiological role of breast milk leptin in body weight control in developing infants.
Leptin, a hormone that regulates food intake and energy metabolism, is present in breast milk. The aim of this study was to determine whether milk leptin concentration is correlated with maternal circulating leptin and BMI and with body weight gain of infants.. A group of 28 non-obese women (BMI between 16.3 and 27.3 kg/m(2)) who breast-fed their infants for at least 6 months and their infants were studied. Venous blood and milk samples were obtained from mothers at 1, 3, 6, and 9 months of lactation, and leptin concentration was determined. Infant body weight and height were followed until 2 years of age.. During the whole lactation period, milk leptin concentration correlated positively with maternal plasma leptin concentration and with maternal BMI. In addition, milk leptin concentration at 1 month of lactation was negatively correlated with infant BMI at 18 and 24 months of age. A better negative correlation was also found between log milk leptin concentration at 1 and at 3 months of lactation and infant BMI from 12 to 24 months of age.. We concluded that, in a group of non-obese mothers, infant body weight during the first 2 years may be influenced by milk leptin concentration during the first stages of lactation. Thus, moderate milk-borne maternal leptin appears to provide moderate protection to infants from an excess of weight gain. These results seem to point out that milk leptin is an important factor that could explain, at least partially, the major risk of obesity of formula-fed infants with respect to breast-fed infants. Topics: Adult; Birth Weight; Body Mass Index; Body Weight; Breast Feeding; Child Development; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant; Infant, Newborn; Leptin; Male; Milk, Human | 2006 |
Circulating hormones and hypothalamic energy balance: regulatory gene expression in the Lou/C and Wistar rats.
To ascertain the mechanisms underlying low caloric intake and low body weight in the Lou/C rat, the circulating hormone levels and gene expression of hypothalamic peptides and receptors important in energy balance and the induction of suppressor of cytokine signalling 3 (SOCS3) gene expression in response to leptin challenge were compared with Wistar rats. Plasma leptin levels were lower in the Lou/C rat, as were levels of rat corticosterone, TSH and T4 but not T3. Ghrelin levels were higher in the Lou/C rat. Total leptin receptor (Ob-R) and the long form of the leptin receptor (Ob-Rb) gene expression were lower in the arcuate (ARC) and ventromedial nuclei (VMN) in Lou/C rat. Ghrelin receptor expression in the ARC and VMN was lower in Lou/C than in Wistar rats. However, agouti gene-related peptide (AgRP) and neuropeptide Y (NPY) gene expression were higher in the Lou/C rat. There was no difference in the level of cocaine- and amphetamine-regulated transcript gene expression in the ARC, but both were higher in the paraventricular nuclei of the Lou/C breed. There was no difference in Ob-R gene expression in, or [(125)I]leptin binding to, the choroid plexus. SOCS3 mRNA induction in response to leptin was lower in the Lou/C rat. This study reveals that the comparatively low plasma leptin, TSH and T4 levels, and high ghrelin levels together with high levels of AgRP and NPY gene expression seen in the Lou/C rat are indicative of a strong drive to eat and decreased energy expenditure, which are in direct opposition to the comparatively low body weight and adiposity of this rat strain. Topics: Agouti-Related Protein; Animals; Body Weight; Choroid Plexus; Corticosterone; Energy Intake; Energy Metabolism; Gene Expression; Gene Expression Regulation; Ghrelin; Hypothalamic Hormones; In Situ Hybridization; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Neuropeptide Y; Peptide Hormones; Protein Binding; Random Allocation; Rats; Rats, Mutant Strains; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Thyrotropin; Thyroxine; Triiodothyronine | 2006 |
Influence of porcine genotype on the abundance of thyroid hormones and leptin in sow milk and its impact on growth, metabolism and expression of key adipose tissue genes in offspring.
Neonatal mortality is greater in commercial porcine genotypes, compared with the ancient Meishan breed that rapidly lay down adipose tissue; this may be related to hormones, such as triiodothyronine (T(3)) or leptin. Leptin is present in maternal milk; however, the extent to which this supply provides the neonate with leptin is unknown, but may play a role in growth and development. We investigated whether thyroid hormones and leptin concentrations in maternal milk differed between genotypes; and whether this influenced piglet concentrations or expression of genes involved in adipose tissue regulation. Eight Meishan and six commercial sows were entered into the study and milk samples from the day of parturition to day 4 postpartum was taken daily. The median birth weight piglet in each litter had a daily venous blood sample taken and was euthanised on day 4. Gene expressions of IGF-I, IGF-binding protein 3 (IGFBP-3), peroxisome proliferators activated receptor (PPAR)gamma and glucocorticoid receptor (GR) were measured in adipose tissue using real-time PCR. T(3) was increased in Meishan milk, but not in piglet plasma. Milk thyroxine was similar between breeds but commercial piglet levels were significantly higher. Leptin was higher in commercial sow milk throughout the study. Milk leptin was strongly correlated to plasma leptin during the first postnatal days and also to organ and body weight in Meishan piglets that also had significantly higher expression of GR, but not IGF-I, IGFBP-3 or PPARgamma. In conclusion, we have found a significant disparity in the provision of thyroid hormones in Meishan and commercial sow's milk. These changes are not always translated to plasma concentrations of hormone in the piglet. Leptin appears to have a stronger role in growth and development in the Meishan genotype compared with commercial; along with the increased GR expression, this may also represent a potential mechanism behind the rapid accumulation of adipose tissue in Meishan piglets. Topics: Adipose Tissue; Animals; Animals, Newborn; Body Weight; Female; Gene Expression; Genotype; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Milk; Organ Size; PPAR gamma; Receptors, Glucocorticoid; Reverse Transcriptase Polymerase Chain Reaction; Sus scrofa; Swine; Thyroid Hormones; Triiodothyronine | 2006 |
Increased leptin and decreased ghrelin level after smoking cessation.
Smoking cessation is associated with transient increases in body weight. Leptin and ghrelin are known to be major mediators of appetite, weight and the reward pathway. Therefore, this study assessed the changes in the plasma leptin and ghrelin level and their relationship with the body weight and appetite after smoking cessation in the Korean population. Eighteen subjects, who had stopped smoking for 2 months were enrolled in this study. The body mass index (BMI), body fat mass (BFM), waist-hip ratio (WHR), weight and appetite were measured before and after smoking cessation. In addition, the plasma leptin and ghrelin levels were measured. The BMI, BFM, WHR, weight and appetite were significantly higher than baseline in those who had gave up smoking for 2 months (p<0.05). The plasma leptin concentration increased and the plasma ghrelin level decreased after smoking cessation. The change in the leptin level was positively correlated with the change in the body mass index and body fat mass. These results do not support the direct mediation of the leptin-ghrelin-neuropeptide Y (NPY) system on weight gain after smoking cessation. It appears that weight and appetite is regulated by a more complicated mechanism after smoking cessation. Topics: Adult; Appetite; Body Composition; Body Mass Index; Body Weight; Cotinine; Electric Impedance; Female; Ghrelin; Humans; Leptin; Male; Peptide Hormones; Smoking; Smoking Cessation | 2006 |
Effects of pine needle extract on differentiation of 3T3-L1 preadipocytes and obesity in high-fat diet fed rats.
The present study examined the anti-obesity effects of pine needle extract (PNE) in 3T3-L1 preadipocytes and in vivo studies. PNE treatment suppressed both glycerol-3-phosphate dehydrogenase activity and expression of peroxisome proliferator-activated receptor (PPAR) gamma in cultured 3T3-L1 adipocytes. To investigate the effect of PNE on obesity in rats fed high-fat diet, four types of diet, which included a normal diet (ND), high-fat diet (HFD), ND+PNE, and HFD+PNE diets, were fed to the rats ad libitum for 6 weeks. The PNE supplement significantly decreased body weight gain and visceral fat mass compared to the HFD group. The total cholesterol, TG, and leptin levels in the plasma were significantly reduced by PNE supplementation compared with those of the HFD group. Histological findings in liver tissue showed that PNE supplementation alleviated steatosis induced by HFD. In conclusion, PNE treatment suppressed differentiation of 3T-L1 adipocytes, in part by down-regulating expression of PPAPgamma mRNA, and reduced adipose tissue mass, hyperlipidemia, and hepatic steatosis in obese rats fed HFD. Therefore, pine needle water extract may be considered for use in therapy to control obesity. Topics: 3T3-L1 Cells; Adipocytes; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cell Differentiation; Dietary Fats; Leptin; Lipids; Liver; Male; Mice; Organ Size; Pinus; Plant Extracts; PPAR gamma; Rats; Rats, Sprague-Dawley; Stem Cells | 2006 |
Beta2-adrenoceptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic activation.
Obesity is a growing public health problem. It has been reported that beta2-adrenoceptor polymorphisms are associated with obesity. This study examines the associations of beta2-adrenoceptor polymorphism with relationships between plasma norepinephrine (NE) and leptin to evaluate further the mechanisms of obesity.. In 329 normotensive (BP <140/90 mm Hg) men with a wide range of BMI (17.0 to 36.5 kg/m2), we measured BMI, total body fat mass, waist-to-hip ratio (W/H), BP, plasma NE, leptin, and the beta2-(Arg16Gly, Gln27Glu) adrenoceptor polymorphisms. The subjects consisted of 206 nonobese (BMI <25 kg/m2) and 123 overweight or obese (BMI >or=25 kg/m2) men.. Overweight or obese subjects had a significantly higher frequency of Gly16 and Glu27 alleles compared with nonobese subjects. The subjects carrying Gly16 or Glu27 alleles regardless of BMI had greater total fat mass, W/H and plasma leptin compared with those without the Gly16 or Glu27 alleles, indicating that Gly16 and Glu27 alleles of the beta2-adrenoceptor gene are related to obesity and fat mass. Only in the nonobese subjects who carried the Gly16 and Glu27 alleles was there a high plasma NE level, but similar in overweight or obese subjects. To evaluate leptin-mediated sympathetic activation, we performed linear regression analyses between plasma leptin and NE. In groups with and without the Gly16 or Glu27 alleles, plasma leptin correlated with NE, but the slope in the group carrying the Gly16 or Glu27 allele was significantly lower than that without the Gly16 or Glu27.. The findings demonstrate a strong and significant association of the Gly16 and Glu27 alleles with obesity. Lower slopes between leptin and NE in the subjects carrying these beta2-adrenoceptor polymorphisms indirectly indicate a blunted leptin-mediated sympathetic nerve activity. We propose that the beta2-adrenoceptor polymorphisms related to blunted leptin-mediated sympathetic activation offers further proof for the mechanisms of obesity. Topics: Adult; Alleles; Blood Pressure; Body Weight; Cohort Studies; Gene Expression Regulation; Gene Frequency; Glutamic Acid; Glycine; Humans; Leptin; Linear Models; Male; Middle Aged; Norepinephrine; Obesity; Polymorphism, Genetic; Receptors, Adrenergic, beta-2; Receptors, Leptin; Sympathetic Nervous System | 2006 |
Developmental and nutritional regulation of the prepubertal bovine mammary gland: II. Epithelial cell proliferation, parenchymal accretion rate, and allometric growth.
It is well documented that elevated nutrient intake prior to puberty reduces prepubertal mammary development in the bovine. The companion paper demonstrated that age at harvest is a primary determinant of parenchymal (PAR) mass and that any effects of elevated energy intake on mechanisms regulating mammary development are dwarfed by this effect of time. Therefore, it is hypothesized that while causing a decrease in prepubertal PAR mass, elevated nutrient intake will have no effect on growth characteristics of the mammary gland. The objectives of this experiment were to evaluate the effects of increased nutrient intake from early in life on 1) mammary epithelial cell proliferation, 2) mammary PAR DNA accretion rates, and 3) the dynamics of prepubertal allometric PAR growth. Holstein heifers (n = 78) were fed from 45 kg of body weight either elevated (E) or restricted (R) levels of nutrients to support 950 (E) or 650 (R) g/d of body weight gain. Six heifers per treatment were harvested at 50-kg increments from 100 to 350 kg of body weight. Heifers on the E plane of nutrition had higher plasma leptin and less PAR DNA than their body weight-matched R-intake cohorts. Despite this reduction in PAR DNA, treatment did not negatively influence mammary epithelial cell proliferation or the PAR DNA accretion rate. Dynamics of allometric and isometric mammary growth were also unaffected by the level of nutrient intake, as was exit from allometric growth. This work represents the first demonstrating that the level of nutrient intake and the concomitant increase in plasma leptin have no measurable influence on 1) the rate of PAR DNA accretion, 2) mammary epithelial cell proliferation, or 3) total PAR mass and, by default, the local or systemic controls that coordinate these processes. Topics: Animal Nutritional Physiological Phenomena; Animals; Body Weight; Cattle; Cell Proliferation; Diet; DNA; Epithelial Cells; Female; Least-Squares Analysis; Leptin; Mammary Glands, Animal; Regression Analysis | 2006 |
Identification of nesfatin-1 as a satiety molecule in the hypothalamus.
The brain hypothalamus contains certain secreted molecules that are important in regulating feeding behaviour. Here we show that nesfatin, corresponding to NEFA/nucleobindin2 (NUCB2), a secreted protein of unknown function, is expressed in the appetite-control hypothalamic nuclei in rats. Intracerebroventricular (i.c.v.) injection of NUCB2 reduces feeding. Rat cerebrospinal fluid contains nesfatin-1, an amino-terminal fragment derived from NUCB2, and its expression is decreased in the hypothalamic paraventricular nucleus under starved conditions. I.c.v. injection of nesfatin-1 decreases food intake in a dose-dependent manner, whereas injection of an antibody neutralizing nesfatin-1 stimulates appetite. In contrast, i.c.v. injection of other possible fragments processed from NUCB2 does not promote satiety, and conversion of NUCB2 to nesfatin-1 is necessary to induce feeding suppression. Chronic i.c.v. injection of nesfatin-1 reduces body weight, whereas rats gain body weight after chronic i.c.v. injection of antisense morpholino oligonucleotide against the gene encoding NUCB2. Nesfatin-1-induced anorexia occurs in Zucker rats with a leptin receptor mutation, and an anti-nesfatin-1 antibody does not block leptin-induced anorexia. In contrast, central injection of alpha-melanocyte-stimulating hormone elevates NUCB2 gene expression in the paraventricular nucleus, and satiety by nesfatin-1 is abolished by an antagonist of the melanocortin-3/4 receptor. We identify nesfatin-1 as a satiety molecule that is associated with melanocortin signalling in the hypothalamus. Topics: alpha-MSH; Animals; Anorexia; Appetite Regulation; Body Weight; Calcium-Binding Proteins; DNA-Binding Proteins; Dose-Response Relationship, Drug; Feeding Behavior; Gene Expression Profiling; Hypothalamus; Injections, Intraventricular; Leptin; Male; Mice; Nerve Tissue Proteins; Nucleobindins; Obesity; Rats; Rats, Wistar; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Receptors, Melanocortin; Satiety Response; Signal Transduction | 2006 |
Adipose atrophy in cancer cachexia: morphologic and molecular analysis of adipose tissue in tumour-bearing mice.
Extensive loss of adipose tissue is a hallmark of cancer cachexia but the cellular and molecular basis remains unclear. This study has examined morphologic and molecular characteristics of white adipose tissue in mice bearing a cachexia-inducing tumour, MAC16. Adipose tissue from tumour-bearing mice contained shrunken adipocytes that were heterogeneous in size. Increased fibrosis was evident by strong collagen-fibril staining in the tissue matrix. Ultrastructure of 'slimmed' adipocytes revealed severe delipidation and modifications in cell membrane conformation. There were major reductions in mRNA levels of adipogenic transcription factors including CCAAT/enhancer binding protein alpha (C/EBPalpha), CCAAT/enhancer binding protein beta, peroxisome proliferator-activated receptor gamma, and sterol regulatory element binding protein-1c (SREBP-1c) in adipose tissue, which was accompanied by reduced protein content of C/EBPalpha and SREBP-1. mRNA levels of SREBP-1c targets, fatty acid synthase, acetyl CoA carboxylase, stearoyl CoA desaturase 1 and glycerol-3-phosphate acyl transferase, also fell as did glucose transporter-4 and leptin. In contrast, mRNA levels of peroxisome proliferators-activated receptor gamma coactivator-1alpha and uncoupling protein-2 were increased in white fat of tumour-bearing mice. These results suggest that the tumour-induced impairment in the formation and lipid storing capacity of adipose tissue occurs in mice with cancer cachexia. Topics: Adenocarcinoma; Adipose Tissue; Animals; Atrophy; Blotting, Western; Body Weight; Cachexia; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Protein-beta; Female; Gene Expression; Glucose Transporter Type 4; Ion Channels; Leptin; Male; Mice; Mice, Inbred Strains; Microscopy, Electron; Mitochondrial Proteins; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Uncoupling Protein 2 | 2006 |
Photoperiodic regulation in energy intake, thermogenesis and body mass in root voles (Microtus oeconomus).
The present study was designed to examine whether photoperiod alone was effective to induce seasonal regulations in physiology in root voles (Microtus oeconomus) from the Qinghai-Tibetan plateau noted for its extreme cold environment. Root voles were randomly assigned into either long photoperiod (LD; 16L:8D) or short photoperiod (SD; 8L:16D) for 4 weeks at constant temperature (20 degrees C). At the end of acclimation, SD voles showed lower body mass and body fat coupled with higher energy intake than LD voles. SD greatly enhanced thermogenic capacities in root voles, as indicated by elevated basal metabolic rate (BMR), nonshivering thermogenesis (NST), mitochondrial protein content and uncoupling protein-1 (UCP1) content in brown adipose tissue (BAT). Although no variations in serum leptin levels were found between SD and LD voles, serum leptin levels were positively correlated with body mass and body fat mass, and negatively correlated with energy intake and UCP1 content in BAT, respectively. To summarize, SD alone is effective in inducing higher thermogenic capacities and energy intake coupled with lower body mass and body fat mass in root voles. Leptin is potentially involved in the photoperiod induced body mass regulation and thermogenesis in root voles. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Arvicolinae; Body Weight; Energy Intake; Female; Ion Channels; Leptin; Male; Mitochondrial Proteins; Photoperiod; Thermogenesis; Uncoupling Protein 1 | 2006 |
Deletion of the serotonin 2c receptor from transgenic mice overexpressing leptin does not affect their lipodystrophy but exacerbates their diet-induced obesity.
The binding of leptin to hypothalamic neurons elicits inhibition of orexigenic NPY/AgRP neurons and stimulation of anorexigenic POMC/CART neurons. Projections of serotonergic neurons onto POMC neurons suggest that leptin and serotonin converge onto POMC neurons to regulate body weight. We probed the interaction of these pathways by generating transgenic mice overexpressing leptin (LepTg) without 5HT2c receptors. On a chow diet, the lean phenotype of LepTg mice was unaffected by the absence of 5HT2c receptors, whereas on a high fat diet, LepTg/5HT2c receptors knockout mice showed an exacerbation of diet-induced obesity. POMC mRNA levels were low in LepTg, 5HT2c receptors knockout and LepTg/5HT2c receptors knockout mice, demonstrating that perturbations of the 5HT2c receptor and leptin pathways, either alone or in combination, negatively impact on POMC expression. Thus, on a chow diet, leptin action is independent of 5HT2c receptors whereas on a high fat diet 5HT2c receptors are required for the attenuation of obesity. Topics: Agouti-Related Protein; Animals; Body Weight; Diet; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Lipodystrophy; Male; Mice; Mice, Knockout; Neuropeptide Y; Neuropeptides; Obesity; Pro-Opiomelanocortin; Receptor, Serotonin, 5-HT2C; Receptors, Leptin | 2006 |
Long-term angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARgamma.
To clarify the mechanism of the effects of angiotensin II AT(1) receptor antagonists on adipose tissue, we treated 8 week-old male Wistar Kyoto rats with the angiotensin II AT(1) receptor antagonist Candesartan cilexetil (10 mg/kg/day) for 18 weeks. Candesartan cilexetil reduced body weight gain, decreased fat tissue mass due to hypotrophy of epididymal and retroperitoneal adipose tissue and decreased adipocyte size without changing the number of adipocytes. Candesartan cilexetil decreased serum leptin levels and epididymal leptin mRNA, increased serum adiponectin levels and epididymal adiponectin mRNA, decreased epididymal tumor necrosis factor alpha (TNFalpha) mRNA, and increased fatty acid synthase mRNA. Considered free of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist activity, Candesartan cilexetil increased epididymal expression of PPARgamma mRNA. The effects of Candesartan cilexetil on adipokine production and release may be attributable to PPARgamma activation and/or decrease in adipocyte cell size. In addition, Candesartan cilexetil treatment increased the expression of epididymal angiotensin II AT(2) receptor mRNA and protein and decreased the expression of renin receptor mRNA. These results suggest that Candesartan cilexetil influences lipid metabolism in adipose tissue by promoting adipose tissue rearrangement and modulating adipokine expression and release. These effects are probably consequences of local angiotensin II AT(1) receptor inhibition, angiotensin II AT(2) receptor stimulation, and perhaps additional angiotensin II-independent mechanisms. Our results indicate that the activity of local renin-angiotensin system plays an important role in adipose tissue metabolism. The decrease in the pro-inflammatory cytokine TNFalpha and the increase in the anti-inflammatory adipokine adiponectin indicate that Candesartan cilexetil may exert significant anti-inflammatory properties. Topics: Adipocytes; Adiponectin; Adipose Tissue; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Blood Glucose; Blood Pressure; Blotting, Western; Body Weight; Drinking; Eating; Epididymis; Gene Expression; Leptin; Lipids; Male; PPAR gamma; Rats; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrazoles; Time Factors | 2006 |
Neuropeptide Y deficiency attenuates responses to fasting and high-fat diet in obesity-prone mice.
Neuropeptide Y (NPY) stimulates feeding and weight gain, but deletion of the NPY gene does not affect food intake and body weight in mice bred on a mixed genetic background. We reasoned that the orexigenic action of NPY would be evident in C57Bl/6J mice susceptible to obesity. NPY deficiency has no significant effect in mice fed a normal rodent diet. However, energy expenditure is elevated during fasting, and hyperphagia and weight gain are blunted during refeeding. Expression of agouti-related peptide (AGRP) in the hypothalamus is increased in NPY knockout (NPYko) than wild-type mice, but unlike wild type there is no further increase in AGRP when NPYko mice are fasted. Moreover, NPYko mice have higher oxygen consumption and uncoupling protein-1 expression in brown adipose tissue during fasting. The failure of an increase in orexigenic peptides and higher thermogenesis may contribute to attenuation of weight gain when NPYko mice are refed. C57Bl/6J mice lacking NPY are also less susceptible to diet-induced obesity (DIO) as a result of reduced feeding and increased energy expenditure. The resistance to DIO in NPYko mice is associated with a reduction in nocturnal feeding and increased expression of anorexigenic hypothalamic peptides. Insulin, leptin, and triglyceride levels increase with adiposity in both wild-type and NPYko mice. Topics: Aging; Animals; Appetite; Blood Glucose; Body Weight; Corticosterone; Dietary Fats; Eating; Fasting; Female; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Neuropeptide Y; Obesity; Oxygen Consumption; Thyroxine; Weight Gain | 2006 |
Regulation of corticotropin-releasing factor and its types 1 and 2 receptors by leptin in rats subjected to treadmill running-induced stress.
The present study was conducted to investigate the long-term effects of subchronic elevation of central leptin levels on the expression of corticotropin-releasing factor (CRF) and its types 1 and 2 receptors in the brain of rats subjected to treadmill running-induced stress. PBS or recombinant murine leptin was infused continuously for a period of 5 days into the third ventricle of rats with the aid of osmotic minipumps at a delivery rate of 2 mug/day. On the fifth day of infusion, rats were killed under resting conditions or after a session of treadmill running, which is known to induce a stress response in rats. Leptin treatment significantly decreased food intake, body weight, white adipose tissue weight, glucose and insulin plasma contents, and blunted the treadmill running-induced elevation in plasma levels of corticosterone. Leptin infusion prevented stress-induced de novo synthesis of CRF in the paraventricular hypothalamic nucleus (PVN), which was measured using the intronic probe for CRF heteronuclear RNA. The induction of the type 1 CRF receptor (CRF(1)R) in the PVN and supraoptic nucleus in running rats was also significantly blunted by leptin. In contrast, leptin treatment strongly increased the expression of type 2 CRF receptor (CRF(2)R) in the ventromedial hypothalamic nucleus (VMH). The present results suggest that subchronic elevation of central levels of leptin blunts treadmill running-induced activation of the hypothalamic-pituitary-adrenal axis through the inhibition of activation of the CRFergic PVN neurons, and potentially enhances the anorectic CRF effects via the stimulation of expression of CRF(2)R in the VMH. Topics: Adipose Tissue; Animals; Anorexia; Blood Glucose; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Eating; Image Interpretation, Computer-Assisted; In Situ Hybridization; Insulin; Leptin; Male; Paraventricular Hypothalamic Nucleus; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; RNA, Messenger; Running; Stress, Physiological; Ventromedial Hypothalamic Nucleus | 2006 |
Genetic modulation of hormone levels and life span in hybrids between laboratory and wild-derived mice.
Previously we showed that mouse stocks derived from wild-caught progenitors are long-lived relative to genetically heterogeneous mice derived from laboratory-adapted strains. Here we replicate this life-span effect, and show that F2 hybrids between wild-derived and laboratory-derived stocks have intermediate survival patterns. Moreover, wild-derived mice are small, lean, and slow to mature, and have low serum insulin-like growth factor-I (IGF-I) relative to genetically heterogeneous mice. These traits, too, were at intermediate levels in the F2 hybrids. Furthermore, serum IGF-I at 6 months was a significant predictor of life span in two different populations of F2 hybrid mice. Pooling across stocks, life span was negatively correlated with body weight and serum IGF-I levels, and positively correlated with age at vaginal patency and serum leptin levels. Overall, these finding suggest that wild-derived mice harbor alleles that increase longevity, perhaps through effects on growth, maturation, and early-life hormone levels. Topics: Adrenal Cortex Hormones; Aging; Animals; Animals, Laboratory; Animals, Wild; Body Weight; Chimera; Insulin-Like Growth Factor I; Leptin; Longevity; Mice; Mice, Inbred Strains; Phenotype; Sexual Maturation; Thyroxine | 2006 |
Feeding scallop shell powder induces the expression of uncoupling protein 1 (UCP1) in white adipose tissue of rats.
Previously we found that the organic components in scallop shell promote lipolysis in differentiated 3T3-L1 and C3H10T1/2 adipocyte cells, and that incorporating scallop shell powder into the diet of rats reduced the amount of white adipose tissue. In this study, we used RT-PCR to investigate the effect of ingesting scallop shell powder on the gene expression profile of uncoupling proteins (UCPs) regulating energy metabolism in rats. Feeding of scallop shell powder increased mRNA levels of UCP1 and UCP2 in white adipose tissue. By contrast, scallop shell powder had no effect on the expression of UCP1 in brown adipose tissue, although the expression level of UCP2 mRNA decreased significantly. These results suggest that feeding scallop shell powder increases gene expression of UCP1 that may regulate energy metabolism in white adipose tissue, resulting in the observed reduction in weight of white adipose tissue. Topics: Adipose Tissue, White; Animal Feed; Animals; Body Weight; Gene Expression Regulation; Ion Channels; Leptin; Male; Mitochondrial Proteins; Pectinidae; Rats; Rats, Wistar; RNA, Messenger; Uncoupling Protein 1; Uncoupling Protein 2 | 2006 |
High-dose chromium(III) supplementation has no effects on body mass and composition while altering plasma hormone and triglycerides concentrations.
Chromium is generally believed to be an essential element and is often claimed to have value as a weight loss or muscle building agent. Recent studies in humans and rats have failed to demonstrate effects on body composition, although recent studies with pharmacological doses of the cation [Cr(III)3O(O2CCH2CH3)6(H2O)3]+ (or Cr3) (< or =1 mg Cr/kg body mass) in rats have noted a trend toward body mass loss and fat mass loss. Thus, the effects of large gavage doses of Cr3 (1-10 mg Cr/kg) on body mass, organ mass, food intake, and blood plasma variables (insulin, glucose, leptin, cholesterol, and triglycerides) were examined over a 10-wk period using male Sprague-Dawley rats. No effects on body composition were noted, although Cr3 administration lowered (p < 0.05) plasma insulin, leptin, and triglycerides concentrations. As Cr3 is absorbed greater than 10-fold better than commercially available nutritional supplements, the lack of an effect of the Cr(III) compound at these levels of administration clearly indicates that Cr(III) supplements do not have an effect on body composition at any reasonable dosage. Topics: Animals; Aspartame; Body Composition; Body Weight; Chromium; Eating; Insulin; Leptin; Male; Organ Size; Organometallic Compounds; Rats; Rats, Sprague-Dawley; Saccharin; Triglycerides | 2006 |
Temporal evaluation of the thyroid function of rats programmed by leptin treatment on the neonatal period.
Hormones and malnutrition can imprint several changes in the beginning of life that programs homeostatic changes in the adulthood. We analyzed the thyroid function in 21, 30, 60 and 150 days old animals that were injected with leptin on the first 10 days of life, to determine whether this corresponds to a critical period for the establishment of the hormonal imprinting in the programming of the thyroid function. Pups were divided, within 24 hours of birth, into two groups: Lep group, which was injected once daily with 8 microg/100 g B.W. of recombinant mouse leptin for the first 10 days of lactation, and C-control group that received the same volume of saline. Lep group had higher leptin concentration at days 30 (+6 x , p<0.001) and 150 (+108%, p<0.05) than the controls. These animals had lower serum TT4 (-13%; p<0.05) and TT3 (-17.3%; p<0.002) at 30 days and higher serum TT4 and FT4 concentrations at 150 days (+17.5% and +10%, p<0.05 %, respectively, p<0.05) with lower serum TSH concentrations at 60 (-38.5%, p<0.05) and 150 days (-46%, p<0.05). These animals had also lower hepatic mitochondrial alpha-glycerol-3-phosphate dehydrogenase (mGPDH) activity at 21 (-22.5%; p<0.05), 30 (-50.4%; p<0.05) and 150 days (-40%; p<0.05) than the controls. These data show that the leptin injection in the beginning of lactation cause a hypothyroidism on the offspring as soon as 30 days of age and this alteration may be the imprinted factor for the programming of a higher thyroid function at the adulthood. Topics: Age Factors; Animals; Animals, Newborn; Body Weight; Glyceraldehyde-3-Phosphate Dehydrogenases; Leptin; Male; Rats; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine | 2006 |
A signaling role for leptin in puberty onset in female rats?
The brain might initiate puberty in response to adequate leptin signaling from the periphery. We studied the link between whole body fat, plasma leptin levels, and puberty onset, in both controls and food-restricted female Wistar rats from age 22 to 42 days. Body fat correlated positively with the prevailing plasma leptin levels (r = 0.776) and with the time of puberty onset, i.e. vaginal opening (VO) (r = 0.691). Blood samples collected every other day at ZT 2, 6, and 12, showed a diurnal rhythm in leptin levels with a nadir at ZT 6. Furthermore, leptin levels increased over the pubertal period. Food restriction (FR) delayed the time of VO considerably (median VO at 38 vs 28 d), and body fat and plasma leptin levels were lower in the FR group (p <0.01), although the positive correlation between body fat and leptin levels remained. Only the absolute, but not the relative amount of body fat increased with age. These data support the notion that leptin could indeed serve as the link between nutritional status and the reproductive axis, and in this way participate in the timing of puberty. Topics: Adipose Tissue; Animals; Body Weight; Female; Food Deprivation; Histocytochemistry; Leptin; Male; Nutritional Status; Ovary; Rats; Rats, Wistar; Sexual Maturation | 2006 |
Relationship between ghrelin and anthropometrical, body composition parameters and testosterone levels in boys at different stages of puberty.
The aim of this study was to investigate the relationships between fasting serum ghrelin concentration, anthropometrical and body composition data in boys at different pubertal stages. Sixty healthy non-obese Estonian schoolboys (10 to 18 yr) were divided into 3 groups based on Tanner classification--group I was prepubertal, group II included stages 2 and 3, and group III stages 4 and 5. Additionally, we analyzed subjects as a total group. Fasting ghrelin, leptin, testosterone, insulin and glucose were collected between 08:00 and 10:00 h. Body fat % and lean body mass (LBM) were determined by dual-energy X-ray absorptiometry. Fasting ghrelin decreased, while leptin and insulin did not change and testosterone increased during puberty. There was a negative correlation between serum ghrelin and testosterone concentrations in group II (r=-0.51, p<0.05) and in the total group (r=-0.59, p<0.001). Ghrelin was also related to body height, body mass and LBM in group II and total group also with body mass index in total group. Stepwise multiple regression analysis showed that body height from auxological, LBM from body composition and testosterone from biochemical data explained 38.1, 41.7 and 33.7% of the ghrelin variance in the total group, respectively. In conclusion, body height, LBM and serum testosterone are the major determinants of serum ghrelin among parameters studied. Negative correlation between serum ghrelin and testosterone concentrations indicates that ghrelin may also have a role in male pubertal development. Topics: Adolescent; Blood Glucose; Body Composition; Body Height; Body Mass Index; Body Size; Body Weight; Child; Ghrelin; Humans; Insulin; Leptin; Male; Peptide Hormones; Puberty; Testosterone | 2006 |
Rats with low brain angiotensinogen do not exhibit insulin resistance during early aging.
During aging increases in body weight, insulin resistance, and elevated systolic pressure contribute to the development of metabolic syndrome. Long-term systemic blockade of the renin-angiotensin system (RAS) with either an angiotensin (Ang) II type 1 (AT1) receptor antagonist or angiotensin converting enzyme inhibitor improves insulin sensitivity and decreases risk of new onset (type II) diabetes. However, the role of the brain RAS in mediating development of insulin insensitivity during aging is not known. Therefore, we compared responses to an oral glucose load in transgenic rats with selective antisense suppression of brain angiotensinogen (ASrAogen); (mRen2)27 rats with high brain angiotensin II; and control Hannover Sprague-Dawley (SD) rats, at wk 16 and 68 of age. ASrAogen animals had lower body weight than either SD or (mRen2)27 rats at both ages (p < 0.001). The oral glucose tolerance test at 16 wk in (mRen2)27 animals revealed a higher glucose-insulin index (154,421 +/- 11,231 units; p < 0.05) and a lower glucose-insulin index in ASrAogen rats (41,580 +/- 10,923 units, p < 0.05) compared to SD rats (97,134 +/- 19,822 units), suggesting insulin resistance in the (mRen2)27 and enhanced insulin sensitivity in the ASrAogen relative to SD rats. At 68 wk, the glucose-insulin index remained low in the ASrAogen rats as evidence of maintained insulin sensitivity during aging compared with either SD or (mRen2)27 (p < 0.05). SD animals do not differ from (mRen2)27 rats at 68 wk indicating the development of a state of relative insulin resistance with increased age in the SD rats. Moreover, there was a positive correlation (r = 0.44; p < 0.05) between body weight and the glucose-insulin index in SD, but not ASrAogen or (mRen2)27 rats. The relationships between insulin and leptin, insulin and glucose, and leptin and body weight observed in SD rats were absent in ASrAogen and (mRen2)27 rats. We conclude that the glial RAS plays a role in development of insulin resistance as well as influencing weight gain associated with early aging. Topics: Aging; Angiotensinogen; Animals; Blood Glucose; Body Weight; Brain Chemistry; Insulin; Insulin Resistance; Leptin; Male; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley | 2006 |
Transplantation of wild-type white adipose tissue normalizes metabolic, immune and inflammatory alterations in leptin-deficient ob/ob mice.
Leptin-deficient ob/ob mice exhibit several metabolic and immune abnormalities, including thymus atrophy and markedly reduced inflammatory responses. We evaluated whether transplantation of wild-type (WT) white adipose tissue (WAT) into ob/ob mice could mimic the effect of recombinant leptin administration in normalizing metabolic, immune and inflammatory abnormalities. Female ob/ob mice received a subcutaneous transplantation of WAT obtained from WT littermates. A separate group of ob/ob mice was sham-operated. Despite raising leptin levels to only 15% of those observed in WT mice, WAT transplantation normalized metabolic abnormalities (glycemia, ALT, liver weight) in ob/ob mice and prevented further body weight gain. The transplanted group demonstrated normalization of thymus and spleen cellularity, thymocyte subpopulations and rates of thymocyte apoptosis. In the model of dextran sulfate sodium-induced colitis, WAT transplantation restored inflammation to levels equivalent to those of WT mice. Colonic production of IL-6 and MIP-2 was markedly reduced in the non-transplanted ob/ob group compared to transplanted ob/ob and WT mice. Our data indicate that WAT transplantation is an effective way to normalize metabolic as well as immune and inflammatory parameters in ob/ob mice. The threshold of leptin sufficient to normalize metabolic, immune and inflammatory function is significantly lower than levels present in lean WT mice. Finally, leptin derived exclusively from WAT is sufficient to normalize metabolic, immune and inflammatory parameters in ob/ob mice. Topics: Adiponectin; Adipose Tissue, White; Animals; Atrophy; Body Weight; Colitis; Dextran Sulfate; Female; Leptin; Mice; Mice, Obese; Obesity; Resistin; Spleen; Thymus Gland | 2006 |
Impact of periconceptional nutrition on maternal and fetal leptin and fetal adiposity in singleton and twin pregnancies.
It has been proposed that maternal nutrient restriction may alter the functional development of the adipocyte and the synthesis and secretion of the adipocyte-derived hormone, leptin, before birth. We have investigated the effects of restricted periconceptional undernutrition and/or restricted gestational nutrition on fetal plasma leptin concentrations and fetal adiposity in late gestation. There was no effect of either restricted periconceptional or gestational nutrition on maternal or fetal plasma leptin concentrations in singleton or twin pregnancies during late gestation. In ewes carrying twins, but not singletons, maternal plasma leptin concentrations in late gestation were directly related to the change in ewe weight that occurred during the 60 days before mating [maternal leptin = 0.9 (change in ewe weight) + 7.8; r = 0.6, P < 0.05]. In twin, but not singleton, pregnancies, there was also a significant relationship between maternal and fetal leptin concentrations (maternal leptin = 0.5 fetal leptin + 4.2, r = 0.63, P < 0.005). The relative mass of perirenal fat was also significantly increased in twin fetal sheep in the control-restricted group (6.0 +/- 0.5) compared with the other nutritional groups (control-control: 4.1 +/- 0.4; restricted-restricted: 4.4 +/- 0.4; restricted-control: 4.3 +/- 0.3). In conclusion, the impact of maternal undernutrition on maternal plasma leptin concentrations during late gestation is dependent on fetal number. Furthermore, we have found that there is an increased fetal adiposity in the twins of ewes that experienced restricted nutrition throughout gestation, and this may be important in the programming of postnatal adiposity. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Female; Fetal Development; Fetal Weight; Fetus; Kidney; Leptin; Pregnancy; Prenatal Nutritional Physiological Phenomena; Sheep; Twins | 2005 |
Impaired glucose homeostasis and mitochondrial abnormalities in offspring of rats fed a fat-rich diet in pregnancy.
We previously reported that prenatal and suckling exposure to a maternal diet rich in animal fat leads to cardiovascular dysfunction in young adult rat offspring with subsequent development of dyslipidemia and hyperglycemia. We have further investigated glucose homeostasis in adult female offspring by euglycemic-hyperinsulinemic clamp and by dynamic assessment of glucose-stimulated insulin secretion in isolated, perifused pancreatic islet cells. Additionally, given the link between reduced mitochondrial DNA (mtDNA) content and the development of type 2 diabetes mellitus, we have measured mtDNA in organs from young adult animals. Sprague-Dawley rats were fed a diet rich in animal fat or normal chow throughout pregnancy and weaning. Infusion of insulin (5 mU.kg(-1).min(-1)) resulted in a higher steady-state plasma insulin concentration in 1-year-old offspring of fat-fed dams (OHF, n = 4) vs. offspring of control dams (OC, n = 4, P < 0.01). Glucose-stimulated insulin secretion in isolated islets from 9-mo-old OHF was significantly reduced compared with OC (n = 4, P < 0.05). Transmission electron micrography showed altered insulin secretory granule morphology in OHF pancreatic beta-cells. Kidney mtDNA was reduced in 3-mo-old OHF [16S-to-18S gene ratio: OC (n = 10) 1.05 +/- 0.19 vs. OHF (n = 10) 0.66 +/- 0.06, P < 0.05]. At 6 mo, gene chip microarray of OHF aorta showed reduced expression of the mitochondrial genome. Prenatal and suckling exposure to a diet rich in animal fat leads to whole body insulin resistance and pancreatic beta-cell dysfunction in adulthood, which is preceded by reduced tissue mtDNA content and altered mitochondrial gene expression. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Dietary Fats; Female; Gene Expression; Homeostasis; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Lipids; Metabolic Syndrome; Mitochondria; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena; Rats; Rats, Sprague-Dawley | 2005 |
Anti-inflammatory effect of the ghrelin agonist growth hormone-releasing peptide-2 (GHRP-2) in arthritic rats.
Chronic arthritis induces hypermetabolism and cachexia. Ghrelin is a gastrointestinal hormone that has been proposed as a treatment to prevent cachexia. The aim of this work was to examine the effect of administration of the ghrelin agonist growth hormone-releasing peptide-2 (GHRP-2) to arthritic rats. Male Wistar rats were injected with Freund's adjuvant, and 15 days later arthritic and control rats were daily injected with GHRP-2 (100 microg/kg) or with saline for 8 days. Arthritis induced an increase in serum ghrelin (P < 0.01) and a decrease in serum concentrations of leptin (P < 0.01), whereas GHRP-2 administration increased serum concentrations of leptin. GHRP-2 increased food intake in control rats but not in arthritic rats. However, in arthritic rats GHRP-2 administration ameliorated the external symptoms of arthritis, as it decreased the arthritis score (10.4 +/- 0.8 vs. 13.42 +/- 0.47, P < 0.01) and the paw volume. In addition, circulating IL-6 and nitrites/nitrates were increased by arthritis, and GHRP-2 treatment decreased the serum IL-6 levels (P < 0.01). To elucidate whether GHRP-2 is able to modulate IL-6 release directly on immune cells, peritoneal macrophage cultures were incubated with GHRP-2 or ghrelin, the endogenous ligand of the growth hormone (GH) secretagogue receptor. Both GHRP-2 (10(-7) M) and ghrelin (10(-7) M) prevented endotoxin-induced IL-6 and decreased nitrite/nitrate release from peritoneal macrophages in vitro. These data suggest that GHRP-2 administration has an anti-inflammatory effect in arthritic rats that seems to be mediated by ghrelin receptors directly on immune cells. Topics: Adrenocorticotropic Hormone; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Blood; Body Weight; Corticosterone; Eating; Foot; Freund's Adjuvant; Ghrelin; Inflammation; Interleukin-6; Leptin; Lipopolysaccharides; Macrophages, Peritoneal; Male; Nitrates; Nitrites; Oligopeptides; Peptide Hormones; Rats; Rats, Wistar | 2005 |
Effect of short-term cigarette smoke exposure on body weight, appetite and brain neuropeptide Y in mice.
Although nicotinic receptors have been demonstrated in hypothalamic appetite-regulating areas and nicotine administration alters food intake and body weight in both animals and humans, the mechanisms underlying the effects of smoking on appetite circuits remain unclear. Conflicting effects of nicotine on the major orexigenic peptide, neuropeptide Y (NPY), have been observed in the brain, but the effects of smoking are unknown. Thus, we aimed to investigate how cigarette smoking affects body weight, food intake, plasma leptin concentration, hypothalamic NPY peptide, adipose mass and mRNA expression of uncoupling proteins (UCP), and tumor necrosis factor (TNF) alpha. Balb/C mice (8 weeks) were exposed to cigarette smoke (three cigarettes, three times a day for 4 consecutive days) or sham exposed. Body weight and food intake were recorded. Plasma leptin and brain NPY were measured by radioimmunoassay. UCPs and TNF alpha mRNA were measured by real-time PCR. Food intake dropped significantly from the first day of smoking, and weight loss became evident within 2 days. Brown fat and retroperitoneal white fat masses were significantly reduced, and plasma leptin concentration was decreased by 34%, in line with the decreased fat mass. NPY concentrations in hypothalamic subregions were similar between two groups. UCP1 mRNA was decreased in white fat and UCP3 mRNA increased in brown fat in smoking group. Short-term cigarette smoke exposure led to reduced body weight, food intake, and fat mass. The reduction in plasma leptin concentration may have been too modest to increase NPY production; alternatively, change in NPY or its function might have been offset by nicotine or other elements in cigarette smoke. Topics: Adipose Tissue; Animals; Appetite Regulation; Body Weight; Brain; Carrier Proteins; Disease Models, Animal; Down-Regulation; Drug Administration Schedule; Energy Metabolism; Hypothalamus; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mitochondrial Proteins; Neuropeptide Y; Nicotine; RNA, Messenger; Smoking; Time Factors; Tobacco Use Disorder; Tumor Necrosis Factor-alpha; Uncoupling Protein 1; Uncoupling Protein 3 | 2005 |
Topiramate is an insulin-sensitizing compound in vivo with direct effects on adipocytes in female ZDF rats.
We have studied the in vivo and in vitro effects of Topiramate (TPM) in female Zucker diabetic fatty (ZDF) rats. After weight matching, drug treatment had a marked effect to lower fasting glucose levels of relatively normoglycemic animals as well as during an oral glucose tolerance test. The glucose clamp studies revealed a approximately 30% increased glucose disposal, increased hepatic glucose output (HGO) suppression from approximately 30 to 60%, and an increased free fatty acid suppression from 40 to 75%. Therefore, TPM treatment led to enhanced insulin sensitivity at the level of tissue glucose disposal (increased ISGDR), liver (increased inhibition of HGO), and adipose tissue (enhanced suppression of lipolysis). When soleus muscle strips of control or TPM-treated ZDF rats were studied ex vivo, insulin-stimulated glucose transport was not enhanced in the drug-treated animals. In contrast, when isolated adipocytes were studied ex vivo, a marked increase (+55%) in insulin-stimulated glucose transport was observed. In vitro treatment of muscle strips and rat adipocytes showed no effect on glucose transport in muscle with a 40% increase in insulin-stimulated adipocyte glucose transport. In conclusion, 1) TPM treatment leads to a decrease in plasma glucose and increased in vivo insulin sensitivity; 2) insulin sensitization was observed in adipocytes, but not muscle, when tissues were studied ex vivo or in vitro; and 3) TPM directly enhances insulin action in insulin-resistant adipose cells in vitro. Thus the in vivo effects of TPM treatment appear to be exerted through adipose tissue. Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Deoxyglucose; Eating; Fatty Acids, Nonesterified; Female; Fructose; Glucose; Glucose Tolerance Test; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Liver; Muscle, Skeletal; Ovary; Rats; Rats, Zucker; Topiramate | 2005 |
Relationship of serum leptin with age, body weight, body mass index, and bone mineral density in healthy mainland Chinese women.
Serum leptin concentration is associated with age, fat and bone mineral density (BMD), and there are ethnic differences in physique and BMD values. The relationship between serum leptin concentration and BMD in Chinese women is presently unknown. We examined the relationship of serum leptin concentration with age, body weight, BMI and BMD in mainland Chinese women.. Serum leptin concentration in a population of 676 Chinese females, aged 20-80 years (45.4+/-14.8 years, mean+/-S.D.), was measured using an enzyme-linked immunosorbent assay (ELISA). BMD values were measured by dual-energy X-ray absorptiometry (DXA) at a number of sites: the posteroanterior lumbar spine (PA, L1-L4), lateral lumbar spine (Lat, L2-L4), hip (including the femoral neck (FN) and total hip (T-hip)), and forearm (one-third region (RU1/3) and total region (RUT)). The relationship between changes in serum leptin concentration with age, body weight, height, body mass index (BMI) and BMD values at six sites were analyzed using 10 different regression models, and the models giving the best fit were selected.. The cubic regression model best described the changes in serum leptin concentration with age (R(2)=0.048, p<0.001) and body weight (R(2)=0.352, p<0.001), while the quadratic regression model was best for serum leptin concentration changes with BMI (R(2)=0.410, p<0.001); serum leptin concentration was not correlated with height. Serum leptin concentration was significantly higher in postmenopausal than premenopausal women (p<0.001). Serum leptin concentration was correlated with Lat BMD (R(2)=0.012, p<0.018), FN BMD (R(2)=0.006, p<0.041) and T-hip BMD (R(2)=0.013, p<0.004) in the whole population. In premenopausal women, leptin was positively associated with BMD except for Lat (R(2)=0.029-0.055, p<0.008); in postmenopausal women, leptin was also positively associated with AP, FN, T-hip BMD (R(2)=0.026-0.042, p<0.007). However, after adjusting for BMI not for body weight, there was no association between serum leptin concentration and age. Meanwhile, after adjustment for age, body weight and BMI, there was no association between serum leptin concentration and BMD values in premenopausal and postmenopausal women.. Age-related changes in serum leptin concentration is dependent on BMI, but not a direct determinant of BMD in Chinese females. Topics: Absorptiometry, Photon; Adult; Aged; Aged, 80 and over; Aging; Body Mass Index; Body Weight; Bone Density; China; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Male; Middle Aged; Regression Analysis | 2005 |
Basomedial hypothalamic injections of neuropeptide Y conjugated to saporin selectively disrupt hypothalamic controls of food intake.
Neuropeptide Y (NPY) conjugated to saporin (NPY-SAP), a ribosomal inactivating toxin, is a newly developed compound designed to selectively target and lesion NPY receptor-expressing cells. We injected NPY-SAP into the basomedial hypothalamus (BMH), just dorsal to the arcuate nucleus (ARC), to investigate its neurotoxicity and to determine whether ARC NPY neurons are required for glucoprivic feeding. We found that NPY-SAP profoundly reduced NPY Y1 receptor and alpha MSH immunoreactivity, as well as NPY, Agouti gene-related protein (AGRP), and cocaine and amphetamine-related transcript mRNA expression in the BMH. NPY-SAP lesions were localized to the injection site with no evidence of retrograde transport by hindbrain NPY neurons with BMH terminals. These lesions impaired responses to intracerebroventricular (icv) leptin (5 microg/5 microl x d) and ghrelin (2 microg/5 microl), which are thought to alter feeding primarily by actions on ARC NPY/AGRP and proopiomelanocortin/cocaine and amphetamine-related transcript neurons. However, the hypothesis that NPY/AGRP neurons are required downstream mediators of glucoprivic feeding was not supported. Although NPY/AGRP neurons were destroyed by NPY-SAP, the lesion did not impair either the feeding or the hyperglycemic response to 2-deoxy-D-glucose-induced blockade of glycolysis use. Similarly, responses to glucagon-like peptide-1 (GLP-1, 5 microg/3 microl icv), NPY (5 microg/3 microl icv), cholecystokinin octapeptide (4 microg/kg ip), and beta-mercaptoacetate (68 mg/kg ip) were not altered by the NPY-SAP lesion. Thus, NPY-SAP destroyed NPY receptor-expressing neurons in the ARC and selectively disrupted controls of feeding dependent on those neurons but did not disrupt peptidergic or metabolic controls dependent upon circuitry outside the BMH. Topics: Agouti-Related Protein; alpha-MSH; Amphetamines; Animals; Arcuate Nucleus of Hypothalamus; Binding, Competitive; Body Weight; Catecholamines; Cholecystokinin; Cocaine; Dopamine Uptake Inhibitors; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Inhibitory Concentration 50; Intercellular Signaling Peptides and Proteins; Leptin; Ligands; Male; Models, Biological; Neurons; Neuropeptide Y; Peptide Fragments; Peptide Hormones; Peptides; Plant Proteins; Pro-Opiomelanocortin; Protein Binding; Protein Precursors; Proteins; Rats; Rats, Sprague-Dawley; Rhombencephalon; RNA, Messenger; Thioglycolates; Time Factors; Toxins, Biological | 2005 |
Reduced anorexic effects of insulin in obesity-prone rats fed a moderate-fat diet.
Rats prone to develop diet-induced obesity (DIO) have reduced central sensitivity to many metabolic and hormonal signals involved in energy homeostasis. High-fat diets produce similar defects in diet-resistant (DR) rats. To test the hypothesis that genotype and diet exposure would similarly affect central insulin signaling, we assessed the anorectic effects of 8 mU third ventricular (iv3t) insulin before and after 4 wk intake of a 31% fat, high-energy (HE) diet intake in outbred (OutB) rats. Rats were retrospectively designated as DR or DIO by their low or high weight gains on HE diet. Before the HE diet, iv3t insulin reduced 4-h and 24-h chow intake by 53% and 69% in DR rats but by only 17% and 27% in DIO rats, respectively. Also, the anorectic response to iv3t insulin in OutB rats was inversely correlated (r = 0.72, P = 0.002) with subsequent 4-wk weight gain on the HE diet. Similarly, in selectively bred (SB) chow-fed DR rats, 8 mU iv3t insulin reduced 4-h and 24-h intake by 21% and 22%, respectively, but had no significant effect in SB DIO rats. Four-week HE diet intake reduced 4-h and 24-h insulin-induced anorexia by 45% in OutB DR rats and completely abolished it in SB DR rats. Reduced insulin responsiveness was unassociated with differences in arcuate nucleus insulin receptor mRNA expression between DIO and DR rats or between rats fed chow or HE diet. These data suggest that DIO rats have a preexisting reduction in central insulin signaling, which might contribute to their becoming obese on the HE diet. However, since the HE diet reduced central insulin sensitivity in DR rats but did not make them obese, it is likely that other brain areas are involved in insulin's anorectic action or that other pathways contribute to the development and maintenance of obesity. Topics: Animals; Appetite Depressants; Arcuate Nucleus of Hypothalamus; Body Weight; Diet; Dietary Fats; Hypoglycemic Agents; Injections, Intraventricular; Insulin; Insulin Resistance; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2005 |
Circannual leptin and ghrelin levels of the blue fox (Alopex lagopus) in reference to seasonal rhythms of body mass, adiposity, and food intake.
The aim of the study was to investigate the circannual rhythms of leptin and ghrelin in the blue fox, a variant of the endangered arctic fox, in relation to its seasonal cycles of body mass, adiposity and food intake. The effects of long-term fasting and exogenous melatonin treatment on these weight-regulatory hormones were also investigated. The leptin concentrations of the blue fox increased during the autumnal accumulation of fat and decreased during the wintertime and vernal weight loss periods. The leptin levels peaked 2-6 weeks before the maximum values were observed for the body mass indices, voluntary food intake, and body masses. The ghrelin concentrations fluctuated widely during the autumn but decreased in the winter in association with suppression of food intake. Exogenous melatonin advanced the seasonal changes in the food intake of the blue fox but did not affect the seasonal rhythms of leptin and ghrelin concentrations. The leptin concentrations did not respond to the 3-week fasting periods in a consistent way, but the ghrelin levels increased due to food deprivation. In addition to the amount of fat in the body the leptin secretion of the blue fox may be regulated also by other factors. The blue fox may also express seasonal changes in its leptin sensitivity. Our results reinforce the hypothesis that leptin does not function as an acute indicator of body adiposity in seasonal carnivores but rather as a long-term signal of nutritional status. Topics: Analysis of Variance; Animals; Body Composition; Body Weight; Eating; Finland; Food Deprivation; Foxes; Ghrelin; Leptin; Melatonin; Peptide Hormones; Seasons | 2005 |
Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome.
In humans, a hyperactivity of glucocorticoid metabolism was postulated to be involved in the intrauterine programming of the metabolic syndrome in adulthood. We studied in rats the effects of overfeeding, obtained by reducing the size of the litter in the immediate postnatal period, a time crucial for neuroendocrine maturation such as late gestation in humans. Overfeeding induced early-onset obesity and accelerated the maturation of the hypothalamo-pituitary-adrenal (HPA) axis together with an upregulation of adipose tissue glucocorticoid receptor (GR) mRNA. In adulthood, neonatally overfed rats presented with moderate increases in basal and stress-induced corticosterone secretion and striking changes in visceral adipose tissue glucocorticoid signaling, that is, enhanced GR and 11beta-hydroxysteroid dehydrogenase type 1 mRNA levels. The above-mentioned alterations in the endocrine status of overfed rats were accompanied by a moderate overweight status and significant metabolic disturbances comparable to those described in the metabolic syndrome. Our data demonstrate for the first time that postnatal overfeeding accelerates the maturation of the HPA axis and leads to permanent upregulation of the HPA axis and increased adipose tissue glucocorticoid sensitivity. Thus, the experimental paradigm of postnatal overfeeding is a powerful tool to understand the pathophysiology of glucocorticoid-induced programming of metabolic axes. Topics: Adipose Tissue; Aging; Animals; Blood Glucose; Body Weight; Diet; Disease Models, Animal; Fatty Acids, Nonesterified; Glucocorticoids; Insulin; Leptin; Metabolic Syndrome; Obesity; Rats; Rats, Wistar; Weaning | 2005 |
Moderate caloric restriction, but not physiological hyperleptinemia per se, enhances mitochondrial oxidative capacity in rat liver and skeletal muscle--tissue-specific impact on tissue triglyceride content and AKT activation.
The study aimed at determining, in lean tissues from nonobese rats, whether physiological hyperleptinemia with leptin-induced reduced caloric intake and/or calorie restriction (CR) per se: 1) enhance mitochondrial-energy metabolism gene transcript levels and oxidative capacity; and 2) reduce triglyceride content. Liver and skeletal muscles were collected from 6-month-old Fischer 344 rats after 1-wk leptin sc infusion (0.4 mg/kg . d: leptin + approximately 3-fold leptinemia vs. ad libitum-fed control) or moderate CR (-26% of those fed ad libitum) in pair-fed animals (CR). After 1 wk: 1) leptin and CR comparably enhanced transcriptional expression of mixed muscle mitochondrial genes (P < 0.05 vs. control); 2) CR independently increased (P < 0.05 vs. leptin-control) hepatic mitochondrial-lipooxidative gene expression and oxidative capacity; 3) hepatic but not muscle mitochondrial effects of CR were associated (P < 0.01) with increased activated insulin signaling at AKT level (P < 0.05 vs. leptin-control); 4) liver and muscle triglyceride content were comparable in all groups. In additional experiments, assessing time course of posttranscriptional CR effects, 3-wk superimposable CR (P < 0.05): 1) increased both liver and muscle mitochondrial oxidative capacity; and 2) selectively reduced muscle triglyceride content. Thus, in nonobese adult rat: 1) moderate CR induces early increments of mitochondrial-lipooxidative gene expression and time-dependent increments of oxidative capacity in liver and mixed muscle; 2) sustained moderate CR alters tissue lipid distribution reducing muscle but not liver triglycerides; 3) mitochondrial-lipid metabolism changes are tissue-specifically associated with hepatic AKT activation; 4) short-term physiological hyperleptinemia has no independent stimulatory effects on muscle and liver mitochondrial-lipooxidative gene expression. Increased lean tissue oxidative capacity could favor substrate oxidation over storage during reduced nutrient availability. Topics: Animals; Body Weight; Caloric Restriction; Eating; Leptin; Lipid Metabolism; Male; Mitochondria, Liver; Mitochondria, Muscle; Muscle, Skeletal; Organ Specificity; Oxidation-Reduction; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred F344; Triglycerides | 2005 |
Running wheel activity prevents hyperphagia and obesity in Otsuka long-evans Tokushima Fatty rats: role of hypothalamic signaling.
Otsuka Long-Evans Tokushima fatty (OLETF) rats lacking cholecystokinin-A receptors are hyperphagic, obese, and diabetic. Although exercise attenuates OLETF rats' obesity, the mechanisms underlying the effects of exercise are unclear. In this study, we determined the effects of running wheel activity on patterns of body weight gain, food intake, and hypothalamic gene expression. We demonstrate that voluntary running activity beginning at 8 wk of age normalized meal patterns, food intake, body weight, and plasma levels of glucose and leptin in OLETF rats. During the initial exercise period, corticotropin-releasing factor (CRF) mRNA expression was significantly elevated in the dorsomedial hypothalamus (DMH) but not in the paraventricular nucleus in both OLETF and control Long-Evans Tokushima rats. In response to long-term exercise, arcuate nucleus (Arc) neuropeptide Y (NPY), and proopiomelanocortin as well as DMH NPY and CRF mRNA expression were increased in Long-Evans Tokushima rats. In contrast, whereas exercising OLETF rats had increased Arc NPY and DMH CRF expression, Arc proopiomelanocortin and DMH NPY mRNA levels were not elevated. Finally, we demonstrate that the effects of exercise on body weight in OLETF rats were long lasting. Although food intake and body weight were increased in OLETF rats when running wheels were locked, weights did not return to those of sedentary OLETF rats. Together, these data suggest that the elevation of DMH CRF expression may mediate the short-term feeding inhibitory effects of exercise and that exercise limits the elevation of DMH NPY expression to account for the overall prevention of OLETF rats' obesity. Topics: Animals; Blood Glucose; Body Weight; Corticotropin-Releasing Hormone; Eating; Hyperphagia; Hypothalamus; Leptin; Male; Neuropeptide Y; Obesity; Physical Conditioning, Animal; Pro-Opiomelanocortin; Rats; Rats, Inbred OLETF; Rats, Long-Evans; RNA, Messenger; Running; Signal Transduction | 2005 |
Perinatal essential fatty acid deficiency influences body weight and bone parameters in adult male rats.
Fetal and postnatal nutrition have long-term effects on the risk for development of diseases late in life in humans and animals. The aim of the present study was to investigate the effect of dietary deficiency of essential fatty acids (EFA) in the perinatal period on later body weight and bone mass. During late gestation and throughout lactation, rats were fed a control or an EFA-deficient (EFAD) diet. At 3 weeks of age the offspring were weaned onto an ordinary chow and followed until adult age. The mean body weight of adult rats receiving the EFAD diet during the perinatal period was significantly increased from 12 weeks of age compared to the controls (P<0.05). Analysis by peripheral quantitative computerized tomography (pQCT) at 44 weeks of age showed that the trabecular volumetric bone mineral density (BMD) of the femur was significantly decreased (P<0.05) but the cortical bone mineral content, cortical area, and cortical thickness were increased (P<0.05) in the EFAD group of rats. The length of the femur was not affected. In conclusion, neonatal EFA deficiency was in adult rats associated with increased body weight and significant changes in both cortical and trabecular bone. The results indicate that regulatory mechanisms related to bone mass seemed to be programmed by EFA in the perinatal period. The nature of this modulation needs to be identified. Topics: Animal Feed; Animals; Body Weight; Bone and Bones; Bone Development; Fatty Acids, Essential; Insulin-Like Growth Factor I; Leptin; Male; Rats; Rats, Sprague-Dawley | 2005 |
Acute and chronic administration of immunomodulators induces anorexia in Zucker rats.
To investigate the possible involvement of leptin signaling in lipopolysaccharide (LPS) anorexia, we compared the anorectic effect of LPS in genetically obese (fa/fa) Zucker rats and in their lean (Fa/?) counterparts. The effects of interleukin-1beta (IL-1beta) and muramyl dipeptide (MDP) were also tested. LPS [100 microg/kg body weight (BW)], IL-1beta (2 microg/kg BW) and MDP (2.2 mg/kg BW) injected intraperitoneally (i.p.) at lights out reduced food intake similarly in obese and lean rats. LPS injection at 500 or 1000 microg/kg BW (i.p.) also reduced food intake and BW similarly in obese and lean rats, but obese regained BW faster than lean rats. LPS (2.45 microg or 9.8 microg/h/rat) administered chronically with i.p. implanted osmotic pumps reduced food intake similarly on experimental day 1, regardless of the genotype. After day 3, the lean rats' anorectic response and recovery were dose-dependent, whereas the anorectic response in obese rats was minimally affected by dose (significant dose effect only on day 3). Again, obese rats regained lost BW faster than lean rats. These results do not support a role for leptin as the sole mediator of anorexia induced by bacterial products (LPS and MDP) and IL-1beta. Topics: Analysis of Variance; Animals; Anorexia; Body Weight; Dose-Response Relationship, Drug; Drug Administration Schedule; Eating; Immunologic Factors; Leptin; Male; Obesity; Rats; Rats, Zucker; Thinness; Time Factors | 2005 |
Induction of leptin receptor expression in the liver by leptin and food deprivation.
Leptin resistance is a common feature of obesity and the metabolic syndrome. However, the regulated expression of the leptin receptor (Ob-R) has not been studied in detail. Expression profiling of liver mRNA in leptin-treated wild-type mice revealed a marked increase in leptin receptor mRNA levels, which had not previously been described. This was confirmed by isoform-specific real-time PCR, which showed a >25-fold increase in the mRNAs encoding the short forms (Ob-Ra, Ob-Rc) and a >10-fold increase in the mRNA encoding the long (Ob-Rb) form of the leptin receptor in liver. In parallel, we also observed induction of plasma-soluble leptin receptor (SLR) protein by leptin administration, pair feeding, and short term food restriction. However, induction of SLR by leptin is abolished in mice with selective deletion of Ob-R from liver using Cre-LoxP technology. These data suggest that the liver is a major source of Ob-R mRNA expression under conditions of negative energy balance. Membrane-bound Ob-R is then shed into the circulation as SLR. Our study thus reveals an unexpected role of the liver in modulating total circulating leptin levels and possibly its biological activity. Topics: Animals; Blotting, Northern; Body Weight; Cell Membrane; Electrophoresis, Polyacrylamide Gel; Food Deprivation; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Placenta; Protein Isoforms; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Time Factors | 2005 |
Early dietary intervention: long-term effects on blood pressure, brain neuropeptide Y, and adiposity markers.
Early life nutrition impacts on subsequent risk of obesity and hypertension. Several brain chemicals responsible for both feeding and cardiovascular regulation are altered in obesity. We examined effects of early postnatal overnutrition on blood pressure, brain neuropeptide Y (NPY), and adiposity markers. Rat pup litters were adjusted to either 3 or 12 male animals (overnutrition and control, respectively) on day 1 of life. After weaning, rats were given either a palatable high-fat diet or standard chow. Smaller litter pups were significantly heavier by 17 days of age. By 16 wk, the effect of litter size was masked by that of diet, postweaning. Small and normal litter animals fed a high-fat diet had similar increases in body weight, plasma insulin, leptin, and adiponectin concentrations, leptin mRNA, and fat masses relative to chow-fed animals. An increase in 11beta-hydroxysteroid dehydrogenase-1 mRNA in white adipose tissue, and a decrease in uncoupling protein-1 mRNA in brown adipose tissue in both small litter groups at 16 wk of age, may represent a programming effect of the altered litter size. NPY concentration in the paraventricular nucleus of the hypothalamus was reduced in high fat-fed groups. Blood pressure was significantly elevated at 13 wk in high-fat-fed animals. This study demonstrates that overnourishment during early postnatal development leads to profound changes in body weight at weaning, which tended to abate with maturation. Thus the effects of long-term dietary intervention postweaning can override those of litter size-induced obesity. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adiponectin; Adipose Tissue, Brown; Animals; Animals, Newborn; Blood Pressure; Blotting, Northern; Body Weight; Brain; Carrier Proteins; Dietary Fats; Female; Insulin; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tumor Necrosis Factor-alpha; Uncoupling Protein 1 | 2005 |
Effects of propylene glycol on carcass traits and its related gene expression in Korean native steers.
The effects of propylene glycol (PEG) on performance, ruminal fermentation, blood glucose and insulin, carcass traits, and abundance of IGF-1 mRNA in LM and leptin mRNA in adipose tissue were examined in 20 Korean native steers, with 10 each in control and PEG-fed groups, respectively. Propylene glycol mixed with concentrate diet was provided daily at a rate of 2.5 mL/kg BW(0.75). Experimental animals were fed a concentrate diet to 1.8% of BW twice daily plus rice straw ad libitum during the 4-mo period before marketing. Daily DMI and ADG did not differ between control and PEG-fed steers. Steers receiving PEG displayed an increase (P = 0.044) in propionate concentration, whereas acetate concentration decreased (P = 0.032). Although blood glucose was not affected, serum insulin was increased (P = 0.047) by PEG feeding. Propylene glycol did not affect carcass weight, 13th-rib fat depth, marbling score, or lipid content of LM. The backfat of PEG-fed steers did not differ in leptin mRNA from control steers, whereas increased leptin mRNA was found in i.m. fat with PEG feeding. There was no treatment effect on the level of IGF-1 mRNA in the LM of the tested steers. These results indicate that the amount of PEG fed to steers was not sufficient to improve marbling score through enhanced ruminal propionate and insulin. The role of increased i.m. leptin mRNA level in PEG-fed steers remains to be further elucidated. Topics: Adipose Tissue; Animal Feed; Animals; Blood Glucose; Body Composition; Body Weight; Cattle; DNA Primers; Fatty Acids, Volatile; Gene Expression; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Meat; Propylene Glycol; Random Allocation; RNA, Messenger; Rumen | 2005 |
Dexamethasone impairs muscle energetics, studied by (31)P NMR, in rats.
Glucocorticoid treatments are associated with increased whole-body oxygen consumption. We hypothesised that an impairment of muscle energy metabolism can participate in this increased energy expenditure.. To investigate this possibility, we have studied muscle energetics of dexamethasone-treated rats (1.5 mg kg(-1) day(-1) for 6 days), in vivo by (31)P NMR spectroscopy. Results were compared with control and pair-fed (PF) rats before and after overnight fasting.. Dexamethasone treatment resulted in decreased phosphocreatine (PCr) concentration and PCr:ATP ratio, increased ADP concentration and higher PCr to gamma-ATP flux but no change in beta-ATP to beta-ADP flux in gastrocnemius muscle. Neither 4 days of food restriction (PF rats) nor 24 h fasting affected high-energy phosphate metabolism. In dexamethasone-treated rats, there was an increase in plasma insulin and non-esterified fatty acid concentration.. We conclude that dexamethasone treatment altered resting in vivo skeletal muscle energy metabolism, by decreasing oxidative phosphorylation, producing ATP at the expense of PCr. Topics: 3-Hydroxybutyric Acid; Adenine Nucleotides; Animals; Body Weight; Dexamethasone; Energy Metabolism; Fatty Acids, Nonesterified; Hydrogen-Ion Concentration; Insulin; Leptin; Magnetic Resonance Spectroscopy; Male; Muscle, Skeletal; Oxygen Consumption; Phosphates; Phosphocreatine; Phosphorus Radioisotopes; Rats; Rats, Sprague-Dawley | 2005 |
Influence of precalving feed allowance on periparturient metabolic and hormonal responses and milk production in grazing dairy cows.
Fifty-two multiparous dairy cows were allocated to 4 treatments consuming 5.4, 8.2, 10.0, or 11.0 kg/d of pasture dry matter per cow for 27 +/- 9.6 d precalving. This equated to 1.3, 1.9, 2.4, and 2.6% of body weight (BW; not including the conceptus weight). Following calving, all cows were fed ad libitum on pasture. Blood was sampled 17 d precalving, on day of calving, and on d 1, 2, 3, 4, 7, 14, 28, and 35 postcalving. Results suggest that the near-term grazing dairy cow requires 1.05 MJ of ME/kg of BW(0.75) and that previous estimates of energy requirements were underestimated. Precalving plasma concentrations of glucose, insulin-like growth factor-1, and leptin increased quadratically with increasing pasture intake. This was associated with precalving plasma concentrations of growth hormone that declined linearly, and concentrations of nonesterified fatty acids and beta-hydroxybutyrate that declined quadratically with increasing dry matter intake (DMI). Postcalving plasma concentrations of these metabolites showed no lasting effect of precalving feeding. The effect of precalving nutrition on milk production was small, and other than milk fat, was confined to wk 1 postcalving. Milk fat yield increased with increasing precalving DMI and calving body condition score until wk 3 post-calving, after which treatment effects were not evident. These results indicate that the level of feeding in grazing dairy cows during the last month before calving has only small effects on cow metabolic and hormonal status, and on milk production in the first 5 wk of lactation. Topics: 3-Hydroxybutyric Acid; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Body Composition; Body Weight; Calcium; Cattle; Fatty Acids, Nonesterified; Female; Growth Hormone; Hormones; Insulin-Like Growth Factor I; Lactation; Leptin; Lipids; Magnesium; Milk; Parturition; Postpartum Period; Pregnancy; Prenatal Care | 2005 |
Effect of crude saponin of Korean red ginseng on high-fat diet-induced obesity in the rat.
The anti-obesity effects of crude saponin (CS) of Korean red ginseng (KRG) were investigated in the rat fed a high-fat (HF) diet. Male Sprague-Dawley (SD) rats became obese by feeding the HF diet over 5 weeks, while the control rats were fed a normal diet, and then both groups were treated with CS (200 mg/kg, i.p.) for 3 weeks. The body weight, food consumption, adipose tissues, and expression of appetite peptides such as leptin and neuropeptide Y (NPY) were investigated in rats fed normal and HF diet after treatment of CS. Administration of CS reduced body weight, food intake, and fat content in HF diet rats in a manner similar to those of the normal diet fed rats. The hypothalamic NPY expression and serum leptin level were reduced in HF diet rats after CS treatment. Our results suggest that CS may be useful in the treatment of obesity and related disorders as anti-obesity agents. Topics: Adipose Tissue; Animals; Body Weight; Dietary Fats; Disease Models, Animal; Drug Administration Schedule; Eating; Gene Expression; Hypothalamus; Injections, Intraperitoneal; Korea; Leptin; Male; Neuropeptide Y; Obesity; Panax; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Saponins; Time Factors | 2005 |
Leptin, cell proliferation and crypt fission in the gastrointestinal tract of intravenously fed rats.
Many peptides, hormones and growth factors have been implicated in the control of cell renewal in the gastrointestinal epithelium. Leptin is present in the stomach and salivary glands and leptin receptors are seen throughout the gut. Leptin can stimulate mitogen-activated protein kinase activity in vitro and short-term infusion has been reported to have a proliferative action on the colon in vivo, suggesting a biological link between obesity, physical activity and colon cancer. Food intake is one of the most important determinants of intestinal mucosal cell renewal, thus any direct effects of leptin on the gut may be hidden. This problem has been avoided experimentally by maintaining animals on total parenteral nutrition (TPN). Male Wistar rats were anaesthetized and cannulae were inserted into the jugular vein to deliver the TPN diet to which had been added 0, 0.5, 2.5, or 10 mg/kg of recombinant murine leptin. Orally fed rats were also studied. After 6 days of treatment, all animals were injected with vincristine and killed 2 h later. Tissue weight was recorded and crypt cell proliferation (arrested metaphases) and crypt fission were scored in 'microdissected' crypts. Leptin infusion led to a small decrease in body weight and in the weight of the caecum. Intestinal cell proliferation was significantly reduced by TPN when compared to the orally fed rats, but the addition of leptin had no effect on the small intestine or colon. Crypt fission was also significantly lowered in the TPN group. Fission was slightly but significantly increased in the proximal and mid-colon of the leptin-treated rats, but was decreased in the distal colon. Although leptin did not significantly alter cell proliferation, it had significant effects on the process of crypt fission in the colon, which varied according to the exact locality. Topics: Animals; Body Weight; Cell Proliferation; Colon; Dose-Response Relationship, Drug; Gastrointestinal Tract; Intestine, Small; Leptin; Male; MAP Kinase Signaling System; Models, Biological; Organ Size; Parenteral Nutrition; Peptides; Rats; Rats, Wistar; Time Factors | 2005 |
Leptin-like effects of MTII are augmented in MSG-obese rats.
To evaluate whether MTII, a melanocortin receptor 3/4 agonist, is working in hypophagic and hypothermogenic obese model, we measured food intake, body weight, oxygen consumption, and fat mass following intracerebroventricular (i.c.v.) infusion of MTII in monosodium glutamate (MSG)-induced obese rats. MTII, or artificial cerebrospinal fluid (aCSF), was infused into i.c.v. with an osmotic minipump for 1 week. MSG-obese rats were induced by neonatal injection of MSG. Five-month-old MSG rats were characterized by hypophagia, lower oxygen consumption, hyperleptinemia, and obesity compared to age-matched control rats. The infusion of MTII decreased their food intake, visceral fat, and body weight in MSG-obese rats compared with aCSF-infused rats. The oxygen consumption was increased by MTII treatment in MSG-obese rats compared with aCSF as well as pair fed (PF) rats. Interestingly, these leptin-like effects of MTII were greater in MSG-obese rats than in controls, which might be related to the increased expression of melanocortin receptor 4 (MC4R) in the hypothalamus of MSG-obese rats. Our results suggested that both anorexic and thermogenic mechanisms were activated by MTII in the MSG-obese rats and contributed to the decrease in body weight and fat mass. Moreover, there was a sensitization to MTII caused by upregulation of the melanocortin receptor in the MSG-obese rats. Topics: alpha-MSH; Animals; Body Weight; Carbon Dioxide; Eating; Fatty Acids, Nonesterified; Female; Food Additives; Humans; Leptin; Male; Obesity; Oxygen Consumption; Pregnancy; Pro-Opiomelanocortin; Random Allocation; Rats; Receptor, Melanocortin, Type 4; Receptors, Leptin; Sodium Glutamate | 2005 |
Effects of maternal leptin treatment during lactation on the body weight and leptin resistance of adult offspring.
We investigate whether leptin treatment to lactating rats affects food intake, body weight and leptin serum concentration and its anorectic effect on their adult offspring. Lactating rats were divided into 2 groups: Lep-single injected with recombinant rat leptin (8 microg/100 g of body weight, daily for the last 3 consecutive days of lactation) and control group (C) that received the same volume of saline. After weaning all pups had free access to the control diet, their body weight and food intake were monitored at each 4 days until 180 days of age, when they were tested for its food intake and response to either leptin (0.5 mg/kg body wt, ip) or saline vehicle. The offspring of the leptin-treated dams gained more weight and had higher food intake from day 37 onward (p<0.05), higher amount of retroperitoneal white adipose tissue (RPWAT) (37%, p<0.05) and higher leptin serum concentration (40%, p<0.05) at 180 days of age compared to control group. The food intake at 2, 4, 6 and 24 h was unaffected after acute injection of leptin in these animals, suggesting resistance to the anorectic effect of leptin. The maternal leptin treatment during lactation makes their adult offspring more susceptible to overweight with resistance to the anorectic effect of leptin. Topics: Animals; Appetite Depressants; Body Weight; Eating; Female; Humans; Lactation; Leptin; Maternal Exposure; Mothers; Rats; Rats, Wistar | 2005 |
Long-Evans and Sprague-Dawley rats exhibit divergent responses to refeeding after caloric restriction.
Mature male Sprague-Dawley (SD) and Long-Evans (LE) rats were instrumented with telemetry transmitters for measurement of heart rate (HR) and housed in room calorimeters for assessment of food intake and oxygen consumption (Vo(2)) at standard laboratory temperatures (23 degrees C) to examine physiological responses to caloric restriction (CR; 60% of baseline ad libitum calories for 2 wk) and refeeding. Ad libitum controls had stable food intake (84-88 kcal/day) and gained weight at rates of 3-4 g/day. Groups from both strains assigned to CR exhibited similar patterns of weight loss and reductions in Vo(2) and HR. Upon refeeding, SD rats exhibited a mild, transient hyperphagic response (1 day) accompanied by sustained suppression of Vo(2) and HR that remained evident 8 days after refeeding. In contrast, LE rats exhibited sustained daily hyperphagia that persisted 8 days after refeeding and was accompanied by a complete restoration of HR and Vo(2). The lower HR and Vo(2) observed during refeeding in SD rats were not due to reduced locomotor activity. The results reveal a strain-dependent divergent response to recovery from CR. We conclude that during recovery from CR, homeostatic stimulation of appetite or suppression of energy expenditure may occur selectively to restore body weight. Topics: Animals; Behavior, Animal; Body Composition; Body Temperature Regulation; Body Weight; Caloric Restriction; Calorimetry, Indirect; Eating; Heart Rate; Hemodynamics; Leptin; Male; Organ Size; Oxygen Consumption; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Species Specificity | 2005 |
Liver-specific protein-tyrosine phosphatase 1B (PTP1B) re-expression alters glucose homeostasis of PTP1B-/-mice.
Protein-tyrosine phosphatase 1B (PTP1B) is an important negative regulator of insulin and leptin signaling in vivo. Mice lacking PTP1B (PTP1B-/- mice) are hyper-responsive to insulin and leptin and resistant to diet-induced obesity. The tissue(s) that mediate these effects of global PTP1B deficiency remain controversial. We exploited the high degree of hepatotropism of adenoviruses to assess the role of PTP1B in the liver. Liver-specific re-expression of PTP1B in PTP1B-/- mice led to marked attenuation of their enhanced insulin sensitivity. This correlated with, and was probably caused by, decreased insulin-stimulated tyrosyl phosphorylation of the insulin receptor (IR) and IR substrate 2-associated phosphatidylinositide 3-kinase activity. Analysis using phospho-specific antibodies for the IR revealed preferential dephosphorylation of Tyr-1162/1163 compared with Tyr-972 by PTP1B in vivo. Our findings show that the liver is a major site of the peripheral action of PTP1B in regulating glucose homeostasis. Topics: Adenoviridae; Animals; Binding Sites; Blood Glucose; Body Weight; Gene Transfer Techniques; Glucose; Glucose Tolerance Test; Humans; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Insulin; Lac Operon; Leptin; Liver; Male; Mice; Mice, Knockout; Mice, Transgenic; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Receptor, Insulin; Time Factors; Tyrosine | 2005 |
Expression of adiponectin and its receptors in swine.
Adiponectin is an adipocyte-derived hormone that plays an important role in lipid metabolism and glucose homeostasis. Objectives of this study were 1) to determine the presence and distribution of adiponectin and its receptors 1 and 2 (adipoR1 and adipoR2) in porcine tissues; 2) to characterize pig adiponectin, adipoR1, and adipoR2 mRNA levels in various fat depots from three different breeds of pigs; and 3) to study, in stromal-vascular cell culture, the effects of leptin and tumor necrosis factor-alpha (TNFalpha) on pig adiponectin, adipoR1, and adipoR2 gene expression. To this end, fat Chinese Upton Meishan (UM, n = 10), lean Ham Line (HL, n = 10), and Large White (LW, n = 10) gilts were used. We report the isolation of partial cDNA sequences of pig adipoR1 and adipoR2. Porcine-deduced AA sequences share 97 to 100% homology with human and murine sequences. Pig adipoR1 mRNA is abundant in skeletal muscle, visceral fat, and s.c. fat tissues, whereas adipoR2 mRNA is predominantly expressed in liver, heart, skeletal muscle, and visceral and s.c. fat tissues. Pig adiponectin mRNA levels in s.c. and visceral fat tissues were not associated with plasma insulin and glucose in fasting animals. Subcutaneous (r = -0.44, P < 0.05), visceral (r = -0.43, P < 0.05), and total body fat (r = -0.42, P < 0.05) weights were negatively correlated with adiponectin mRNA levels measured in visceral, but not s.c., fat. Pig adipoR1 and adipoR2 mRNA levels, in visceral fat, were less expressed in fat UM gilts than in the lean HL gilts (P < 0.05). Inverse associations were found between s.c. (r = -0.57, P < 0.01), visceral (r = -0.46, P < 0.05), and total body fat (r = -0.56, P < 0.01) weights and adipoR2 mRNA levels in visceral fat only. We were unable to find such associations for adipoR1 mRNA levels in the overall gilt population. The current study demonstrated that TNFalpha downregulates adiponectin and adipoR2, but not adi-poR1, mRNA levels in stromal-vascular cell culture. Moreover, leptin significantly decreased adiponectin mRNA levels, whereas there was no effect on adiponectin receptors. We conclude that adiponectin and adi-poR2 mRNA levels, but not adipoR1, are modulated in pig visceral fat tissues. Furthermore, our results indicate that TNFalpha interferes with adiponectin function by downregulation of adipoR2 but not of adipoR1 mRNA levels in pigs. Topics: Adiponectin; Adipose Tissue; Amino Acid Sequence; Animals; Blood Chemical Analysis; Body Weight; Cells, Cultured; DNA Primers; Down-Regulation; Fatty Acid-Binding Proteins; Female; Gene Expression; Humans; Leptin; Molecular Sequence Data; Receptors, Adiponectin; Swine; Tumor Necrosis Factor-alpha | 2005 |
Pregnancy increases plasma leptin in nulliparous but not primiparous goats while lactation depresses it.
Most dairy ruminants are still lactating during early pregnancy, which could induce hormonal adaptations different from those observed during pregnancy alone. The incidence of concomitant lactation and pregnancy on plasma leptin has not been studied, and physiological factors involved in its regulation have not been addressed in goats. We assayed leptinemia throughout the pregnancy-lactation cycle in nulliparous and primiparous goats, starting 165 days prior to parturition and finishing 59 days after. During the first half of pregnancy, primiparous goats were lactating. Lactating non-pregnant primiparous goats were studied in parallel. Plasma leptin increased (+49%) up to mid-pregnancy in nulliparous, but not in primiparous goats. Furthermore, leptinemia was similar between pregnant and non-pregnant lactating primiparous goats, suggesting a strong leptinemia down-regulation by late lactation. Plasma leptin decreased from mid-pregnancy to parturition, more markedly in nulliparous goats, and remained depressed during early lactation at a similar level in both female types. It was lower, at 130 days of pregnancy, in goats carrying two fetuses. The leptinemia down-regulation by late pregnancy was highlighted by the lack of plasma leptin increase after drying-off late-pregnant primiparous goats, while it strongly increased in non-pregnant goats. The observation of leptinemia increase only in nulliparous goats suggests that it is not an essential endocrine adaptation during early pregnancy. By contrast, in both female types, the low leptinemia during transition from late pregnancy to lactation, and during late lactation, may be important for the adaptations that occur during lactation such as the partitioning of energy and nutrients towards essential functions and/or hyperphagia. Topics: Animals; Animals, Newborn; Body Weight; Female; Goats; Lactation; Leptin; Litter Size; Parity; Pregnancy; Pregnancy, Animal; Radioimmunoassay | 2005 |
Topiramate does not alter expression in rat brain of enzymes of arachidonic acid metabolism.
When administered chronically to rats, drugs that are effective in bipolar disorder-lithium and the anticonvulsants, valproic acid and carbamazepine-have been shown to downregulate the expression of certain enzymes involved in brain arachidonic acid (AA) release and cyclooxygenase (COX)-mediated metabolism. Phase II clinical trials with the anticonvulsant topiramate [2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] suggest that this drug may also be effective for bipolar disorder.. To see if topiramate has effects similar to those of the other three drugs, we administered topiramate to rats for 14 days at 20 mg/kg, p.o. twice daily.. Compared with p.o. vehicle, topiramate treatment did not significantly affect the brain activity or protein level of cytosolic phospholipase A2, secretory PLA2, or Ca2+-independent iPLA2. Additionally, brain protein levels of COX-1, COX-2, 5-lipoxygenase, and cytochrome P450 epoxygenase were unchanged.. These results suggest that topiramate does not modify expression of the enzymes involved in brain AA metabolism that have been shown to be targeted by lithium, valproic acid, or carbamazepine. If topiramate proves effective in bipolar disorder, it may not act by modulating brain AA metabolism. In view of the proven anticonvulsant effect of topiramate, our results also suggest that the AA cascade is not involved in the anti-seizure properties of the drug. Topics: Administration, Oral; Animals; Arachidonic Acid; Blotting, Western; Body Weight; Brain; Fructose; Immunoenzyme Techniques; Leptin; Male; Phospholipases A; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred F344; Time Factors; Topiramate | 2005 |
Introduction of a high-energy diet acutely up-regulates hypothalamic cocaine and amphetamine-regulated transcript, Mc4R and brown adipose tissue uncoupling protein-1 gene expression in male Sprague-Dawley rats.
Obesity is an escalating problem in Western societies. Susceptibility to weight gain within an obesogenic environment is variable. It remains unclear how the range of weight gain responses are generated. It is possible that an individual's immediate and/or sustained appetite for apparently palatable foods, or metabolic adaptations to a new diet could be important. The present study therefore examined the short- to medium-term effects of a high-energy (HE) diet on bodyweight, food intake, and energy balance-related signalling systems. Sprague-Dawley rats were fed either chow or an HE diet for 12 h, 24 h, 48 h or 14 days. Blood hormones and metabolites were assayed, and expression of uncoupling protein-1 (UCP-1) and hypothalamic energy-balance related genes were determined by Northern blotting or in situ hybridisation, respectively. Short-term exposure (12 h, 24 h, 48 h) to the HE diet had no effect on grams of food consumed, but caloric intake was increased. Exposure to HE diet for 14 days (medium term) established a bodyweight differential of 7.7 g, and animals exhibited a transient increase in caloric intake of 5 days duration. Terminal levels of leptin, insulin, glucose and non-esterified fatty acids (NEFAs) were all increased in HE-fed animals. UCP-1 mRNA was elevated in interscapular brown adipose tissue from HE-fed rats only at 12 h. Cocaine and amphetamine-regulated transcript (CART) and Mc4R gene expression in the hypothalamus were increased after 12 h and 24 h on an HE diet, respectively. The rats appear to passively over-consume calories as a result of consuming a similar weight of a more energy dense food. This evokes physiological responses, which adjust caloric intake over several days. Circulating NEFA and insulin concentrations, UCP-1, Mc4R and CART gene expression are increased as an immediate consequence of consuming HE diet, and may be involved in countering hypercaloric intake. Circulating leptin is increased in the HE-fed animals after 48 h, reflecting their increasing adiposity. Topics: Animal Feed; Animals; Blood Glucose; Body Weight; Carrier Proteins; Energy Intake; Energy Metabolism; Fatty Acids, Nonesterified; Gene Expression; Hypothalamus; Insulin; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Nerve Tissue Proteins; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Uncoupling Protein 1; Up-Regulation | 2005 |
Mice with MCH ablation resist diet-induced obesity through strain-specific mechanisms.
Genetics and environment contribute to the development of obesity, in both humans and rodents. However, the potential interaction between genes important in energy balance, strain background, and dietary environment has been only minimally explored. We investigated the effects of genetic ablation of melanin-concentrating hormone (MCH), a neuropeptide with a key role in energy balance, with chow and a high-fat diet (HFD) in two different mouse strains, one obesity-prone (C57BL/6) and the other obesity-resistant (129). Substantial differences were seen in wild-type (WT) animals of different strains. 129 animals had significantly lower levels of spontaneous locomotor activity than C57BL/6; however, 129 mice gained less weight on both chow and HFD. In both strains, deletion of MCH led to attenuated weight gain compared with WT counterparts, an effect secondary to increased energy expenditure. In both strains, feeding a HFD led to further increases in energy expenditure in both WT and MCH-KO mice; however, this increase was more pronounced in 129 mice. In addition, mice lacking MCH have a phenotype of increased locomotor activity, an effect also seen in both strains. The relative increase in activity in MCH(-/-) mice is modest in animals fed chow but increases substantially when animals are placed on HFD. These studies reinforce the important role of MCH in energy homeostasis and indicate that MCH is a plausible target for antiobesity therapy. Topics: Animals; Body Composition; Body Weight; Diet; Disease Susceptibility; Eating; Energy Metabolism; Genetic Predisposition to Disease; Glucose Tolerance Test; Hypothalamic Hormones; Insulin; Leptin; Melanins; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Motor Activity; Obesity; Oxygen Consumption; Pituitary Hormones; Species Specificity; Thermogenesis | 2005 |
Age-related decline in caloric intake and motivation for food in rhesus monkeys.
Human studies have documented age-related declines in caloric intake that are pronounced at advanced ages. We examined caloric intake from a longitudinal study of aging in 60 male and 60 female rhesus monkeys (Macaca mulatta) collected for up to 10 years. Monkeys were provided a standardized, nutritionally fortified diet during two daily meals, and intake was measured quarterly. About half of the monkeys were on a regimen of caloric restriction (CR) representing about a 30% reduction in caloric intake compared to controls (CON) of comparable age and body weight. CR was applied to determine if this nutritional intervention retards the rate of aging in monkeys similar to observations in other mammalian studies. Following reproductive maturity at 6 years of age, there was a consistent age-related decline in caloric intake in these monkeys. Although males had higher intake than females, and CON had higher intake compared to CR, the sex and diet differences converged at older ages (>20 years); thus, older CR monkeys were no longer consuming 30% less than the CON. When adjusted for body weight, an age-related decline in caloric intake was still evident; however, females had higher intake compared to males while CR monkeys still consumed less food, and again differences converged at older ages. Motivation for food was assessed in 65 of the monkeys following at least 8 years in their respective diet groups. Using an apparatus attached to the home cage, following an overnight fast, monkeys were trained to reach out of their cage to retrieve a biscuit of their diet by pushing open a clear plastic door on the apparatus. The door was then locked, and thus the biscuit was irretrievable. The time spent trying to retrieve the biscuit was recorded as a measure of motivation for food. We observed an age-related decline in this measure, but found no consistent differences in retrieval time between CR and CON groups of comparable age and time on diet. The results demonstrate an age-related decline in food intake and motivation for food in rhesus monkeys paralleling findings in humans; however, we found no evidence that monkeys on a long-term CR regimen were more motivated for food compared to CON. Examining the relationship of selected blood proteins to food intake following 7-11 years on the study, we found a negative correlation between globulin and intake among males and females after accounting for differences in age. In addition, a positive correlation was observed bet Topics: Age Factors; Aging; Albumins; Animals; Behavior, Animal; Body Weight; Caloric Restriction; Energy Intake; Feeding Behavior; Female; Globulins; Leptin; Longitudinal Studies; Macaca mulatta; Male; Motivation; Reaction Time; Sex Factors | 2005 |
Role of adiposity hormones in the mouse during fasting and winter-acclimatization.
The influence of fasting and winter-acclimatization (cold and short-day acclimatization) on mouse plasma leptin, ghrelin, growth hormone (GH) and melatonin concentrations was determined from blood samples taken at mid-day and midnight. A 16-h fast decreased the plasma leptin but almost doubled the plasma ghrelin concentrations which contribute to energy saving, appetite stimulation and, in the case of leptin, to inhibition of reproduction. Winter-acclimatization did not affect plasma ghrelin concentrations, whereas leptin decreased to the same level as in fasting. The low leptin concentrations possibly enable an increased caloric intake for the purpose of thermogenesis. Fasting and winter-acclimatization seemed to abolish the diurnal leptin rhythm, but had no effect on that of ghrelin. Plasma melatonin concentration correlated negatively with ghrelin, suggesting a possible role for melatonin in the regulation of ghrelin concentration. SNS-activity and insulin appear to be the main regulators of leptin plasma concentration in the mouse, rather than melatonin as in some seasonal mammals. Interestingly, endogenous ghrelin did not stimulate GH secretion, which is a well-documented reaction to exogenous ghrelin injections. Topics: Acclimatization; Animals; Body Weight; Circadian Rhythm; Fasting; Ghrelin; Growth Hormone; Leptin; Male; Melatonin; Mice; Mice, Inbred C57BL; Peptide Hormones; Photoperiod; Seasons | 2005 |
Long term consequences of low birthweight on postnatal growth, adiposity and brain weight at maturity in sheep.
Low birth weight (LBW) as a result of restricted fetal growth increases the risk for later metabolic diseases and adiposity. However the relationship between LBW and postnatal growth and adult body composition has not been fully investigated. We have used sheep to determine the effects of LBW on postnatal growth and body composition at maturity. LBW was induced by twinning and placental embolization. At birth, LBW lambs were 38% lighter than controls (2.8 +/- 0.2 vs 4.4 +/- 0.3 kg, P<0.05), but had caught up in bodyweight by 8 weeks after birth. At approximately 2.3 years, bodyweights were not different between groups, but there were reductions in absolute (-8%) and relative (-17%) brain weights of LBW sheep (P<0.05) compared to controls. X-ray absorptiometry showed that the mature LBW sheep, compared to controls, had greater amounts of lean muscle (38.1 +/- 1.3 vs 35.3 +/- 0.5 kg, P<0.05) and tended to have more body fat (12.2 +/- 1.2 vs 9.6 +/- 0.9 kg; P=0.1); at autopsy abdominal fat mass was greater in LBW sheep (3.06 +/- 0.26 vs 2.20 +/- 0.25 kg, P<0.05). Plasma leptin concentrations were not different between groups. We conclude that, in sheep, LBW is associated with early postnatal catch-up in body weight, but body composition is permanently altered such that, relative to controls, adiposity is increased and brain weight is decreased. Topics: Absorptiometry, Photon; Adipose Tissue; Animals; Birth Weight; Body Composition; Body Constitution; Body Weight; Brain; Leptin; Organ Size; Sheep; Time Factors; Weight Gain | 2005 |
The effect of a leptin single nucleotide polymorphism on quality grade, yield grade, and carcass weight of beef cattle.
Feedlot producers could optimize the value of cattle in a given market grid if they were able to improve the uniformity of the body composition between cattle among loads. Allelic variation due to a single nucleotide transition (cytosine [C] to thymine [T] transition that results in a Arg25Cys) has been demonstrated to be associated with higher leptin mRNA levels in adipose tissue and increased fat deposition in mature beef, but the effect on economically important carcass traits has not been investigated in either market-ready steers or heifers. Therefore, the objective of this study was to determine the effects of a leptin SNP on the quality grade (QG), yield grade (YG), and weight of beef carcasses. A slaughter trial was conducted using 1,435 crossbred finished heifers and 142 crossbred finished steers as they entered the slaughter facility. Canada QG tended (main effect of genotype P = 0.16, but P < 0.01 for both CC vs. TT and CT vs. TT) to be affected by leptin genotype. Specifically, 7.6 and 7.1% more TT carcasses graded Canada AAA or higher than the CT and CC carcasses, respectively, which supports the suggestion that the leptin SNP is associated with carcass fat. The proportion of carcasses grading Canada YG 1, 2, or 3 was affected (P < 0.01, P = 0.05, and P = 0.02 for YG 1, 2, and 3) by leptin genotype. The proportion of TT carcasses of Canada YG 1 was 12.5 and 15.1% lower than that of CT and CC carcasses, respectively, indicating that rearing animals under the same management and feeding system may result in greater carcass fat and a lower probability of the proportion of carcasses grading YG 1 within certain genotypes. The carcass weights of animals with the CC genotype tended (P = 0.07) to be higher than those of the TT genotype (365.5 vs. 362.3 kg). No significant difference was observed between the TT and CT genotypes in carcass weight. The observed associations between leptin genotype and carcass characteristics may represent an opportunity to genetically identify animals that are most likely to reach specific marketing groups. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Canada; Cattle; DNA Primers; Female; Gene Frequency; Genotype; Leptin; Male; Meat; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Random Allocation; Sex Factors | 2005 |
Effect of dietary carbohydrate source on the development of obesity in agouti transgenic mice.
Our objective was to evaluate the effects of a qualitative change in dietary carbohydrate source on body weight and adiposity in a rodent model of diet-induced obesity.. We evaluated the effects of high-fat diets (basal) varying in carbohydrate source in aP2-agouti transgenic mice. In the ad libitum study, animals were given free access to the basal diet or one of four test diets for 6 weeks. In two of the diets, dietary carbohydrate was derived from a single source: mung bean noodles (MUNG) or rolled oats (ROLL). The remaining diets were designed to mimic commercially available instant oatmeal with added sugar (IO-S) or flavored instant oatmeal (IO-F). In the energy-restricted study, animals were given ad libitum access to the basal diet for 6 weeks. Subsequently, animals were assigned to one of six treatment groups for 6 weeks. One group was continued on the basal diet ad libitum. The remaining groups were maintained with energy restriction (70% ad libitum) on either the basal, MUNG, ROLL, IO-S, or IO-F diet.. Subcutaneous fat pad mass was significantly higher (p<0.05) in the energy-restricted basal and IO-S groups compared with the energy-restricted ROLL diet. Similarly, visceral fat pad mass was significantly lower with ROLL and MUNG diets (p<0.05 for both) compared with basal and IO-S diets, and the insulin:glucose ratio was reduced (by 23% to 34%, p<0.05) in these two diets compared with all others. In ad libitum-fed animals, liver fatty acid synthase expression was 43% to 62% lower (p<0.05) with ROLL and MUNG diets compared with all others.. These data suggest that a qualitative change in dietary carbohydrate source modulates body weight and adiposity. Topics: Adipose Tissue; Agouti Signaling Protein; Animals; Avena; Blood Glucose; Body Weight; Carrier Proteins; Dietary Carbohydrates; Energy Intake; Fabaceae; Fatty Acid Synthases; Fatty Acid-Binding Proteins; Food Deprivation; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Transgenic; Obesity; Organ Size; Triglycerides | 2005 |
Energy metabolic profile of mice after chronic activation of central NPY Y1, Y2, or Y5 receptors.
Neuropeptide Y (NPY), a 36-amino acid peptide with orexigenic properties, is expressed abundantly in the central nervous system and binds to several NPY receptor subtypes. This study examines the roles of the NPY Y1, Y2, and Y5 receptor(s) in energy homeostasis.. We administered intracerebroventricular NPY (3 microg/d) or selective peptide agonists for the Y1, Y2, and Y5 receptor subtypes to C57Bl/6 mice for 6 days by mini-osmotic pumps to assess the role of each receptor subtype in NPY-induced obesity. Energy expenditure (EE) and respiratory quotient (RQ) were studied using indirect calorimetry. Adiposity was measured by DXA scanning and fat pad dissection. Insulin sensitivity was tested by whole-blood glucose measurement after an insulin challenge.. Central administration of the selective Y1 agonist, Y5 agonist, or NPY for 6 days in mice significantly increased body weight, adiposity, and RQ, with significant hyperphagia in the Y5 agonist- and NPY-treated groups but not in the Y1 agonist-treated group. The NPY, Y1, or Y5 agonist-treated mice had little change in total EE during ad libitum and pair-feeding conditions. Conversely, selective activation of the Y2 receptor reduced feeding and resulted in a significant, but transient, weight loss.. Central activation of both Y1 and Y5 receptors increases RQ and adiposity, whereas only Y5 receptor activation reduces energy expended per energy ingested. Selective activation of Y2 autoreceptors leads to hypophagia and transient weight loss, with little effect on total EE. Our study indicates that all three NPY receptor subtypes may play a role in regulating energy homeostasis in mice. Topics: Absorptiometry, Photon; Adipose Tissue; Animals; Body Composition; Body Weight; Bone Density; Calorimetry, Indirect; Energy Metabolism; Injections, Intraventricular; Insulin; Leptin; Mice; Mice, Inbred C57BL; Neuropeptide Y; Organ Size; Receptors, Neuropeptide Y; Statistics, Nonparametric | 2005 |
Serotonin transporter mRNA expression in the dorsal raphe nucleus of a tumor bearing mouse.
This study was conducted to determine if an oral squamous cell carcinoma alters mRNA expression of serotonin transporter (5-HTT) in the central nervous system. KB cell line derived from a human oral squamous cell carcinoma was inoculated into nude mice, and mRNA expression level of 5-HTT in the dorsal raphe nucleus (DRN) was examined by in situ hybridization when the tumor mass reached to -10% of total body weight. Plasma leptin levels were determined by radioimmunoassay method using a commercial kit. 5-HTT mRNA level was significantly decreased in the DRN of tumor bearing mice, compared to the age-matching non-tumor control. Plasma leptin level decreased concomitantly in tumor bearing mice. These results suggest that oral carcinoma may suppress 5-HTT gene expression in the central nervous system, perhaps in relation with decreased plasma leptin level. Topics: Animals; Body Weight; Carcinoma, Squamous Cell; DNA, Complementary; Gene Expression Regulation, Neoplastic; Humans; Leptin; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; Nerve Tissue Proteins; Radioimmunoassay; Raphe Nuclei; RNA, Messenger; Serotonin; Serotonin Plasma Membrane Transport Proteins | 2005 |
Leptin effects on food and water intake in lines of chickens selected for high or low body weight.
There is an association between autonomic nervous system output and obesity. The sympathetic nervous system stimulates lipid metabolism and regulates food intake and, hence, body weight. Leptin, produced by adipocytes in proportion to their size, has been shown to directly stimulate the satiety center. In the experiment reported here, food and water intake were compared after intracerebroventricular administration of human recombinant leptin to lines of chickens that had undergone divergent selection for over 45 generations from a common White Rock base population for high (HWS) or low (LWS) body weight at 8 weeks-of-age. Leptin caused a linear decrease in food intake in chickens from the LWS line whereas no effect was observed in those from the HWS line. The HWS chickens tended to have reduced water intake post leptin administration. Others reported that leptin decreased food intake in both broiler and Leghorn chickens. Leptin concentration in the central nervous system may not contribute directly to the difference of body weight between HWS and LWS chickens. Topics: Animals; Body Weight; Brain; Chickens; Dose-Response Relationship, Drug; Drinking; Eating; Humans; Injections, Intraventricular; Leptin; Male; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; Selection, Genetic | 2005 |
Acute insulin-induced elevations of circulating leptin and feeding inhibition in lean but not obese rats.
Insulin has been shown to stimulate leptin mRNA expression acutely in rat adipose tissue, but its short-term effects on circulating leptin levels, and subsequent feeding behavior, have not been well described. We used 11-mo-old female selectively bred obesity-resistant (OR) and obesity-prone (OP) Sprague-Dawley rats maintained on laboratory chow to investigate this question. At testing, body weights and basal leptin levels of the OP rats were significantly elevated compared with the OR rats. In the 3-h fasted state, injection of 2.0 U insulin/kg ip resulted in significant elevations of plasma leptin at 4 h postinjection in both OP and OR groups (hour 4, +2.50 and +5.98 ng/ml, respectively). In separate feeding tests with the same groups, intake of laboratory chow pellets was significantly inhibited during hours 2-4 after 2.0 U/kg of insulin in the OR (-80.1%, P < 0.05), but not in the OP group, compared with intake after saline injections. In feeding tests with palatable moderately high-fat pellets after 2.0 and 3.0 U insulin/kg ip, significant decreases between hours 2 and 4 in intake were seen in the OR group only (-41.0 and -68.3%, respectively). Thus feeding inhibition coincides with insulin-induced elevations of plasma leptin in lean but not obese Sprague-Dawley rats. Our data suggest that elevations of leptin within the physiological range may contribute to short-term inhibition of food intake in rats and that this process may be stimulated by feeding-related insulin release. Topics: Animals; Body Weight; Disease Susceptibility; Eating; Feeding Behavior; Female; Injections, Intraperitoneal; Insulin; Leptin; Obesity; Rats; Rats, Sprague-Dawley; Thinness | 2005 |
Acute third ventricular administration of leptin decreases protein and fat in self-selecting rats.
The peripheral administration of leptin reduces food intake (FI) body weight gain (BWG) and modifies food choice. The aim of this study was to examine the effect of acute cerebral injections of leptin on food selection in rats. Male rats were first adapted to the food choice paradigm (protein, carbohydrate, fat) for 3 weeks. They were then implanted with a cannula in the third ventricle. Leptin (leptin group=L) or saline (control group=C) injections were performed at either the beginning or the end of the night at 4-day intervals. FI was recorded continuously, 3 days before, during and then after injections. Rats were sacrificed 86 h after the second injection. After both injections, BWG and FI were reduced. The reduction in FI concerned only nocturnal intake, whatever the timing of the injection. When the injection was given at the beginning of the night, the reductions after a 1-h latency period were -45% and -27.5% during the first and second days, respectively. Following the second injection, the same effects were observed immediately (-16% and -41%, respectively). Only the fat and protein intakes were significantly reduced. This lower FI was due to a reduction in meal size and duration. The reduction resulted in a lower BWG and total white adipose tissue mass. At the time of sacrifice, 6 h after food deprivation, leptinemia and insulinemia were reduced in leptin-treated rats. Glycemia values were identical. It was thus demonstrated that central leptin was a satiation factor rather than a satiety factor. Topics: Animal Feed; Animals; Appetite Regulation; Body Weight; Dietary Fats; Dietary Proteins; Eating; Food Preferences; Injections, Intraventricular; Insulin; Leptin; Male; Rats; Rats, Wistar; Statistics, Nonparametric | 2005 |
Effects of white adipose tissue grafts on total body fat and cellularity are dependent on graft type and location.
Surgical removal of body fat (lipectomy) triggers compensatory increases in nonexcised white adipose tissue (WAT), thus restoring adiposity levels in many species, including Siberian hamsters. In Siberian hamsters, when their lipectomized WAT is transplanted to another site (autologous grafts, no net change in body fat), healthy grafts result, but the lipectomy-induced compensatory increases in nonexcised WAT masses are exaggerated, an effect that apparently occurs only when the grafts contact intact WAT. When WAT is added to nonlipectomized hamsters to increase body fat, native WAT pads do not decrease. Thus WAT addition or removal-replacement does not induce compensatory WAT responses consistent with total body fat regulation as does WAT subtraction. Therefore, we tested whether the exaggerated response to lipectomy occurring with autologous WAT transplantation is dependent on graft site placement and whether the donor graft source [inguinal or epididymal WAT (IWAT, EWAT), sibling vs. nonsibling] affected body fat responses to WAT additions in nonlipectomized hamsters. Lipectomized hamsters received subcutaneous autologous EWAT grafts placed remotely from other WAT (ventrum) or in contact with intact WAT (dorsum), whereas intact hamsters received EWAT or IWAT grafts from sibling or nonsibling donors. The exaggerated response to lipectomy only occurred when grafts were in contact with intact WAT. EWAT, but not IWAT, additions to nonlipectomized siblings or nonsiblings increased native IWAT and retroperitoneal WAT mass but not EWAT mass compared with controls. Collectively, WAT transplantation to either lipectomized or nonlipectomized hamsters increased body fat contingent on graft contact with intact or native WAT. Topics: Adaptation, Physiological; Adipose Tissue; Animals; Body Weight; Cricetinae; Eating; Leptin; Lipectomy; Male; Organ Size; Phodopus; Siblings; Tissue Donors; Transplantation, Autologous; Transplantation, Heterotopic | 2005 |
Effect of starvation on hepatic acyl-CoA synthetase, carnitine palmitoyltransferase-I, and acetyl-CoA carboxylase mRNA levels in rats.
This study investigated the effect of starvation on mRNA levels of hepatic acyl coenzyme A synthetase (ACS), carnitine palmitoyltransferase-I (CPT-I), and acetyl coenzyme A carboxylase (ACC) and on serum concentrations of leptin, insulin, and glucose in male Sprague-Dawley rats.. Rats were fed an AIN-76 diet for 5 wk and then assigned to a normal group (NG) and a starvation group (SG). The SG was starved for 48 h and the NG was fasted for 12 h before being killed. Serum and hepatic lipids and serum levels of leptin, insulin, and glucose were determined. Expressions of ACS, CPT-1, and ACC mRNA were assessed in liver.. Serum concentrations of triacylglycerol and high-density lipoprotein cholesterol in the SG were lower than those in the NG. Serum concentrations of low-density lipoprotein cholesterol in the SG were significantly higher than in the NG. Hepatic concentrations of total lipid in the SG were significantly higher than those in the NG, and triacylglycerol concentrations in the SG were significantly lower than those in the NG. Serum concentrations of leptin and glucose in the SG were significantly lower than those in the NG. The ratio of abdominal fat to total body weight in the SG was lower than that in the NG. Hepatic ACS and CPT-I mRNA levels in the SG were significantly higher than those in the NG, but hepatic ACC mRNA levels were lower in the SG than in the NG.. We demonstrated that starvation increases hepatic levels of ACS and CPT-I and decreases transcription levels of ACC, implicating increases in fatty acid oxidation. This research demonstrates a coordinated regulation of ACS, CPT-I, and ACC mRNA levels and serves to enhance our understanding of the molecular mechanisms underlying fatty acid metabolism during starvation. Topics: Abdomen; Acetyl-CoA Carboxylase; Adipose Tissue; Animals; Blood Glucose; Blotting, Northern; Body Weight; Carnitine O-Palmitoyltransferase; Cholesterol; Coenzyme A Ligases; Insulin; Leptin; Lipid Metabolism; Liver; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Starvation; Triglycerides | 2005 |
Differential regulation of hepatic gene expression by starvation versus refeeding following a high-sucrose or high-fat diet.
The objective of this work was to determine the effects of starvation versus refeeding following a high-sucrose diet (HS) or high-fat diet (HF) on fatty acid metabolism in mice.. The mice were fed an AIN-76 control diet (CD), a modified HS, or an HF. The three dietary groups were subdivided into three groups each: those fed experimental diets for 12 wk, mice starved for 48 h after 12 wk on an experimental diet, and those with the same starvation treatment but with 72 h of refeeding after starvation, respectively.. Serum total cholesterol levels of CD and HF groups decreased and then increased under starvation and refeeding states, respectively. Refeeding HS and HF increased serum levels of low-density lipoprotein (LDL) cholesterol compared with refeeding of the CD group. Starvation significantly increased hepatic levels of total cholesterol in the HS and HF groups compared with the CD group. Hepatic acyl coenzyme A (CoA) synthetase (ACS) levels in the CD and HS groups but not the HF group increased and then decreased under starved and refed states, respectively; an opposite regulation was observed in the HF group. Levels of hepatic acetyl-CoA carboxylase (ACC) in the HS and HF groups were significantly increased by refeeding. Hepatic levels of carnitine palmitoyltransferase-I mRNA were significantly enhanced by starvation and refeeding in the HS group but decreased in CD and then increased in the HF group.. Changes in dietary energy nutrients, fasting, and refeeding affect hepatic ACS, CPT-I, and ACC mRNA expression, and these results will serve to enhance our understanding of the molecular mechanisms underlying regulation of fatty acid metabolism. Topics: Acetyl-CoA Carboxylase; Animals; Blood Glucose; Blotting, Northern; Body Weight; Carnitine O-Palmitoyltransferase; Cholesterol; Coenzyme A Ligases; Diet; Dietary Fats; Eating; Energy Intake; Fatty Acids; Gene Expression; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred ICR; RNA, Messenger; Starvation; Sucrose; Sweetening Agents | 2005 |
Proopiomelanocortin gene variants are associated with serum leptin and body fat in a normal female population.
A major quantitative trait locus (QTL) determining leptin levels has been linked to the proopiomelanocortin (POMC) region on chromosome 2. Most studies, based on under 350 lean or obese subjects, have shown no association between POMC SNP 8246 C/T and serum leptin, but significant associations have been reported with RsaI 8246 C/T SNP haplotypes. We have investigated association of four POMC SNPs with body composition and serum leptin in 2758 normal Caucasian female subjects (mean age 47.4+/-12.5 years), from the St Thomas' UK Adult Twin Registry (Twins UK): RsaI and 51 G/C in the 5'UTR and 8246 C/T and 7965 C/T in the 3'UTR. Under the recessive model, the 8246 T allele (freq. 0.18) was significantly associated with higher mean BMI (P=0.032) and total fat (P=0.046, both after age adjustment). Significant associations were maintained in sib-TDT with waist (P=0.049), total fat (P=0.037) and emerged with serum leptin (P=0.016). Initial significant associations between RsaI (-) allele (freq. 0.30) and higher waist (P=0.04) or % central fat (P=0.02) were not maintained in sib-TDT. No significant associations were found between body composition or serum leptin and RsaI/8246 C/T haplotype and none with 51 G/C (freq. 0.01) or 7965 C/T (freq. 0.004). There was minimal pairwise LD between the four loci, apart from RsaI and 8246 C/T (D'=-0.78 (P<0.0001)). Associations of BMI, weight and total fat with SNPs in regions flanking the POMC gene in this powerful study suggest that regulation of POMC expression may be influential in determining body weight. Topics: Adipose Tissue; Adult; Body Mass Index; Body Weight; Female; Genotype; Haplotypes; Humans; Leptin; Middle Aged; Obesity; Phenotype; Polymorphism, Single Nucleotide; Pro-Opiomelanocortin | 2005 |
Transgenic overexpression of neuromedin U promotes leanness and hypophagia in mice.
Recent work has shown that neuromedin U (NmU), a peptide initially identified as a smooth muscle contractor, may play a role in regulating food intake and energy homeostasis. To further evaluate this putative function, we measured food intake, body weight, energy expenditure and glucose homeostasis in transgenic mice that ubiquitously overexpress murine proNmU. NmU transgenic mice were lighter and had less somatic and liver fat, were hypophagic, and had improved insulin sensitivity as judged by an intraperitoneal insulin tolerance test. Transgenic mice had higher levels of hypothalamic NPY, POMC and MCH mRNA. There was no difference in O2 consumption between genotypes; however, NmU transgenic mice displayed a modest increase in respiratory quotient during food deprivation and refeeding. There were no behavioral disturbances in the NmU transgenic mice that could account for the results (e.g. changes in locomotor activity). When placed on a high-fat diet, transgenic mice remained lighter than wild-type mice and ate less, but gained weight at a rate similar to wild-type mice. Despite the increased weight gain with high-fat feeding, glucose tolerance was significantly improved in the transgenic mice. These findings support the hypothesized role of NmU as an endogenous anorexigenic peptide. Topics: Animals; Anorexia; Body Composition; Body Weight; Brain; Calorimetry, Indirect; Eating; Energy Metabolism; Genetic Engineering; Glucose; Glucose Tolerance Test; Homeostasis; In Situ Hybridization; Insulin; Leptin; Male; Mice; Mice, Transgenic; Neuropeptides; Polymerase Chain Reaction | 2005 |
Leptin and body weight regulation in patients with anorexia nervosa before and during weight recovery.
Leptin has been considered a starvation hormone, but its role in malnourished patients is unknown.. We aimed to characterize the role of leptin in metabolic adaptation in women with anorexia nervosa (AN).. In a cross-sectional study, 57 women with AN [mean (+/-SD) body mass index (kg/m(2)) on admission: 15.2 +/- 1.5] were compared with 49 healthy, normal-weight women (mean body mass index: 22.3 +/- 2.3). Nineteen patients were reinvestigated during weight gain 43 and 84 d after baseline. We measured serum concentrations of leptin, soluble leptin receptor, insulin, ghrelin, and thyroid hormones [thyrotropin, triiodothyronine (T(3)), and thyroxine]; fat mass (FM) and fat-free mass (FFM); resting energy expenditure (REE); energy intake; and eating behavior.. Compared with values in the control women, leptin, T(3), REE, FM, and FFM were lower in the women with AN, but the leptin secretion rate was not significantly different. Leptin correlated with FM (r = 0.83, P < 0.001), T(3) (r = 0.68, P < 0.001), respiratory quotient (r = -0.47, P < 0.001), and REE (r = 0.58, P < 0.001). The association with REE weakened after adjustment for FFM and disappeared after further adjustment for T(3). Hunger and appetite had positive, whereas satiety and restraint had negative, associations with leptin. During weight gain (9.0 +/- 3.3 kg in 84 d), serum leptin and the leptin secretion rate increased. Changes in leptin secretion were associated with energy intake and REE. The initial changes in the leptin secretion rate (ie, the difference between baseline and 43 d) were negatively associated with changes in body weight from 43 to 84 d.. Leptin contributes to metabolic adaptation in women with AN. The leptin response is associated with weight gain. Topics: Adolescent; Adult; Anorexia Nervosa; Basal Metabolism; Body Mass Index; Body Weight; Case-Control Studies; Cross-Sectional Studies; Eating; Energy Intake; Energy Metabolism; Female; Humans; Leptin; Middle Aged; Nutritional Status | 2005 |
Troglitazone reduces leptinemia during experimental dexamethasone-induced stress.
Recently, we found that profound anorexia observed in a catabolic model induced by chronic glucocorticoid (dexamethasone, Dex) injection could be associated with strong hyperleptinemia. To investigate the implication of leptin in this catabolic stress response, we used a model whereby leptin secretion was inhibited using troglitazone (Trg) concomitantly with a Dex-induced-stress injection.. Adult rats (3 months, n=12) were stressed with a Dex injection (1.5 mg/kg/day ip, 5 days) and either treated (DXTG+, n=6) or not (DXTG-, n=6) with Trg (60 mg/kg/day sc, 5 days). These DXTG+ and DXTG- groups were compared with an untreated ad libitum group and a pair-fed group receiving saline ip instead of the Dex injection. The effects of troglitazone treatment on leptin gene expression in adipose tissue, blood glucose, insulin, and on hepatic parameters under stress conditions were determined.. Trg treatment specifically diminished leptinemia (30%, DXTG+ vs DXTG-, p<0.05). Insulinemia and glycemia remained unchanged, as did leptin gene expression; food intake improved, but hepatic capacities did not show any alteration.. Trg is a useful agent in exploring certain potential effects of leptin on metabolic and immune disorders occurring during aggression. Topics: Adipocytes; Adipose Tissue; Animals; Anorexia; Blood Glucose; Body Weight; Chemical and Drug Induced Liver Injury; Chromans; Dexamethasone; Disease Models, Animal; Eating; Glucocorticoids; Hypoglycemic Agents; Insulin; Leptin; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stress, Physiological; Thiazolidinediones; Troglitazone | 2005 |
Alleles on rat chromosome 4 (D4Got41-Fabp1/Tacr1) regulate subphenotypes of obesity.
The use of inbred animal models is an essential component of the genetic dissection of complex diseases. Because quantitative trait loci for serum triglycerides, total cholesterol, and body weight were mapped on chromosome 4 in a cross of BioBreeding/OttawaKarlsburg (BB/OK) and spontaneously hypertensive (SHR) rats, we established a congenic BB.SHR rat strain by introgressing a SHR segment of chromosome 4 (D4Got41-Tacr1) into a BB/OK background. The phenotype of these BB.SHR rats (BB.4S) confirmed the quantitative trait loci. To discover whether the phenotype of BB.4S can only be attributed to the SHR segment per se, we established an additional congenic BB.WOKW strain by introgressing a similar segment of chromosome 4 (D4Got41-Fabp1) of the Wistar Ottawa Karlsburg RT1(u) rat into a BB/OK background, termed briefly BB.4W.. Male normoglycemic BB/OK (20), BB.4S (20), and BB.4W (16) rats were longitudinally studied for body weight, serum triglycerides, total and high-density lipoprotein-cholesterol, and glucose tolerance. At the end of the observation period (32 weeks), serum insulin, leptin, and adiposity index (AI) were determined.. Congenic BB.4S and BB.4W were significantly heavier, and AI, serum triglycerides, and total cholesterol values were significantly elevated in BB.4S and BB.4W compared with BB/OK but more pronounced in BB.4S. The highest serum insulin was found in BB.4W and highest leptin in BB.4S. Because the body weight gain and AI were comparable between BB.4S and BB.4W, the obviously higher insulin levels in BB.4W and higher leptin values in BB.4S suggest that the two congenics most probably define two subphenotypes of obesity and provide the unique opportunity to study their genetics. Topics: Alleles; Animals; Body Composition; Body Weight; Cholesterol, HDL; Chromosome Mapping; Crosses, Genetic; Glucose Tolerance Test; Insulin; Leptin; Male; Obesity; Phenotype; Rats; Rats, Inbred BB; Rats, Inbred SHR; Triglycerides | 2005 |
The role of insulin receptor substrate 2 in hypothalamic and beta cell function.
Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in beta cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and beta cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced beta cell mass. Overt diabetes did not ensue, because beta cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced beta cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in beta cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis. Topics: Animals; Body Weight; Electrophysiology; Energy Metabolism; Genotype; Glucose; Homeostasis; Hypothalamus; Insulin; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Phosphoproteins; Pro-Opiomelanocortin; Receptor, Insulin; Recombinant Fusion Proteins | 2005 |
[The study on mechanism of appetite regulation in diet-induced obesity resistant rats].
To explore the cause of decreasing intake food of diet-induced obesity resistant (DIO-R) rats.. Fifty male Sprague-dawley (SD) rats were randomly divided into control group and high-fat group and they were fed with basic diet and high-fat diet respectively for 13 weeks. DIO-R and diet-induced obesity (DIO) rats were selected according to their body weight and the quantity of energy intake, then observing the changes of the total food intake, the level of serum leptin and plasma NPY were determined by radioimmunoassay and the contents of the melanocortin receptor-4 (MCR-4) in brain were determined by Western Blot.. The total food intake of DIO-R rats was (1 679.1 +/- 146.8) g. The total food intake of DIO rats was (1 818.4 +/- 148.9) g. The total food intake of DIO-R rats was lower than that of DIO rats (P < 0.05). The level of plasma NPY of DIO-R rats was (795.24 +/- 83.59) ng/L. The level of plasma NPY of DIO rats was (1 007.14 +/- 172.83) ng/L. The level of plasma NPY of DIO-R rats was lower than that of the DIO rats (P < 0.05). The levels of serum leptin of basic, DIO-R and DIO rats was (4.80 +/- 0.75) microg/L, (9.17 +/- 1.19) microg/L and (9.32 +/- 1.04) microg/L. The level of serum leptin of rats in high-fat diet group was increased as compared with the rats in basic diet group, but there was no significant difference between DIO-R and DIO rats (P > 0.05). The levels of brain MCR-4 of basic, DIO-R and DIO rats were (342 +/- 31) mm2, (455 +/- 33) mm2, (355 +/- 30) mm2. High fat diets increased the content of brain MCR-4 in DIO-R rats.. DIO-R rats decreased appetite by increasing expression of ob gene to reduce activity of NPY pathway and activate the MCR-4 pathway, and thus inhibit the increase body of weight. Topics: Animals; Appetite; Blotting, Western; Body Weight; Brain; Dietary Fats; Disease Models, Animal; Energy Intake; Leptin; Male; Neuropeptide Y; Obesity; Radioimmunoassay; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4 | 2005 |
Obesity and metabolic syndrome in circadian Clock mutant mice.
The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance. Topics: Adipocytes; Animals; Body Weight; Brain; Circadian Rhythm; CLOCK Proteins; Dietary Fats; Energy Intake; Energy Metabolism; Feeding Behavior; Hepatocytes; Hyperglycemia; Hyperlipidemias; Insulin; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Motor Activity; Mutation; Neuropeptides; Obesity; Trans-Activators; Weight Gain | 2005 |
Effects of zinc deficiency and supplementation on plasma leptin levels in rats.
The effects of zinc deficiency and supplementation on plasma leptin levels were studied in Sprague-Dawley rats. After 6 wk on a zinc-deficient diet containing 0.65 ppm Zn/g, the mean body weight was significantly lower than that of normal or zinc-supplemented rats, which showed no difference among them. The plasma leptin and zinc levels were lowest in zinc-deficient animals and highest in those that received a normal diet and daily intraperitioneal injections of 3 mg Zn/kg. These results indicate that zinc deficiency leads to a significant inhibition in plasma leptin levels, whereas zinc supplementation significantly increases plasma leptin. Topics: Animals; Body Weight; Diet; Leptin; Male; Rats; Rats, Sprague-Dawley; Zinc | 2005 |
Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome.
Both environmental and genetic factors play important roles in the development of the metabolic syndrome. To elucidate how these factors interact under normal conditions, C57Bl/6 (B6) and 129S6/SvEvTac (129) mice were placed on a low-fat or high-fat diet. Over 18 weeks, the 129 strain developed features of the metabolic syndrome, notably obesity, hyperinsulinemia, and glucose intolerance only on the high-fat diet; the B6 strain on the other hand developed these features on both diets. High-fat feeding of both strains led to decreased serum triglycerides, hepatic steatosis, and hypercholesterolemia; however, B6 mice developed worse steatosis and a larger increase in LDL cholesterol. Both B6 background and high-fat feeding increased sterol regulatory element-binding protein-1c (SREBP-1c), a key regulator of lipogenic gene transcription, and its downstream targets. Stearoyl-CoA desaturase 1 (SCD1), an enzyme that regulates monounsaturated fatty acid (MUFA) synthesis, was also increased at the mRNA and enzyme activity levels by both high-fat feeding and B6 background. Furthermore, lipid analysis revealed increased hepatic triglycerides and MUFAs in B6 and high-fat-fed mice. Thus, dietary fat and genetic background act through SREBP-1c and SCD1 to affect hepatic lipid metabolism contributing to the development of the metabolic syndrome. Topics: Animals; Blood Glucose; Body Weight; CCAAT-Enhancer-Binding Proteins; Diet, Fat-Restricted; Dietary Fats; DNA-Binding Proteins; Hypercholesterolemia; Insulin; Leptin; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Transcription Factors | 2005 |
Hyper- or hypoleptinemia in subjects with zinc deficiency?
Topics: Adipocytes; Animals; Body Weight; Gene Expression Regulation; Leptin; Rats; RNA, Messenger; Zinc | 2005 |
Serum hormone levels and anthropometric characteristics in girls with hyperandrogenism.
Polycystic ovary syndrome is considered to originate during puberty. The aim of this study was to investigate hormonal status in relationship to anthropometric data in girls with premature adrenarche and adolescent girls with hyperandrogenism, as these conditions are related to polycystic ovary syndrome in adulthood.. 20 girls with premature adrenarche (aged 4.9-10.2 years), 21 postmenarcheal girls with hirsutism (aged 13.3-17.8 years), 2 groups (n=13 in each) of healthy volunteers of similar age and body mass index participated in the study.. Serum testosterone and dehydroepiandrosterone sulphate levels were significantly higher in all patients than in controls. Free androgen index and leptin levels were significantly higher, and sex-hormone-binding globulin lower in hirsute adolescents vs. controls. Birth weight standard deviation scores were comparable in all 4 groups. Serum dehydroepiandrosterone sulphate negatively correlated with birth weight standard deviation scores in the group of girls with premature adrenarche (r=-0.57, p<0.001). By linear regression, 76% in variation of serum leptin levels could be explained by subscapular skinfold thickness standard deviation scores, and by serum sex-hormone-binding globulin, insulin, and dehydroepiandrosterone sulphate levels in all participants. Mean age of onset of menarche was younger in hirsute girls vs. controls (12.1+/-1.3 vs. 13.5+/-1.3 years, p=0.004).. Inverse correlation of dehydroepiandrosterone sulphate levels and weight at birth indicates relationship between premature adrenarche in girls and fetal growth. Higher leptin levels in adolescents with hyperandrogenism than in healthy girls show possible involvement of leptin in pathogenesis of hyperandrogenism. Topics: Adolescent; Age Factors; Birth Weight; Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Dehydroepiandrosterone Sulfate; Female; Hirsutism; Humans; Hyperandrogenism; Insulin; Leptin; Linear Models; Menarche; Polycystic Ovary Syndrome; Puberty, Precocious; Risk Factors; Testosterone | 2005 |
Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats.
Leptin resistance is generally considered a consequence of obesity. We postulated that leptin resistance is associated with diminished hypothalamic leptin signalling capacity and that leptin resistance is causal to obesity. We assessed maximal leptin-mediated binding of the transcription factor signal transducer and activator of transcription 3 (STAT3), and the response to high-fat feeding in lean leptin-resistant rats.. Recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control vector were administered by intracerebroventricular injection to lean F344 x BN rats for up to 150 days, and food consumption, body weight, serum leptin and glucose tolerance were measured. Leptin-mediated hypothalamic transcription factor binding was assessed at day 150 following an intracerebroventricular injection of 2 mug leptin. Rats pretreated with either control or rAAV-leptin vector for 94 days were given a high-fat diet, and energy intake, body weight gain and adiposity were examined.. The rAAV-leptin-treated rats initially responded to leptin gene delivery then became leptin-resistant. They displayed persistent submaximal hypothalamic leptin signalling and enhanced insulin sensitivity, yet maximal hypothalamic signalling capacity was decreased by more than 50%. On a high-fat diet, the leptin-resistant rats consumed more energy, gained more weight and accumulated greater visceral fat mass than controls.. The maximal hypothalamic leptin signalling capacity was diminished in leptin-resistant rats receiving central rAAV-leptin gene therapy. Moreover, this leptin-invoked leptin resistance perturbs the regulation of energy homeostasis in response to high fat exposure, producing augmented energy consumption. This, coupled with potential hypersensitivity to insulin, creates a milieu favouring fat deposition. Our data suggest that leptin resistance is both a consequence and cause of obesity. Topics: Animals; Body Weight; Diet; DNA, Complementary; Feeding Behavior; Glucose Tolerance Test; Injections, Intraventricular; Insulin; Leptin; Male; Obesity; Rats; Rats, Inbred BN; Rats, Inbred F344; Signal Transduction; Weight Gain | 2005 |
Abdominal obesity, insulin resistance, and colon carcinogenesis are increased in mutant mice lacking gastrin gene expression.
The authors recently reported that gastrin gene knockout (GAS-KO) mice had an increased risk for colon carcinogenesis in response to azoxymethane (AOM) compared with their wild type (WT) littermates. In the current report, the authors discuss the predisposition of GAS-KO mice to develop obesity and metabolic hormonal changes that may contribute to their increased risk of colon carcinogenesis.. The weight and deposition of fat was monitored in the mice over a 14 month period, using magnetic resonance imaging and nuclear magnetic resonance techniques. Changes in plasma concentrations of ghrelin, leptin, insulin, and glucose were assessed using radioimmunoassay analysis and enzyme-linked immunosorbent assays. Preneoplastic markers of colon carcinogenesis (aberrant crypt foci [ACFs]), in response to AOM, were measured in a subset of obese versus lean GAS-KO mice and were compared with the markers in WT mice.. Increases in visceral adiposity were evident by age 2 months in GAS-KO mice, resulting in macroscopic obesity by age 7 months. Hyperinsulinemia and insulin:glucose ratios were increased significantly in GAS-KO mice as young as 1 month and preceded alterations in nonfasting leptin and ghrelin levels. The number of ACFs per mouse colon were increased significantly in the following order: obese GAS-KO mice > lean GAS-KO mice > WT mice. Fasting plasma insulin levels were 0.88 +/- 0.1 ng/mL, 1.45 +/- 0.3, and 2.76 +/- 0.9 ng/mL in the WT, GAS-KO lean, and GAS-KO obese mice, respectively.. The current results suggest the novel possibility that loss of amidated gastrins may increase adipogenesis, hyperinsulinemia, and colon carcinogenesis in GAS-KO mice. The increase in colon carcinogenesis may be due in part to hyperinsulinemia, increased obesity, and other associated hormone changes that were measured in GAS-KO mice. Topics: Animals; Azoxymethane; Body Weight; Carcinogens; Colonic Neoplasms; Gastrins; Gene Expression; Ghrelin; Glucose; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Magnetic Resonance Imaging; Male; Mice; Mice, Knockout; Obesity; Peptide Hormones; Precancerous Conditions; Radioimmunoassay; Thinness | 2005 |
Hyperinsulinaemia triggered by dietary conjugated linoleic acid is associated with a decrease in leptin and adiponectin plasma levels and pancreatic beta cell hyperplasia in the mouse.
Dietary supplementation with conjugated linoleic acids (CLA) has a fat-reducing effect in various species, but induces severe hyperinsulinaemia and hepatic steatosis in the mouse. This study aimed to determine the causes of the deleterious effects of CLA on insulin homeostasis.. The chronology of adipose and liver weight, hepatic triglyceride accumulation and selected blood parameters, including lipids, insulin, leptin and adiponectin, was determined in C57BL/6J female mice fed a 1% isomeric mixture of CLA for various periods of time ranging from 2 to 28 days. Insulin secretion was measured in 1-h static incubations of pancreatic islets, and pancreas morphometric parameters were determined in mice fed CLA for 28 days.. Plasma levels of leptin and adiponectin sharply decreased after 2 days of CLA feeding, although adipose tissue mass only decreased after day 6. Hyperinsulinaemia developed at day 6 and consistently worsened up to day 28, in parallel with increases in hepatic lipid content. Islets from CLA-fed mice displayed three- to four-fold increased rates of glucose-stimulated insulin secretion, both in the absence and presence of isobutyl methylxanthine or carbachol. The increased insulin-releasing capacity of islets from CLA-fed mice was explained by an increase in beta cell mass and number.. The data suggest that CLA supplementation induces a profound reduction of leptinaemia and adiponectinaemia, followed by hyperinsulinaemia due to the increased secretory capacity of pancreatic islets, leading, in turn, to liver steatosis. These observations cast doubt on the safety of dietary supplements containing CLA. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Disease Models, Animal; Female; Hyperinsulinism; Hyperplasia; Insulin; Insulin Secretion; Intercellular Signaling Peptides and Proteins; Islets of Langerhans; Leptin; Linoleic Acids, Conjugated; Liver; Mice; Mice, Inbred C57BL; Organ Size; Triglycerides | 2005 |
Type 2 diabetes mouse model TallyHo carries an obesity gene on chromosome 6 that exaggerates dietary obesity.
The TallyHo (TH) mouse strain is a polygenic model for Type 2 diabetes with obesity. Genetic analysis in backcross progeny from a cross between F1 [C57BL/6J (B6) x TH] and TH mice mapped a quantitative trait locus (QTL) named TH-associated body weight 2 (tabw2) to chromosome 6. The TH-derived allele is associated with increased body weight. As a first step to identify the molecular basis of this obesity QTL, we constructed a congenic line of mice on the B6 genetic background that carries a genomic region from TH mice containing tabw2. Congenic mice homozygous for tabw2 (B6.TH-tabw2/tabw2) fed a chow diet exhibited slightly, but significantly, higher body weight and body fat and plasma leptin levels compared with controls (B6.TH-+/+). This difference was exacerbated when the animals were maintained on a high-fat and high-sucrose (HFS) diet. The diet-induced obesity in tabw2 congenic mice is accompanied by hyperleptinemia, mild hyperinsulinemia, impaired glucose tolerance, and reduced glucose uptake in adipose tissue in response to insulin administration. Using F2 progeny fed a HFS diet from an intercross of B6.TH-tabw2/+ mice, we were able to refine the map position of the tabw2 obesity susceptibility locus to a 15-cM region (95% confidence interval) extending distally from the marker D6Mit102. In summary, tabw2 congenic mice are a new animal model for diet-induced obesity that will be valuable for the study of gene-diet interactions. Topics: Alleles; Animals; Body Weight; Chromosomes, Mammalian; Crosses, Genetic; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Female; Genetic Predisposition to Disease; Genotype; Glucose; Glucose Tolerance Test; Hyperinsulinism; Leptin; Lod Score; Male; Mice; Mice, Congenic; Obesity; Physical Chromosome Mapping | 2005 |
A retinoid X receptor antagonist, HX531, improves leptin resistance without increasing plasma leptin level in KK-Ay mice under normal dietary conditions.
4-(5 H -2,3-(2,5-Dimethyl-2,5-hexano)-5-methyl-8-nitrodibenzo[b,e][1,4]diazepin-11-yl)benzoic acid (HX531) is a novel retinoid X receptor antagonist. This study provides evidence that HX531 improves leptin resistance without increasing plasma leptin levels in KK-A y mice, an animal model with high plasma leptin levels and leptin resistance. Under normal dietary conditions, 3 weeks of treatment with HX531 (0.03% and 0.06% food admixture) in KK-A y mice decreased plasma leptin levels in a dose- and time-dependent manner, in addition to decreasing body weight and mesenteric fatty tissue weight. To evaluate the effect of HX531 on leptin resistance, leptin was injected intraperitoneally in the KK-A y mice for 4 days after 1 week of treatment with HX531 (0.06% food admixture). This pretreatment with HX531 resulted in exogenously administered leptin causing a significant decrease in food intake. These results suggested that HX531 decreased plasma leptin levels accompanied by a decrease in fatty tissue content in the KK-A y mice and a simultaneous improvement in leptin resistance. This is the first report that HX531 improves leptin resistance without increasing plasma leptin level in KK-A y mice, under normal dietary conditions. Topics: 3-Hydroxybutyric Acid; Adipose Tissue; Animals; Benzoates; Biphenyl Compounds; Body Temperature; Body Weight; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Drug Resistance; Eating; Food Deprivation; Leptin; Male; Mesentery; Mice; Mice, Inbred Strains; Rectum; Retinoid X Receptors | 2005 |
Orexin a stimulates hypothalamic-pituitary-adrenal (HPA) axis function, but not food intake, in the absence of full hypothalamic NPY-ergic activity.
Neonatal monosodium L-glutamate (MSG) treatment destroys hypothalamic arcuate nucleus neuronal bodies, thus inducing several metabolic abnormalities. As a result, rats develop a phenotype characterized by hyperleptinemia and by impaired NPY but normal preproorexin hypothalamic mRNAs expression. Thus, our study was designed to explore whether hypothalamic effects of orexin A on food intake and glucocorticoid production develop in the absence of full hypothalamic NPY-ergic activity. For this purpose we evaluated, in control and MSG-treated rats, the consequences of intracerebroventricular (icv) orexin A administration on food intake and changes in circulating levels of ACTH and glucocorticoid. Our results indicate that orexin A icv treatment stimulated hypothalamic-pituitary-adrenal (HPA) axis activity in both MSG-damaged and normal animals, with this response even more pronounced in neurotoxin-damaged rats. Conversely, food intake was only enhanced by icv orexin A injection in normal rats. Our study further supports that acute hypothalamic effects of orexin A on food intake and glucocorticoid production are due to independent neuronal systems. While intact arcuate nucleus activity is needed for the orexinergic effect induced by icv orexin A administration, conversely, orexin A-stimulated HPA axis function takes place even in the absence of full NPY-ergic activity. Topics: Adrenocorticotropic Hormone; Animals; Body Weight; Corticosterone; Eating; Female; Food Deprivation; Hypothalamo-Hypophyseal System; Intracellular Signaling Peptides and Proteins; Leptin; Neuropeptide Y; Neuropeptides; Orexins; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium Glutamate; Statistics, Nonparametric | 2005 |
PPARalpha activators may be good candidates as antiaging agents.
Aging is associated with a metabolic decline characterized by the development of changes in fat distribution, obesity, and insulin resistance. Dysfunctional humoral and cell-mediated immune responses occur with age, and these aberrations have been implicated in the increased incidence of infectious diseases, hyporesponsiveness to vaccination, and the etiology of numerous chronic degenerative diseases. All these metabolic and immune alterations are associated with a variety of age-related diseases that subsequently result in increased mortality. Leptin can modulate many of the metabolic alterations characteristic of aging. Leptin resistance has been implicated in the pathogenesis of obesity-related complications involving abnormalities of lipid metabolism that resemble those of old age. Increased plasma leptin levels with aging suggest resistance to leptin action and may explain why elderly subjects have abdominal obesity and insulin resistance. Leptin's failure may be considered for the metabolic decline seen with aging. Peroxisome proliferator-activated receptor (PPAR)-alpha, the transcription factor for the mitochondrial and peroxisomal enzymes of beta-oxidation, and its target enzymes, are upregulated by hyperleptinemia. PPARalpha has been shown to mediate the action of the hypolipidemic drugs of the fibrate class on lipid and lipoprotein metabolism. PPARalpha activators furthermore improve glucose homeostasis and influence body weight and energy homeostasis. The administration of agents capable of activating the PPARalpha was found to restore the cellular redox balance, evidenced by a lowering of tissue lipid peroxidation, an elimination of constitutively active NF-kappaB, loss in spontaneous inflammatory cytokine production, and ailing in the aging immunity. Topics: Aging; Animals; Blood Glucose; Body Weight; Energy Metabolism; Gene Expression Regulation; Glucose; Homeostasis; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Lipoproteins; Models, Biological; Obesity; Oxidation-Reduction; PPAR alpha; Trans-Activators; Transcription Factors; Up-Regulation | 2005 |
Gender differences in association of plasma adiponectin with obesity reflect resultant insulin resistance in non-diabetic Japanese patients with schizophrenia.
Adipose tissues poorly produce adiponectin in the population with increased body fat mass and diabetes mellitus. It was investigated whether hypoadiponectinemia is associated with obesity and insulin resistance in patients with chronically medicated schizophrenia. A cross-sectional study was designed for 73 non-diabetic Japanese patients with schizophrenia. The patients aged <70 years with body mass index (BMI) > or =18.5 were selected. Anthropometrics and blood parameters including fat-derived cytokines were measured, and then the BMI and homeostasis model assessment-insulin resistance (HOMA-IR) was calculated. The variables were compared between the non-obesity (BMI, 18.5-24.9) and obesity (> or = 25.0) groups, and between genders. Plasma adiponectin negatively correlated with BMI (r = -0.554, P < 0.0003) and HOMA-IR (r = -0.380, P = 0.007) in men, but not in women. The obesity group in men, as compared with the non-obesity group, showed significantly lower plasma adiponectin (P = 0.008) and higher HOMA-IR (P < 0.05), but not in women. Plasma leptin showed a significant positive correlation with BMI (r = 0.604, P < 0.0001 in men; r = 0.763, P < 0.0001 in women) and HOMA-IR (r = 0.618, P < 0.0001 in men; r = 0.679, P < 0.0001 in women). The mean plasma leptin in the obesity group was significantly higher than that in the non-obesity group (P < 0.01 in men; P < 0.01 in women). In contrast to plasma leptin, plasma adiponectin showed gender difference in relation to BMI and HOMA-IR. Topics: Adiponectin; Adult; Aged; Blood Glucose; Body Mass Index; Body Weight; Cross-Sectional Studies; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Japan; Leptin; Male; Middle Aged; Obesity; Schizophrenia; Sex Characteristics | 2005 |
Ghrelin does not influence gastric emptying in obese subjects.
To evaluate the relationship between fasting plasma concentrations of ghrelin and gastric emptying in obese individuals compared with lean subjects.. We included 20 obese patients (9 men and 11 women, BMI > 30 kg/m2) and 16 nonobese control subjects (7 men and 9 women, BMI < or = 25 kg/m2). Gastric emptying of solids (egg sandwich labeled with radionuclide) was measured at 120 minutes with (99m)Tc-single photon emission computed tomography imaging. Ghrelin and leptin were analyzed by radioimmunoassay and ELISA methods, respectively.. The gastric half-emptying time was similar in obese men and women (67.8 +/- 14.79 vs. 66.6 +/- 13.56 minutes) but significantly shorter (p < 0.001) than in the control population (men: 88.09 +/- 11.72 minutes; women: 97.25 +/- 10.31 minutes). Ghrelin levels were significantly lower in obese subjects (131.37 +/- 47.67 vs. 306.3 +/- 45.52 pg/mL; p < 0.0001 in men and 162.13 +/- 32.95 vs. 272.8 +/- 47.77 pg/mL; p < 0.0001 in women). A negative correlation between gastric emptying and fasting ghrelin levels was observed only in lean subjects (y = -0.2391x + 157.9; R2 = 0.95). Also, in the lean group, ghrelin was the only significant independent determinant of gastric emptying, explaining 98% of the variance (adjusted R2) in a multiple regression analysis.. This report shows that, in humans, gastric emptying is faster in obese subjects than in lean controls and that, whereas ghrelin is the best determinant of gastric kinetics in healthy controls, this action is lost in obesity. Topics: Adult; Aging; Body Mass Index; Body Weight; Fasting; Female; Gastric Emptying; Ghrelin; Humans; Kinetics; Leptin; Male; Middle Aged; Obesity; Peptide Hormones; Regression Analysis | 2005 |
Antioxidant treatment normalizes nitric oxide production, renal sodium handling and blood pressure in experimental hyperleptinemia.
Recent studies suggest that adipose tissue hormone, leptin, is involved in the pathogenesis of arterial hypertension. However, the mechanism of hypertensive effect of leptin is incompletely understood. We investigated whether antioxidant treatment could prevent leptin-induced hypertension. Hyperleptinemia was induced in male Wistar rats by administration of exogenous leptin (0.25 mg/kg twice daily s.c. for 7 days) and separate groups were simultaneously treated with superoxide scavenger, tempol, or NAD(P)H oxidase inhibitor, apocynin (2 mM in the drinking water). After 7 days, systolic blood pressure was 20.6% higher in leptin-treated than in control animals. Both tempol and apocynin prevented leptin-induced increase in blood pressure. Plasma concentration and urinary excretion of 8-isoprostanes increased in leptin-treated rats by 66.9% and 67.7%, respectively. The level of lipid peroxidation products, malonyldialdehyde + 4-hydroxyalkenals (MDA+4-HNE), was 60.3% higher in the renal cortex and 48.1% higher in the renal medulla of leptin-treated animals. Aconitase activity decreased in these regions of the kidney following leptin administration by 44.8% and 45.1%, respectively. Leptin increased nitrotyrosine concentration in plasma and renal tissue. Urinary excretion of nitric oxide metabolites (NO(x)) was 57.4% lower and cyclic GMP excretion was 32.0% lower in leptin-treated than in control group. Leptin decreased absolute and fractional sodium excretion by 44.5% and 44.7%, respectively. Co-treatment with either tempol or apocynin normalized 8-isoprostanes, MDA+4-HNE, aconitase activity, nitrotyrosine, as well as urinary excretion of NO(x), cGMP and sodium in rats receiving leptin. These results indicate that oxidative stress-induced NO deficiency is involved in the pathogenesis of leptin-induced hypertension. Topics: Acetophenones; Aconitate Hydratase; Aldehydes; Animals; Antioxidants; Blood Pressure; Body Weight; Creatine; Cyclic GMP; Cyclic N-Oxides; Drinking; Eating; Hypertension; Isoprostanes; Kidney; Leptin; Male; Malondialdehyde; Natriuresis; Nitric Oxide; Rats; Rats, Wistar; Reactive Nitrogen Species; Sodium; Spin Labels; Tyrosine | 2005 |
Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor.
Epidemiological evidence suggests that sex differences exist in type 2 diabetes. Men seem to be more susceptible than women to the consequences of obesity and sedentary lifestyle, possibly because of differences in insulin sensitivity and regional body fat deposition. Thus, lacking androgen receptor (AR) in male individuals may promote insulin resistance. To determine whether lacking AR in male individuals contributes to in vivo insulin resistance, an AR knockout model (AR(-/y)) was used to study the correlation between AR and insulin resistance. Progressive reduced insulin sensitivity and impaired glucose tolerance were seen in AR(-/y) mice with advancing age. Aging AR(-/y) mice displayed accelerated weight gain, hyperinsulinemia, and hyperglycemia, and loss of AR contributes to increased triglyceride content in skeletal muscle and liver. Leptin is higher in serum of AR(-/y) mice. Treatment with exogenous leptin fails to stimulate weight loss in AR(-/y) mice in advanced age, suggesting leptin resistance in the AR(-/y/) mice. Exogenous dihydrotestosterone replacement fails to reverse the metabolic abnormalities and insulin resistance in AR(-/y) mice. Our in vivo studies demonstrate that androgen-AR plays key roles in the development of insulin and leptin resistance, which may contribute to the development of type 2 diabetes and cardiovascular disease. Topics: Adipose Tissue; Aging; Animals; Blood Glucose; Body Weight; Female; Insulin Resistance; Leptin; Lipid Metabolism; Male; Mice; Mice, Knockout; Receptors, Androgen | 2005 |
Mapping of the interface between leptin and the leptin receptor CRH2 domain.
Despite the impact of the leptin system on body weight and other physiologic processes, little is known about the binding of leptin to its receptor. The extracellular domain of the leptin receptor consists of two cytokine receptor homology (CRH) domains separated by an immunoglobulin-like domain, and followed by two juxtamembrane fibronectin type III modules. The CRH2 domain functions as a high-affinity binding site for leptin, and we previously demonstrated interaction with helices A and C of leptin. In this work, we constructed a homology model for the leptin/CRH2 complex and performed a detailed mutation analysis of the CRH2/leptin interface. Using both cell-based and in vitro binding assays using the isolated CRH2 domain, we show the critical role of hydrophobic interactions between Leu 13 and Leu 86 of leptin and Leu 504 in CRH2 in leptin binding and signalling. This binding pattern closely resembles the interaction of other four-helix bundle long chain cytokines with the CRH domain of their cognate receptors. Topics: Amino Acid Sequence; Amino Acid Substitution; Animals; Binding Sites; Body Weight; Chlorocebus aethiops; COS Cells; Humans; Leptin; Molecular Sequence Data; Mutagenesis; Protein Binding; Protein Structure, Tertiary; Receptors, Cell Surface; Receptors, Leptin | 2005 |
Seasonal reproduction in the mare: possible role of plasma leptin, body weight and immune status.
The primary objective of this study was to evaluate the possible role of leptin, body weight and immune status on reproductive activity throughout the transition period from cyclicity to seasonal anestrus, during anestrus and resumption of ovarian activity in Lusitano mares. Mares in good body condition were monthly monitored throughout 2 years (10 mares in each year) for evaluation of their reproductive status by sequential ultrasonography and plasma progesterone determinations. On the second year, all mares were weighed. Progesterone and leptin were assayed by radioimmunoassay (RIA). Parameters of the immune status (phagocytosis and oxidative burst of neutrophils, characterisation of circulating lymphocyte subsets) were also evaluated. Phagocytosis and oxidative burst in blood neutrophils were measured by flow cytometry using commercially available kits. Lymphocyte subsets were assessed by indirect immunofluorescence staining after incubation with monoclonal antibodies specific for CD2, CD19, CD4, CD8 cells markers by flow cytometry. Natural killer cells and B cells were estimated mathematically. No significant difference was found in phagocytosis, oxidative burst and circulating lymphocyte subsets at anestrus and at either phase of the estrous cycle (p>0.05), suggesting that the immune status of the mare was not influenced by the seasonal changes in ovarian activity. This study also suggests that body weight has a direct relationship with plasma leptin levels. Increased concentrations of this hormone in circulation might be associated with the restart or maintenance of ovarian cyclicity in Lusitano mares. Topics: Anestrus; Animals; B-Lymphocytes; Body Weight; Estrous Cycle; Female; Flow Cytometry; Horses; Immunity; Immunophenotyping; Killer Cells, Natural; Leptin; Lymphocyte Count; Lymphocyte Subsets; Neutrophils; Phagocytosis; Pregnancy; Progesterone; Reproduction; Respiratory Burst; Seasons | 2005 |
Increased body fat in mice with a targeted mutation of the paternally expressed imprinted gene Peg3.
Peg3 encodes a C2H2 type zinc finger protein that is implicated in a novel physiological pathway regulating core body temperature, feeding behavior, and obesity in mice. Peg3+/- mutant mice develop an excess of abdominal, subcutaneous, and intra-scapular fat, despite a lifetime of lower food intake than wild-type animals. However, they start life with reduced fat reserves and are slower to enter puberty. These mice maintain a lower core body temperature, fail to respond to a cold challenge, and have lower metabolic activity as measured by oxygen consumption. Plasma leptin levels are significantly higher than in wild types, and Peg3+/- mice appear to have developed leptin resistance. Administration of exogenous leptin resulted in a significant reduction in food intake in wild-type mice that was not observed in Peg3+/- mutants. This mutation, which is strongly expressed in hypothalamic tissue during development, has the capacity to regulate multiple events relating to energy homeostasis. Topics: Adipose Tissue; Animals; Body Composition; Body Temperature; Body Weight; Eating; Energy Metabolism; Female; Hypothalamus; Kruppel-Like Transcription Factors; Leptin; Male; Mice; Motor Activity; Mutation; Neuropeptide Y; Obesity; Oxygen Consumption; Pro-Opiomelanocortin; Protein Kinases; RNA, Messenger; Sexual Maturation; Transcription Factors | 2005 |
Role of leptin and melanocortin signaling in uremia-associated cachexia.
The pathogenesis of cachexia in patients with uremia is unknown. We tested the hypothesis that uremia-associated cachexia is caused by leptin signaling through the hypothalamic melanocortin receptor 4 (MC4-R). We performed either subtotal nephrectomy (N) or sham operations in WT, leptin receptor-deficient (db/db), and MC4-R knockout (MC4-RKO) mice. The animals were on 17% protein diets, and none of the uremic animals were acidotic. WT-N mice produced a classic syndrome of cachexia characterized by decreased food intake, increased metabolic rate, and loss of lean body mass. Corrected leptin levels were elevated. db/db mice and MC4-RKO mice resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. Likewise, treatment of WT mice with intracranial agouti-related peptide reversed the cachexic effects of uremia on appetite, weight gain, body composition, and metabolic rate. Gene expression of ubiquitin C and proteasome subunits C2, C3, and C9 was not changed in the uremic animals, suggesting that other pathways are involved in this model of nonacidotic uremic cachexia. The results of this study suggest that elevated circulating levels of cytokines such as leptin may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system. Topics: Agouti-Related Protein; Animals; Body Weight; Cachexia; Eating; Gene Expression Regulation; Humans; Leptin; Mice; Mice, Knockout; Peptide Fragments; Proteasome Endopeptidase Complex; Receptor, Melanocortin, Type 4; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Ubiquitin C; Uremia | 2005 |
Regulation of body weight and thermogenesis in seasonally acclimatized Brandt's voles (Microtus brandti).
Seasonal changes in an animal's morphology, physiology, and behavior are considered to be an adaptive strategy for survival and reproductive success. In the present study, we examined body weight and several behavioral, physiological, hormonal, and biochemical markers in seasonally acclimatized Brandt's voles (Microtus brandti) to test our hypothesis that Brandt's voles can decrease energy intake associated with decrease in body weight, body fat content, serum leptin level, and increasing thermogenesis in winter conditions. We found that the body weight of Brandt's voles was lowest in winter (December to February) and highest in spring and early summer (May to June). This seasonal variation in body weight was associated with changes in other markers examined. For example, the winter decrease in body weight was accompanied by increased energy intake and enhanced nonshivering thermogenesis (NST) as well as by decreased body fat mass and reduced levels of circulating leptin. Further, circulating levels of leptin were positively correlated with body weight and body fat mass, and negatively correlated with energy intake and uncoupling protein 1 contents. Together, these data do not support our hypothesis and suggest that leptin may be involved in this process and serve as a starvation signal in Brandt's voles. Topics: Acclimatization; Animals; Arvicolinae; Basal Metabolism; Body Composition; Body Weight; Energy Intake; Leptin; Seasons; Statistics, Nonparametric; Thermogenesis | 2005 |
Central leptin differentially modulates ultradian secretory patterns of insulin, leptin and ghrelin independent of effects on food intake and body weight.
We tested the hypothesis that leptin acts centrally to differentially modulate the ultradian communication of leptin, insulin and ghrelin with the hypothalamus. The ultradian fluctuation of these hormones in plasma after central leptin gene therapy was analyzed. Increased leptin transgene expression in the hypothalamus significantly decreased energy intake and body weight concomitant with severe hypoleptinemia and hypoinsulinemia resulting from drastically suppressed peak heights with unchanged frequency discharge of these hormones. Ghrelin secretion was, however, increased solely due to increased pulse amplitude. In pair-fed control rats leptin and ghrelin secretion was unchanged. In conclusion, independent of restraint on caloric intake and weight, leptin acting centrally modulates only the pulse amplitude of ultradian rhythmicity of the three afferent signals involved in the hypothalamic integration of energy balance. Since rhythmic discharge patterns dictate target response of hormones, these findings reveal a novel hypothalamic action of leptin in the pathophysiology of the obesity-dependent metabolic syndrome. Topics: Adenoviridae; Animals; Body Weight; Eating; Energy Metabolism; Female; Gene Transfer Techniques; Genetic Therapy; Ghrelin; Hypothalamus; Insulin; Leptin; Metabolic Diseases; Obesity; Peptide Hormones; Rats; Rats, Sprague-Dawley; Transgenes | 2005 |
Calorie restriction modulates renal expression of sterol regulatory element binding proteins, lipid accumulation, and age-related renal disease.
Sterol regulatory element binding proteins (SREBP) are major regulators of fatty acid and cholesterol synthesis. This study found that age-related renal matrix deposition and proteinuria were associated with increased renal expression of SREBP-1 and SREBP-2 and increased renal accumulation of triglyceride and cholesterol. Because calorie restriction (CR) modulates age-related renal disease, it then was determined whether the effects of CR are mediated partially by modulation of renal lipid metabolism. Compared with ad libitum (AL)-fed 24-month-old (24 m) F344BN rats, CR resulted in significant decreases in extracellular matrix accumulation (periodic acid-Schiff staining and immunofluorescence of type IV collagen and fibronectin) and proteinuria. A significant decrease was also observed in the renal expression of growth factors (connective tissue growth factor and vascular endothelial growth factor) and matrix metalloproteinase inhibitor (plasminogen activator inhibitor-1). These structural and functional changes were associated with significant decreases in renal nuclear SREBP-1 (5.2 in 24 m AL versus 3.3 densitometry units in 24 m CR; P < 0.01) and SREBP-2 (7.1 in 24 m AL versus 4.1 densitometry units in 24 m CR; P < 0.01) protein abundance and renal triglyceride and cholesterol contents. It is interesting that serum leptin level was significantly increased as a function of aging, and CR resulted in significant reduction in serum leptin level. Because it was shown previously that increased renal expression of SREBP-1a per se caused renal lipid accumulation, glomerulosclerosis, and proteinuria, the results suggest that CR modulates age-related renal disease in part by modulation of renal SREBP expression and renal lipid accumulation. Topics: Aging; Animals; Blotting, Western; Body Weight; Caloric Restriction; Cholesterol; Densitometry; Extracellular Matrix; Fatty Acids; Glycosylation; Kidney; Kidney Diseases; Leptin; Lipids; Microscopy, Fluorescence; Models, Biological; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred F344; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2; Sterol Regulatory Element Binding Proteins; Time Factors; Triglycerides | 2005 |
Seasonal changes in serum leptin of the feral raccoon (Procyon lotor) determined by canine-leptin-specific ELISA.
Several reports have been published on blood leptin concentrations in feral animals, including members of the Carnivora, using a commercially available multi-species radioimmunoassay (RIA) kit with anti-human leptin antibody. However, we observed weak immunoreactivity between recombinant canine leptin and anti-human leptin antibody, suggesting a limitation in the applicability of the RIA kit for leptin assays in Carnivora species. We tested the applicability of RIA and sandwich enzyme-linked immunosorbent assay (ELISA) with anti-canine leptin antibody to assay blood leptin in the dog (Canis familiaris) and the raccoon (Procyon lotor). When RIA was used for recombinant canine leptin and dog sera, values were much lower than those determined by ELISA at higher concentrations (>10 ng/ml), while rather higher at lower concentrations (<2 ng/ml). A similar discrepancy between the two methods was found for serum leptin concentrations in raccoons. Clear seasonal variations were observed by ELISA, but not by RIA, with high values in autumn (3.46+/-0.45 ng/ml) and low values in spring and summer (0.71+/-0.07 ng/ml). Serum leptin concentrations in raccoons correlated positively with their body weight (r=0.753) and body mass index (r=0.755), corroborating our previous findings of a strong positive correlation between serum leptin concentrations and body fat content in dogs. Thus, the canine leptin ELISA is useful for assays of dog and raccoon leptin, and blood leptin is a good marker of nutritional condition in the species of Carnivora assayed in this study. Topics: Animals; Body Mass Index; Body Weight; Dogs; Enzyme-Linked Immunosorbent Assay; Evaluation Studies as Topic; Leptin; Raccoons; Radioimmunoassay; Seasons | 2005 |
Recombinant leptin promotes atherosclerosis and thrombosis in apolipoprotein E-deficient mice.
The direct role of leptin in vascular disease remains controversial. The objective of this study was to examine the effects of leptin treatment on atherosclerosis and thrombosis in atherosclerotic-prone mice.. Sixteen-week-old, male apolipoprotein E-deficient mice were treated with injections of recombinant leptin (125 microg per day IP; n=10) or vehicle (n=10) for 4 weeks. Leptin treatment resulted in reduced epididymal fat (352+/-30.7 versus 621+/-61.5 mg; P=0.005) and fasting insulin (0.57+/-0.25 versus 1.7+/-0.22 ng/mL; P=0.014). Despite these metabolic benefits, leptin treatment resulted in an increase in atherosclerosis (8.0+/-0.95% versus 5.4+/-0.59% lesion surface coverage; P<0.05). Leptin treatment also resulted in a shortened time to occlusive thrombosis after vascular injury (21+/-2.1 versus 34.6+/-5.4 minutes; P=0.045).. These studies indicate that exogenous leptin promotes atherosclerosis and thrombosis and support the concept that elevations of leptin may increase the risk for cardiovascular disease. Topics: Adiposity; Animals; Apolipoproteins E; Atherosclerosis; Body Weight; Cholesterol; Cytokines; Fasting; Fluorescent Dyes; Insulin; Leptin; Male; Mice; Mice, Mutant Strains; Recombinant Proteins; Rose Bengal; Thrombosis; Triglycerides | 2005 |
Perigestational suppression of weight gain with central leptin gene therapy results in lower weight F1 generation.
The efficacy of central leptin therapy on weight homeostasis through various phases of reproduction, pregnancy outcome and postnatal, prepubertal and pubertal growth of offspring was assessed. Enhanced leptin transgene expression after a single intracerebroventricular injection of recombinant adeno-associated virus vector encoding the leptin gene (rAAV-lep) decreased calorie intake and weight in adult nulliparous female rats. rAAV-lep treated rats conceived normally, displayed unremarkable pregnancy rate, parturition and delivered normal sized litters. Significantly lower weight was maintained through gestation, lactation, and post-lactation periods. The maintenance of a modest weight reduction was accompanied by voluntarily reduced calorie intake, increased thermogenic energy expenditure, decreased adiposity as reflected by drastically reduced leptin levels, and suppressed insulin and insulin-like growth factor 1 levels through lactation and post-lactation in rAAV-lep treated dams. The offspring at birth weighed significantly less than those of controls and this lower weight range was sustained during postnatal, prepubertal, pubertal and adult (3 months old) periods, contemporaneous with metabolic circulating hormones in the normal range. For the first time we show the persistent efficacy of central leptin gene therapy to suppress weight gain through all phases of reproduction, lactation and post-lactation in dams and reveal the potential imprinting link to producing lower weight in the F1 generation. Topics: Adipose Tissue; Animals; Appetite Regulation; Body Weight; Eating; Female; Gene Expression; Genetic Therapy; Hypothalamus; Insulin; Insulin-Like Growth Factor I; Lactation; Leptin; Male; Obesity; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Weight Gain | 2005 |
Prolactin inhibition in lactating rats changes leptin transfer through the milk.
Malnutrition during lactation reduces milk production and changes pup's leptin serum levels. To test prolactin role in this nutritional state, we evaluated whether prolactin suppression during lactation changes serum leptin in dams, its transfer through the milk, and pup's serum leptin. Lactating rats were treated with bromocryptine (1 mg/twice a day, s.c.) or saline three days before sacrifice (days 2-4 or days 19-21). Food intake and body weight were measured until sacrifice (4th and 21st day). Serum prolactin and leptin were determined by radioimmunoassay. Bromocryptine injected dams had lower serum prolactin and milk production as expected. The mothers presented lower food ingestion (day 21: -25%), lower body weight (day 4: -12%; day 21: -10%), higher serum leptin (day 4: +68%), lower milk leptin on the 4th day (11 times) and higher (8 times) on the 21st day. The offspring of bromocryptine-treated mothers presented lower body weight in both periods of lactation and lower serum leptin on the 4th day (-40%) and higher on the 21st day (+37%) of lactation. We suggest that prolactin, through its effect on leptin secretion into the milk, may play an important role in signalizing maternal nutritional status to the pups. Topics: Animals; Body Weight; Bromocriptine; Eating; Female; Hormone Antagonists; Lactation; Leptin; Milk; Prolactin; Radioimmunoassay; Rats; Rats, Wistar | 2005 |
Transient increase of plasma ghrelin after laparoscopic adjustable gastric banding in morbid obesity.
Ghrelin is a peptide hormone with orexigenic properties that is produced by the stomach. Ghrelin and leptin are thought to be the main regulators of appetite and body weight. The present study was aimed at evaluating the effect of weight reduction after laparoscopic adjustable gastric banding (LAGB) on metabolic parameters and energy balance regulatory peptides. Patients were evaluated before and 6, 12, 24 or 36 months after the procedure, and a blood sample was obtained. Ghrelin rose 6 and 12 months after LABG, and then returned to near-baseline levels. In our study, the correlation between ghrelin and BMI was weak, but a strong significant correlation was maintained between leptin and BMI. We conclude that ghrelin is mainly stimulated by the negative caloric balance, and hypothesize that ghrelin is involved in maintaining a stable body weight, while leptin signals the body energy store; both hormones together are part of a more complex feedback mechanism. Topics: Adult; Appetite; Body Mass Index; Body Weight; Female; Follow-Up Studies; Gastroplasty; Ghrelin; Hormones; Humans; Insulin; Insulin-Like Growth Factor I; Laparoscopy; Leptin; Male; Obesity, Morbid; Peptide Hormones; Time Factors | 2005 |
Correlations between leptin, body composition, bone mineral density, and bone metabolism in kidney transplant recipients.
In kidney transplant recipients leptin levels are often elevated and bone mineral density (BMD) decreased. However, to date there are no about correlations between leptin and BMD in this population. It has been suggested that leptin is a predictor of BMD in postmenopausal women. Moreover, leptin acts as a marker of fat stores. We examined the relationships between leptinemia, some markers of nutritional status, BMD, and bone metabolism in kidney transplant recipients. We also assessed whether leptin was a significant and independent predictor of BMD in this population.. BMD and fat content (global, percentage, trunk) were measured using dual-energy X-ray absorptiometry in 27 kidney allograft recipients. Markers of bone turnover and leptin were studied using commercially available kits.. Leptin correlated with the percentage of body fat, trunk fat, lean body mass, serum creatinine, and urea. Insulin growth factor binding protein 1 was negatively related to waist-hip ratio and global and trunk fat, whereas BMD of the lumbar spine was correlated with the daily dose of prednisone, azathioprine, cyclosporine trough levels, serum calcium, as well as osteoprotegerin level.. Leptin levels are associated with graft function and body fat in kidney allograft recipients. Leptin is not related to nutritional status, BMD, or bone metabolism in kidney allograft recipients, but is associated with the current dosage of immunosuppressants and the serum calcium. Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Aged; Body Composition; Body Weight; Bone and Bones; Bone Density; Calcium; Creatinine; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Leptin; Middle Aged; Transplantation, Homologous | 2005 |
Impact of nutrition on oocyte quality: cumulative effects of body composition and diet leading to hyperinsulinemia in cattle.
The present study sought to assess the combined effects of body composition and diet (level of feeding) on the postfertilization developmental potential of oocytes recovered from heifers using ultrasound-guided transvaginal follicular aspiration and to relate oocyte quality to the metabolic status of these animals. By collecting oocytes on repeated occasions spanning several weeks, it was possible to assess the cumulative effects of changes in nutritional status on oocyte quality over this period. Twenty-four heifers of low and moderate body condition were placed on one of two levels of feeding (equivalent to once or twice the maintenance requirements of these animals). Oocytes were recovered at two defined time points within each of three successive estrous cycles and were matured, fertilized, and cultured to the blastocyst stage in vitro. The results show that the effect of feeding level on oocyte quality is dependent on the body condition of the animal, with the high level of feeding being beneficial to oocytes from animals of low body condition but detrimental to oocytes from animals of moderately high body condition. Furthermore, the effects of high levels of feeding on oocyte quality were cumulative, with blastocyst yields for relatively fat heifers on twice the maintenance requirement deteriorating with time relative to yields for relatively thin heifers on the same level of feeding. Finally, a significant proportion of the moderately fat animals on the high level of feeding were hyperinsulinemic, and we show, to our knowledge for the first time in ruminants, that this condition is associated with impaired oocyte quality. Topics: Animal Nutritional Physiological Phenomena; Animals; Blastocyst; Body Composition; Body Weight; Cattle; Cattle Diseases; Diet; Female; Fertilization in Vitro; Glucose Tolerance Test; Hyperinsulinism; Insulin; Insulin-Like Growth Factor I; Leptin; Oocytes; Ovarian Follicle | 2005 |
High-fat diet-induced ultradian leptin and insulin hypersecretion are absent in obesity-resistant rats.
Sprague-Dawley rats fed a high-fat diet (HFD) are either obesity prone (OP) or obesity resistant (OR). We tested the hypothesis that differences in the ultradian rhythmic patterns of insulin and ghrelin in OP vs. OR rats promote obesity in OP rats.. Rats were fed regular chow or an HFD, and ultradian fluctuations in leptin, insulin, and ghrelin were analyzed in blood samples collected at 5-minute intervals from intrajugular cannulae of freely moving rats.. Regular chow feeding resulted in a slow weight gain accompanied by small increases in insulin and leptin and a decrease in ghrelin discharge, with only the pulse amplitude significantly altered. Similar changes were observed in OR rats, despite HFD consumption. In contrast, OP rats exhibited a high rate of weight gain and marked hyperinsulinemia, hyperleptinemia, and hypoghrelinemia; amplitude was altered, but frequency was stable. In a short-term experiment, HFD elicited similar secretory patterns of smaller magnitude even in the absence of weight gain.. We showed that three hormonal signals of disparate origin involved in energy homeostasis were secreted in discrete episodes, and only the pulse amplitude component was vulnerable to age and HFD consumption. Increases in insulin and leptin and decreases in ghrelin pulse amplitude caused by HFD were exaggerated in OP rats relative to OR rats and preceded the weight increase. These findings show that a distinct genetic predisposition in the endocrine organs of OR rats confers protection against high-fat intake-induced ultradian hypersecretion of obesity-promoting hormonal signals. Topics: Animals; Body Weight; Circadian Rhythm; Cluster Analysis; Dietary Fats; Eating; Feedback; Female; Ghrelin; Insulin; Insulin Secretion; Leptin; Obesity; Peptide Hormones; Periodicity; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric | 2005 |
Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and leptin on hypothalamic mRNA expression of factors participating in food intake regulation in a TCDD-sensitive and a TCDD-resistant rat strain.
An acutely toxic dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to a drastically and permanently reduced feed intake and wasting by an unknown mechanism. We focused on the possible interference of TCDD with hypothalamic factors known to take part in the regulation of eating and metabolism, utilizing the over 1000-fold TCDD-sensitivity difference between Long-Evans (Turku/AB; L-E) and Han/Wistar (Kuopio) rats. The mRNA expression of 18 hypothalamic factors (including NPY, AgRP, and CART) was measured by quantitative RT-PCR at 6, 24 and 96 h after TCDD administration. The effects of TCDD were compared with those of leptin and with feed restriction employing a TCDD dose that elicited a severe reduction of feed intake in L-E rats. TCDD mainly modified expression of orexigenic factors causing an initial suppression followed by reversal to enhanced expression by 96 h. The latter was also seen in feed-restricted controls. In contrast, leptin altered both orexigenic and anorexigenic factor mRNAs in a more even manner and its effects were clustered at 6 h. The transient nature of feeding-promoting factor suppression does not strongly support a key role for this phenomenon in TCDD-induced wasting syndrome. However, the fact that TCDD mainly affected orexigenic factors and the temporal differences in response found between the rat strains warrant further research. Topics: Animals; Appetite Regulation; Body Weight; Drug Resistance; Gene Expression Regulation; Hypothalamus; Leptin; Polychlorinated Dibenzodioxins; Rats; Rats, Long-Evans; Rats, Wistar; RNA, Messenger | 2005 |
Targeted overexpression of leptin to keratinocytes in transgenic mice results in lack of skin phenotype but induction of early leptin resistance.
The epidermis has a great potential as a bioreactor to produce proteins with systemic action. However, the consequences of ectopic epidermal protein overexpression need to be carefully addressed to avoid both local and systemic adverse effects. Thus, the long-term effects of leptin on skin physiology have not been studied, and the metabolic consequences of sustained keratinocyte-derived leptin overexpression are unknown. Herein we describe that very high serum leptin levels can be achieved from a cutaneous source in transgenic mice in which leptin cDNA overexpression was driven by the keratin K5 gene regulatory sequences. Histopathological analysis including the study of skin differentiation and proliferation markers in these transgenic mice revealed that keratinocyte-derived leptin overexpression appears not to have any impact on cutaneous homeostasis. Although young K5-leptin transgenic mice showed remarkable thinness and high glucose metabolism as shown in other leptin transgenic mouse models, a marked leptin insensitivity become apparent as early as 3-4 months of age as demonstrated by increased weight gain and insulin resistance development. Other signs of leptin/insulin resistance included increased bone mass, organomegaly, and wound healing impairment. In addition, to provide evidence for the lack of untoward effects of leptin on epidermis, this transgenic mouse helps us to establish the safe ranges of keratinocyte-derived leptin overexpression and may be useful as a model to study leptin resistance. Topics: Adipose Tissue; Animals; Animals, Newborn; Body Weight; Cell Differentiation; Drug Resistance; Energy Intake; Epidermal Cells; Epidermis; Keratin-15; Keratin-5; Keratinocytes; Keratins; Leptin; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Skin; Wound Healing | 2005 |
Relationship between serum concentrations of leptin, soluble leptin receptor, testosterone and IGF-I, and growth during the first year of postnatal life in the male rhesus monkey, Macaca mulatta.
Subnormal leptin levels in low birth weight infants may allow for catch-up growth during infancy. Scant data are available that relate growth with circulating leptin during normal infancy in primates. The current study objective was to examine the association between serum leptin, its soluble receptor (sOB-R), testosterone and IGF-I concentrations, and body weight during infancy in male rhesus monkeys.. Hormone levels were assessed longitudinally in animals (n = 7) from birth until 1 year of age.. Body weight increased during the first 6 months of life and was strongly correlated with rising IGF-I levels and, as IGF-I plateaued and then declined during the second half of the year, body weight gain decelerated. In contrast, leptin levels declined gradually with age during the first year of life in conjunction with increasing body weight. There was no association between body weight gain and serum leptin levels or between serum testosterone and leptin values. Since sOB-R levels also declined with leptin values, it does not appear that levels of bioavailable leptin changed during infancy.. The data do not support the contention that leptin regulates growth during infancy, but the close association between IGF-I levels and body weight suggested that this hormone may regulate growth in infant male monkeys. The failure to observe an association between serum testosterone and leptin concentrations suggested that leptin is not involved in the activation of the hypothalamic-pituitary -testicular axis during this developmental period. Topics: Animals; Body Weight; Hypothalamo-Hypophyseal System; Insulin-Like Growth Factor I; Leptin; Macaca mulatta; Male; Neurosecretory Systems; Pituitary-Adrenal System; Receptors, Cell Surface; Receptors, Leptin; Solubility; Testis; Testosterone | 2005 |
Different response of senescent female Sprague-Dawley rats to gemfibrozil and rosiglitazone administration.
Eighteen-month-old Sprague-Dawley rats present age-related alterations in lipid and glucose metabolism and are resistant to the effect of PPARalpha-activating hypolipidemic drugs, such as gemfibrozil. We tested if these animals were responsive to the administration of rosiglitazone, an insulin-sensitizer acting on PPARgamma. We determined in 18-month-old female Sprague-Dawley rats treated for 21 days with a daily dose of 3mg gemfibrozil/kg or 3mg rosiglitazone/kg: (i) plasma concentrations of total cholesterol (TC), triglycerides (TG), nonesterified fatty acids (NEFA), glucose, insulin and leptin, (ii) hepatic concentrations of TG, NEFA and cholesteryl esters (CE), and (iii) the liver expression and binding activity of peroxisome proliferator-activated receptor alpha (PPARalpha), and several of its target genes, hepatic nuclear factor-4 (HNF-4), and liver X receptor alpha (LXRalpha). Although gemfibrozil induced mild effects on hepatic PPARalpha, HNF-4, and LXRalpha, only rosiglitazone significantly reduced plasma TG (59%), glucose (19%), insulin (61%), and leptin (66%), and liver TG (43%), CE (49%), and NEFA (27%). These changes were associated to an increased body weight gain and a decrease in visceral fat (8.7-fold and 37% vs. control females, respectively). The beneficial effect of rosiglitazone treatment in 18-month-old female rats could be related to a direct effect on white adipose tissue. Topics: Adipose Tissue; Aging; Animals; Blood Glucose; Body Weight; Cholesterol; Diet; DNA-Binding Proteins; Fatty Acids, Nonesterified; Female; Gemfibrozil; Hepatocyte Nuclear Factor 4; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Leptin; Liver; Liver X Receptors; Orphan Nuclear Receptors; PPAR alpha; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Thiazolidinediones; Triglycerides | 2005 |
Dietary fish oil positively regulates plasma leptin and adiponectin levels in sucrose-fed, insulin-resistant rats.
Insulin resistance and adiposity induced by a long-term sucrose-rich diet (SRD) in rats could be reversed by fish oil (FO). Regulation of plasma leptin and adiponectin levels, as well as their gene expression, by FO might be implicated in these findings. This study was designed to evaluate the long-term regulation of leptin and adiponectin by dietary FO in a dietary model of insulin resistance induced by long-term SRD in rats and to determine their impact on adiposity and insulin sensitivity. Rats were randomized to consume a control diet (CD; n = 25) or an SRD (n = 50) for 7 mo. Subsequently, the SRD-fed rats were randomized to consume SRD+FO or to continue on SRD for an additional 2 mo. Long-term SRD induced overweight and decreased both plasma leptin and adiponectin levels without change in gene expression. Dyslipidemia, adiposity, and insulin resistance accompanied these modifications. Shifting the source of fat to FO for 2 mo increased plasma levels of both adipokines, reversed insulin resistance and dyslipidemia, and improved adiposity. These results were not associated with modifications in gene expression. These results suggest that increasing both adipokines by dietary FO might play an essential role in the normalization of insulin resistance and adiposity in dietary-induced, insulin-resistant models. Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Cell Size; Diet; Dietary Fats, Unsaturated; Energy Intake; Fish Oils; Gene Expression; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Lipids; Liver; Male; Obesity; Rats; Rats, Wistar; Sucrose; Triglycerides | 2005 |
Correlation between blood and milk serum leptin in goats and growth of their offspring.
Boer and Boer crossbred meat-type does were used in two experiments to determine whether goat milk serum contains leptin and to investigate possible correlations of milk and serum leptin in does and subsequent growth of their offspring. Blood and milk samples were collected within 2 h of kidding (d 0) from 20 (Exp. 1; spring) or 22 does (Exp. 2; the following fall). Blood milk samples were then collected again on d 0.5, 1, 3, 5, 7, 14, 21, 28, 35, 42, 49, and 56 (Exp. 1) or d 0.5, 1, 2, 3, 4, 5, 6, 7, 14, and 21 (Exp. 2). Body weights of kids were recorded on d 0, and BW of kids and does were recorded weekly beginning on d 7 (kids) or 21 (does), with BCS also recorded for does beginning on d 28 for Exp. 1 and on d 0.5, 1, 2, 3, 4, 5, 6, 7, 14, and 21 for Exp. 2. Leptin was detected in colostral milk and was influenced by days postpartum, decreasing (P < 0.001) over time with an average of 4.4 +/- 0.3 ng/mL (Exp. 1) and 18.1 +/- 1.0 ng/mL (Exp. 2) on d 0 compared with 1.0 +/- 0.3 ng/mL on d 56 (Exp. 1) and 2.9 +/- 0.2 ng/mL on d 21 (Exp. 2). Day postpartum and milk serum leptin were negatively correlated (P < 0.001) for Exp. 1 (r = -0.27) and Exp. 2 (r = -0.46). For Exp. 1 only, blood serum leptin tended (P = 0.09) to be influenced by day, with a weak positive correlation (r = 0.15; P < 0.02). Weak positive correlations (P < 0.01) were found between blood serum leptin and doe BCS (r = 0.42 in Exp. 1, and r = 0.13 in Exp. 2) and doe BW (r = 0.44 in Exp. 1, and r = 0.26 in Exp. 2), with the absence of a stronger relationship likely due in part to the short time period measured and the lack of significant changes in BCS and BW during that time. In conclusion, leptin was present in milk and blood serum of does, and blood serum leptin was weakly correlated with doe BW and BCS, but it was not related to kid BW. Therefore, further studies are needed to clarify the relationships involving milk and serum leptin in goats. Topics: Animals; Animals, Newborn; Body Weight; Female; Goats; Leptin; Milk | 2005 |
The relationship between blood leptin level and bone density is specific to ethnicity and menopausal status.
Leptin, the obesity hormone, has been linked to bone mineralization and tumorigenesis. In addition, both bone mineral density (BMD) and postmenopausal breast cancer are associated with obesity, but the interrelationships between obesity, leptin, BMD, and breast cancer are not yet clear. In particular, there is little published research comparing white and black women in terms of these variables. We obtained blood specimens for leptin analysis from a group of 320 breast cancer patients and controls with an ethnic composition of 49% white women and 51% black women. Distal and proximal radial BMD (DBMD and PBMD) were measured by dual-energy X-ray absorptiometry, and age- and ethnicity-specific standardized scores (Z-scores) were calculated for bone density. Blood leptin levels were determined by radioimmunoassay. Blood leptin level was not linked to breast cancer risk. Leptin levels were significantly higher in black women than in white women and were also significantly higher in obese and overweight women than in normal-weight women. Black women weighed more and had a higher body mass index (BMI) than white women. After controlling for BMI, leptin was correlated with DBMD ( r = .17; P < .05) and PBMD ( r = .21; P < .05) in whites, but not in blacks. Leptin was also correlated with both distal and proximal Z-scores in postmenopausal women ( r = .14 and .13; P < .05). Thus leptin may be a predictor for BMD in a population that is prone to have a low BMD, and this relationship is independent of the effect of body weight on leptin levels. Our results suggest that ethnicity and menopausal status should be considered when comparing results from different studies. Topics: Black People; Body Mass Index; Body Weight; Bone Density; Breast Neoplasms; Female; Hormone Replacement Therapy; Humans; Leptin; Menopause; Middle Aged; White People | 2005 |
Exogenously administered leptin leads to weight loss and increased physical activity in the marsupial Sminthopsis crassicaudata.
The adipose tissue derived cytokine leptin, modifies energy balance via effects on both food intake and energy expenditure. It is not clear, however, whether the component of energy expenditure accounted for by voluntary (nonexercise) physical activity is increased in response to leptin. The aim of this study was to investigate the effect of exogenously administered leptin on physical activity in the marsupial Sminthopsis crassicaudata. Body weight, tail width and food intake, were measured daily and physical activity was measured hourly in normal lean S. crassicaudata (n=8) with ad libitum access to standard laboratory diet. After 5 days baseline the animals were divided into two equal groups (n=4), and either human recombinant leptin (2.5 mg/kg) or placebo was administered twice daily intraperitoneally. Approximately 81% of the total daily activity during the baseline period occurred during the nocturnal phase. After 9 days of leptin administration, there were significant decreases in body weight (P<0.001) and fat content (P<0.01), which were not accompanied by a decrease in total energy intake. Overall daily physical activity increased (P=0.028); this effect was confined to the dark phase (P=0.033). We conclude that in lean S. crassicaudata the exogenous administration of human recombinant leptin results in a decrease in adiposity which occurs in the absence of a measurable effect on food intake and is associated with an increase in non-exercise physical activity at least over the duration of this study. Topics: Adipose Tissue; Animals; Body Weight; Circadian Rhythm; Eating; Humans; Leptin; Male; Marsupialia; Motor Activity; Recombinant Proteins; Tail; Weight Loss | 2005 |
Influence of feeding status on neuronal activity in the hypothalamus during lipopolysaccharide-induced anorexia in rats.
Fasting attenuates disease-associated anorexia, but the mechanisms underlying this effect are not well understood. In the present study, we investigated the extent to which a 48 h fast alters hypothalamic neuronal activity in response to the anorectic effects of lipopolysaccharide in rats. Male rats were fed ad libitum or fasted, and were injected with i.p. saline or lipopolysaccharide (250 microg/kg). Immunohistochemistry for Fos protein was used to visualize neuronal activity in response to lipopolysaccharide within selected hypothalamic feeding regulatory nuclei. Additionally, food intake, body weight, plasma interleukin-1 and leptin levels, and the expression of mRNA for appetite-related neuropeptides (neuropeptide Y, proopiomelanocortin and cocaine-amphetamine-regulated transcript) were measured in a time-related manner. Our data show that the pattern of lipopolysaccharide-induced Fos expression was similar in most hypothalamic nuclei whatever the feeding status. However, we observed that fasting significantly reduced lipopolysaccharide-induced Fos expression in the paraventricular nucleus, in association with an attenuated lipopolysaccharide-induced anorexia and body weight loss. Moreover, lipopolysaccharide reduced fasting-induced Fos expression in the perifornical area of the lateral hypothalamus. Lipopolysaccharide-induced circulating levels of interleukin-1 were similar across feeding status. Finally, fasting, but not lipopolysaccharide, affected circulating level of leptin and appetite-related neuropeptides expression in the arcuate nucleus. Together, our data show that fasting modulates lipopolysaccharide-induced anorexia and body weight loss in association with neural changes in specific hypothalamic nuclei. Topics: Animals; Anorexia; Behavior, Animal; beta-Endorphin; Body Weight; Cell Count; DNA-Binding Proteins; Eating; Enzyme-Linked Immunosorbent Assay; Feeding Behavior; Food Deprivation; Gene Expression Regulation; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Interleukin-1; Interleukin-1beta; Leptin; Lipopolysaccharides; Male; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Oncogene Proteins v-fos; Peptide Fragments; Pro-Opiomelanocortin; Rats; Rats, Wistar; STAT3 Transcription Factor; Time Factors; Trans-Activators | 2005 |
Suppression of fat deposition for the life time with gene therapy.
Unexpended energy is stored as fat in the body and increased rate of fat accretion culminates in obesity. Obesity increases the risks of many diseases several folds and shortens life span. A progressive deficit in the central feedback effects of leptin, a peptide produced by fat cells and hypothalamus, results in increased weight gain and obesity. This article summarizes our experimental findings to show that a stable increase in leptin availability in the hypothalamus alone with the aid of leptin gene therapy suppresses fat accretion and metabolic hormones for nearly the lifetime of laboratory rodents. Consequently, central leptin gene therapy is a novel modality that offers a viable therapeutic option to reduce fat depots and attendant metabolic sequelae implicated in obesity-related illnesses. Topics: Animals; Body Weight; Energy Intake; Fats; Feedback, Physiological; Female; Genetic Therapy; Leptin; Obesity; Rats; Rats, Sprague-Dawley; Time Factors; Treatment Outcome | 2005 |
Galanin-like peptide rescues reproductive function in the diabetic rat.
Galanin-like peptide (GALP) is expressed in the hypothalamic arcuate nucleus and is regulated by leptin and insulin. Centrally administered GALP stimulates gonadotropin secretion and sexual behavior in the rat. Type 1 diabetes is associated with reduced expression of GALP, as well as an overall decline in reproductive function. We postulated that tonic activity of GALP in the brain is required to sustain normal reproductive activity. To test this hypothesis, we examined whether central (intracerebroventricular) immunoblockade of GALP would reduce sexual behaviors and serum levels of luteinizing hormone (LH) in normal adult male rats. We found that GALP antibody reversibly reduced serum levels of LH and abolished male sexual behaviors (P < 0.05 and 0.001, respectively). Second, we tested whether intracerebroventricular GALP could restore normal plasma LH levels and sexual behavior in diabetic animals. We compared groups of diabetic rats that received intracerebroventricular GALP or vehicle and found that GALP increased serum levels of LH and sexual behavior. Third, we examined whether intracerebroventricular administration of affinity-purified GALP antibody could block the effect of insulin and leptin in reversing the effects of diabetes on LH and sexual behavior. We found that treatment of diabetic animals with insulin and leptin nearly normalized LH levels and sexual behaviors; however, this effect was attenuated by intracerebroventricular administration of GALP antibody (P < 0.05). These observations demonstrate that endogenous GALP provides trophic support to the neuroendocrine reproductive axis, including sexual behavior. Topics: Animals; Antibodies; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Eating; Female; Galanin-Like Peptide; Injections, Intraventricular; Insulin; Leptin; Male; Rats; Rats, Sprague-Dawley; Reproduction; Sexual Behavior, Animal | 2005 |
The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity.
Leptin is required for normal energy and glucose homeostasis. The hypothalamic arcuate nucleus (ARH) has been proposed as an important site of leptin action. To assess the physiological significance of leptin signaling in the ARH, we used mice homozygous for a FLPe-reactivatable, leptin receptor null allele (Lepr(neo/neo) mice). Similar to Lepr(db/db) mice, these mice are obese, hyperglycemic, hyperinsulinemic, infertile, and hypoactive. To selectively restore leptin signaling in the ARH, we generated an adeno-associated virus expressing FLPe-recombinase, which was delivered unilaterally into the hypothalamus using stereotaxic injections. We found that unilateral restoration of leptin signaling in the ARH of Lepr(neo/neo) mice leads to a modest decrease in body weight and food intake. In contrast, unilateral reactivation markedly improved hyperinsulinemia and normalized blood glucose levels and locomotor activity. These data demonstrate that leptin signaling in the ARH is sufficient for mediating leptin's effects on glucose homeostasis and locomotor activity. Topics: Alleles; Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Body Weight; Cell Nucleus; DNA Nucleotidyltransferases; Fertility; Glucose; Green Fluorescent Proteins; Homeostasis; Homozygote; Hypothalamus; Immunohistochemistry; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Genetic; Motor Activity; Neurons; Oxygen Consumption; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Time Factors | 2005 |
Molecular mechanisms associated with leptin resistance: n-3 polyunsaturated fatty acids induce alterations in the tight junction of the brain.
High-fat diets cause peripheral leptin resistance, and dietary lipid composition affects sensitivity to leptin. We examined the role of n-3 polyunsaturated fatty acid (PUFA) in peripheral leptin resistance. Dietary PUFAs (0.4% wt/wt) caused insensitivity to peripherally but not intracerebroventricularly administered leptin. n-3 PUFA increased body weight, associated with a significant reduction of leptin concentration in the cerebrospinal fluid. Dietary n-3 PUFA reduced transport of endogenous or exogenously administered leptin into the brain, associated with increased expression of hypothalamic occludin, but caused no change in expression of leptin receptors, proteins associated with leptin signaling or other tight junction proteins. Continuous intracerebroventricular infusion of an antisense morpholino oligonucleotide targeted to occludin mRNA reversed n-3 PUFA-induced insensitivity to peripherally administered leptin. We conclude that n-3 PUFA induces peripheral leptin resistance via an increase in the expression of hypothalamic occludin, reducing paracellular transport of leptin into the brain. Topics: Animals; Body Weight; Brain; Diet; Drug Resistance; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Hypothalamus; Leptin; Male; Membrane Proteins; Occludin; Rats; Rats, Wistar; RNA, Messenger; Signal Transduction; Tight Junctions | 2005 |
The relationship between serum resistin, leptin, adiponectin, ghrelin levels and bone mineral density in middle-aged men.
Body weight is a significant predictor of bone mass. Hormonal factors such as sex hormones, insulin, leptin and adiponectin are thought to play a role in the mechanisms controlling the association of body weight and fat mass with bone mass. However, contradictory results have been reported for the association between serum adipocytokines and bone mineral density (BMD). We therefore examined whether the serum adipocytokine and ghrelin levels, markers of fat metabolism, are associated with BMD in male adults.. For 80 male adults (average age 54.5 +/- 6.4 years; average body mass index (BMI) 24.4 +/- 2.5 kg/m2), the correlations between serum resistin, leptin, adiponectin and ghrelin levels with BMD were investigated.. Among the adipocytokines, serum resistin levels were negatively correlated with lumbar spine BMD (r = -0.237, P = 0.05). After adjustment was made for age and BMI, log-transformed serum leptin showed a significant negative correlation with lumbar spine BMD, which was not seen on bivariate analysis (r = -0.237, P = 0.039). Femoral neck BMD was marginally associated only with serum adiponectin levels (r = -0.226, P = 0.062). In multiple regression analyses, among the adipokines, only resistin was a significant determinant of lumbar spine BMD, although the variance was small (R2 = 0.256). Serum ghrelin levels were not correlated with the BMD of either body site.. Serum resistin level showed a significant negative correlation with lumbar spine BMD, although the variance was small. Further studies are needed to elucidate the role of adipocytokines in bone metabolism. Topics: Adiponectin; Adult; Age Factors; Aged; Body Mass Index; Body Weight; Bone Density; Cholesterol; Estradiol; Femur Neck; Ghrelin; Hormones, Ectopic; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Lumbar Vertebrae; Male; Middle Aged; Peptide Hormones; Resistin; Triglycerides; Waist-Hip Ratio | 2005 |
Targeted intestinal overexpression of the immediate early gene tis7 in transgenic mice increases triglyceride absorption and adiposity.
Following loss of functional small bowel surface area due to surgical resection, the remnant gut undergoes an adaptive response characterized by increased crypt cell proliferation and enhanced villus height and crypt depth, resulting in augmented intestinal nutrient absorptive capacity. Previous studies showed that expression of the immediate early gene tis7 is markedly up-regulated in intestinal enterocytes during the adaptive response. To study its role in the enterocyte, transgenic mice were generated that specifically overexpress TIS7 in the gut. Nucleotides -596 to +21 of the rat liver fatty acid-binding protein promoter were used to direct abundant overexpression of TIS7 into small intestinal upper crypt and villus enterocytes. TIS7 transgenic mice had increased total body adiposity and decreased lean muscle mass compared with normal littermates. Oxygen consumption levels, body weight, surface area, and small bowel weight were decreased. On a high fat diet, transgenic mice exhibited a more rapid and proportionately greater gain in body weight with persistently elevated total body adiposity and increased hepatic fat accumulation. Bolus fat feeding resulted in a greater increase in serum triglyceride levels and an accelerated appearance of enterocytic, lamina propria, and hepatic fat. Changes in fat homeostasis were linked to increased expression of genes involved in enterocytic triglyceride metabolism and changes in growth with decreased insulin-like growth factor-1 expression. Thus, TIS7 overexpression in the intestine altered growth, metabolic rate, adiposity, and intestinal triglyceride absorption. These results suggest that TIS7 is a unique mediator of nutrient absorptive and metabolic adaptation following gut resection. Topics: Adipose Tissue; Animals; Blotting, Northern; Body Composition; Body Weight; Calorimetry; Cell Proliferation; Enterocytes; Fatty Acid-Binding Proteins; Gene Expression Regulation; Glucose; Growth Hormone; Homeostasis; Immediate-Early Proteins; Immunoblotting; Immunohistochemistry; Insulin; Insulin-Like Growth Factor I; Intestinal Mucosa; Leptin; Lipids; Liver; Membrane Proteins; Mice; Mice, Transgenic; Microscopy, Electron; Oxygen Consumption; Promoter Regions, Genetic; Rats; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Triglycerides; Up-Regulation | 2005 |
Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice.
Leptin regulates energy balance and body weight by activating its receptor LEPRb and multiple downstream signaling pathways, including the STAT3 and the IRS2/PI 3-kinase pathways, in the hypothalamus. Leptin stimulates activation of LEPRb-associated JAK2, which initiates cell signaling. Here we identified SH2-B, a JAK2-interacting protein, as a key regulator of leptin sensitivity, energy balance, and body weight. SH2-B homozygous null mice were severely hyperphagic and obese and developed a metabolic syndrome characterized by hyperleptinemia, hyperinsulinemia, hyperlipidemia, hepatic steatosis, and hyperglycemia. The expression of hypothalamic orexigenic NPY and AgRP was increased in SH2-B(-/-) mice. Leptin-stimulated activation of hypothalamic JAK2 and phosphorylation of hypothalamic STAT3 and IRS2 were significantly impaired in SH2-B(-/-) mice. Moreover, overexpression of SH2-B counteracted PTP1B-mediated inhibition of leptin signaling in cultured cells. Our data suggest that SH2-B is an endogenous enhancer of leptin sensitivity and required for maintaining normal energy metabolism and body weight in mice. Topics: Adaptor Proteins, Signal Transducing; Animals; Body Weight; DNA-Binding Proteins; Enzyme Activation; Female; Homeostasis; Hypothalamus; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Janus Kinase 2; Leptin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Phosphoproteins; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Signal Transduction; STAT3 Transcription Factor; Trans-Activators | 2005 |
Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype.
Agouti-related protein (AgRP) and neuropeptide Y (NPY) are colocalized in arcuate nucleus (arcuate) neurons implicated in the regulation of energy balance. Both AgRP and NPY stimulate food intake when administered into the third ventricle and are up-regulated in states of negative energy balance. However, mice with targeted deletion of either NPY or AgRP or both do not have major alterations in energy homeostasis. Using bacterial artificial chromosome (BAC) transgenesis we have targeted expression of a neurotoxic CAG expanded form of ataxin-3 to AgRP-expressing neurons in the arcuate. This resulted in a 47% loss of AgRP neurons by 16 weeks of age, a significantly reduced body weight, (wild-type mice (WT) 34.7+/-0.7 g vs. transgenic mice (Tg) 28.6+/-0.6 g, P<0.001), and reduced food intake (WT 5.0+/-0.2 vs. Tg 3.6+/-0.1 g per day, P<0.001). Transgenic mice had significantly reduced total body fat, plasma insulin, and increased brown adipose tissue UCP1 expression. Transgenic mice failed to respond to peripherally administered ghrelin but retained sensitivity to PYY 3-36. These data suggest that postembryonic partial loss of AgRP/NPY neurons leads to a lean, hypophagic phenotype. Topics: Adipose Tissue; Agouti-Related Protein; Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Blotting, Northern; Body Composition; Body Weight; Carrier Proteins; Chromosomes, Artificial, Bacterial; DNA, Complementary; Exons; Feeding Behavior; Gene Deletion; Ghrelin; Hypothalamus; In Situ Hybridization; Insulin; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Membrane Proteins; Mice; Mice, Transgenic; Mitochondrial Proteins; Models, Genetic; Neurons; Neuropeptide Y; Peptide Hormones; Phenotype; Polymerase Chain Reaction; Protein Structure, Tertiary; Proteins; Radioimmunoassay; RNA, Messenger; Thinness; Time Factors; Transgenes; Uncoupling Protein 1; Up-Regulation | 2005 |
Proinflammatory cytokines and leptin are increased in serum of prepubertal obese children.
It has not yet been shown in prepubertal children how cytokines, leptin, and body mass, as well as parameters of obesity are interrelated. The aim of this study was to explore the relation between circulating levels of some cytokines with leptin and body mass index. A case control study was carried out in obese children of both sexes. An obese group was carried out with 63 school prepubertal children and a control group comprised the same number of nonobese children paired by age and by sex. Mean serum leptin concentration was significantly higher in the obese children at 19.9 +/- 7.4 ng/mL, than the control group (7.9 +/- 5.1 ng/mL). Serum IL-1beta, IL-6, and TNF-alpha levels were also significantly higher in the obese group than controls (33.0 +/- 8.9, 45.2 +/- 11.8, and 9.2 +/- 2.3 pg/mL, versus 3.6 +/- 1.0, 13.1 +/- 3.9, and 3.9 +/- 1.0 pg/mL, resp). In controversy, serum IL-2 level was diminished in the obese group as 0.4 +/- 0.1 versus 0.9 +/- 0.1 U/L. Obesity may be a low-grade systemic inflammatory disease. Obese prepubertal children have elevated serum levels of IL-1beta , IL-6, and TNF-alpha which are known as markers of inflammation. Topics: Body Weight; Case-Control Studies; Child; Female; Humans; Interleukin-1; Interleukin-6; Leptin; Male; Obesity; Puberty; Tumor Necrosis Factor-alpha | 2005 |
Plasma leptin and antipsychotic-induced body weight gain.
Topics: Antipsychotic Agents; Body Weight; Humans; Leptin; Schizophrenia | 2005 |
Estrogen regulation of adiposity and fuel partitioning. Evidence of genomic and non-genomic regulation of lipogenic and oxidative pathways.
Menopause is associated with increased adiposity and greater risk of metabolic disease. In the ovariectomized (OVX) rodent model of menopause, increased adiposity is prevented by estrogen (E2) replacement, reflecting both anorexigenic and potentially metabolic actions of E2. To elucidate metabolic and molecular mechanisms by which E2 regulates fat storage and fat mobilization independently of reduced energy intake, C57 BL/6 mice were ovariectomized, randomized to estrogen (OVX-E2) or control pellet implants (OVX-C), and pairfed for 40 days. E2 treatment was associated with reduced adipose mass and adipocyte size and down-regulation of lipogenic genes in adipocytes under the control of sterol-regulatory element-binding protein 1c. Adipocytes of OVX-E2 mice contained >3-fold more perilipin protein than adipocytes of pairfed control (OVX) mice, and this difference was associated with enhanced ex vivo lipolytic response to catecholamines and with greater levels of serum-free fatty acids following fasting. As in adipose tissue, E2 decreased the expression of lipogenic genes in liver and skeletal muscle. In the latter, E2 appears to promote the partitioning of free fatty acids toward oxidation and away from triglyceride storage by up-regulating the expression of peroxisome proliferation activator receptor-delta and its downstream targets and also by directly and rapidly activating AMP-activated protein kinase. Thus, novel genomic and non-genomic actions of E2 promote leanness in OVX mice independently of reduced energy intake. Topics: Adipocytes; Adiponectin; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Blotting, Western; Body Weight; Carrier Proteins; Catecholamines; Cells, Cultured; Culture Media, Serum-Free; Down-Regulation; Electrophoresis, Polyacrylamide Gel; Estrogens; Female; Gene Expression Regulation; Genome; Glucose; Insulin; Leptin; Lipids; Liver; Mice; Mice, Inbred C57BL; Multienzyme Complexes; Muscle, Skeletal; Oxygen; Perilipin-1; Phosphoproteins; PPAR delta; Protein Serine-Threonine Kinases; Resistin; Reverse Transcriptase Polymerase Chain Reaction; Sterol Regulatory Element Binding Protein 1; Time Factors; Triglycerides; Up-Regulation | 2005 |
[Effects of early weaning on the blood glucose, blood lipid and hormone of rat fed a high fat diet].
To observe the effects of early weaning on the blood glucose, blood lipid and hormone of rat fed a high fat diet.. Male Wistar rats were randomly divided into two groups after born 17 days according to body weight. One group was early weaned in the 17th day, the other was breastfed until the 24th day. After 4 weeks fed with basic diet, 12 rats were randomly selected from each group and were sacrificed. The other rats of each group were further randomly divided into 2 groups according to body weight. One group was fed a high fat diet, the other was fed the basic diet. The rats were sacrificed respectively at the end of the experiment. The blood glucose, serum lipids, and hormones were measured.. Compared with the normal weaning rats, the weight and fat pad of early weaning rats significantly increased and the level of blood glucose, serum lipids, insulin, leptin also increased significantly (P < 0.05), the level of HDL, FT3 decreased (P < 0.05).. The tendency of obesity in early weaning rats were more obvious than normal weaning rats after fed a high fat diet. Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Feeding Behavior; Insulin; Leptin; Lipids; Male; Random Allocation; Rats; Rats, Wistar; Time Factors; Weaning | 2005 |
Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity.
Both human linkage studies and MC3R knockout mouse models suggest that the MC3R may play an important role in energy homeostasis. Here we show that among 355 overweight and nonoverweight children, 8.2% were double homozygous for a pair of missense MC3R sequence variants (Thr6Lys and Val81Ile). Such children were significantly heavier (BMI and BMI SD score: P < 0.0001), had more body fat (body fat mass and percentage fat mass: P < 0.001), and had greater plasma leptin (P < 0.0001) and insulin concentrations (P < 0.001) and greater insulin resistance (P < 0.008) than wild-type or heterozygous children. Both sequence variants were more common in African-American than Caucasian children. In vitro expression studies found the double mutant MC3R was partially inactive, with significantly fewer receptor binding sites, decreased signal transduction, and less protein expression. We conclude that diminished MC3R expression in this double MC3R variant may be a predisposing factor for excessive body weight gain in children. Topics: Adipose Tissue; Adolescent; Black or African American; Body Weight; Child; Child, Preschool; Female; Gene Expression; Genetic Linkage; Genotype; Humans; Insulin; Leptin; Male; Mutation, Missense; Obesity; Polymorphism, Genetic; Receptor, Melanocortin, Type 3; White People | 2005 |
Growth, metabolism, and blood pressure disturbances during aging in transgenic rats with altered brain renin-angiotensin systems.
Transgenic rats with targeted decreased glial expression of angiotensinogen (ASrAogen rats) did not show an increase in systolic pressure compared with Sprague-Dawley (SD) rats during aging (15-69 wk of age). ASrAogen animals had lower body weights throughout the study, similar to reports for animals with systemic knockout of angiotensinogen or treated long term with renin-angiotensin system (RAS) blockers. Further characterization of indexes of growth and metabolism in ASrAogen rats compared with (mRen2)27 and SD rats, which express elevated versus normal brain and tissue angiotensin II levels, respectively, revealed that serum leptin was 100-200% higher in SD and (mRen2)27 rats at 46 wk and 69 wk of age. Consistent with low serum leptin, ASrAogen rats had higher food intake (73%) compared with SD or (mRen2)27 rats. (mRen2)27 rats had higher resting insulin levels than ASrAogen rats at all ages. Insulin levels were constant during aging in ASrAogen rats, whereas an increase occurred in SD rats, leading to higher insulin levels at 46 and 69 wk of age compared with ASrAogen rats. IGF-1 was comparable among strains at all ages, but (mRen2)27 rats had longer and ASrAogen rats had shorter tail lengths versus SD rats at 15 wk of age. In conclusion, reduced expression of glial angiotensinogen blunts the age-dependent rise in insulin levels and weight gain, findings that mimic the effects of long-term systemic blockade of the RAS or systemic knockout of angiotensinogen. These data implicate glial angiotensinogen in the regulation of body metabolism as well as hormonal mechanisms regulating blood pressure. Topics: Aging; Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Body Weight; Brain; Heart Rate; Insulin; Leptin; Neuroglia; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Tail | 2005 |
Central administration of resistin promotes short-term satiety in rats.
Several hormones expressed in white adipose tissue influence food intake at the central level. We sought to determine whether resistin, a circulating adipose-derived hormone in rodents, has actions on the hypothalamus by determining the effects of central resistin injection on food intake and on hypothalamic Fos protein expression.. As resistin expression in adipose tissue is influenced by altered nutritional status, we studied the effect of central resistin in both fed and pre-fasted rats.. In fasted rats, central injection of resistin decreased food intake acutely and increased the number of cells that express Fos protein in the arcuate nucleus but not in any other hypothalamic structure. The effect on food intake was dose-dependent and did not result in the formation of a conditioned taste aversion.. Taken together, these results provide the first evidence documenting a central action of resistin, which could be involved in a feedback loop targeting the hypothalamus. On the other hand, since we observed resistin mRNA in the arcuate and ventromedial nuclei of the hypothalamus, it is also possible that brain-derived resistin serves as a neuropeptide involved in the regulation of energy homeostasis. However, since resistin-induced satiety was modest and transient, as central administration for several days did not affect body weight, the physiological relevance and therapeutic potential of the observed principal phenomenon may be limited. Topics: Adiponectin; Animals; Body Weight; Eating; Hormones, Ectopic; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Injections, Intraventricular; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Proto-Oncogene Proteins c-fos; Rats; Resistin; RNA, Messenger; Satiety Response; Statistics, Nonparametric; Taste | 2005 |
Skeletal bone morphology is resistant to the high amplitude seasonal leptin cycle in the Siberian hamster.
Recent studies have suggested that the adipocyte-derived hormone, leptin, plays a role in the regulation of metabolism. Here, we tested this hypothesis in the seasonally breeding Siberian hamster, as this species exhibits profound seasonal changes in adiposity and circulating leptin concentrations driven by the annual photoperiodic cycle. Male hamsters were kept in either long (LD) or short (SD) photoperiods. Following exposure to short photoperiods for 8 weeks animals exhibited a significant weight-loss and a 16-fold reduction of serum leptin concentrations. At Week 9, animals in both photoperiods were infused with leptin or PBS via osmotic mini-pump for 14 days. Chronic leptin infusion mimicked LD-like concentrations in SD-housed animals and caused a further decline in body weight and adipose tissue. In LD-housed animals, leptin infusion resulted in a significant elevation of serum concentrations above natural LD-like levels, but had no discernable effect on body weight or overall adiposity. Both bending and compression characteristics and histomorphometric measurements of trabecular bone mass were unaltered by leptin treatment or photoperiod. Our data therefore show that despite a high natural amplitude cycle of leptin, this hormone has no apparent role in the regulation of bone metabolism, and therefore do not support recent propositions that this hormone is an important component in the metabolism of bone tissue. Topics: Animals; Biomechanical Phenomena; Body Weight; Bone and Bones; Cricetinae; Female; Infusions, Intravenous; Leptin; Male; Phodopus; Photoperiod; Reproduction; Seasons | 2005 |
Prospective evaluation of leptin and neuropeptide Y (NPY) serum levels in girls with anorexia nervosa.
The pathogenesis of anorexia nervosa (AN) remains still unclear. It has been reported that neuropeptides may play a role in the control of appetite and hormone release contributing to hormonal disturbances in AN. However the question if neuropeptide alterations are consequence or cause of malnutrition is still unresolved.. Serum leptin, neuropeptide Y (NPY) concentrations as well as hormones (FSH, LH, estradiol, cortisol and fT4) serum levels were prospectively estimated in 19 girls aged 11.7-17.7 years (mean 15.5 years) with anorexia nervosa (AN) at the admission to the hospital (baseline) and at follow-up after 7.21+ 2.32 months of treatment. The treatment consisted of hypercaloric diet, psychotherapy and vitamins supplementation.. Mean leptin concentration significantly increased from 7.99 + 2.6 to 9.98 + 2.48 microg/ml (p<0.01), whereas mean NPY concentration significantly decreased from 34.10 + 9.81 to 29.6 + 8.04 pmol/l (p<0.01). Leptin/BMI ratio was constant, while NPY/BMI ratio decreased. There were no significant differences between leptin and NPY serum concentrations at baseline and follow-up in eumenorrheic vs. amenorrheic patients. Simple linear correlation analysis showed negative correlation between leptin and NPY concentrations at baseline (r=-0.67; p<0.05) and at follow-up (r=-0.76; p<0.05) only in eumenorrheic subgroup. There were no significant correlations between leptin, NPY and BMI and body weight values.. 1) Serum concentration of leptin increases and serum concentration of NPY decreases significantly during the treatment of anorectic girls. 2) These changes do not correspond with increasing body weight and BMI suggesting disregulation of appetite and body weight control mechanisms in AN. 3) Altered neuroregulation of the neuropeptides (leptin and NPY) secretion may contribute persistent amenorrhea after weight gain in anorectic patients with low initial BMI. Topics: Adolescent; Amenorrhea; Anorexia Nervosa; Appetite; Body Weight; Child; Energy Intake; Estradiol; Female; Follicle Stimulating Hormone; Humans; Hydrocortisone; Leptin; Luteinizing Hormone; Neuropeptide Y; Psychotherapy; Thyroxine; Vitamins | 2005 |
Relationship between plasma leptin concentrations and carcass composition in fattening mutton: a comparison with ultrasound results.
Positive relationships between circulating leptin concentrations and body fat content have been established in sheep when covering a rather broad range of age and/or body weight. The usefulness of leptin measurements for predicting carcass fat has yet to be evaluated specifically in fattening lambs. We therefore measured plasma leptin concentrations in 56 male lambs half and half Merino Mutton and Blackheaded Mutton. Subcutaneous fat thickness was measured by ultrasound 1 day before the lambs were slaughtered at 35 or 45 kg live weight. Carcass composition was determined by tissue dissection. The coefficients of correlations between leptin and the different amounts in fat depots ranged from 0.40 to 0.56 within the two live weight groups, and from 0.53 to 0.64 when taking the two groups together. Carcass fat percentage was estimated by leptin concentrations with the same accuracy (R2 = 0.34) as with ultrasound fat thickness. The accuracy was higher for leptin in the 35 kg-group whereas the accuracy was higher for ultrasound fat thickness in the 45 kg-group (R2 = 0.26 vs. 0.31). A combination of leptin and ultrasound fat thickness clearly enhanced the precision of estimation in all groups. Further investigations on the influence of factors such as breed, gender, duration of feed withdrawal or photoperiod on the association between leptin and carcass composition are necessary before the suitability of plasma leptin concentration for practical application can be evaluated. Topics: Adipose Tissue; Aging; Animals; Body Composition; Body Weight; Leptin; Male; Predictive Value of Tests; Sensitivity and Specificity; Sheep; Ultrasonography; Weight Gain | 2005 |
In vivo leptin infusion impairs insulin and leptin signalling in liver and hypothalamus.
Leptin resistance contributes to the pathogenesis of common obesity related metabolic diseases, including insulin resistance. However, the relationship between leptin and insulin resistance is not clearly established. Here, we show that induced hyperleptinemia by leptin infusion alters insulin signalling in rat liver. Leptin infusion clearly reduced the insulin or leptin dependent IRS-1/IRS-2 association to p85 regulatory subunit of PI 3-kinase. Leptin infusion also abolished STAT-3 phosphorylation in response to insulin or leptin and similar results were obtained for MAP-kinase phosphorylation. Hypothalamic leptin resistance was also induced by leptin infusion since leptin was unable to induce STAT-3 phosphorylation. These results provide evidence that induced hyperleptinemia can contribute to the onset of insulin resistance at least at the hepatic level. Topics: Animals; Body Weight; Eating; Hypothalamus; Infusions, Parenteral; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Leptin; Liver; Male; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Rats; Rats, Wistar; Sheep; Signal Transduction; STAT3 Transcription Factor | 2005 |
Severe bone alterations under beta2 agonist treatments: bone mass, microarchitecture and strength analyses in female rats.
Beta2 adrenergic agonists are widely used in therapeutics and as doping agents by athletes. However, their effects on bone tissue, especially bone microarchitecture, remain poorly understood. Using three-dimensional (3D) microtomography, dual-energy X-ray absorptiometry, biomechanical testing and enzyme-linked immunosorbent assay, we evaluated the effects of two beta2 agonists, clenbuterol and salbutamol, on bone in growing rats.. Twelve-week-old Wistar female rats (N = 39), divided in 3 groups, received during 6 weeks either salbutamol (4 mg/kg/day), clenbuterol (2 mg/kg/day) or normal saline (0.5 ml/kg/day) by subcutaneous injections.. After 6 weeks, the salbutamol and clenbuterol groups displayed lower bone mineral content (BMC), femoral length and cortical width than controls. Clenbuterol treatment further reduced bone mineral density. Bone microarchitecture was clearly altered by clenbuterol, as evidenced by lower trabecular number (-40.40%; P < 0.001), connectivity and trabecular bone volume (-42.85%; P < 0.001), leading to lower ultimate force. Clenbuterol significantly increased muscle mass (P < 0.01) and reduced fat mass when compared to controls. Salbutamol did not seem to have any effect on bone microarchitecture or body composition. Both beta2 agonists increased the bone resorption marker (C-terminal collagen crosslinks) without any change of a bone formation marker. At the end of the treatment, a drop in leptin was seen in the clenbuterol group only. Leptin levels were correlated with BMC (r = 0.69, P = 0.003).. These results confirm the deleterious effect of beta2 agonists on bone mass and show the negative effects of clenbuterol on trabecular bone microarchitecture. Bone loss occurred independently from muscle mass but was related to fat mass. A leptin-mediated effect on bone tissue seems likely. These pathophysiological effects may have important consequences in human therapeutics and doping. Topics: Adrenergic beta-Agonists; Albuterol; Animals; Biomechanical Phenomena; Body Weight; Bone and Bones; Bone Density; Calcification, Physiologic; Clenbuterol; Collagen; Dose-Response Relationship, Drug; Female; Femur; Intra-Abdominal Fat; Leptin; Lumbar Vertebrae; Muscles; Osteocalcin; Osteogenesis; Rats; Rats, Wistar | 2005 |
The effects of fenofibrate on metabolic and vascular changes induced by chocolate-supplemented diet in the rat.
Current evidences suggest that diet per se plays an important role in genesis of metabolic and vascular function abnormalities. We have investigated the effects of addition of a high-fat diet (chocolate) in the presence or absence of short-term (7 days) administration of fenofibrate on metabolic and vascular changes in adult male Wistar rats. Despite similarities in total body weight in all groups, compared with control fed groups, chocolate-supplemented animals had significantly higher plasma triacylglyceride and non-esterified fatty acids and leptin (for all, P<0.01), but not glucose or insulin levels. Fenofibrate treatment corrected metabolic changes. In the mesenteric arteries, responses to KCl and noradrenaline were significantly (for both, P<0.01) higher in chocolate-supplemented group. Furthermore, vasorelaxant responses to carbamylcholine, but not to sodium nitroprusside, were significantly (P<0.01) reduced in the chocolate-supplemented group. Although fenofibrate failed to improve noradrenaline and KCl responses, it was effective in improving carbamylcholine-induced vasorelaxation. These data suggest that high-fat diet has a profound effect on plasma lipid profile and vascular function. Furthermore, fenofibrate treatment may ameliorate high-fat diet effects on vascular function and metabolic changes. Topics: Animals; Body Weight; Cacao; Carbachol; Dietary Supplements; Dose-Response Relationship, Drug; Endothelium, Vascular; Energy Intake; Fatty Acids, Nonesterified; Fenofibrate; Hematocrit; Hypolipidemic Agents; In Vitro Techniques; Leptin; Male; Mesenteric Arteries; Myocardium; Nitroprusside; Norepinephrine; Potassium Chloride; Random Allocation; Rats; Rats, Wistar; Triglycerides; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents | 2005 |
Brain-derived neurotrophic factor plays a role as an anorexigenic factor in the dorsal vagal complex.
Brain-derived neurotrophic factor (BDNF) has recently been implicated as an anorexigenic factor in the central control of food intake. Previous studies focused on the hypothalamus as a probable site of action for this neurotrophin. It was demonstrated that BDNF is an important downstream effector of melanocortin signaling in the ventromedial hypothalamus. In this study, we addressed whether BDNF can modulate food intake in the hindbrain autonomic integrator of food intake regulation, i.e. the dorsal vagal complex (DVC). To this end, we used two complementary methodological approaches in adult rats. First, we measured the effects of intraparenchymal infusions of exogenous BDNF within the DVC on food intake and body weight. Second, we measured the endogenous BDNF protein content in the DVC and hypothalamus after food deprivation, refeeding, or peripheral treatments by the anorexigenic hormones leptin and cholecystokinin (CCK). BDNF infusion within the DVC induced anorexia and weight loss. In the DVC, BDNF protein content decreased after 48 h food deprivation and increased after refeeding. Acute and repetitive peripheral leptin injections induced an increase of the BDNF protein content within the DVC. Moreover, peripheral CCK treatment induced a transient increase of BDNF protein content first in the DVC (30 min after CCK) and later on in the hypothalamus (2 h after CCK). Taken together, these results strongly support the view that BDNF plays a role as an anorexigenic factor in the DVC. Our data also suggest that BDNF may constitute a common downstream effector of leptin and CCK, possibly involved in their synergistic action. Topics: Animal Feed; Animals; Anorexia; Body Weight; Brain Stem; Brain-Derived Neurotrophic Factor; Cholecystokinin; Drinking; Drug Synergism; Eating; Food Deprivation; Humans; Hypothalamus; Injections; Leptin; Male; Rats; Rats, Wistar; Recombinant Proteins; Time Factors; Vagus Nerve | 2005 |
Serum and gene expression levels of leptin and adiponectin in rats susceptible or resistant to diet-induced obesity.
The aim of the present study was to identify the role of leptin and adiponectin in the development of resistance or susceptibility to diet-induced obesity in rats. For this purpose, male Wistar rats were fed with standard laboratory diet (control group) or cafeteria diet. After 15 days, two groups of rats with different response respect to the cafeteria diet were identified, and were assigned as diet-induced obesity (DIO) and diet resistant (DR) rats. The high-fat diet induced a very significant increase in both body and fat mass weight in DIO group. However, DR rats, gained even less weight than control-fed animals. Food intake was increased in cafeteria-fed rats (both DIO and DR) in comparison to control group; but hyperphagia was higher in DIO rats. In addition, feed efficiency (the ratio of weight gained to calories consumed) was significantly decreased in DR as compared to DIO rats. Regarding leptin, a significant increase in both adipose tissue gene expression and serum levels was observed in DIO rats in comparison with other groups (control and DR). A significant increase in both adiponectin circulating levels and adipose tissue mRNA expression was also observed in DIO animals as compared with the other groups. These data suggest that the susceptibility to obesity of DIO rats might be secondary, at least in part, to an earlier development of leptin resistance, which could lead to alterations in food intake (hyperphagia) and energetic metabolism. However, neither changes in leptin or adiponectin seem to be involved in the adaptive mechanisms that confer resistance to high fat intake. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Diet; Dietary Fats; Disease Susceptibility; Eating; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Hyperphagia; Leptin; Male; Obesity; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Triglycerides | 2005 |
Homeostatic model assessment (HOMA) index cut-off values to identify the metabolic syndrome in children.
The aim of the study was to establish the best cut-off value for the homeostatic model assessment (HOMA) index in identifying children and adolescents with the metabolic syndrome. The study included 72 non-obese and 68 obese children aged 7 to 16 years. Obesity is defined using the criteria proposed by Cole et al., being included as metabolic syndrome variables waist circumference, systolic blood pressure, diastolic blood pressure and seric values of glucose, uric acid, fasting insulin, leptin, triglycerides and HDL-cholesterol. Children were considered as having the metabolic syndrome when four or more characteristics showed abnormal values. The HOMA index was calculated as the product of the fasting plasma insulin level (microU/mL) and the fasting plasma glucose level (mmol/L), divided by 22.5. HOMA index cut-offs from the 5th to the 95th percentile were used. A receiver operating characteristic (ROC) curve was generated using the different HOMA cut-offs for the screening of the metabolic syndrome. The areas under the ROC curve, 95% confidence intervals, and the point to the ROC curve closest to 1, were calculated. The area under the ROC curve was 0.863 (95% C.I.: 0.797, 0.930). The point closest to 1 corresponds to the 60th percentile of the HOMA index distribution in our sample. HOMA index value at the 60th percentile was 2.28. Cut-off values corresponding to a range of HOMA index from the 50 to the 75 percentile, showed similar distances to 1. HOMA index values for percentiles 50 to 75 ranged from 2.07 to 2.83. In conclusion, HOMA index could be a useful tool to detect children and adolescents with the metabolic syndrome. HOMA cut-off values need to be defined in the paediatric population; however, values near to 3 seem to be adequate. Topics: Adolescent; Anthropometry; Blood Glucose; Blood Pressure; Body Composition; Body Height; Body Mass Index; Body Weight; Child; Cholesterol, HDL; Fasting; Female; Humans; Insulin; Leptin; Male; Metabolic Syndrome; ROC Curve; Sensitivity and Specificity; Triglycerides; Uric Acid | 2005 |
Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats.
Age-related obesity is associated with impaired hypothalamic pro-opiomelanocortin (Pomc) gene expression. We assessed whether overproduction of POMC in the hypothalamus ameliorates age-related obesity in rats.. Recombinant adeno-associated virus (rAAV) encoding Pomc (rAAV-Pomc) or control vector was delivered bilaterally into the basomedial hypothalamus of aged obese rats with coordinates targeting the arcuate nucleus. Energy balance, glucose metabolism, brown adipose tissue thermogenesis and mRNA levels of hypothalamic neuropeptides and melanocortin receptors were assessed.. Forty-two days after Pomc gene delivery, hypothalamic Pomc expression increased 12-fold while agouti-related protein and neuropeptide Y mRNA levels remained unchanged. Using a punch technique, we detected the highest Pomc RNA level in the arcuate nucleus. Pomc overexpression reduced food consumption from day 10 after vector injection, but this anorexic effect abated by day 30. In contrast, there was a steady decrease in body weight without apparent attenuation. Pomc gene delivery decreased visceral adiposity and induced uncoupling protein 1 in brown adipose tissue in aged rats. Serum NEFA and triglyceride levels were also diminished by rAAV-Pomc treatment. Improved glucose metabolism and insulin sensitivity were observed on day 36 but not day 20 after Pomc gene delivery. The expression of hypothalamic melanocortin 3 and 4 receptor decreased by 17% and 25%, respectively in rAAV-Pomc rats.. This study demonstrates that targeted Pomc gene therapy in the hypothalamus reduces body weight and visceral adiposity, and improves glucose and fat metabolism in aged obese rats. Thus long-term activation of the central melanocortin system may be a viable strategy to combat age-related obesity and diabetes. Topics: Adipose Tissue, Brown; Aging; Agouti-Related Protein; Animals; Body Weight; Cholesterol; Dependovirus; Eating; Fatty Acids, Nonesterified; Genetic Therapy; Genetic Vectors; Glucose; Glucose Intolerance; Glucose Tolerance Test; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Obesity; Peptide Hormones; Pro-Opiomelanocortin; Rats; Rats, Inbred F344; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Triglycerides | 2005 |
Regulation of the pituitary growth hormone-releasing hormone receptor in ageing male and female LOU rats: new insights into healthy ageing.
Ageing is characterised by a decrease of somatotroph functionality, involving growth hormone-releasing hormone receptor (GHRH-R). The present study was conducted in LOU/C/jall (LOU) rats, a strain described as a model of healthy ageing, which is characterised by a low adiposity and long life expectancy without developing severe pathologies. Effects of age and diet (chow versus self-selection), on levels of anterior pituitary GHRH-R mRNA transcripts, were assessed in male and female LOU rats. The effect of age on pituitary GHRH-R functionality was examined in the anterior pituitary of both males and females fed chow diet. Moreover, serum insulin-like growth factor-I (IGF-I), T4 and leptin were measured because changes in their concentration could affect GHRH-R expression. In the pituitary of 18-month-old male and female LOU/C/jall rats fed standard chow, the level of 2.5-kb GHRH-R mRNA transcript, coding for functional GHRH-R, was significantly decreased. In 24- to 34-month-old males and females, it progressively returned to the level of younger animals, suggesting an enrichment of the group with survivors maintaining functional GHRH-R. In males and females repeatedly submitted to self-selection, this phenomenon was not observed. Studies with the GHRH-R agonist, Fluo-GHRH, revealed that 73% of 16-18-month-old male and female rats studied did not show an increase of fluorescence density characteristic of receptor-mediated internalisation upon incubation at 37 degrees C. In the other 27%, the increase of fluorescence was identical to that observed in pituitaries of young rats, suggesting the presence of an optimal level of functional GHRH-R. Serum levels of leptin, free T4 and total IGF-I decreased more drastically in ageing males and in rats fed a self-selection diet. A positive correlation was demonstrated between leptin and IGF-I levels in ageing males and females fed standard chow and ageing females submitted to a self-selection regimen. In conclusion, healthy ageing in LOU rats fed chow diet appears to be associated with a maintenance of functional pituitary GHRH-R levels found in younger rats but not necessarily with those of serum leptin, T4 and IGF-I. Topics: Aging; Animals; Blotting, Northern; Body Weight; Diet; Female; Fluorescent Dyes; Insulin-Like Growth Factor I; Leptin; Male; Pituitary Gland; Radioimmunoassay; Rats; Rats, Inbred Strains; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; RNA, Messenger; Thyroxine | 2005 |
Ghrelin, adiponectin, and leptin do not predict long-term changes in weight and body mass index in older adults: longitudinal analysis of the Rancho Bernardo cohort.
Ghrelin, leptin, and adiponectin are associated with body size in cross-sectional studies; it is unknown whether these hormones predict long-term changes in body size. Multilevel models were used to study associations between fasting serum hormones, measured in 698 men and 619 women (60-91 years) in samples collected at baseline (1984-1987), and changes in weight and body mass index, assessed repeatedly over a follow-up period of up to 18 years (median, 4.7 years). Baseline weight was -1.5 kg lower for a one-standard-deviation increment in ghrelin and -3.3 kg lower for a one-standard-deviation increment in adiponectin, similar in men and women. For leptin, baseline weight was 12.1 kg higher for a one-standard-deviation increment in men, compared with 5.7 kg in women (sex-interaction p < or = 0.0001). Ghrelin and adiponectin did not affect weight change; their associations with weight were constant over time, indicated by nonsignificant hormone-by-time interactions. The positive association between leptin and weight became slightly weaker over time. Results were similar when investigating repeated measures of body mass index. From this analysis of Rancho Bernardo Study data, the authors conclude that ghrelin, adiponectin, and leptin do not predict weight gain beyond reflecting the influence of attained body size on future changes in weight or body mass index. Topics: Adiponectin; Aged; Aged, 80 and over; Body Mass Index; Body Weight; California; Chi-Square Distribution; Female; Ghrelin; Humans; Leptin; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Obesity; Peptide Hormones; Predictive Value of Tests; Prospective Studies | 2005 |
Influences of dietary soy isoflavones on metabolism but not nociception and stress hormone responses in ovariectomized female rats.
Isoflavones, the most abundant phytoestrogens in soy foods, are structurally similar to 17beta-estradiol. Few studies have examined the nociception and stress hormone responses after consumption of soy isoflavones.. In this study, ovariectomized (OVX) female Long-Evans rats were fed either an isoflavone-rich diet (Phyto-600) or an isoflavone-free diet (Phyto-free). We examined the effects of soy isoflavones on metabolism by measuring body weights, food/water intake, adipose tissue weights as well as serum leptin levels. Also, circulating isoflavone levels were quantified. During chemically induced estrous, nociceptive thresholds were recorded. Then, the animals were subjected to a stressor and stress hormone levels were quantified.. Body weights were significantly lower in Phyto-600 fed rats compared to Phyto-free values within one week and during long-term consumption of soy isoflavones. Correspondingly, Phyto-600 fed animals displayed significantly less adipose deposition and lower serum leptin levels than Phyto-free values. However, rats on the Phyto-600 diet displayed greater food/water intake compared to Phyto-free levels. No changes in thermal pain threshold or stress hormone levels (ACTH and corticosterone) were observed after activation of the hypothalamic-pituitary-adrenal (HPA) stress axis.. In summary, these data show that consumption of soy isoflavones 1) increases metabolism, demonstrated by significantly decreased body weights, adipose tissue deposition and leptin levels, but 2) does not alter nociception or stress hormone responses, as indexed by thermal pain threshold, serum corticosterone and ACTH levels in chemically-induced estrous OVX rats. Topics: Adrenocorticotropic Hormone; Animals; Body Weight; Corticosterone; Diet; Drinking; Eating; Female; Glycine max; Isoflavones; Leptin; Metabolism; Ovariectomy; Pain Measurement; Rats; Rats, Long-Evans; Restraint, Physical | 2005 |
Neurogenesis in the hypothalamus of adult mice: potential role in energy balance.
Ciliary neurotrophic factor (CNTF) induces weight loss in obese rodents and humans, and for reasons that are not understood, its effects persist after the cessation of treatment. Here we demonstrate that centrally administered CNTF induces cell proliferation in feeding centers of the murine hypothalamus. Many of the newborn cells express neuronal markers and show functional phenotypes relevant for energy-balance control, including a capacity for leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3). Coadministration of the mitotic blocker cytosine-beta-d-arabinofuranoside (Ara-C) eliminates the proliferation of neural cells and abrogates the long-term, but not the short-term, effect of CNTF on body weight. These findings link the sustained effect of CNTF on energy balance to hypothalamic neurogenesis and suggest that regulated hypothalamic neurogenesis in adult mice may play a previously unappreciated role in physiology and disease. Topics: Animals; Body Weight; Bromodeoxyuridine; Cell Proliferation; Ciliary Neurotrophic Factor; Cytarabine; Doublecortin Domain Proteins; Energy Metabolism; Hypothalamus; Injections, Intraventricular; Leptin; Male; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Neurons; Neuropeptide Y; Neuropeptides; Pro-Opiomelanocortin; Receptor, Ciliary Neurotrophic Factor; RNA, Messenger; STAT3 Transcription Factor | 2005 |
The effects of zinc deficiency and testosterone supplementation on leptin levels in castrated rats and their relation with LH, FSH and testosterone.
The aim of this study was to investigate how zinc-deficiency and testosterone supplementation, both in combination and individually, affect plasma LH, FSH and leptin levels in castrated rats.. Group 1, Control Group. Group 2, Castration Group. Group 3, Testosterone Group. Group 4, Zinc-deficient Group. Group 5, Testosterone, Zinc-deficient Group. Group 6, Zinc-deficient, Castration Group. Group 7, Testosterone, Castration Group. Group 8, Zinc-deficient, Testosterone, Castration Group.. Plasma zinc, leptin, LH, FSH, free and total testosterone levels were measured.. Group 2 had the highest levels of leptin and LH, besides having the highest FSH levels together with Group 6 (p<0.01). Groups 5 and 8 had the lowest leptin levels (p<0.01). Leptin levels in Groups 4 and 7 were higher than those in Groups 5 and 8, but lower than those in all other groups (p<0.01). LH levels in Group 4 were not different than those in Groups 3, 5 and 8, but significantly lower than those in all other groups (p<0.01). Free and total testosterone levels were higher in Group 4 than in castration groups that were not supplemented testosterone, but were lower in the former than in all others (p<0.01).. Plasma LH may be more effective than testosterone on plasma leptin and zinc can be an important mediator of the effect LH exercises on leptin. Topics: Animals; Body Weight; Follicle Stimulating Hormone; Leptin; Luteinizing Hormone; Male; Orchiectomy; Rats; Rats, Sprague-Dawley; Testosterone; Zinc | 2005 |
Fasting-induced increases of arcuate NPY mRNA and plasma corticosterone are blunted in the rat experienced neonatal maternal separation.
This study was conducted to examine the effects of neonatal maternal separation on the hypothalamic expression of feeding peptides in later life. Pups in maternal separation (MS) groups were separated from their dam for 3 h daily from postnatal day (PND) 1-14, while pups in non-handled (NH) groups were left undisturbed. Rats were sacrificed on PND 60 to examine the gene expression of neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) in the hypothalamic arcuate nucleus by mRNA in situ hybridization. Half of the rats from each group were food-deprived for 48 h before sacrifice. POMC mRNA expression increased in the free fed MS group compared with the free fed NH group. Food deprivation significantly decreased the arcuate POMC mRNA level in both groups. Body weight gain, basal levels of plasma corticosterone, leptin, and arcuate NPY mRNA were not modulated by experience of neonatal maternal separation. However, fasting-induced increases of plasma corticosterone and arcuate NPY expression were blunted in MS rats. These results suggest that neonatal maternal separation may increase the basal expression level of arcuate POMC mRNA, while inhibit the fasting-induced expression of arcuate NPY mRNA, later in life. Lastly, the altered expression of arcuate NPY mRNA, but not of arcuate POMC mRNA, appeared to be related with altered activity of the hypothalamic-pituitary-adrenal gland axis in offspring by neonatal maternal separation. Topics: Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Body Weight; Corticosterone; Fasting; Feeding Behavior; Female; In Situ Hybridization; Leptin; Mothers; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2005 |
Mutated-leptin gene transfer induces increases in body weight by electroporation and hydrodynamics-based gene delivery in mice.
To investigate whether in vivo gene transfer causes leptin-antagonistic effects on food intake, animal body weight and fat tissue weight, the R128Q mutated-leptin gene, an R to Q substitution at position 128 of mouse leptin, was transferred into mouse liver and leg muscle by electroporation and hydrodynamics-based gene delivery. Mutated-leptin gene transfer by electroporation caused significant increases in body weight at 5 days and after (5.4% increase relative to control; p<0.05). Hydrodynamics-based gene delivery of the mutated-leptin gene also caused an increase in body weight (3.0% increase relative to control; p<0.05). Mutated-leptin gene transfer by electroporation significantly increased the tissue weight of epididymal white fat and neuropeptide Y mRNA expression in the hypothalamus compared with those of the control group 3 weeks after gene transfer (p<0.05). These results suggest that mutated-leptin gene transfer successfully produced leptin-antagonistic effects by modulating the central regulator of energy homeostasis. Also, the extent of leptin-antagonistic effects by electroporation was much higher than hydrodynamics-based gene delivery, with at least single gene transfer. Topics: Adipose Tissue, Brown; Agouti-Related Protein; Animals; Body Weight; Carrier Proteins; Eating; Electroporation; Energy Metabolism; Gene Transfer Techniques; Hypothalamus; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred ICR; Mitochondrial Proteins; Mutation; Neuropeptide Y; Point Mutation; Proteins; RNA, Messenger; Sequence Analysis, DNA; Uncoupling Protein 1 | 2005 |
Serum leptin levels and insulin resistance are associated with gallstone disease in overweight subjects.
To establish an association between the serum leptin levels and the development of gallstone disease (GD).. We carried out a non-matched case-controlled study in a university hospital in Mexico City. Two hundred and eighty-seven subjects were included: 97 cases with gallstones and 190 controls. Body mass index (BMI), fasting plasma leptin, insulin, serum lipid, and lipoprotein levels were measured. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Unconditional logistic regression analysis (univariate and multivariate) stratified by BMI was used to calculate the risk of GD.. The multivariate conditional regression analysis revealed a model for those patients with BMI <30. The selected variables in the model were HOMA-IR index with OR = 1.31, P = 0.02 and leptin higher than median with OR = 2.11, P = 0.05. In the stratum of BMI >=30, we did not find a useful model.. We concluded that insulin resistance and the development of GD appears to be associated with serum leptin levels in subjects with overweight, but not in obese subjects with similar metabolic profiles. Topics: Adult; Body Weight; Case-Control Studies; Female; Gallstones; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Regression Analysis | 2005 |
Altered hypothalamic signaling and responses to food deprivation in rats fed a low-carbohydrate diet.
To model how consuming a low-carbohydrate (LC) diet influences food intake and body weight.. Food intake and body weight were monitored in rats with access to chow (CH), LC-high-fat (HF), or HF diets. After 8 weeks, rats received intracerebroventricular injections of a melanocortin agonist (melanotan-II) and antagonist (SHU9119), and feeding responses were measured. At sacrifice, plasma hormones and hypothalamic expression of mRNA for proopiomelanocortin (POMC), melanocortin-4 receptor, neuropeptide Y (NPY), and agouti related protein (AgRP) were assessed. A second set of rats had access to diet (chow or LC-HF) for 4 weeks followed by 24 h food deprivation on two occasions, after which food intake and hypothalamic POMC, NPY, and AgRP mRNA expression were measured.. HF rats consumed more food and gained more weight than rats on CH or LC-HF diets. Despite similar intakes and weight gains, LC-HF rats had increased adiposity relative to CH rats. LC-HF rats were more sensitive to melanotan-II and less sensitive to SHU9119. LC-HF rats had increased plasma leptin and ghrelin levels and decreased insulin levels, and patterns of NPY and POMC mRNA expression were consistent with those of food-deprived rats. LC-HF rats did not show rebound hyperphagia after food deprivation, and levels NPY, POMC, and AgRP mRNA expression were not affected by deprivation.. Our results demonstrate that an LC diet influences multiple systems involved in the controls of food intake and body weight. These data also suggest that maintenance on an LC-HF diet affects food intake by reducing compensatory responses to food deprivation. Topics: 3-Hydroxybutyric Acid; Animals; Blood Glucose; Body Weight; Dietary Carbohydrates; Food Deprivation; Ghrelin; Hypothalamus; Insulin; Leptin; Male; Peptide Hormones; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction | 2005 |
[Acupuncture for treatment of simple obesity and its effect on serum leptin level of the patient].
To explore the therapeutic effect and the mechanism of acupuncture in reducing body weight.. Fifty cases of simple obesity were randomly divided into an acupuncture group and a drug control group, 25 cases in each group. The patients in the acupuncture group were treated with body acupuncture at Tianshu (ST 25), Guanyuan (CV 4), etc, electroacupuncture and ear point tapping and pressing therapy (Shenmen, Endocrine, etc. were selected); the patients in the control group were treated with oral administration of sibutramine. The serum leptin level before and after treatment were determined and the therapeutic effect in reducing body weight was assessed.. The total effective rate was 88.0% in the acupuncture group and 80. 0% in the control group, with no significant difference between the two groups (P>0.05); after treatment, the serum leptin level in both the two groups decreased significantly (P<0.01), and the decreasing amplitude in the acupuncture group was superior to that in the control group (P<0.05).. Acupuncture therapy has a definite therapeutic effect in reducing body weight, and the improvement of serum leptin level of the patient is possibly one of the mechanisms of acupuncture in reducing body weight. Topics: Acupuncture Points; Acupuncture Therapy; Body Weight; Electroacupuncture; Humans; Leptin; Obesity | 2005 |
Is ghrelin a signal for the development of metabolic systems?
Ghrelin, produced in the stomach, acts on growth hormone secretagogue receptors (GHSRs) in hypothalamic neurons to potently increase food intake. However, male mice with deletions of ghrelin (Ghrl-/- mice) or GHSR (Ghsr-/- mice) display normal growth and regulation of food intake. Furthermore, adult Ghrl-/- mice display a normal sensitivity to high-fat diet-induced obesity. These findings from early studies raised the question as to whether the ghrelin system is an essential component for the regulation of food intake and body weight homeostasis. However, recent studies by Wortley et al. and Zigman et al. demonstrate that Ghrl-/- and Ghsr-/- mice are resistant to diet-induced obesity when fed a high-fat diet during the early post-weaning period. This commentary highlights 3 key issues raised by these 2 reports: (a) the impact of ghrelin on the development of metabolic systems; (b) the constitutive activity of GHSR; and (c) gender differences in the sensitivity to deletion of the ghrelin signaling system. Topics: Animal Feed; Animals; Body Weight; Diet; Female; Food; Gene Deletion; Ghrelin; Hypothalamus; Leptin; Male; Mice; Mice, Transgenic; Models, Biological; Neurons; Obesity; Peptide Hormones; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Sex Factors; Signal Transduction; Steroids | 2005 |
Mice lacking ghrelin receptors resist the development of diet-induced obesity.
Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Since its discovery, accumulating evidence has suggested that ghrelin may play a role in signaling and reversing states of energy insufficiency. For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity. However, recent loss-of-function studies have raised questions regarding the physiological significance of ghrelin in regulating these processes. Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons. We show that when fed a high-fat diet, both female and male GHSR-null mice eat less food, store less of their consumed calories, preferentially utilize fat as an energy substrate, and accumulate less body weight and adiposity than control mice. Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow. GHSR deletion also affected locomotor activity and levels of glycemia. These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control. Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity. Topics: Adipose Tissue; Alleles; Analysis of Variance; Animal Feed; Animals; Blood Glucose; Blotting, Southern; Blotting, Western; Body Composition; Body Weight; Crosses, Genetic; Diet; DNA; Female; Gene Deletion; Genetic Predisposition to Disease; Genotype; Ghrelin; Heterozygote; Homeostasis; Hyperglycemia; Insulin-Like Growth Factor I; Leptin; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C57BL; Models, Genetic; Neurons; Obesity; Peptide Hormones; Phenotype; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Recombinant Proteins; Recombination, Genetic; RNA, Messenger; Signal Transduction; Silver Staining; Time Factors | 2005 |
Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight.
Maintenance of a reduced body weight is accompanied by decreased energy expenditure that is due largely to increased skeletal muscle work efficiency. In addition, decreased sympathetic nervous system tone and circulating concentrations of leptin, thyroxine, and triiodothyronine act coordinately to favor weight regain. These "weight-reduced" phenotypes are similar to those of leptin-deficient humans and rodents. We examined metabolic, autonomic, and neuroendocrine phenotypes in 10 inpatient subjects (5 males, 5 females [3 never-obese, 7 obese]) under 3 sets of experimental conditions: (a) maintaining usual weight by ingesting a liquid formula diet; (b) maintaining a 10% reduced weight by ingesting a liquid formula diet; and (c) receiving twice-daily subcutaneous doses of leptin sufficient to restore 8 am circulating leptin concentrations to pre-weight-loss levels and remaining on the same liquid formula diet required to maintain a 10% reduced weight. During leptin administration, energy expenditure, skeletal muscle work efficiency, sympathetic nervous system tone, and circulating concentrations of thyroxine and triiodothyronine returned to pre-weight-loss levels. These responses suggest that the weight-reduced state may be regarded as a condition of relative leptin insufficiency. Prevention of weight regain might be achievable by strategies relevant to reversing this leptin-insufficient state. Topics: Adult; Body Composition; Body Mass Index; Body Weight; Calorimetry; Diet, Reducing; Energy Intake; Energy Metabolism; Female; Humans; Leptin; Male; Muscle, Skeletal; Neurosecretory Systems; Obesity; Phenotype; Thyroxine; Time Factors; Triiodothyronine; Weight Loss | 2005 |
Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons.
To investigate whether phosphatidylinositol-3 kinase (PI3K) signaling mediates the metabolic effects of hypothalamic leptin action, adenoviral gene therapy was used to direct expression of leptin receptors to the area of the hypothalamic arcuate nucleus (ARC). This intervention markedly improved insulin sensitivity in genetically obese, leptin-receptor-deficient Koletsky (fa(k)/fa(k)) rats via a mechanism that was not dependent on reduced food intake but was attenuated by approximately 44% by third-ventricular infusion of the PI3K inhibitor LY294002. Conversely, ARC-directed expression of a constitutively active mutant of protein kinase B (PKB/Akt, an enzyme activated by PI3K) mimicked the insulin-sensitizing effect of restored hypothalamic leptin signaling in these animals, despite having no effect on food intake or body weight. These findings suggest that hypothalamic leptin signaling is an important determinant of glucose metabolism and that the underlying neuronal mechanism involves PI3K. Topics: Adenoviridae; Animals; Animals, Genetically Modified; Blood Glucose; Body Weight; Chromones; Enzyme Inhibitors; Genetic Therapy; Glucose; Green Fluorescent Proteins; Hypothalamus; Insulin; Leptin; Male; Morpholines; Neurons; Phosphatidylinositol 3-Kinases; Rats; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Time Factors | 2005 |
Impact of gonadotropin administration on folliculogenesis in prepubertal ob/ob mice.
Female leptin deficient (ob/ob) mice exhibit abnormal ovarian folliculogenesis resulting in an impaired ability to reproduce. This effect may be related to the hypogonadotropic state of these animals, or leptin may directly modulate ovarian follicle development. In the present study we assessed whether exogenous gonadotropin administration would normalize folliculogenesis and induce ovulation in immature ob/ob animals. Eight 26-day-old ob/ob and eight control mice were injected sc with pregnant mare serum gonadotropin followed 48 h later with a sc injection of human chorionic gonadotropin. Animals were killed 24 h later. Gonadotropin (GTH) administration increased both ovarian and uterine weights in control mice, but this effect was attenuated in leptin deficient animals. The number of preantral follicles was greater in ob/ob mice than controls, but in GTH-treated animals the number of antral follicles was subnormal in the ovaries of leptin deficient animals. Ob/ob animals also failed to ovulate in response to GTH, and the protective actions of GTH against granulosa cell apoptosis and follicular atresia were attenuated in these animals. Interestingly, however, serum levels of estradiol and progesterone were higher in ob/ob mice than controls, regardless of whether or not the animals received GTH treatment. We conclude that the ovarian responsiveness to GTH is subnormal in leptin deficient animals suggesting that leptin may modulate the process of folliculogenesis by directly altering the sensitivity of the ovary to GTH. Topics: Animals; Apoptosis; Body Weight; Cell Differentiation; Chorionic Gonadotropin; Estradiol; Female; Follicular Atresia; Gonadotropins, Equine; Granulosa Cells; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Organ Size; Ovarian Follicle; Ovulation; Progesterone; Sexual Maturation | 2005 |
Leptin, ghrelin, and adiponectin in epileptic patients treated with valproic acid.
The authors studied 40 epileptic patients treated with valproate and 40 healthy controls for at least 2 years. At the end of follow-up, 15 epileptic patients (37.5%) had development of obesity. They showed circulating leptin and insulin levels significantly higher and ghrelin and adiponectin levels significantly lower than those of patients who did not gain weight. Topics: Adiponectin; Adipose Tissue; Adolescent; Adult; Anticonvulsants; Appetite Regulation; Body Weight; Brain; Epilepsy; Female; Ghrelin; Humans; Insulin; Leptin; Obesity; Peptide Hormones; Up-Regulation; Valproic Acid | 2005 |
Influence of maternal pre-pregnancy body composition and diet during early-mid pregnancy on cardiovascular function and nephron number in juvenile sheep.
The prenatal diet can program an individual's cardiovascular system towards later higher resting blood pressure and kidney dysfunction, but the extent to which these programmed responses are directly determined by the timing of maternal nutritional manipulation is unknown. In the present study we examined whether maternal nutrient restriction targeted over the period of maximal placental growth, i.e. days 28-80 of gestation, resulted in altered blood pressure or kidney development in the juvenile offspring. This was undertaken in 6-month-old sheep born to mothers fed control (100-150 % of the recommended metabolisable energy (ME) intake for that stage of gestation) or nutrient-restricted (NR; 50 % ME; n 6) diets between days 28 and 80 of gestation. Controls were additionally grouped according to normal (>3, n 7) or low body condition score (LBCS; <2, n 6), thereby enabling us to examine the effect of maternal body composition on later cardiovascular function. From day 80 to term (approximately 147 d) all sheep were fed to 100 % ME. Offspring were weaned at 12 weeks and pasture-reared until 6 months of age when cardiovascular function was determined. Both LBCS and NR sheep tended to have lower resting systolic (control, 85 (se 2); LBCS, 77 (se 3); NR, 77 (se 3) mmHg) and diastolic blood pressure relative to controls. Total nephron count was markedly lower in both LBCS and NR relative to controls (LBCS, 59 (se 6); NR, 56 (se 12) %). Our data suggest that maternal body composition around conception is as important as the level of nutrient intake during early pregnancy in programming later cardiovascular health. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Animals; Blood Glucose; Blood Pressure; Body Composition; Body Weight; Diet; Energy Intake; Female; Hydrocortisone; Kidney; Leptin; Nephrons; Pregnancy; Pregnancy, Animal; Prenatal Nutritional Physiological Phenomena; Random Allocation; Sheep | 2005 |
Combined effects of dietary protein type and fat level on the body fat-reducing activity of conjugated linoleic acid (CLA) in rats.
The interaction of dietary protein type and fat level on the body fat-reducing activity of conjugated linoleic acid (CLA) was studied in male rats fed diets containing casein (CAS) or soy protein (SOY) as a protein source with low fat (LF, 6.0% soybean oil) or high fat (HF, 13.0% soybean oil) combinations for 4 weeks. CLA was added at the 1.0% level to all diets. The weight of perirenal adipose tissue tended to be lower in the SOY groups than in the corresponding CAS groups, and the difference between the LF diets was significant. The weight of epididymal adipose tissue showed a similar but insignificant trend. The weight of brown adipose tissue was heaviest on the SOY-HF diet and lowest on two CAS diets, the SOY-LF diet being intermediate. The concentration of serum leptin was lowest on the SOY-LF diet and was significantly lower than that of the corresponding CAS group, but this difference disappeared when the dietary fat level increased. The serum cholesterol-lowering activity of SOY in relation to CAS was reproduced even when CLA was given. Thus the body fat-reducing activity of CLA was most marked when rats were fed the SOY-LF diet. Although the CAS-HF diet increased body fat deposition, the magnitude of the reduction by lowering dietary fat level was more marked than in the case of SOY. These results indicate a complicated interaction of dietary manipulations with the body fat-reducing effect of CLA, but the combination of CLA with the SOY-LF diet appears to be an appropriate approach. Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Caseins; Cytokines; Diet; Dietary Fats; Dietary Proteins; Epididymis; Fatty Acids; Leptin; Linoleic Acid; Lipid Metabolism; Lipids; Liver; Male; Organ Size; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Soybean Proteins; Weight Gain | 2005 |
[Cord blood leptin concentration and somatic parameters of smoking mother's newborns].
Leptin is a peptide synthesised in white fat tissue adipocytes. It plays a key role in appetite regulation and body mass development. The leptin's concentration is correlated with body fat magazines. This hormone has also anorectic and sympatheticomimetic function. Leptin's concentration measured early after birth is strictly connected with birth-weight. Smoking during pregnancy leads to decrease of plasma leptin concentration in newborn. The aim of the study was estimation of the leptin level in umbilical cord blood of children born from smoking and no-smoking women. Some other somatic parameters were also analysed. A cohort of 210 women and their children born in the Institute of Obstetrics and Gynaecology Medical University of Gdansk was examined. The estimation of frequency of smoking during pregnancy was analysed by questionnaire done in this group. Samples of the umbilical cord blood were collected after birth and leptin concentration was analysed by standard RIA method. Significantly lower leptin concentration in smoking mothers' newborns was stated. Children born from smoking mothers had significantly lower birth weight and length. The frequency of smoking during pregnancy in analysed region is lower in compare to previous years. Topics: Adipocytes; Adult; Body Weight; Cohort Studies; Female; Fetal Blood; Humans; Infant, Newborn; Leptin; Male; Radioimmunoassay; Smoking; Surveys and Questionnaires | 2005 |
Exercise enhances insulin and leptin signaling in the cerebral cortex and hypothalamus during dexamethasone-induced stress in diabetic rats.
Exercise and dexamethasone (DEX) are known to have opposite effects on peripheral insulin resistance. However, their effects and mechanism on brain glucose metabolism have been poorly defined. We investigated the modulation of the hypothalamo-pituitary-adrenal (HPA) axis and insulin/leptin signaling associated with glucose utilization in the brains of 90% pancreatectomized diabetic rats, which had been administered two dosages of DEX and exercised for 8 weeks. The data revealed that the administration of a high dose (0.1 mg/kg body weight/day) of DEX (HDEX) attenuated insulin signaling in the cerebral cortex and hypothalamus, whereas exercise potentiated their insulin signaling along with induction of IRS2 expression. In parallel with the modulated signaling, glucose utilization, such as glycogen storage and glycogen synthase activity, was suppressed by DEX in the cortex and hypothalamus, while exercise offset the DEX effects. Despite a decrease in epididymal fat mass, HDEX increased serum leptin levels, possibly due to an activated HPA axis, while exercise suppressed the increment. However, DEX reduced leptin-induced STAT3 phosphorylation in the cortex and hypothalamus, and it increased AMP-activated protein kinase (AMPK) phosphorylation only in the hypothalamus. Exercise reversed the phosphorylation of STAT3 and AMPK which had been modulated by DEX. In conclusion, exercise improves insulin and leptin signaling in the cerebral cortex and hypothalamus of diabetic rats exacerbated with HDEX, contributing to the regulation of body weight and glucose homeostasis. Topics: Adrenocorticotropic Hormone; AMP-Activated Protein Kinase Kinases; Animals; Blood Glucose; Body Weight; Cerebral Cortex; Corticosterone; Dexamethasone; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Eating; Glucocorticoids; Glycation End Products, Advanced; Hippocampus; Homeostasis; Hypothalamo-Hypophyseal System; Hypothalamus; Insulin; Leptin; Male; Phosphorylation; Physical Conditioning, Animal; Pituitary-Adrenal System; Protein Kinases; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor; Stress, Physiological | 2005 |
Chronic neuropeptide Y infusion into the lateral ventricle induces sustained feeding and obesity in mice lacking either Npy1r or Npy5r expression.
Neuropeptide Y (NPY) is a powerful orexigenic neurotransmitter. The NPY Y1 and Y5 receptors have been implicated in mediating the appetite-stimulating activity of NPY. To further investigate the importance of these two receptors in NPY-induced hyperphagia after chronic central administration, we used mice lacking either Npy1r or Npy5r expression. NPY infusion into the lateral ventricle of wild-type mice stimulated food intake and induced obesity over a 7-d period. Fat pad weight as well as plasma insulin, leptin, and corticosterone levels were strongly increased in NPY-treated mice. In addition, NPY infusion resulted in a significant decrease in hypothalamic NPY and proopiomelanocortin expression. Interestingly, the lack of either Npy1r or Npy5r expression in knockout mice did not affect such feeding response to chronic NPY infusion. Moreover, the obesity syndrome that developed in these animals was similar to that in wild-type animals. Taken together, these data strongly suggest biological redundancies between Y1 and Y5 receptor signaling in the NPY-mediated control of food intake. Topics: Adipose Tissue; Animals; Body Weight; Corticosterone; Drinking; Eating; Feeding Behavior; Hyperphagia; Injections, Intraventricular; Insulin; Lateral Ventricles; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptors, Neuropeptide Y; RNA, Messenger | 2004 |
Impaired coordination of nutrient intake and substrate oxidation in melanocortin-4 receptor knockout mice.
Mutations in the melanocortin-4 receptor (MC4R) are associated with obesity. The obesity syndrome observed in humans with MC4R haploinsufficiency is similar to that observed in MC4R knockout mice, including increased longitudinal growth, hyperphagia, and fasting hyperinsulinemia. For comparison with other commonly investigated models of obesity and insulin resistance, we have backcrossed Mc4r-/- mice into the C57BL/6J (B6) background. Female obese Mc4r-/- mice exhibit reduced energy expenditure and an attenuated increase in fatty acid (FA) oxidation after exposure to high-fat diets compared with obese Lepob/Lepob mice. The reduced energy expenditure and FA oxidation correlates with changes in hepatic gene expression. The expression of genes involved in FA oxidation increased in obese Lepob/Lepob mice compared with wild-type and obese Mc4r-/- mice. In contrast, a key lipogenic enzyme, FA synthase (FAS), is increased in obese Mc4r-/- mice compared with obese Lepob/Lepob mice. Hyperinsulinemia, increased FAS mRNA expression and hepatic steatosis appear to be secondary to obesity in B6 Mc4r-/- mice. However, Mc4r-/- mice in a mixed genetic background develop severe hepatic steatosis at an early age. This might suggest an important role of the MC4R in regulating liver FA metabolism that is masked on the B6 background. Interestingly, the 10- to 20-fold increase in liver triglyceride in the outbred strain of Mc4r-/- mice is not always associated with fasting hyperinsulinemia or increased FAS mRNA expression. This observation suggests that changes in liver secondary to triglyceride accumulation lead to hyperinsulinemia and increased hepatic FAS expression in Mc4r-/- mice. Topics: Animals; Body Weight; Dietary Fats; Eating; Fatty Acid Synthases; Fatty Acids; Fatty Liver; Female; Gene Expression; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Leptin; Lipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Oxidation-Reduction; Phosphoproteins; Receptor, Melanocortin, Type 4; Triglycerides | 2004 |
Obesity is a chronic, relapsing neurochemical disease.
The debate about whether obesity should be called a disease continues. From a clinical perspective, it meets the criteria needed to call it a disease. It has an etiology--an imbalance between energy intake and expenditure. It has a pathogenesis in the feedback systems involving leptin, neurochemicals in the brain, and the neural and endocrine messages that respond to the intake of food. The pathology of obesity lies in its enlarged fat cells, and the pathophysiology lies in the changes in the secretion of products from these enlarged fat cells, including cytokines, procoagulants, inflammatory peptides, and angiotensinogen. These secretory products of fat cells and the increased mass of fat are responsible for the associated metabolic diseases, such as diabetes, hypertension, heart disease, sleep apnea, and some sorts of cancer. Treatments consist of techniques to alter the balance between energy intake and energy expenditure. This constellation of factors leads to the conclusion that obesity should be called a disease. Topics: Body Weight; Chronic Disease; Energy Metabolism; Female; Humans; Leptin; Male; Obesity; Recurrence; Risk Factors | 2004 |
Blunted fasting-induced decreases in plasma and CSF leptin concentrations in obese rats: the role of increased leptin secretion.
Fasting substantially decreases plasma leptin concentration. However, in obesity, the fasting-induced decrease in leptin concentration is blunted or absent. The objective of the current study was to determine in diet-induced obese (DIO) rats the contribution of altered leptin secretion and leptin expression to the blunted nutritional regulation of leptin concentration. Fasting-induced decreases in plasma leptin concentration were greater in lean (standard chow (SC)) rats compared to DIO (approximately 79 vs approximately 48%, P<0.05 for DIO vs SC). CSF leptin was significantly reduced by fasting in SC (approximately 46%) but not in DIO. Fasting decreased adipose tissue leptin secretion in both SC and DIO, but the decrease was greater in SC (average approximately 74%) compared to DIO (average approximately 44%, P<0.05, DIO vs SC). Additionally, leptin secretion in fasted DIO was substantially greater (average approximately 175%) than in fasted SC (P<0.05). Adipose tissue leptin protein content was increased by approximately 80% in DIO compared to SC (P<0.05). We conclude that a probable cause of blunted fasting-induced decreases in leptin concentration in obesity is elevated leptin secretion, which possibly results from increased leptin gene expression. Topics: Adipose Tissue; Animals; Body Weight; Fasting; Insulin; Leptin; Male; Obesity; Rats; Rats, Wistar | 2004 |
Impaired glucose homeostasis in mice lacking the alpha1b-adrenergic receptor subtype.
To assess the role of the alpha1b-adrenergic receptor (AR) in glucose homeostasis, we investigated glucose metabolism in knockout mice deficient of this receptor subtype (alpha1b-AR-/-). Mutant mice had normal blood glucose and insulin levels, but elevated leptin concentrations in the fed state. During the transition to fasting, glucose and insulin blood concentrations remained markedly elevated for at least 6 h and returned to control levels after 24 h whereas leptin levels remained high at all times. Hyperinsulinemia in the post-absorptive phase was normalized by atropine or methylatropine indicating an elevated parasympathetic activity on the pancreatic beta cells, which was associated with increased levels of hypothalamic NPY mRNA. Euglycemic clamps at both low and high insulin infusion rates revealed whole body insulin resistance with reduced muscle glycogen synthesis and impaired suppression of endogenous glucose production at the low insulin infusion rate. The liver glycogen stores were 2-fold higher in the fed state in the alpha1b-AR-/- compared with control mice, but were mobilized at the same rate during the fed to fast transition or following glucagon injections. Finally, high fat feeding for one month increased glucose intolerance and body weight in the alpha1b-AR-/-, but not in control mice. Altogether, our results indicate that in the absence of the alpha1b-AR the expression of hypotalamic NPY and the parasympathetic nervous activity are both increased resulting in hyperinsulinemia and insulin resistance as well as favoring obesity and glucose intolerance development during high fat feeding. Topics: Animals; Blood Glucose; Body Weight; Glucagon; Glucose; Glycogen; Homeostasis; Hyperinsulinism; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Mutant Strains; Mice, Obese; Receptors, Adrenergic; Receptors, Adrenergic, alpha-1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors | 2004 |
Transgenic complementation of leptin receptor deficiency. II. Increased leptin receptor transgene dose effects on obesity/diabetes and fertility/lactation in lepr-db/db mice.
We have generated mice that are homozygous for a leptin receptor transgene that is expressed exclusively in neurons (NSE-LEPR-B). We had previously shown that this transgene in the hemizygous state is effective in ameliorating almost all aspects of leptin receptor deficiency. Now, we show that the transgene, in the homozygous state, almost fully corrects the excess adiposity of LEPR-deficient (db/db) mice. Body composition analyses indicate that the transgene is able to restrain the massive increase in adiposity observed in LEPR-deficient mice. Examination of hypothalamic agouti gene-related peptide and proopiomelanocortin mRNA shows normalization of these leptin-regulated transcripts. Interestingly, despite normalization of circulating leptin concentrations by the transgene in the fed state, transgenic db3J/db mice did not show fasting-induced reductions of circulating leptin. Increased adiposity of the transgenic db/db mice at 4 wk of age, immediately postweaning, suggests that the transgene is less effective in correcting the preferential fat deposition caused by LEPR deficiency. We noted that the morphology of brown adipose tissue is nearly normal, concordant with the cold tolerance conferred by the transgene. Aspects of the diabetes phenotype are also corrected: glucose and insulin concentrations are nearly normal, and islet hyperplasia is greatly diminished. The transgene also corrects the infertility of db/db females and confers the ability to lactate sufficiently to nurse normal-sized litters. Finally, the slightly increased adiposity and mild insulin resistance of transgenic db/db dams were not a contributory factor to the increased fat content of transgenic db/db male progeny. Topics: Adaptation, Physiological; Adipose Tissue; Animals; Body Composition; Body Weight; Diabetes Mellitus; Female; Fertility; Gene Dosage; Gene Expression Regulation; Lactation; Leptin; Male; Mice; Mice, Knockout; Mice, Transgenic; Obesity; Receptors, Cell Surface; Receptors, Leptin; Transgenes | 2004 |
Inhibition of uncoupling protein expression during lactation: role of leptin.
Uncoupling proteins (UCPs) are mitochondrial proteins that play a role in regulation of energy expenditure by uncoupling respiration from ATP synthesis. Lactation is a physiological condition characterized by negative energy balance due to the loss of energy sources to the production of milk. The objective of the current study was to investigate whether UCP mRNA and protein expressions were altered during lactation compared with those after 48 h of fasting. Lactation significantly reduced serum leptin levels, and removal of pups for 48 h increased serum leptin to higher levels than those observed in control rats. Compared with control rats, mRNA expression of UCP1 and UCP3 in brown adipose tissue (BAT) was dramatically reduced during lactation and fasting. The reduction in mRNAs was reflected by a lowered UCP1 protein level, and to some extent, UCP3 protein. Treatment of lactating rats with exogenous leptin (3 mg/kg) or removal of pups for 48 h completely reversed the down-regulation of UCP1 and UCP3 mRNA expression in BAT, and pup removal led to a recovery of protein expression. In contrast to BAT, UCP3 expression in skeletal muscle was increased in fasted rats and decreased during lactation. Similar changes were observed in serum free fatty acid levels. These changes are consistent with the idea that the utilization of free fatty acids as a fuel source is spared during lactation. As in BAT, leptin treatment and removal of pups were able to restore changes in mRNA expression of UCP3 in skeletal muscle during lactation. The present results suggest that the inhibition of leptin secretion during lactation is involved in the down-regulation of UCP expression in BAT and skeletal muscle, which, in turn, is responsible for the decrease in metabolic fuel oxidation and thermogenesis. Topics: Adipose Tissue, Brown; Animals; Body Weight; Carrier Proteins; Drinking; Eating; Energy Metabolism; Fasting; Fatty Acids; Fatty Acids, Nonesterified; Female; Gene Expression Regulation; Ion Channels; Lactation; Leptin; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Muscle, Skeletal; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thermogenesis; Uncoupling Protein 1; Uncoupling Protein 3 | 2004 |
Photoperiodic regulation of leptin sensitivity in the Siberian hamster, Phodopus sungorus, is reflected in arcuate nucleus SOCS-3 (suppressor of cytokine signaling) gene expression.
We present the first evidence that suppressor of cytokine signaling-3 (SOCS3), a protein inhibiting Janus kinase/signal transducer and activator of transcription (STAT) signaling distal of the leptin receptor, conveys seasonal changes in leptin sensitivity in the Siberian hamster. Food deprivation (48 h) reduced SOCS3 gene expression in hamsters acclimated to either long (LD) or short (SD) photoperiods, suggesting that leptin signals acute starvation regardless of photoperiod. However, SOCS3 mRNA levels were substantially lower in the hypothalamic arcuate nucleus of hamsters acclimated to SD than in those raised in LD. In juveniles raised in LD, a rapid increase in SOCS3 mRNA was observed within 4 d of weaning, which was completely prevented by transfer to SD on the day of weaning. The early increase in SOCS3 gene expression in juvenile hamsters in LD clearly preceded the establishment of different body weight trajectories in LD and SD. In adult LD hamsters, SOCS3 mRNA was maintained at an elevated level despite the chronic food restriction imposed to lower body weight and serum leptin to or even below SD levels. A single injection of leptin in SD hamsters elevated SOCS3 mRNA to LD levels, whereas leptin treatment had no effect on SOCS3 gene expression in LD hamsters. Our results suggest that the development of leptin resistance in LD-acclimated hamsters involves SOCS3-mediated suppression of leptin signaling in the arcuate nucleus. Increased SOCS3 expression in LD hamsters is independent of body fat and serum leptin levels, suggesting that the photoperiod is able to trigger the biannual reversible switch in leptin sensitivity. Topics: Acclimatization; Age Factors; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Cricetinae; Energy Metabolism; Female; Food Deprivation; Gene Expression; Leptin; Male; Phodopus; Photoperiod; Repressor Proteins; RNA, Messenger; Transcription Factors | 2004 |
Feeding and temperature responses to intravenous leptin infusion are differential predictors of obesity in rats.
Obesity is frequently associated with leptin resistance. The present study investigated whether leptin resistance in rats is present before obesity develops, and thus could underlie obesity induced by 16 wk exposure to a liquid, palatable, high-energy diet (HED). Before HED exposure, male Wistar rats (weighing between 330 and 360 g) received intravenous infusions of 20 microg leptin 2 h before dark (approximately 57 microg/kg rat). Relative to saline infusion, this caused a highly variable effect on food intake (ranging between -94 and +129%), with food intake suppression that appeared negatively correlated with HED-induced increases in body weight gain, caloric intake, adiposity, and plasma leptin levels. In contrast, leptin's thermogenic response was positively correlated to body weight gain linked to weights of viscera, but not to adiposity. Before HED exposure, leptin unexpectedly increased food intake in some rats (fi+, n = 8), whereas others displayed the normal reduction in food intake (fi-, n = 7). HED-exposed fi+ rats had higher plasma leptin levels, retroperitoneal fat pad weight, HED intake, and body weight gain than fi- and chow-fed rats. These parameters were also higher in HED-exposed fi-rats relative to chow rats, except for plasma leptin concentrations. It is concluded that leptin's reduced efficacy to suppress food intake could predict obesity on an HED. An unexpected orexigenic effect of leptin might potentially contribute to this as well. Topics: Animals; Body Temperature; Body Weight; Diet; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Hormones; Injections, Intravenous; Leptin; Male; Nutritional Status; Obesity; Organ Size; Rats; Rats, Wistar; Weight Gain | 2004 |
Responsiveness to peripherally administered melanocortins in lean and obese mice.
To elucidate mechanisms of melanocortin action, we investigated the effects of a melanocortin receptor agonist (melanotetan II [MTII]) in lean C57BL/6J and obese (DIO, ob/ob, UCP1-DTA) mice. MTII administration (100 microg q.i.d. i.p.) for 24 h results in similar weight loss but a more pronounced decrease of food intake in DIO mice. After 4 and 8 days of MTII treatment, however, the reduction in both food intake and body weight is more pronounced in DIO mice than in lean mice. MTII administration for 24 h prevents food deprivation-induced alterations in hypothalamic neuropeptide Y (NPY) and liver adiponectin receptor 1 and adiponectin receptor 2 mRNA expression, but does not alter hypothalamic mRNA expression of melanocortin 4 receptor or adiponectin serum and mRNA expression levels. NPY and agouti gene-related protein (AgRP) mRNA expression after 8 days of MTII is increased to levels comparable to pair-fed mice. In summary, 1) MTII is an effective treatment for obesity and related metabolic defects in leptin-resistant (DIO, UCP1-DTA) and leptin-sensitive (ob/ob) mouse models of obesity; 2) the effects of MTII on food intake and body weight are more pronounced in DIO mice than in lean mice; 3) the tachyphylactic effect after prolonged MTII administration appears to be, at least in part, caused by a compensatory upregulation of NPY and AgRP mRNA levels, whereas decreasing leptin levels may play a very minor role in mediating tachyphylaxis; and 4) alterations in adiponectin receptor mRNA expression after fasting or MTII treatment may contribute to altered insulin sensitivity and needs to be studied further. Topics: alpha-MSH; Animals; Body Weight; Energy Intake; Gene Expression Regulation; Leptin; Liver; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Obese; Neuropeptide Y; Receptors, Adiponectin; Receptors, Cell Surface; Thinness; Time Factors | 2004 |
Cocaine- and amphetamine-regulated transcript in the arcuate nucleus stimulates lipid metabolism to control body fat accrual on a high-fat diet.
Previous studies have indicated a relationship between cocaine- and amphetamine-related transcript (CART) and leptin. The present study used quantitative PCR and in situ hybridization to examine this CART-leptin relationship in different animal models. With CART injection, the function of this pathway was also investigated. The results demonstrate that CART mRNA in the arcuate nucleus (ARC) was significantly increased in subjects fed a high-fat diet (HFD) compared to low-fat diet (LFD). It was also elevated in obese vs. lean rats and in normal-weight obesity-prone vs. obesity-resistant rats. In each group tested, CART mRNA in the ARC was positively correlated specifically with circulating levels of leptin. Its close association specifically with leptin was further supported by a stimulatory effect of this hormone on CART expression. This leptin-CART relationship in the ARC, in contrast, was less consistent or undetectable in the paraventricular nucleus and lateral hypothalamus. Central injection of CART peptide (55-102) increased circulating non-esterified fatty acid levels and decreased lipoprotein lipase activity in adipose tissue. These results suggest that, on a fat-rich diet, this leptin-CART pathway originating in the ARC inhibits excessive body fat accrual by causing a shift from lipid storage toward lipid mobilization. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Body Weight; Dietary Fats; Gene Expression; Leptin; Lipid Metabolism; Lipoprotein Lipase; Male; Nerve Tissue Proteins; Obesity; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2004 |
Differential modulation of energy balance by leptin, ciliary neurotrophic factor, and leukemia inhibitory factor gene delivery: microarray deoxyribonucleic acid-chip analysis of gene expression.
Most obese animal models, whether associated with genetic, diet-induced, or age-related obesity, display pronounced leptin resistance, rendering leptin supplement therapy ineffective in treating obesity. Ciliary neurotrophic factor (CNTF) has been recently used to invoke leptin-like signaling pathways, thereby circumventing leptin resistance. In the current study, we characterize immediate and long-term molecular events in the hypothalamus of rats exposed to the sustained ectopic expression of leptin, CNTF, or leukemia inhibitory factor, another neurocytokine of IL-6 family, all delivered centrally via a viral vector. The respective transgene-encoded ligands induced similar but not identical metabolic responses as assessed by the reduction in body weight gain and changes in food intake. To define molecular mechanisms of weight-reducing and anorexigenic action of cytokines, we have analyzed the gene expression profiles of 1300 brain-specific genes in the hypothalami of normal rats subjected to the prolonged cytokine action for 10 wk. We present evidence that constitutive expression of cytokines in the brain induces changes in gene expression characteristic of chronic inflammation leading to either temporal weight reduction (CNTF) or severe cachexia (leukemia inhibitory factor). Our results convey a cautionary note regarding potential use of the tested cytokines in therapeutic applications. Topics: Animals; Body Weight; Ciliary Neurotrophic Factor; Dependovirus; DNA; Eating; Energy Metabolism; Gene Expression; Gene Transfer Techniques; Genetic Vectors; Interleukin-6; Leptin; Leukemia Inhibitory Factor; Male; Oligonucleotide Array Sequence Analysis; Rats; Rats, Sprague-Dawley | 2004 |
Enhancement of development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice.
Epidemiological studies have shown that obesity and diabetes mellitus may be risk factors for colon cancer. However, the underlying mechanisms of how these chronic diseases promote colon carcinogenesis remain unknown. C57BL/KsJ-db/db mice have obese and diabetic phenotypes because of disruption of the leptin receptor. The present study was designed to investigate whether development of azoxymethane (AOM)-induced dysplastic and early neoplastic (premalignant) lesions of the colon is modulated in db/db mice. Homozygous db/db mice, heterozygous db/+ mice and littermate controls (+/+) were injected with AOM under food restriction ( approximately 10.8 kcal/mouse/day) and killed 5 weeks after the carcinogen treatment. Their colons were assessed for premalignant lesions induced by AOM. We found a significant increase in the multiplicity of the total premalignant lesions in db/db mice when compared with db/+ or +/+ mice. Phenotypically, serum leptin and insulin levels in db/db mice were significantly higher than those in db/+ or +/+ mice, whereas the body weights and glucose levels in blood of db/db, db/+ and +/+ mice were comparable. In addition, immunostaining of the leptin receptor and insulin-like growth factor-I receptor showed up-regulation of these protein levels specifically in the lesions. Our data indicate that development of AOM-induced premalignant lesions is enhanced in db/db mice with hyperleptinemia and hyperinsulinemia. The results have important implications for further exploration of the possible underlying events that affect the positive association between colon cancer and chronic diseases (obesity and diabetes). Topics: Animals; Azoxymethane; Blood Glucose; Body Weight; Carcinogens; Colonic Neoplasms; Diabetes Mellitus, Experimental; Heterozygote; Homozygote; Hyperinsulinism; Immunoblotting; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Precancerous Conditions; Receptor, IGF Type 1; Receptors, Cell Surface; Receptors, Leptin | 2004 |
Dietary L-carnitine increases plasma leptin concentrations of gestating sows fed one meal per day.
Thirty-four sows (parity=1.8; BW=206 kg) were used to determine the influence of L-carnitine and/or chromium tripicolinate on plasma leptin concentrations of gestating sows fed one meal daily. Treatments were arranged in a 2 x 2 factorial with main effects of carnitine (0 or 50 ppm) and chromium (0 or 200 ppb). Diets were fed for approximately 167 days (through one gestation, the following lactation, the interval from weaning to estrus, and 28 days into the following gestation) prior to blood collection. Leptin concentration was determined in plasma that was collected at feeding, every 15 min for the first 3h after feeding, and at 6, 9, 15, 20, and 24h after feeding. Sows fed diets containing carnitine had greater (P<0.02) overall mean plasma leptin concentrations and greater (P<0.05) leptin concentrations at 2.25, 3, 6, 15, 20, and 24h after feeding compared to sows fed either the control diet or the diet containing chromium. Leptin concentrations of sows fed diets containing carnitine also were greater (P<0.05) than control sows at 2.5 and 2.75 h postprandial and greater than (P<0.05) sows fed diets with both carnitine and chromium at 6h after feeding. Chromium had no effect (P>0.10) on plasma leptin concentration. These results suggest that dietary carnitine, but not chromium, increases circulating leptin in gestating sows fed one meal per day. These results may help to explain the improvements in reproductive function previously observed from feeding sows diets containing carnitine. Topics: Animals; Body Weight; Carnitine; Female; Leptin; Picolinic Acids; Pregnancy; Random Allocation; Swine | 2004 |
Leptin receptor-deficient MMTV-TGF-alpha/Lepr(db)Lepr(db) female mice do not develop oncogene-induced mammary tumors.
Being overweight is a risk factor for postmenopausal breast cancer and is associated with an increased incidence and shortened latency of spontaneous and chemically induced mammary tumors in rodents. However, leptin-deficient obese Lep(ob)Lep(ob) female mice have reduced incidences of spontaneous and oncogene-induced mammary tumors. Of interest, leptin enhances the proliferation of human breast cancer cell lines in which leptin receptors are expressed, which suggests that leptin signaling plays a role in tumor development. We evaluated oncogene-induced mammary tumor development in obese MMTV-TGF-alpha/Lepr(db)Lepr(db) mice that exhibit a defect in OB-Rb, which is considered to be the major signaling isoform of the leptin receptor. Lepr and MMTV-TGF-alpha mice were crossed, and the offspring were genotyped for oncogene expression and the determination of Lepr status. Lean MMTV-TGF-alpha/Lepr(+)Lepr(+) (homozygous) and MMTV-TGF-alpha/Lepr(+)Lepr(db) (heterozygous) mice and obese MMTV-TGF-alpha/Lepr(db)Lepr(db) mice were monitored until age 104 weeks. Body weights of MMTV-TGF-alpha/ Lepr(db)Lepr(db) mice were significantly heavier than those of the lean groups. No mammary tumors were detected in MMTV-TGF-alpha/Lepr(db)Lepr(db) mice, whereas the incidence of mammary tumors in MMTV-TGF-alpha/Lepr(+)Lepr(+) and MMTV-TGF-alpha/ Lepr(+)Lepr(db) mice was 69% and 82%, respectively. Examination of mammary tissue whole mounts indicated an absence of duct formation and branching for MMTV-TGF-alpha/Lepr(db)Lepr(db) mice. Both age at mammary tumor detection and tumor burden (tumors/mouse and tumor weights) were similar for the lean genotypes. Serum leptin levels of MMTV-TGF-alpha/Lepr(db)Lepr(db) mice were 12-20-fold higher than levels of lean mice. Thus, despite elevated serum leptin levels, leptin receptor-deficient MMTV-TGF-alpha/Lepr(db)Lepr(db) mice do not develop mammary tumors. This study provides additional evidence that leptin and its cognate receptor may be involved in mammary tumorigenesis. Topics: Animals; Body Weight; Disease Models, Animal; Female; Leptin; Mammary Neoplasms, Experimental; Mammary Tumor Virus, Mouse; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Obesity; Oncogenes; Receptors, Cell Surface; Receptors, Leptin; Survival Analysis; Transforming Growth Factor alpha | 2004 |
Additive effects of leptin and topiramate in reducing fat deposition in lean and obese ob/ob mice.
The objective of the present study was to investigate the effects of the antiepileptic drug topiramate (TPM) on components of energy balance in lean and obese (ob/ob) mice in the presence or absence of leptin. Lean and ob/ob mice infused with either leptin or phosphate-buffered saline were treated with TPM for 7 days. TPM was mixed into the diet and administered at a dose of 60 mg/kg/day, whereas leptin was infused at the rate of 100 microg/kg/day using osmotic minipumps, which were subcutaneously implanted in the interscapular region. Food intake and body weight were monitored throughout the study. Body composition was measured prior to and following treatment with TPM and leptin, using dual-energy X-ray absorptiometry (DEXA). Glucose (glucose oxidase method) and insulin (radioimmunoassay) were also determined. TPM and leptin significantly reduced body weight gain, food intake and body fat gain in obese mice. The effects of TPM and leptin on fat gain were also statistically significant in lean animals. There was no interaction of TPM and leptin on the energy balance variables, the effects of the two substances being additive instead. Leptin abrogated hyperinsulinemia in obese mutants whereas TPM did not alter insulin levels in either lean or obese mice. The combination of leptin and TPM led to the normalization of glucose levels in obese mice. Our study demonstrates an effect of TPM in leptin-deficient animals, which suggests that TPM does not require the presence of leptin to exert its effect. They also show that the effects of leptin and TPM can be additive. The treatment with leptin in ob/ob mice neither accentuated nor blunted the effect of TPM on energy balance. Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Anticonvulsants; Appetite Regulation; Body Composition; Body Weight; Drug Interactions; Drug Synergism; Energy Metabolism; Female; Fructose; Infusion Pumps, Implantable; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Topiramate | 2004 |
Isomers of conjugated linoleic acid differ in their effects on angiogenesis and survival of mouse mammary adipose vasculature.
Dietary conjugated linoleic acid (CLA) is a cancer chemopreventive agent that has been shown to inhibit angiogenesis in vivo and in vitro, and to decrease vascular endothelial growth factor (VEGF) and Flk-1 concentrations in the mouse mammary gland. To determine which isomer mediates the antiangiogenic effects of CLA in vivo, the effects of diets supplemented with 5 or 10 g/kg c9,t11- or t10,c12-CLA isomers were compared in CD2F1Cr mice. Both isomers inhibited functional vascularization of a matrigel pellet in vivo and decreased serum VEGF concentrations; the t10,c12 isomer also decreased the proangiogenic hormone leptin (P < 0.05). Additionally, the t10,c12 isomer, but not c9,t11-CLA, rapidly induced apoptosis of the white and brown adipocytes as well as the preexisting supporting vasculature of the mammary fat pad (P < 0.05). Independent of this isomer-specific adipose apoptotic effect, both isomers induced a rapid and reversible decrease in the diameter of the unilocular adipocytes (P < 0.05). The ability of both CLA isomers to inhibit angiogenesis in vivo may contribute to their ability to inhibit carcinogenesis. Moreover, we propose that each CLA isomer uniquely modifies the mammary stromal "soil" in a manner that is useful for chemoprevention of breast cancer. Topics: Adipocytes; Animals; Body Weight; Diet; Female; Leptin; Linoleic Acids, Conjugated; Mammary Glands, Animal; Mice; Neovascularization, Pathologic; Stereoisomerism; Vascular Endothelial Growth Factor A | 2004 |
Adipose depot-specific modulation of angiotensinogen gene expression in diet-induced obesity.
Adipose tissue represents an important source of angiotensinogen (AGT). We investigated the effect of obesity induced by a high-fat diet on the expression of mouse (mAGT) and human AGT (hAGT) genes in liver, kidney, and heart and different adipose depots in normal mice (C57BL/6J), and in transgenic mice expressing the hAGT gene under the control of its own promoter. Mice were fed a high-fat diet (45% kcal) or normal chow (10% kcal) for 10 and 20 wk. The expression of mAGT and hAGT mRNA was quantified using an RNAse protection assay. Mice on the high-fat diet exhibited increased weight, fat mass, and plasma leptin. Expression of mAGT or hAGT genes was not affected by high-fat diet in nonadipose tissues, brown adipose tissue, or subcutaneous white fat. In contrast, high-fat diet increased both mAGT and hAGT gene expression in visceral adipose depots (omental, reproductive, and perirenal fat). Thus obesity-induced by a high-fat diet is associated with a tissue-specific increased expression of both mouse and human AGT genes in intra-abdominal adipose tissue. Our findings also suggest that 1.2 kb of regulatory sequences present in the hAGT transgene are sufficient to transcriptionally respond to a high-fat diet in an adipose-specific and depot-specific manner. Topics: Adipose Tissue; Angiotensinogen; Animals; Body Weight; Dietary Fats; Gene Expression; Hypertension; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; RNA, Messenger | 2004 |
Effects of ovariectomy on the neuroendocrine axes regulating reproduction and energy balance in young cynomolgus macaques.
Degeneration of the ovary in middle-aged women results in castrate levels of ovarian steroids and increased gonadotropin secretion from the anterior pituitary gland. Ageing in women is also accompanied by significant changes in energy homeostasis. We have observed alterations in hypothalamic morphology and gene expression in older women, including hypertrophy and increased gene expression of neurokinin B (NKB) neurones, elevated levels of gonadotropin releasing-hormone (GnRH) mRNA and decreased numbers of neurones expressing pro-opiomelanocortin (POMC) mRNA. To determine if loss of ovarian steroids could produce comparable changes in gene expression in young primates, we measured the effects of ovariectomy on NKB, GnRH and POMC gene expression in young cynomolgus monkeys. We also measured serum leptin and body weight to examine the consequences of ovariectomy on energy balance. NKB neurones in the infundibular nucleus of ovariectomized monkeys were larger, more numerous and displayed increased levels of NKB mRNA compared to those of intact controls. Moreover, ovariectomy increased the number of neurones expressing GnRH gene transcripts and elevated serum luteinizing hormone. By contrast, several parameters related to energy balance, including POMC gene expression, serum leptin and body weights, were unchanged by ovariectomy. Thus, the rise in NKB and GnRH gene expression in older women was simulated by ovariectomy in monkeys, but the changes in POMC gene expression and energy balance were not. This study provides strong support for the hypothesis that ovarian failure contributes to the increased NKB and GnRH gene expression observed in postmenopausal women. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Disease Models, Animal; Energy Metabolism; Female; Gene Expression Regulation; Gonadotropin-Releasing Hormone; Hypertrophy; Leptin; Macaca fascicularis; Menopause; Neurokinin B; Neurons; Neurosecretory Systems; Ovariectomy; Ovary; Pro-Opiomelanocortin; Random Allocation; RNA, Messenger | 2004 |
CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity.
There is growing evidence for an implication of the CB1 receptor subtype of the endocannabinoid system in the regulation of eating and fat deposition. To further define the physiological role of these receptors in the control of energy balance, we characterized the phenotype of CB1 receptor knockout (CB1(-/-)) mice maintained on an obesity-prone regimen or on a standard chow.. CB1(-/-) male mice were compared to wild-type animals (CB1(+/+) male mice) in two feeding paradigms: (1) with a standard laboratory regimen (3.5 kcal/g, 14.5% of energy as fat) and (2) on a free-choice paradigm consisting of offering both the standard laboratory chow and a high-fat diet (HFD) (4.9 kcal/g, 49% of energy as fat).. When maintained on the standard diet, CB1(-/-) mice are lean. At the age of 20 weeks, their body weight and adiposity are, respectively, 24 and 60% lower than that of CB1(+/+) mice. They are slightly hypophagic, but when expressed as percent of body weight, their relative energy intake is similar to that of the wild-type animals. Furthermore, inactivation of CB1 receptors reduces plasma insulin and leptin levels, and enhances the response to intracerebroventricular leptin injection. The free-choice paradigm shows that the preference for a high-fat highly palatable chow is slightly delayed in onset but maintained in CB1(-/-) mice. However, loading CB1(-/-) mice with this obesity-prone diet does not result in development of obesity. Knockout mice do not display hyperphagia or reduction of their relative energy intake in contrast to CB1(+/+) mice, and their feeding efficiency remains low. These data suggest an improved energetic metabolism with the high-fat regimen. Furthermore, the insulin resistance normally occurring in HFD-fed mice is not present in CB1(-/-) mice.. These results provide evidence that the stimulation of CB1 receptors is a key component in the development of diet-induced obesity, and that these receptors and their endogenous ligands are implicated not only in feeding control but also in peripheral metabolic regulations. The lack of effect of SR141716, a selective CB1 receptor antagonist, in CB1(-/-) mice further supports this hypothesis, as this compound was previously shown to display potent anti-obesity properties in diet-induced obese C57BL/6 mice. Topics: Animals; Body Weight; Diet; Dietary Fats; Eating; Energy Intake; Energy Metabolism; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Leptin; Recombinant Proteins; Rimonabant; Thinness | 2004 |
Response of circulating ghrelin levels to insulin therapy in children with newly diagnosed type 1 diabetes mellitus.
Ghrelin is secreted primarily by the stomach, although other tissues such as the pancreas synthesize a minor proportion. The discovery of a new cell type that produces ghrelin in the human pancreas and that this organ expresses GHS-R opens new perspectives in the understanding of the control of glucose metabolism. We have studied 22 children with newly diagnosed type 1 diabetes mellitus at four different points: at diagnosis before insulin therapy, after 48-60 h of insulin therapy, and after 1 and 4 mo of insulin treatment. At each point circulating levels of ghrelin, leptin, IGF-I, IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, and glucose were determined. Ghrelin levels were significantly decreased at diagnosis (573 +/- 68 pg/mL, p < 0.01) compared with controls (867 +/- 38 pg/mL) and remained decreased after insulin therapy (d 2: 595 +/- 68 pg/mL; 1 mo: 590 +/- 61 pg/mL; 4 mo: 538 +/- 67 pg/mL) with no differences before or after insulin treatment. There was a negative correlation between ghrelin levels and body mass index at all of the study points, whereas a negative correlation between ghrelin and glucose concentrations was only observed after insulin therapy. No correlation between ghrelin and HbA1c was found at any point. A positive correlation between ghrelin and IGFBP-1 was found after insulin therapy, but no correlation with other members of the IGF system or leptin was found. In conclusion, these data could indicate a possible link between glucose concentrations and ghrelin; hence, the persisting low ghrelin levels in diabetic children may suggest a defensive mechanism against hyperglycemia. Topics: Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Ghrelin; Glucose; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Linear Models; Male; Pancreas; Peptide Hormones; Radioimmunoassay; Time Factors | 2004 |
Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes.
Hormonal control of metabolic rate can be important in regulating the imbalance between energy intake and expenditure that underlies the development of obesity. In mice fed a high-fat diet, human fibroblast growth factor 19 (FGF19) increased metabolic rate [1.53 +/- 0.06 liters O(2)/h.kg(0.75) (vehicle) vs. 1.93 +/- 0.05 liters O(2)/h.kg(0.75) (FGF19); P < 0.001] and decreased respiratory quotient [0.82 +/- 0.01 (vehicle) vs. 0.80 +/- 0.01 (FGF19); P < 0.05]. In contrast to the vehicle-treated mice that gained weight (0.14 +/- 0.05 g/mouse.d), FGF19-treated mice lost weight (-0.13 +/- 0.03 g/mouse.d; P < 0.001) without a significant change in food intake. Furthermore, in addition to a reduction in weight gain, treatment with FGF19 prevented or reversed the diabetes that develops in mice made obese by genetic ablation of brown adipose tissue or genetic absence of leptin. To explore the mechanisms underlying the FGF19-mediated increase in metabolic rate, we profiled the FGF19-induced gene expression changes in the liver and brown fat. In brown adipose tissue, chronic exposure to FGF19 led to a gene expression profile that is consistent with activation of this tissue. We also found that FGF19 acutely increased liver expression of the leptin receptor (1.8-fold; P < 0.05) and decreased the expression of acetyl coenzyme A carboxylase 2 (0.6-fold; P < 0.05). The gene expression changes were consistent with the experimentally determined increase in fat oxidation and decrease in liver triglycerides. Thus, FGF19 is able to increase metabolic rate concurrently with an increase in fatty acid oxidation. Topics: Acetyl-CoA Carboxylase; Adipose Tissue, Brown; Animals; Body Weight; Diabetes Mellitus; Diet; Fibroblast Growth Factors; Gene Expression; Humans; Leptin; Liver; Metabolism; Mice; Mice, Transgenic; Obesity; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins | 2004 |
Leptin increases hepatic insulin sensitivity and protein tyrosine phosphatase 1B expression.
Leptin has been shown to improve insulin sensitivity and glucose metabolism in obese diabetic ob/ob mice, yet the mechanisms remain poorly defined. We found that 2 d of leptin treatment improved fasting but not postprandial glucose homeostasis, suggesting enhanced hepatic insulin sensitivity. Consistent with this hypothesis, leptin improved in vivo insulin receptor (IR) activation in liver, but not in skeletal muscle or fat. To explore the cellular mechanism by which leptin up-regulates hepatic IR activation, we examined the expression of the protein tyrosine phosphatase PTP1B, recently implicated as an important negative regulator of insulin signaling. Unexpectedly, liver PTP1B protein abundance was increased by leptin to levels similar to lean controls, whereas levels in muscle and fat remained unchanged. The ability of leptin to augment liver IR activation and PTP1B expression was also observed in vitro in human hepatoma cells (HepG2). However, overexpression of PTP1B in HepG2 cells led to diminished insulin-induced IR phosphorylation, supporting the role of PTP1B as a negative regulator of IR activation in hepatocytes. Collectively, our results suggest that leptin acutely improves hepatic insulin sensitivity in vivo with concomitant increases in PTP1B expression possibly serving to counterregulate insulin action and to maintain insulin signaling in proper balance. Topics: Adenoviridae; Animals; Blood Glucose; Body Weight; Cell Line; CHO Cells; Cricetinae; Glucose; Glucose Tolerance Test; Hepatocytes; Humans; Immunoblotting; Insulin; Insulin Secretion; Leptin; Liver; Mice; Mice, Obese; Muscle, Skeletal; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Receptor, Insulin; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Time Factors; Transfection; Up-Regulation | 2004 |
Weight change affects serum leptin and corticosterone in the collared lemming.
The aim of this study was to determine whether photoperiod-induced changes in body and fat mass are accompanied by changes in leptin and corticosterone concentrations in collared lemmings. At weaning, eighty male lemmings were maintained in either long photoperiod (LD, n = 40 ) or short photoperiod (SD, n = 40 ). Ten weeks post-weaning lemmings were weighed and assigned to a secondary photoperiod that consisted of either remaining in the same photoperiod or being transferred to the alternate photoperiod (LD-LD, LD-SD, SD-SD, and SD-LD; n = 20 per group). Ten days post-switch, half the animals from each group were sacrificed. The remaining animals were sacrificed on day 21 post-switch. Blood was collected for determination of serum leptin and corticosterone, and carcasses were analyzed for body composition. LD-SD lemmings gained the most weight, whilst SD-LD lemmings lost weight. SD-LD lemmings had significantly lower leptin levels relative to fat mass than SD-SD lemmings. Corticosterone levels were higher in the SD-LD than SD-SD lemmings on both days 10 and 21. Levels were not significantly different between LD-LD and LD-SD lemmings; however by day 21 the levels were slightly lower in the LD-SD lemmings. Discussion. Lemmings showed seasonally appropriate body weight changes in response to the changing photoperiod. Weight loss was associated with higher corticosterone, and lower leptin levels adjusted for fat mass. Neither relative leptin levels, nor corticosterone levels changed significantly with weight gain. Our results indicate that corticosterone and leptin are associated more with seasonal weight loss than weight gain in lemmings. Topics: Animals; Arvicolinae; Binding, Competitive; Body Composition; Body Weight; Corticosterone; Enzyme-Linked Immunosorbent Assay; Leptin; Male; Photoperiod; Seasons; Weight Gain; Weight Loss | 2004 |
Leptin resistance and enhancement of feeding facilitation by melanin-concentrating hormone in mice lacking bombesin receptor subtype-3.
Mice lacking either bombesin receptor subtype (BRS)-3 or gastrin-releasing peptide receptor (GRP-R) exhibit feeding abnormalities. However, it is unclear how these receptors are associated with feeding regulation. In BRS-3-deficient mice, we found hyperphagia, subsequent hyperleptinemia, and brain leptin resistance that occurred after the onset of obesity. To explore the cause of this phenomenon, we examined changes in feeding responses to appetite-related neuropeptides in BRS-3-deficient, GRP-R-deficient, and wild-type littermate mice. Among orexigenic neuropeptides, the hyperphagic response to melanin-concentrating hormone (MCH) was significantly enhanced in BRS-3-deficient mice but not in GRP-R-deficient mice. In addition, the levels of MCH-R and prepro-MCH mRNAs in the hypothalamus of BRS-3-deficient mice were significantly more elevated than those of wild-type littermates. There was no significant difference in feeding between BRS-3-deficient and wild-type littermate mice after treatment with bombesin (BN), although the hypophagic response to low-dose BN was significantly suppressed in the GRP-R-deficient mice. These results suggest that upregulation of MCH-R and MCH triggers hyperphagia in BRS-3-deficient mice. From these results, we assume that the BRS-3 gene deletion upsets the mechanism by which leptin decreases the expression of MCH-R and that this effect may be mediated through neural networks independent of BN-related peptides such as GRP-R. Topics: Animals; Base Sequence; Body Weight; Bombesin; DNA Primers; Eating; Female; Hypothalamic Hormones; Hypothermia; Leptin; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Knockout; Pituitary Hormones; Receptors, Bombesin; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2004 |
Continuous melatonin treatment and fasting in the raccoon dog (Nyctereutes procyonoides)--vernal body weight regulation and reproduction.
The raccoon dog (Nyctereutes procyonoides) is a canid omnivore with marked seasonal changes in its body adiposity. The aim of this study was to investigate the roles of melatonin, leptin, ghrelin and growth hormone (GH) in weight regulation and reproduction of the species. Sixteen raccoon dogs were treated with continuous-release melatonin implants in Aug 2000 and in Feb 2001 (the MEL group) and 16 animals were sham-operated (the SHAM group). Half of the raccoon dogs were fasted between Nov 27(th) 2000 and Jan 25(th) 2001. The autumnal results have been previously published and this paper reports the vernal data. The leptin concentrations of the SHAM females were high before the mating season, decreased before estrus, increased during gestation and reduced after parturition. The MEL females had higher leptin concentrations than the SHAM females in early March, whereas the MEL males had lower leptin concentrations than the SHAM males in late March. Also the ghrelin and GH concentrations of the SHAM females decreased before estrus. Continuous melatonin treatment advanced the vernal rise in the ghrelin concentrations and the vernal drop and the subsequent rise in the GH concentrations of the females. Melatonin also increased their body mass indices from July to Aug 2001, indicating that it triggers the autumnal accumulation of fat in the species. Topics: Adipose Tissue; Animals; Body Mass Index; Body Weight; Carnivora; Eating; Fasting; Ghrelin; Growth Hormone; Leptin; Melatonin; Peptide Hormones; Reproduction; Seasons | 2004 |
In vivo regulation of SREBP-1c in skeletal muscle: effects of nutritional status, glucose, insulin, and leptin.
Sterol regulatory element binding protein-1c (SREBP-1c), a transcription factor that is important for mediating insulin effects on metabolic gene expression in liver during the fasted-to-fed transition, is also expressed in skeletal muscle. However, the regulation and role of SREBP-1c in skeletal muscle are poorly understood. The present study compared the effects of nutritional status, physiological hyperinsulinemic clamps, and adenovirus-mediated hyperleptinemia (HLEP) in rats on expression of SREBP-1c and other metabolic genes in skeletal muscle. Three- and 6-h refeeding of 18-h-fasted animals increased levels of SREBP-1c mRNA and the SREBP-1 protein (full length and mature) in gastrocnemius muscle (P < 0.05). Fatty acid synthase (FAS) and hexokinase II (HKII) mRNA levels were also increased by refeeding, and uncoupling protein 3 (UCP3) mRNA level was decreased (all P < 0.05). Surprisingly, 3-h hyperinsulinemic clamps did not increase gastrocnemius muscle SREBP-1c and FAS mRNA levels or SREBP-1 protein levels but did increase HKII mRNA levels and decrease UCP3 mRNA levels (P < 0.05). HLEP reduced refeeding-induced increases of SREBP-1c and FAS mRNA levels but did not reduce the level of SREBP-1 protein. We conclude that 1) skeletal muscle SREBP-1c gene expression is regulated by nutritional status in a fashion similar to that observed in liver and adipose tissue, 2) physiological hyperinsulinemia is not sufficient to imitate the effects of refeeding on SREBP-1c gene expression, and 3) leptin suppresses refeeding effects on SREBP-1c mRNA levels. Topics: Animals; Blood Glucose; Blotting, Northern; Body Weight; CCAAT-Enhancer-Binding Proteins; DNA Primers; DNA-Binding Proteins; Eating; Gene Expression Regulation; Glucose Clamp Technique; Hyperinsulinism; Insulin; Leptin; Liver; Male; Muscle, Skeletal; Nutritional Status; Rats; Rats, Wistar; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Transcription Factors | 2004 |
Leptin prevents obesity induced by a high-fat diet after diet-induced weight loss in the marsupial S. crassicaudata.
The aims of this study were to determine in the marsupial Sminthopsis crassicaudata, the effects of leptin on food intake, body weight, tail width (a reflection of fat stores), and leptin mRNA, after caloric restriction followed by refeeding ad libitum with either a standard or high-fat preferred diet. S. crassicaudata (n = 32), were fed standard laboratory diet (LabD; 1.01 kcal/g, 20% fat) ad libitum fo 3 days. On days 4-10, animals received LabD at 75% of basal intake and then (days 11-25) were fed either LabD or a choice of LabD and mealworms (MW; 2.99 kcal/g, 30% fat); during this time, half the animals (n = 8) in each group received either leptin (2.5 mg/kg) or PBS intraperitoneally two times daily. On day 26, animals were killed and fat was removed for assay of leptin mRNA. At baseline, body weight, tail width, and food intake were similar in each group. After caloric restriction, body weight (P < 0.001) and tail width (P < 0.001) decreased. On return to ad libitum feeding in the PBS-treated animals, body weight and tail width returned to baseline in the LabD-fed animals (P < 0.001) and increased above baseline in the MW-fed animals (P < 0.001). In the LabD groups, tail width (P < 0.001) and body weight (P < 0.001) decreased after leptin compared with PBS. In the MW groups, the increase in tail width (P < 0.001) and body weight (P = 0.001) were attenuated after leptin compared with PBS. The expression of leptin mRNA in groups fed MW were greater in PBS than in leptin-treated animals (P < 0.05). Therefore, after diet-induced weight loss, leptin prevents a gain in fat mass in S. crassicaudata; this has potential implications for the therapeutic use of leptin. Topics: Animals; Blood Glucose; Blotting, Northern; Body Weight; Diet, Reducing; Dietary Fats; DNA, Complementary; Eating; Electrophoresis, Agar Gel; Fatty Acids, Nonesterified; Leptin; Male; Marsupialia; Obesity; RNA, Messenger; Tail; Weight Loss | 2004 |
Obesity and endocrine dysfunction in mice with deletions of both neuropeptide Y and galanin.
Neuropeptide Y (NPY) and galanin have both been implicated in the regulation of body weight, yet mice bearing deletions of either of these molecules have unremarkable metabolic phenotypes. To investigate whether galanin and NPY might compensate for one another, we produced mutants lacking both neuropeptides (GAL(-/-)/NPY(-/-)). We found that male GAL(-/-)/NPY(-/-) mice ate significantly more and were much heavier (30%) than wild-type (WT) controls. GAL(-/-)/NPY(-/-) mice responded to a high-fat diet by gaining more weight than WT mice gain, and they were unable to regulate their weight normally after a change in diet. GAL(-/-)/NPY(-/-) mice had elevated levels of leptin, insulin, and glucose, and they lost more weight than WT mice during chronic leptin treatment. Galanin mRNA was increased in the hypothalamus of NPY(-/-) mice, providing evidence of compensatory regulation in single mutants. The disruption of energy balance observed in GAL(-/-)/NPY(-/-) double knockouts is not found in the phenotype of single knockouts of either molecule. The unexpected obesity phenotype may result from the dysregulation of the leptin and insulin systems that normally keep body weight within the homeostatic range. Topics: Animals; Body Weight; Circadian Rhythm; Dietary Fats; Dorsomedial Hypothalamic Nucleus; Eating; Endocrine System; Galanin; Hormones; Insulin; Leptin; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Motor Activity; Neuropeptide Y; Obesity; Phenotype | 2004 |
Pinealectomy alters adipose tissue adaptability to fasting in rats.
This study investigated the effects of pinealectomy and fasting on rat adipose tissue metabolism, as well as on profiles of the hormones directly involved in its regulation (insulin, leptin, and corticosterone). Pinealectomized (PINX) and sham-operated (CONTROL) adult male Wistar rats were killed 6 weeks after surgery, in either fed or fasted (12 and 36 hours) states. Blood samples (for glucose and hormone determinations) and peri-epididymal adipocytes (for in vitro insulin-stimulated glucose uptake, oxidation, and incorporation into lipids) were collected. Pineal ablation decreased insulin-stimulated glucose uptake in adipocytes of both fed and fasted animals without affecting insulin-binding capacity. Pinealectomy attenuated the reduction in the ability to oxidize glucose in both basal and insulin-stimulated states during fasting. This alteration in the ability of adipocytes to oxidize glucose appeared together with a decrease in insulin-induced glucose incorporation into lipids in PINX animals. Additionally, pinealectomized rats showed higher corticosterone levels in both fed and fasted states, and a lower leptinemia with 36 hours of fasting, in comparison to CONTROLs. In conclusion, our data reinforce the hypothesis that the pineal gland has a role in the modulation of adipocyte metabolism, and its absence alters metabolic adaptation to fasting in rats. Topics: Adipocytes; Adipose Tissue; Animals; Blood Glucose; Body Weight; Carbon Dioxide; Cell Size; Corticosterone; Deoxyglucose; Eating; Fasting; Insulin; Leptin; Lipid Metabolism; Male; Pineal Gland; Rats; Rats, Wistar | 2004 |
Mice heterozygous for Atp10c, a putative amphipath, represent a novel model of obesity and type 2 diabetes.
Atp10c is a novel type IV P-type ATPase and is a putative phospholipid transporter. The purpose of this study was to assess the overall effect of the heterozygous deletion of Atp10c on obesity-related phenotypes and metabolic abnormalities in mice fed a high-fat diet. Heterozygous mice with maternal inheritance of Atp10c were compared with heterozygous mice with paternal inheritance of Atp10c and wild-type controls. Body weight, adiposity index, and plasma insulin, leptin and triglyceride concentrations were significantly greater in the mutants inheriting the deletion maternally compared with their sex- and age-matched control male mice fed a 10% fat (% energy) diet and female mice fed a 45% fat (% energy) diet. Glucose and insulin tolerance tests were performed after mice consumed the diets for 4 and 8 wk. Mutants had altered glucose tolerance and insulin response compared with controls, suggesting insulin resistance in both sexes. Mice were killed at 12 wk and routine gross and histological evaluations of the liver, pancreas, adipose tissue, and heart were performed. Histological evaluation showed micro- and macrovesicular lipid deposition within the hepatocytes that was more severe in the mutant mice than in age-matched controls. Although sex differences were observed, our data suggest that heterozygous deletion along with an unusual pattern of maternal inheritance of the chromosomal region containing the single gene, Atp10c, causes obesity, type 2 diabetes, and nonalcoholic fatty liver disease in these mice. Topics: Adenosine Triphosphatases; Adipose Tissue; Animals; Body Composition; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Fatty Liver; Female; Gene Deletion; Glucose Tolerance Test; Heterozygote; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Membrane Transport Proteins; Mice; Myocardium; Obesity; Organ Size; Pancreas; Phenotype; Triglycerides | 2004 |
Ala67Thr polymorphism in the Agouti-related peptide gene is associated with inherited leanness in humans.
A role for melanocortin signaling in the regulation of body weight in humans has been clearly established. Haploinsufficiency of the type 4 melanocortin receptor is associated with early-onset obesity, implying that this receptor provides an important tonic inhibition of weight gain. Agouti-related peptide (AGRP) is an endogenous antagonist of melanocortin signaling. Therefore, loss of AGRP function could lead to the expression of a lean phenotype. We investigated the potential role of AGRP in human weight regulation by examining the association between the Ala67Thr AGRP polymorphism and indices of body composition. Significant associations were found between homozygosity for this mutation (n = 8) and body composition phenotype in 874 subjects of the Quebec family study (QFS). By PCR-RFLP analysis, we have identified eight individuals who are homozygous for the 67Thr variant allele within the QFS population, where none were observed in SAFHS. The eight QFS homozygote individuals have lower weight (-16%; P = 0.02), body mass index (-17%; P = 0.01), fat free mass (-9%; P = 0.002), fat mass (FM) (-20%; P = 0.04), and leptin (-20%; P = 0.02) when compared to those carrying at least one 67Ala allele. Individuals homozygous for the 67Thr allele had a BMI that was either at or slightly below an ideal range for their age. Thus, the Ala67Thr AGRP polymorphism is associated with lower body weight in humans, with the largest effect being observed on body FM. We did not observe any difference in the stability or cellular distribution of the mutant protein in a heterologous expression system, thus the mechanism of this effect requires further investigation. Topics: Adult; Agouti-Related Protein; Animals; Body Mass Index; Body Weight; Female; Gene Frequency; Genotype; Homozygote; Humans; Immunoenzyme Techniques; Intercellular Signaling Peptides and Proteins; Leptin; PC12 Cells; Polymorphism, Genetic; Proteins; Rats; Thinness; Transfection | 2004 |
AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus.
Obesity is an epidemic in Western society, and causes rapidly accelerating rates of type 2 diabetes and cardiovascular disease. The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a 'fuel gauge' to monitor cellular energy status. We investigated the potential role of AMPK in the hypothalamus in the regulation of food intake. Here we report that AMPK activity is inhibited in arcuate and paraventricular hypothalamus (PVH) by the anorexigenic hormone leptin, and in multiple hypothalamic regions by insulin, high glucose and refeeding. A melanocortin receptor agonist, a potent anorexigen, decreases AMPK activity in PVH, whereas agouti-related protein, an orexigen, increases AMPK activity. Melanocortin receptor signalling is required for leptin and refeeding effects on AMPK in PVH. Dominant negative AMPK expression in the hypothalamus is sufficient to reduce food intake and body weight, whereas constitutively active AMPK increases both. Alterations of hypothalamic AMPK activity augment changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance. Topics: Adenylate Kinase; Animals; Body Weight; Energy Metabolism; Feeding Behavior; Glucose; Hormones; Hypothalamus; Insulin; Leptin; Male; Mice; Models, Biological; Receptors, Melanocortin; RNA, Messenger | 2004 |
[Correlation between plasma leptin level and premature infant weight loss].
Leptin is an adipocyte-derived hormone regulating body weight and energy balance in animals and human being. Although the physiological functions of leptin in human are still unclear, its secretion is closely related to fat mass and energy expenditure in both adults and children. This study investigated whether the plasma leptin level was reduced in connection with the weight loss during the neonatal period and try to find out the role of leptin in body weight regulation and energy balance of premature infants.. The radioimmunoassay was used to determine the plasma leptin concentration. The first blood samples were obtained at the delivered, and then collected the samples every two days until the infants' body weight recovered to the birth weight or above. At the same time, the essential fluid and energy for the patients were supplied to keep their physiological functions. One person was appointed to take responsibility to examine the body weight, body length and head circumference. Then computed out their Kaup index from the first day to the seventh or twelfth day.. A total of 26 premature infants were selected into the study, of which 14 cases were male and 12 female, and their gestational age ranged from 30 to 36 weeks. There was a significantly positive correlation between the premature newborns' body weight loss and their plasma leptin levels (the 1st day: n = 26, r = 0.766; the 3rd day: n = 26, r = 0.636; the 5th day: n = 26, r = 0.629; the 7th day: n = 26, r = 0.717; the 9th-12th day: n = 24, r = 0.587; P < 0.01). The time of body weight loss and the plasma leptin level which declined to extremely low were positively correlated. (r = 0.611, P < 0.01). The time when body weight loss declined to extremely low in 26 premature infants ranged form the 3rd to the 9th day after birth [(5.2 +/- 1.6) day], and that of the plasma leptin levels ranged form the 3rd to the 8th day after birth (4.7 +/- 1.4) day. The maximal ranges of the body weight loss and the plasma leptin decrease in 26 premature infants were (6.5 +/- 3.0)% and (59.6 +/- 11.3)%, respectively. In addition, there were significantly positive correlations among the plasma leptin level, the premature newborns' body length (the 1st day: n = 26, r = 0.609, P < 0.01; the 3rd day: n = 26, r = 0.419, P < 0.05; the 5th day: n = 26, r = 0.583, P < 0.01; the 7th day: n = 26, r = 0.626, P < 0.01; the 9th-12th day: n = 24, r = 0.482; P < 0.05), and the Kaup index (the 1st day: n = 26, r = 0.634; the 3rd day: n = 26, r = 0.534; the 5th day: n = 26, r = 0.542; the 7th day: n = 26, r = 0.611; the 9th-12th day: n = 24, r = 0.539; P < 0.01). Although the head circumference correlated positively with the plasma leptin level at the first week after the delivery (the 1st day: n = 26, r = 0.580, P < 0.01; the 3rd day: n = 26, r = 0.417, P < 0.05; the 5th day: n = 26, r = 0.426; P < 0.01). There was a lower correlation between them one week after the delivery (the 7th day: n = 26, r = 0.369; the 9th-12th day: n = 24, r = 0.323; P > 0.05).. There was a significantly positive correlation between the plasma leptin level and the premature newborns weight loss. Leptin may participate in the regulation of energy balance and body weight of premature infants during neonatal life. Leptin may play an important role in growth and development of premature infants. Topics: Body Weight; Humans; Infant, Newborn; Infant, Premature; Leptin; Radioimmunoassay; Time Factors; Weight Loss | 2004 |
Estrogen and raloxifene modulate leptin and its receptor in hypothalamus and adipose tissue from ovariectomized rats.
Obesity, from declining estrogen levels after menopause, increases the risk of heart disease, diabetes, and hypertension. Ovariectomy (OVX) in rats is a good model of estrogen insufficiency. The ensuing mild obesity is useful to study how hypoestrogenism alters adiposity. This study examines the hypothesis that in ovariectomized (OVX) rats modification of estrogen levels or treatment with a selective estrogen receptor modulator, raloxifene (RAL), alters leptinemia and modulates leptin receptor (Ob-R) abundance in hypothalamus and white adipose tissue, similar to the modification of adipose status induced by hypoestrogenism. Mid- and long-term studies (7 and 22 wk) were conducted to monitor the change in leptinemia in rats after estrogen loss by OVX and after estrogen replacement by 17beta-estradiol (OVX+E(2)) or RAL treatment (OVX+RAL). Leptin was significantly higher in OVX rats vs. controls, in a time-dependent manner. This effect was reversed by both E(2) and RAL treatment at 7 wk (P < 0.05) and 22 wk (P < 0.001). Moreover, E(2) or RAL treatment reversed the OVX-induced increases in food intake, body weight, and fat mass content; the modifications of serum parameters were examined to evaluate the different lipid profiles. We also evaluated Ob-R expression in hypothalamus and adipose tissue by Western blot analysis. The expression of the long functional isoform (Ob-Rb) increased at 7 wk only in adipose tissue and decreased at 22 wk in OVX rats in both tissues; these effects were reversed by E(2) or RAL treatment. We provide evidence that central and peripheral Ob-Rb expression is related to modification of estrogen levels. Topics: Adaptation, Physiological; Adipose Tissue; Animals; Body Weight; Cholesterol; Estradiol; Estrogen Antagonists; Female; Hypothalamus; Leptin; Menopause; Ovariectomy; Raloxifene Hydrochloride; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin | 2004 |
Neuroscience. The fat-brain axis enters a new dimension.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Axons; Body Weight; Eating; Excitatory Postsynaptic Potentials; Feeding Behavior; Ghrelin; Homeostasis; Hypothalamus; Leptin; Mice; Mice, Obese; Neurites; Neuronal Plasticity; Neurons; Neuropeptide Y; Neurotransmitter Agents; Paraventricular Hypothalamic Nucleus; Peptide Hormones; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction | 2004 |
Rapid rewiring of arcuate nucleus feeding circuits by leptin.
The fat-derived hormone leptin regulates energy balance in part by modulating the activity of neuropeptide Y and proopiomelanocortin neurons in the hypothalamic arcuate nucleus. To study the intrinsic activity of these neurons and their responses to leptin, we generated mice that express distinct green fluorescent proteins in these two neuronal types. Leptin-deficient (ob/ob) mice differed from wild-type mice in the numbers of excitatory and inhibitory synapses and postsynaptic currents onto neuropeptide Y and proopiomelanocortin neurons. When leptin was delivered systemically to ob/ob mice, the synaptic density rapidly normalized, an effect detectable within 6 hours, several hours before leptin's effect on food intake. These data suggest that leptin-mediated plasticity in the ob/ob hypothalamus may underlie some of the hormone's behavioral effects. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Evoked Potentials; Excitatory Postsynaptic Potentials; Feeding Behavior; gamma-Aminobutyric Acid; Ghrelin; Glutamic Acid; Green Fluorescent Proteins; In Vitro Techniques; Leptin; Luminescent Proteins; Mice; Mice, Obese; Mice, Transgenic; Neuronal Plasticity; Neurons; Neuropeptide Y; Patch-Clamp Techniques; Peptide Hormones; Pro-Opiomelanocortin; Recombinant Fusion Proteins; Synapses; Tetrodotoxin; Transgenes | 2004 |
Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36).
Inactivating mutations of the pro-opiomelanocortin (POMC) gene in both mice and humans leads to hyperphagia and obesity. To further examine the mechanisms whereby POMC-deficiency leads to disordered energy homeostasis, we have generated mice lacking all POMC-derived peptides. Consistent with a previously reported model, Pomc(-/-) mice were obese and hyperphagic. They also showed reduced resting oxygen consumption associated with lowered serum levels of thyroxine. Hypothalami from Pomc(-/-) mice showed markedly increased expression of melanin-concentrating hormone mRNA in the lateral hypothalamus, but expression of neuropeptide Y mRNA in the arcuate nucleus was not altered. Provision of a 45% fat diet increased energy intake and body weight in both Pomc(-/-) and Pomc(+/-) mice. The effects of leptin on food intake and body weight were blunted in obese Pomc(-/-) mice whereas nonobese Pomc(-/-) mice were sensitive to leptin. Surprisingly, we found that Pomc(-/-) mice maintained their acute anorectic response to peptide-YY(3-36) (PYY(3-36)). However, 7 days of PYY(3-36) administration had no effect on cumulative food intake or body weight in wild-type or Pomc(-/-) mice. Thus, POMC peptides seem to be necessary for the normal response of energy balance to high-fat feeding, but not for the acute anorectic effect of PYY(3-36) or full effects of leptin on feeding. The finding that the loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding emphasizes the potential importance of this locus as a site for gene-environment interactions predisposing to obesity. Topics: Animals; Appetite Depressants; Base Sequence; Body Weight; Dietary Fats; DNA Primers; Energy Intake; Hypothalamic Hormones; Hypothalamus; Kinetics; Leptin; Melanins; Mice; Mice, Knockout; Mutagenesis, Site-Directed; Neuropeptide Y; Obesity; Peptide Fragments; Peptide YY; Phenotype; Pituitary Hormones; Polymerase Chain Reaction; Pro-Opiomelanocortin; Transcription, Genetic | 2004 |
Relation between leptin and the metabolic syndrome in elderly women.
Leptin has been shown to be linked to adiposity and insulin resistance in middle-aged participants. However, the association between leptin and metabolic syndrome independently of body fat and body fat distribution has not been evaluated in healthy elderly people.. We studied the independent relation between leptin and the components of the metabolic syndrome in 107 women aged 67-78 years with body mass index (BMI) ranging from 18.19 to 36.16 kg/m2. In all participants, we evaluated BMI, waist and hip circumferences, body composition by dual energy X-ray absorptiometry, fasting, and 2-hour glucose, lipids, insulin, homeostasis model assessment of insulin resistance (HOMA), systolic (SBP), diastolic blood pressure (DBP), and leptin.. Significant correlation was found between leptin, BMI, waist circumference, fat mass, DBP, SBP, cholesterol, triglycerides, insulin, and HOMA. After adjusting for age and waist circumference, as well for age and fat mass, leptin was significantly related to insulin levels, HOMA, and cholesterol. In a stepwise multiple regression analysis using insulin levels or HOMA as dependent variables and age, waist circumference, fat mass, leptin, SBP, DBP, cholesterol, and triglycerides as independent variables, leptin entered the regression first, waist circumference second, and age third.. Our study shows that leptin is significantly related to indices of adiposity in elderly women, and leptin is significantly associated with insulin levels, HOMA, and cholesterol independent of age, body fat, and fat distribution. Leptin, waist circumference, and age together explained 31% and 33% of insulin levels and HOMA variance, respectively, in healthy elderly women. Topics: Age Factors; Aged; Anthropometry; Body Composition; Body Weight; Female; Humans; Insulin; Leptin; Metabolic Syndrome; Regression Analysis | 2004 |
Adiponectin acts in the brain to decrease body weight.
Adiponectin (ADP) is an adipocyte hormone involved in glucose and lipid metabolism. We detected a rise in ADP in cerebrospinal fluid after intravenous (i.v.) injection, consistent with brain transport. In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure. Full-length ADP, mutant ADP with Cys39 replaced with serine, and globular ADP were effective, whereas the collagenous tail fragment was not. Lep(ob/ob) mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels. ADP also potentiated the effect of leptin on thermogenesis and lipid levels. While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH), ADP had no substantial effect on other neuropeptide targets of leptin. In addition, ADP induced distinct Fos immunoreactivity. Agouti (A(y)/a) mice did not respond to ADP or leptin, indicating the melanocortin pathway may be a common target. These results show that ADP has unique central effects on energy homeostasis. Topics: Adiponectin; Agouti Signaling Protein; Animals; Body Weight; Brain; Drug Synergism; Energy Metabolism; Injections, Intraventricular; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Obese; Proteins; Recombinant Proteins | 2004 |
Plasma ghrelin response following a period of acute overfeeding in normal weight men.
Ghrelin, a 28 amino-acid peptide secreted primarily from the stomach has been identified as the endogenous ligand for the growth hormone secretagogue receptor. Ghrelin is suppressed in the postprandial state and has been linked to both type II diabetes and obesity.. To investigate the effects of a period of overfeeding with high-fat dietary supplements on plasma ghrelin levels in nonobese men.. Six healthy males (21-34 y; BMI 21-24 kg/m(2)) underwent the dietary intervention after completing diet and exercise diaries for 7 days. For 3 further weeks subjects followed their own diet diary supplemented with 125 ml single cream and 50 g roasted peanuts (88 g fat, 15 g Protein, 8 g carbohydrate) every day. Oral fat tolerance tests (OFTT) were undertaken at baseline, 7, 14 and 21 days of fat supplementation. The diet was increased in energy by 3.9 MJ/day and from a mean of 29-45% energy intake from fat with a small weight gain noted each week (P=0.009).. Ghrelin concentrations were significantly reduced during the baseline OFTT. The postprandial ghrelin response (AUC) was significantly reduced following 2 weeks of dietary supplementation (P=0.005) increasing the suppression of plasma ghrelin by 18% despite only a 3% increase in body weight. Plasma triacylglycerol (P=0.009) and leptin (P=0.035) concentrations were also elevated and postprandial pancreatic polypeptide levels decreased (P=0.038) following dietary-supplementation.. These results suggest that the metabolic profile associated with obesity, including a reduction in plasma ghrelin levels, may be related to recent dietary energy intake and precedes the development of significant adiposity. Topics: Adult; Analysis of Variance; Body Weight; Dietary Fats; Eating; Fatty Acids, Nonesterified; Gastric Emptying; Ghrelin; Humans; Leptin; Male; Peptide Hormones; Postprandial Period; Triglycerides; Weight Gain | 2004 |
Capasaicin induced deafferentation enhances the effect of electrical vagal nerve stimulation on food intake and body mass.
Study was based on hypothesis that electrical stimulation (ES) with parameters obtained from analysis of vagal afferent discharge fed state may fake brain with satiety state. We evaluated effect of denervation of vagal capsaicin-sensitive afferents on food intake and body weight in rats with ES of vagal nerves using microchip (MC). Group A was scheduled to MC implantation, B to sham operation only, C to MC implantation and capsaicin vagal deafferentation, and D to capsaicin denervation only. ES lasted 24 days. MC parameters were 0.05 Hz, 0.1s, 0.55 V. ES of left vagus significantly reduced total food intake as well as the mean daily intake in groups A and C in comparison to control and D group (ANOVA, F=18.55, p=0.0038). Body weight was lower in group A (3462 g) and C (2727 g) then in control (3814 g) and D (3568 g) (F=25.68, p=0.00068). Leptin decreased in C (165 pg/mL) in comparison to A (625 pg/mL), B (677 pg/mL), and D (612 pg/mL) (p<0,05), mainly due to ES (F=7.27, p=0.019). Glucose was decreased in A (F=5.55, p=0.036) - by 11% and by 16% in C group. Proper vagal neuromodulation results in central and peripheral effects causing food intake and body weight downregulation. Topics: Administration, Topical; Afferent Pathways; Animals; Blood Glucose; Body Weight; Capsaicin; Denervation; Down-Regulation; Eating; Electric Stimulation; Fasting; Insulin; Leptin; Male; Microchemistry; Rats; Rats, Wistar; Vagus Nerve | 2004 |
High-fat diet induced adiposity in mice with targeted disruption of the dopamine-3 receptor gene.
Dopamine (DA) signaling has been implicated in the control of energy balance and ingestive behavior. In the present study, we sought to characterize body weight, body fat and food intake regulation in a mouse with a targeted disruption of the dopamine-3 receptor gene (Drd3). In the first set of experiments male and female wild-type and mutant (Drd3-/-) mice were given access to two different diets varying in fat content. Body weight, food intake, carcass analysis and plasma levels of leptin and insulin were measured. Male Drd3-/- mice have increased body weight and body fat when given access to high fat (HF) diet but not standard rodent chow. The female Drd3-/- mice did not demonstrate increased body weight when given access to either diet, but did have increased body fat on both diets. Plasma leptin and insulin levels reflected the increased adiposity demonstrated in each genotype and gender. These findings suggest the D3-R signaling is involved in the regulation of body weight and body fat when mice are given access to diets differing in palatability and fat content. Topics: Adipose Tissue; Analysis of Variance; Animals; Body Composition; Body Weight; Dietary Fats; Eating; Energy Intake; Female; Gene Silencing; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Dopamine D2; Receptors, Dopamine D3; Sex Factors; Time Factors | 2004 |
Lightheaded.
Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Brain; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Proteins; Weight Loss | 2004 |
Changes in serum ghrelin concentration following biliopancreatic diversion for obesity.
Ghrelin is a recently discovered hormone that is produced mainly by the stomach and that increases food intake in rodents and humans. It has been postulated that the weight loss after gastric bypass surgery for obesity might be related to changes in serum ghrelin concentration.. Serum leptin and ghrelin concentrations were measured in a group of obese patients before biliopancreatic diversion (BPD) and 2 and 12 months postoperatively. Insulin sensitivity was determined from serum glucose and insulin levels according to the homeostatic model of assessment for insulin resistance (HOMA IR).. A sharp drop was observed in body weight, in BMI values, in HOMA IR data, and in serum leptin concentration at 2 and 12 months after BPD, whereas a significant increase of serum ghrelin level was observed at 12 months, when food intake had returned to preoperative levels. A negative correlation between the postoperative changes of serum ghrelin concentration and those of HOMA IR values was observed at 2 and 12 months after BPD.. No evidence upholding a relationship between serum ghrelin concentration and food intake after BPD was seen; the postoperative changes likely reflected the achievement of a new state of energy balance. The negative relationship observed between post-BPD changes in HOMA IR values and changes in serum ghrelin concentration supported the role of insulin in the modulation of ghrelin production. Topics: Biliopancreatic Diversion; Blood Glucose; Body Mass Index; Body Weight; Eating; Female; Ghrelin; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Peptide Hormones | 2004 |
Serum leptin concentration poorly reflects growth and energy and nutrient intake in young children.
We studied whether the serum leptin concentration at age 2 years predicts changes in relative body weight by age 8 and whether the serum leptin concentration is associated with intake of energy and nutrients at age 5.. A total of 156 8-year-old participants of the Special Turku Coronary Risk Factor Intervention Project were chosen to represent children whose relative weight decreased, was stable, or increased during the preceding 6 years. Their serum leptin concentrations were measured in samples collected when they were 2 years. Serum leptin was also measured in 100 5-year-old children in the Special Turku Coronary Risk Factor Intervention Project whose energy and nutrient intakes were analyzed using 4-day food records.. The boys whose relative weight decreased (n = 25), was stable (n = 28), or increased (n = 26) between 2 and 8 years of age had similar serum leptin concentrations at the age of 2 years. The girls whose relative weight decreased (n = 27) had higher serum leptin concentrations at 2 years than the girls whose relative weight remained stable (n = 26) but only when the leptin values were not adjusted for body mass index. The serum leptin concentration was higher in 5-year-old girls than in 5-year-old boys even when adjusted for body mass index. Serum leptin correlated with relative weight in girls and boys (r = 0.65 and r = 0.45, respectively). Serum leptin concentration adjusted for relative weight correlated poorly with intakes of energy, fat, saturated fat, carbohydrates, sucrose, and protein.. Serum leptin concentrations at age 2 poorly predicted changes in relative body weight during the following 6 years and poorly reflected the intake of energy or major nutrients at age 5. Topics: Body Weight; Child; Child, Preschool; Energy Intake; Female; Growth; Humans; Leptin; Male; Nutrition Assessment | 2004 |
Dehydroepiandrosterone up-regulates resistin gene expression in white adipose tissue.
Dehydroepiandrosterone (DHEA), the most abundant steroid hormone in human blood, is considered to be one of fat-reducing hormones. However, the molecular mechanisms underlying DHEA mode of action in obesity has not been fully clarified. The pivotal role in the maintenance of cellular lipid and energy balance is played by peroxisome proliferator-activated receptor alpha (PPARalpha) which acts as transcriptional activator of numerous genes encoding enzymes involved in fatty acid catabolism. Lately published papers suggest that resistin, a low molecular-weight protein produced by adipose tissue, may act as an inhibitor of adipocyte differentiation and could regulate adipose tissue mass. Recent studies have established that the promoter region of the resistin gene contains several putative PPAR response elements. Since DHEA has been characterized as a peroxisome proliferator able to induce hepatic genes through PPARalpha, we hypothesised that DHEA might affect PPARalpha and, subsequently, resistin gene expression in adipose tissue. In order to test this hypothesis, an experiment was performed comparing PPARalpha and resistin gene expression in white adipose tissue (WAT) of male Wistar rats fed standard or DHEA-supplemented (0.6% (w/w)) diet for 2 weeks. DHEA administration to the rats induced PPARalpha and resistin gene expression in WAT (3- and 2.25-fold, respectively; as determined by real-time reverse transcription-polymerase chain reaction (RT-PCR)); reduced body weight, epididymal adipose tissue mass and decreased serum leptin levels. We propose that DHEA may impact on the transcription of resistin gene through a mechanism involving PPARalpha and that an elevated resistin level may lead to an inhibition of adipogenesis and a decrease in adipose tissue mass. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Dehydroepiandrosterone; Diet; Eating; Gene Expression Regulation; Hormones, Ectopic; Humans; Insulin; Leptin; Liver; Male; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Resistin; RNA, Messenger; Transcription Factors; Up-Regulation | 2004 |
Body weight, hormones and T cell subsets as predictors of life span in genetically heterogeneous mice.
Previous studies have shown that T cell subset levels, early life body weight, and levels of leptin and thyroid hormones can each serve, independently, as predictors of life span in populations of genetically heterogeneous mice. New data now confirm, in a replicate cohort, that T cell subset patterns predict longevity, and show that they can do so when measured in mice as young as 8 months of age. Individual T cell subsets, as well as composite indices that combine data from two or more T cell measures at 8 or 18 months, can be combined with 3- and 9-month body weight data to provide better prediction of life span than either immune or weight measures alone. Mice whose immune and weight measures are both in the lowest quartile have mean and maximal life spans that are 18% and 16-25% higher, respectively, than mice in the opposite quartiles for both traits. Thyroxine levels measured at 4 months lead to further improvement over models that combine weight and immune data only. A genome scan provided evidence for loci on chromosomes 2, 12, 13, and 17 that modulate age-sensitive T cell subset patterns at both 8 and 18 months of age. These data show that late-life mortality risks are influenced to a measurable degree by factors that modulate growth trajectory and hormone and immune status in the first third of the life span, and provide clues as to which early life systems deserve further scrutiny as potential mediators of late life disease risk. Topics: Aging; Animals; Body Weight; Chromosomes; Leptin; Life Expectancy; Longevity; Mice; Predictive Value of Tests; T-Lymphocyte Subsets; Thyroid Hormones | 2004 |
Different responsiveness in body weight and hepatic 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 mrna to 11beta-HSD inhibition by glycyrrhetinic acid treatment in obese and lean zucker rats.
Tissue-specific dysregulation of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity in obese humans and animals may be associated with obesity and the metabolic syndrome. We investigated the effect of inhibition of 11beta-HSD with glycyrrhetinic acid (GE), an effective 11beta-HSD inhibitor, on body weight regulation in obese Zucker rats, which have a defect in the leptin receptor gene. GE (280 mg/kg/d) was administered in drinking water to 8-week-old male Zucker rats for 14 weeks. GE had no effect on food intake or weight gain, and did not affect hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels in obese rats. In contrast, average daily food intake and body weight on week 14 were significantly reduced by GE in lean rats (both P <.0001). Hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels were also significantly decreased by GE in lean rats (both P <.05). GE had no significant effect on plasma corticosterone levels in obese rats but lowered them in lean rats (P <.05). Plasma leptin levels declined in both GE-treated obese and lean rats (both P <.01). In conclusion, long-term GE treatment decreased weight gain in lean Zucker rats but not in obese Zucker rats. These findings suggest that the differing responses of 11beta-HSD1 to GE in obese and lean Zucker rats are closely associated with the different weight-gain responses. Furthermore, the weight-lowering effect of GE may require intact leptin receptors. Topics: 11-beta-Hydroxysteroid Dehydrogenases; Animals; Body Weight; Corticosterone; Eating; Gene Expression; Glycyrrhetinic Acid; Isoenzymes; Kidney; Leptin; Liver; Male; Obesity; Rats; Rats, Zucker; RNA, Messenger | 2004 |
Adipocyte expression and circulating levels of leptin increase in both gynaecological and breast cancer patients.
Leptin is a hormone involved in the regulation of body weight and sexual maturation. We previously reported that cancer cachexia was associated with reduced or normal levels of leptin. Here we investigate whether leptin levels are related to cachetic or hormonal status. Circulating leptin and its mRNA from adipose tissue were measured in 87 patients with gynaecological and breast cancers and related to tumour, cachexia and hormonal markers. We found that leptin protein increased in patients with these tumours due to higher mRNA levels. In patients with ovarian cancer, the increased leptin levels were associated with higher circulating follicle-stimulating hormone (FSH). The higher leptin concentrations in patients with endometrial and portio tumours were related to an increase in tissue estrogen receptor (ER) and progesterone receptor (PGR) and, only in the postmenopause, to an increase in circulating estradiol. Patients with breast cancer showed enhanced blood plasma concentrations of progesterone and estradiol, and enhanced tissue levels of ER and PGR associated with increased leptin levels. The data from the present study indicate that, in gynaecological and breast cancers, leptin is related to hormonal status but not to cachexia. We suggest that leptin stimulates the production of sexual hormones, important risk factors for these tumours, and we propose leptin as a novel prognostic marker. Topics: Adipocytes; Biomarkers, Tumor; Body Mass Index; Body Weight; Breast Neoplasms; Cachexia; Case-Control Studies; Female; Humans; Leptin; Neoplastic Cells, Circulating; Ovarian Neoplasms; Receptors, Estrogen; Receptors, Progesterone; Uterine Neoplasms | 2004 |
Adaptation of ghrelin levels to limit body weight gain in the obese Zucker rat.
In this study, we measured the ghrelin, leptin, and insulin variations in lean and obese Zucker fa/fa rats during the acute phase of body weight gain. At 2 months of age, plasma insulin and leptin concentrations in fa/fa rats were, respectively, 470% and 3700% higher than in lean rats (p <0.0001). Plasma ghrelin was significantly lower (-24.6%; p <0.02) than in lean rats. At 6 months of age, ghrelin increased in both genotypes but the difference was no more significant. The inverse correlations existing between ghrelin and either body weight (BW), insulin or leptin at 2 months of age were no more observable in 6-month-old rats. At 6 months of age, the lean rats had the same body weight as the 2-month-old obese rats. In these body weight-matched rats, ghrelin was not correlated with BW but it remained negatively correlated with insulin and leptin. At the same body weight, obese rats had a much lower plasma ghrelin than lean rats (717+/-42 vs. 1754+/-83 pg/ml; p <0.0001). These data indicate that body composition rather than body weight is the primary factor for the down-regulation of the ghrelin system. This down-regulation constitutes a mechanism of defense of the organism against the development of obesity at least during the first part of life. Topics: Animals; Body Weight; Eating; Ghrelin; Homozygote; Insulin; Leptin; Longitudinal Studies; Peptide Hormones; Radioimmunoassay; Rats; Rats, Zucker; Regression Analysis; Weight Gain | 2004 |
A long-term high-protein diet markedly reduces adipose tissue without major side effects in Wistar male rats.
Although there is a considerable interest of high-protein, low-carbohydrate diets to manage weight control, their safety is still the subject of considerable debate. They are suspected to be detrimental to the renal and hepatic functions, calcium balance, and insulin sensitivity. However, the long-term effects of a high-protein diet on a broad range of parameters have not been investigated. We studied the effects of a high-protein diet in rats over a period of 6 mo. Forty-eight Wistar male rats received either a normal-protein (NP: 14% protein) or high-protein (HP: 50% protein) diet. Detailed body composition, plasma hormones and nutrients, liver and kidney histopathology, hepatic markers of oxidative stress and detoxification, and the calcium balance were investigated. No major alterations of the liver and kidneys were found in HP rats, whereas NP rats exhibited massive hepatic steatosis. The calcium balance was unchanged, and detoxification markers (GSH and GST) were enhanced moderately in the HP group. In contrast, HP rats showed a sharp reduction in white adipose tissue and lower basal concentrations of triglycerides, glucose, leptin, and insulin. Our study suggests that the long-term consumption of an HP diet in male rats has no deleterious effects and could prevent metabolic syndrome. Topics: Adipose Tissue; Animals; Biomarkers; Body Composition; Body Weight; Calcium; Diet; Dietary Proteins; DNA Primers; Glutamate-Cysteine Ligase; Glutathione; Glutathione Transferase; Hydrocortisone; Insulin; Kidney; Leptin; Liver; Male; Oxidative Stress; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiobarbituric Acid Reactive Substances | 2004 |
Leptin modulates orexigenic effects of ghrelin and attenuates adiponectin and insulin levels and selectively the dark-phase feeding as revealed by central leptin gene therapy.
We tested the hypothesis that leptin acts centrally and peripherally by different mechanisms to control peripheral hormones that normally regulate weight homeostasis. The paradigm of selectively increasing leptin transgene expression with a single intracerebroventricular injection of adeno-associated viral vectors encoding leptin (rAAV-lep) or green fluorescent protein (control) in the hypothalamus of mutant leptin-deficient ob/ob and wild-type (wt) mice was employed in these experiments. rAAV-lep injection increased hypothalamic leptin expression in the complete absence of peripheral leptin in ob/ob mice; suppressed body weight and adiposity; voluntarily decreased dark-phase food intake; suppressed plasma levels of adiponectin, TNFalpha, free fatty acids and insulin, concomitant with normoglycemia; and elevated ghrelin levels for extended period. Body weight and plasma levels of leptin and metabolic variables were suppressed to a lesser extent in rAAV-lep wt mice without decreasing food intake. The sustained high leptin transgene expression decreased only the dark-phase phagia in both genotypes, but wt mice escaped from leptin restraint during the lights-on phase, resulting in normal overall food intake. Leptin administration rapidly decreased plasma gastric ghrelin and adipocyte adiponectin but not TNFalpha levels, thereby demonstrating a peripheral restraining action of leptin on the secretion of hormones of varied origins. Whereas ghrelin administration readily stimulated feeding in controls, it was completely ineffective in rAAV-lep-treated wt mice. Thus, leptin expressed locally in the hypothalamus counteracted the central orexigenic effects of peripheral ghrelin. Cumulatively, these results identify newer central and peripheral modulatory influences of leptin on hormonal signals of disparate origin implicated in weight homeostasis and metabolic disorders. Topics: Adipocytes; Adiponectin; Animals; Blood Glucose; Body Weight; Circadian Rhythm; Eating; Energy Metabolism; Genetic Therapy; Ghrelin; Hypothalamus; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptide Hormones; Proteins; Tumor Necrosis Factor-alpha | 2004 |
Augmenting leptin circadian rhythm following a weight reduction in diet-induced obese rats: short- and long-term effects.
The current study sought to examine whether leptin injections following a weight reduction in diet-induced obese rats would reduce both the enhanced food intake and body weight (BW) regain observed during the refeeding phase. Female Wistar rats (n = 100, 20 per group) were divided into 5 groups: (1) LEP rats were fed a high-fat (HF) diet (35% wt/wt) for 8 weeks to induce obesity and were then food-restricted (50% ad libitum) with a fortified high-fat diet for 2 weeks to induce a 20% BW loss. These rats were then refed the HF diet ad libtum for another 11 weeks. They were given leptin injections (200 microg/kg BW, twice daily, intraperitoneally ) for 19 days concomitant with the onset of refeeding. (2) SAL rats were treated in the same manner as LEP rats except that they were given saline injections; (3) PF rats were treated like SAL rats except that they were pair-fed with the LEP rats; (4) HFC rats were fed HF diet ad libitum; and (5) LFC rats were fed a low-fat (LF) diet (AIN-93M) ad libitum. Ten rats from each group were killed after leptin treatment and at the end of the study. Food and caloric intakes were monitored, and body composition and plasma glucose, insulin, and leptin levels were assessed at death. Leptin injections after a weight reduction briefly reduced energy intake during the first week only. After 19 days of treatment and to the end of the study, LEP and SAL rats were similar in energy intake, BW (LEP: 393 +/- 11.2 g, SAL: 371 +/- 14.1; difference not significant [NS]) and total body fat percent (LEP: 19.3 +/- 1.5, SAL: 17.6 +/- 1.5; NS). Leptin treatment induced hyperinsulinemia and insulin resistance. All of the metabolic abnormalities observed at the end of treatment period disappeared at the end of the study (8 weeks post-leptin injection). We conclude that bolus leptin injections to manipulate leptin circadian rhythm in diet-induced obese rats after a weight reduction caused temporary insulin resistance and hyperinsulinemia, and were ineffective in influencing food intake, BW, and fat content. Leptin resistance was evident following 1 week of treatment in this study. Leptin treatment had no effect on body fat content both short-term and long-term. Exogenous leptin treatment may, in the long run, increase leptin resistance in diet-induced obese animals. Hence, long-term leptin treatment may not be beneficial to obese individuals consuming a HF diet. Topics: Animal Feed; Animals; Blood Glucose; Body Composition; Body Weight; Circadian Rhythm; Diet, Fat-Restricted; Dietary Fats; Eating; Energy Intake; Female; Insulin; Leptin; Obesity; Rats; Rats, Wistar; Weight Loss | 2004 |
Contributions of dysregulated energy metabolism to type 2 diabetes development in NZO/H1Lt mice with polygenic obesity.
New Zealand Obese (NZO) male mice develop a polygenic juvenile-onset obesity and maturity-onset hyperinsulinemia and hyperglycemia (diabesity). Here we report on metabolic and molecular changes associated with the antidiabesity action of CL316,243 (CL), a beta(3)-adrenergic receptor agonist. Dietary CL treatment initiated at weaning reduced the peripubertal rise in body weight and adiposity while promoting growth without suppressing hyperphagia. The changes in adiposity, in turn, suppressed development of hyperinsulinemia, hyperleptinemia, hyperlipidemia, and hyperglycemia. These CL-induced alterations were reflected by decreased adipose tissue mass, increased expression of transcripts for uncoupling protein-1 (UCP-1), peroxisome proliferator-activated receptor alpha (PPARalpha), peroxisome proliferater-activated receptor coactivator-1 (PGC-1), and robust development of brown adipocyte function in white fat. Increased drug-mediated energy dissipation elicited a 1.5 degrees C increase in whole body temperature under conditions of increased food intake but with no change in physical activity. Indirect calorimetry of mice treated with CL showed both increased energy expenditure and a restoration of a prominent diurnal pattern in the respiratory exchange ratio suggesting improved nutrient sensing. Our data suggest that CL promotes increased energy dissipation in white and brown fat depots by augmenting thermogenesis and by metabolic re-partitioning of energy in a diabesity-protective fashion. This is the first report demonstrating the effects of dietary beta(3)-agonist in preventing the onset of diabesity in a polygenic rodent model of type 2 diabetes. Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Blood Glucose; Body Weight; Carrier Proteins; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dioxoles; Eating; Energy Metabolism; Insulin; Ion Channels; Islets of Langerhans; Leptin; Liver; Male; Membrane Proteins; Mice; Mice, Inbred Strains; Mitochondrial Proteins; Muscle, Skeletal; Obesity; Receptors, Cytoplasmic and Nuclear; Thermogenesis; Transcription Factors; Uncoupling Protein 1 | 2004 |
Expression of kinin receptor mRNA in the HPA axis of type 1 and type 2 diabetic rats.
mRNA levels of kinin B1 and B2 receptors were determined in HPA axis of type 1 (STZ-induced) and type 2 diabetic rats (ZDF and obese Zucker rats). B2 mRNA levels were elevated in hypothalamus of STZ-induced diabetic (STZ-D) and ZDF rats. Pituitary B2 mRNA levels were elevated in ZDF and obese rats. Adrenal B2 mRNA level was attenuated in STZ-D rats. Kinin B1 receptor may not play a role in HPA axis in diabetes since its expression was unchanged. Enhanced mRNA expression of B2 receptors in hypothalamus of STZ-D and ZDF rats parallels a rise in plasma glucose and reflect a functional relationship. Enhanced pituitary B2 mRNA in type 2 and reduced adrenal in type 1 diabetes account for a differential pattern in release of transmitters. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Hypothalamo-Hypophyseal System; Insulin; Leptin; Male; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2004 |
Hypothalamic gene expression is altered in underweight but obese juvenile male Sprague-Dawley rats fed a high-energy diet.
The incidence of obesity, with its associated health risks, is on the increase throughout the western world affecting all age groups, including children. The typical western diet is high in fat and sugar and low in complex carbohydrates. This study looks at the effects of feeding an equivalent high-energy (HE) diet to growing rats. Juvenile male Sprague-Dawley rats that were fed an HE (18.9 kJ/g) diet starting approximately 10 d after weaning gained less weight than littermates fed a nonpurified (14 kJ/g) diet. Despite an initial hyperphagia following the change in diet, HE rats also consumed less energy. Although they exhibited reduced weight gain, HE rats were relatively obese; fat pad weights were elevated for all 4 dissected depots. HE-fed rats exhibited symptoms of developing metabolic syndrome with elevated plasma concentrations of glucose, triglycerides, nonesterified fatty acids, insulin, and leptin. In addition, leptin receptor gene expression in the hypothalamic arcuate nucleus (ARC) and ventromedial nucleus of HE rats was reduced. Consistent with the elevated serum leptin and other peripheral signals in HE rats, hypothalamic gene expression for the orexigenic neuropeptides, neuropeptide Y (ARC and dorsomedial nucleus), and agouti-related peptide (AgRP), was reduced. This reduction in orexigenic signaling and decline in energy intake is consistent with an apparent attempt to counter the further development of an obese state in rats consuming an energy-dense diet. The juvenile Sprague-Dawley rat has potential in the development of a model of childhood diet-induced obesity. Topics: Agouti-Related Protein; Animals; Animals, Newborn; Body Weight; Energy Intake; Gene Expression; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Male; Metabolic Syndrome; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin | 2004 |
Intraventricular insulin and leptin reverse place preference conditioned with high-fat diet in rats.
The authors hypothesized that insulin and leptin, hormones that convey metabolic and energy balance status to the central nervous system (CNS), decrease the reward value of food, as assessed by conditioned place preference (CPP). CPP to high-fat diet was blocked in ad-lib fed rats given intraventricular insulin or leptin throughout training and test or acutely before the test. Insulin or leptin given only during the training period did not block CPP. Thus, elevated insulin and leptin do not prevent learning a food's reward value, but instead block its retrieval. Food-restricted rats receiving cerebrospinal fluid, insulin, or leptin had comparable CPPs. Results indicate that the CNS roles of insulin and leptin may include processes involving memory and reward. Topics: Animals; Behavior, Animal; Body Weight; Conditioning, Operant; Dietary Fats; Drug Interactions; Energy Metabolism; Food Deprivation; Hypoglycemic Agents; Injections, Intraventricular; Insulin; Leptin; Male; Rats; Rats, Sprague-Dawley | 2004 |
Pyruvate prevents restraint-induced immunosuppression via alterations in glucocorticoid responses.
Stress-evoked immunosuppression may reflect increased demands on cellular energy signaled via elevated glucocorticoid concentrations. We hypothesized that treatment with pyruvate, an alternative energy source, would ameliorate restraint-induced elevation of glucocorticoids and that this reduction in glucocorticoid exposure will prevent stress-induced immunosuppression. We provided exogenous pyruvate to mice exposed to repeated restraint and then assessed splenocyte counts and splenocyte proliferation in response to the mitogen, concanavalin A as well as IgM production in response to keyhole limpet hemocyanin. Immune function was suppressed in mice undergoing repeated restraint but not in mice exposed to repeated restraint followed by pyruvate treatment. All mice exposed to restraint, regardless of pyruvate supplementation, displayed equivalent occurrences of repeated elevations in corticosterone concentrations; however, the cumulative exposure to corticosterone after one episode of restraint was reduced in those mice treated with pyruvate after restraint. Finally, we tested the immunoprotective ability of pyruvate supplementation in the presence of chronically elevated corticosterone. Mice implanted with restraint-like concentrations of corticosterone after adrenalectomy decreased splenocyte counts, compared with either unmanipulated mice or mice that were implanted with a cholesterol pellet after adrenalectomy, regardless of pyruvate supplementation. These data suggest that pyruvate does not possess immunoprotective properties in the presence of chronically elevated corticosterone. Pyruvate supplementation preserves immune function during exposure to repeated restraint stressors; altered dynamics of corticosterone concentrations after pyruvate administration may mediate this immunoprotection. Pyruvate prevents restraint-induced immunosuppression via alterations in the glucocorticoid response to restraint. Topics: Animals; Antibody Formation; Body Weight; Cell Count; Cell Division; Corticosterone; Corticotropin-Releasing Hormone; Glucocorticoids; Immune Tolerance; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Paraventricular Hypothalamic Nucleus; Pyruvic Acid; Restraint, Physical; Signal Transduction; Spleen; Stress, Physiological | 2004 |
Changes in cytokine production and impaired hematopoiesis in patients with anorexia nervosa: the effect of refeeding.
The changes in cytokines and hormones involved in hematopoiesis were studied in the serum of 7 girls with anorexia nervosa, 15-24 yr old, on admission and after 5% and 10% weight gain. Hematopoiesis was studied by in-vitro culturing of circulating granulocyte-macrophage colony forming cells and erythroid burst forming cells. Nutritional status was studied by anthropometric measurements and resting energy expenditure. On admission, granulocyte-macrophage colony forming cells and erythroid burst forming cells were significantly lower than in age-matched controls and increased significantly along weight gain. Blood leptin and erythropoietin levels increased significantly with weight gain. TNF-alpha levels tended to decrease while IL-1beta levels were lower than in the controls on admission (p <0.05) and did not change significantly during weight gain. IL-3, GM-CSF and IL-6 were undetected on admission or along weight gain. The changes in granulocyte-macrophage colony forming cells and erythroid burst forming cells positively correlated with changes in resting energy expenditure and fat free mass. These results may suggest that undernutrition affects hematopoiesis as indicated by the reduction of hematopoietic progenitor cells before treatment and the significant increase with weight gain. The changes in the levels of hormones and cytokines known to be involved in hematopoiesis along refeeding may suggest a role for these factors in anorexia nervosa. Topics: Adolescent; Adult; Anorexia Nervosa; Body Weight; Cells, Cultured; Cytokines; Erythropoietin; Female; Hematopoiesis; Hormones; Humans; Leptin; Nutritional Status | 2004 |
Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase.
Insulin resistance, a hallmark of type 2 diabetes, is associated with oxidative stress. However, the role of reactive oxygen species or specific antioxidant enzymes in its development has not been tested under physiological conditions. The objective of our study was to investigate the impact of overexpression of glutathione peroxidase 1 (GPX1), an intracellular selenoprotein that reduces hydrogen peroxide (H(2)O(2)) in vivo, on glucose metabolism and insulin function. The GPX1-overexpressing (OE) and WT male mice (n = 80) were fed a selenium-adequate diet (0.4 mg/kg) from 8 to 24 weeks of age. Compared with the WT, the OE mice developed (P < 0.05) hyperglycemia (117 vs. 149 mg/dl), hyperinsulinemia (419 vs. 1,350 pg/ml), and elevated plasma leptin (5 vs. 16 ng/ml) at 24 weeks of age. Meanwhile, these mice were heavier (37 vs. 27 g, P < 0.001) and fatter (37% vs. 17% fat, P < 0.01) than the WT mice. At 30-60 min after an insulin challenge, the OE mice had 25% less (P < 0.05) of a decrease in blood glucose than the WT mice. Their insulin resistance was associated with a 30-70% reduction (P < 0.05) in the insulin-stimulated phosphorylations of insulin receptor (beta-subunit) in liver and Akt (Ser(473) and Thr(308)) in liver and soleus muscle. Here we report the development of insulin resistance in mammals with elevated expression of an antioxidant enzyme and suggest that increased GPX1 activity may interfere with insulin function by overquenching intracellular reactive oxygen species required for insulin sensitizing. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Glutathione Peroxidase; Glutathione Transferase; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Muscles; Obesity; Phospholipid Hydroperoxide Glutathione Peroxidase; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptor, Insulin; Selenium; Superoxide Dismutase; Thioredoxin-Disulfide Reductase | 2004 |
Reduced leptin concentrations are permissive for display of torpor in Siberian hamsters.
A photoperiod with a short photophase induces a winterlike phenotype in Siberian hamsters that includes a progressive decrease in food intake and body mass and reproductive organ regression, as well as reversible hypothermia in the form of short-duration torpor. Torpor substantially reduces energy utilization and is not initiated until body mass, fat stores, and serum leptin concentrations are at their nadir. Because photoperiod-dependent torpor is delayed until fat reserves are lowest, leptin concentrations may be a permissive factor for torpor onset. This conjecture was tested by implanting osmotic minipumps into Siberian hamsters manifesting spontaneous torpor; the animals received a constant release of leptin or vehicle for 14 days. Exogenous leptin treatment eliminated torpor in a significant proportion of treated hamsters, whereas treatment with the vehicle did not. Similarly, endogenous serum leptin concentrations were markedly reduced in all animals undergoing daily torpor. Although simply reducing leptin concentrations below a threshold value is not sufficient for torpor initiation, reduced leptin concentrations nevertheless appear necessary for its occurrence. It is proposed that drastically reduced leptin concentrations provide a "starvation signal" to an as yet unidentified central mechanism mediating torpor initiation. Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Cold Temperature; Cricetinae; Female; Food Deprivation; Hibernation; Leptin; Male; Motor Activity; Phodopus; Photoperiod; Telemetry | 2004 |
Relationships between bone mass and circulating leptin concentrations in Hutterites.
A limited number of previous studies have shown inverse associations between bone mass or density and circulating leptin in humans. Relationships between bone mass and circulating leptin in Hutterites, who have elevated bone density, are unknown. Knowledge gained from studies in mice suggests that Hutterites exhibit traits consistent with a deficiency in circulating leptin or in leptin signaling. We examined relationships between whole body (WB) and regional (lumbar, total hip, femoral neck, trochanter) bone mineral content (BMC) by dual energy X-ray absorptiometry and circulating leptin in 249 Hutterites (137 female) ages 20-55 years and 72 similarly aged non-Hutterites (37 female). We tested the hypothesis that (1) Hutterites will have low circulating leptin concentrations for a given amount of body fat compared to non-Hutterites, and (2) controlling for body fat, there will be an inverse relationship between BMC and circulating leptin among Hutterites. Hutterites had higher BMC than non-Hutterites at all skeletal sites after adjusting for site-specific bone area, age, and sex (P = 0.02). Hutterite females had higher leptin concentrations than non-Hutterite females [geometric mean and 95% confidence interval (CI): 18.38 (17.18, 19.67) vs. 14.30 (12.55, 16.28), P = 0.001) after adjusting for WB fat mass. Hutterite males also had higher leptin concentrations than non-Hutterite males [geometric mean and 95% CI: 6.53 (6.11, 6.98) vs. 5.62 (4.98, 6.35), P = 0.03) after adjusting for WB fat mass. We used backward stepwise regression to determine significant (P = 0.10) covariates to include in models predicting WB and regional BMC among Hutterites (separately by sex). Subsequently, we entered leptin (log-transformed) to models to test for significance (P = 0.05). After adjusting for covariates, leptin concentration was not a significant predictor of BMC at any site, in either sex, among Hutterites. It is possible that genetic influences that interfere with hypothalamic leptin signaling, in a manner unrelated to adipocyte leptin production, contribute to elevated Hutterite bone density. Topics: Adult; Analysis of Variance; Body Mass Index; Body Weight; Bone Density; Female; Humans; Leptin; Male; Middle Aged; Regression Analysis; South Dakota | 2004 |
Insulin secretory defects and impaired islet architecture in pancreatic beta-cell-specific STAT3 knockout mice.
Normal islet formation and function depends on the action of various growth factors operating in pre- and postnatal development; however, the specific physiological function of each factor is largely unknown. Loss-of-function analyses in mice have provided little information so far, perhaps due to functional redundancies of the growth factors acting on the pancreas. The present study focuses on the role of the transcription factor STAT3 in insulin-producing cells. STAT3 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta-cells, including betacellulin, hepatocyte growth factor, growth hormone, and heparin-binding EGF-like growth factor. To elucidate its role in the beta-cells, the STAT3 gene was disrupted in insulin-producing cells in mice (STAT3-insKO), using a cre-mediated gene recombination approach. Unexpectedly, STAT3-insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older. The mice showed partial leptin resistance, suggesting that expression of the RIP (rat insulin promoter)-cre transgene in hypothalamus partially inhibited the appetite-regulating system. Intraperitoneal glucose tolerance tests, performed in non-obese 5-week-old mice, showed that the STAT3-insKO mice were glucose intolerant. Islet perifusion experiments further revealed a deficiency in early-phase insulin secretion. Whereas islet insulin content or islet mass was not affected, expression levels of GLUT2, SUR1, and VEGF-A were significantly reduced in STAT3-insKO islets. Interestingly, STAT3-insKO mice displayed impaired islet morphology: alpha-cells were frequently seen in central regions of islets. Our present observations demonstrate a unique role of STAT3 in maintaining glucose-mediated early-phase insulin secretion and normal islet morphology. Topics: Animals; Appetite; Blood Glucose; Body Weight; Cell Size; DNA-Binding Proteins; Female; Gene Expression Regulation; Glucose Tolerance Test; Insulin; Islets of Langerhans; Leptin; Male; Mice; Mice, Knockout; Obesity; Promoter Regions, Genetic; Rats; STAT3 Transcription Factor; Trans-Activators; Transgenes | 2004 |
Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase.
AMP-activated protein kinase (AMPK) functions as a fuel sensor in the cell and is activated when cellular energy is depleted. Here we report that alpha-lipoic acid (alpha-LA), a cofactor of mitochondrial enzymes, decreases hypothalamic AMPK activity and causes profound weight loss in rodents by reducing food intake and enhancing energy expenditure. Activation of hypothalamic AMPK reverses the effects of alpha-LA on food intake and energy expenditure. Intracerebroventricular (i.c.v.) administration of glucose decreases hypothalamic AMPK activity, whereas inhibition of intracellular glucose utilization through the administration of 2-deoxyglucose increases hypothalamic AMPK activity and food intake. The 2-deoxyglucose-induced hyperphagia is reversed by inhibiting hypothalamic AMPK. Our findings indicate that hypothalamic AMPK is important in the central regulation of food intake and energy expenditure and that alpha-LA exerts anti-obesity effects by suppressing hypothalamic AMPK activity. Topics: Animals; Anti-Obesity Agents; Body Weight; Cyclic AMP-Dependent Protein Kinases; Eating; Energy Metabolism; Enzyme Activation; Hypothalamus; Leptin; Mice; Muscle, Skeletal; Rats; Thioctic Acid | 2004 |
Body weight and abdominal fat gene expression profile in response to a novel hydroxycitric acid-based dietary supplement.
Obesity is a global public health problem, with about 315 million people worldwide estimated to fall into the WHO-defined obesity categories. Traditional herbal medicines may have some potential in managing obesity. Botanical dietary supplements often contain complex mixtures of phytochemicals that have additive or synergistic interactions. The dried fruit rind of Garcinia cambogia, also known as Malabar tamarind, is a unique source of (-)-hydroxycitric acid (HCA), which exhibits a distinct sour taste and has been safely used for centuries in Southeastern Asia to make meals more filling. Recently it has been demonstrated that HCA-SX or Super Citrimax, a novel derivative of HCA, is safe when taken orally and that HCA-SX is bioavailable in the human plasma as studied by GC-MS. Although HCA-SX has been observed to be conditionally effective in weight management in experimental animals as well as in humans, its mechanism of action remains to be understood. We sought to determine the effects of low-dose oral HCA-SX on the body weight and abdominal fat gene expression profile of Sprague-Dawley rats. We observed that at doses relevant for human consumption dietary HCA-SX significantly contained body weight growth. This response was associated with lowered abdominal fat leptin expression while plasma leptin levels remained unaffected. Repeated high-density microarray analysis of 9960 genes and ESTs present in the fat tissue identified a small set (approximately 1% of all genes screened) of specific genes sensitive to dietary HCA-SX. Other genes, including vital genes transcribing for mitochondrial/nuclear proteins and which are necessary for fundamental support of the tissue, were not affected by HCA-SX. Under the current experimental conditions, HCA-SX proved to be effective in restricting body weight gain in adult rats. Functional characterization of HCA-SX-sensitive genes revealed that upregulation of genes encoding serotonin receptors represent a distinct effect of dietary HCA-SX supplementation. Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Citrates; Dietary Supplements; Down-Regulation; Garcinia cambogia; Gene Expression; Gene Expression Profiling; Glucose Transporter Type 1; Glucose Transporter Type 4; Leptin; Mitochondrial Proteins; Monosaccharide Transport Proteins; Muscle Proteins; Nuclear Proteins; Obesity; Oligonucleotide Array Sequence Analysis; Plant Preparations; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; RNA, Messenger; Up-Regulation | 2004 |
Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis.
Neuroanatomical and electrophysiological studies have shown that hypothalamic POMC neurons are targets of the adipostatic hormone leptin. However, the physiological relevance of leptin signaling in these neurons has not yet been directly tested. Here, using the Cre/loxP system, we critically test the functional importance of leptin action on POMC neurons by deleting leptin receptors specifically from these cells in mice. Mice lacking leptin signaling in POMC neurons are mildly obese, hyperleptinemic, and have altered expression of hypothalamic neuropeptides. In summary, leptin receptors on POMC neurons are required but not solely responsible for leptin's regulation of body weight homeostasis. Topics: Age Factors; alpha-MSH; Animals; Body Composition; Body Weight; Eating; Female; Gene Expression; Green Fluorescent Proteins; Homeostasis; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Leptin; Luminescent Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Neuropeptides; Oxygen Consumption; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sex Factors; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors | 2004 |
Leptin, hunger, and body weight: Influence of gender, tobacco smoking, and smoking abstinence.
Leptin is a hormone involved in body weight and hunger regulation, and may contribute to the inverse relationship between cigarette smoking and body weight. Leptin levels, body mass indices (BMIs), and hunger ratings were determined in 22 nonsmokers (12 male, 10 female) and 19 cigarette smokers (11 male, 8 female). Smokers were tested after ad lib smoking and following a 24-h smoking abstinence period; nonsmokers came to the laboratory once. Leptin levels were not different among the groups. Hunger ratings, however, were higher after smoking abstinence compared to after ad lib smoking and nonsmokers (Ps<.05); levels of hunger did not differ between ad lib smokers and nonsmokers. Men reported higher hunger levels than did women, but women had higher serum leptin levels than did men, regardless of smoking condition (P<.05). Leptin levels were correlated with BMI (P<.05) among smokers only. This first study on leptin responses in female smokers suggests that leptin levels do not change following a 24-h smoking abstinence period and that leptin may not contribute to increased hunger following smoking abstinence. Topics: Adolescent; Adult; Analysis of Variance; Biomarkers; Body Weight; Carbon Monoxide; Cotinine; Female; Humans; Hunger; Leptin; Male; Saliva; Sex Factors; Smoking | 2004 |
The role of insulin, glucagon, dexamethasone, and leptin in the regulation of ketogenesis and glycogen storage in primary cultures of porcine hepatocytes prepared from 60 kg pigs.
A study was conducted to elucidate hormonal control of ketogenesis and glycogen deposition in primary cultures of porcine hepatocytes. Hepatocytes were isolated from pigs (54-68 kg) by collagenase perfusion and seeded into collagen-coated T-25 flasks. Monolayers were established in medium containing fetal bovine serum for 1 day and switched to a serum-free medium for the remainder of the culture period. Hepatocytes were maintained in DMEM/M199 containing 1% DMSO, dexamethasone (10(-6) or 10(-7) M), linoleic acid (3.4 x 10(-5) M), and carnitine (10(-3) M) for 3 days. On the first day of serum-free culture, insulin was added at 1 or 100 ng/ml and glucagon was added at 0, 1, or 100 ng/ml. Recombinant human leptin (200 ng/ml) was added during the final 24 h; medium and all cells were harvested on the third day. Concentrations of acetoacetate and beta-hydroxybutyrate (ketone bodies) in media and glycogen deposition in the cellular compartment were determined. Ketogenesis was highly stimulated by glucagon (1 and 100 ng/ml) and inhibited by insulin. In contrast, glycogen deposition was stimulated by insulin and attenuated by glucagon; high insulin was also associated with a reduction in the ketone body ratio (acetoacetate:beta-hydroxybutyrate). High levels of dexamethasone stimulated ketogenesis, but inhibited glycogen deposition at low insulin. Culture of cells with leptin for 24 h, over the range of insulin, glucagon, and dexamethasone concentrations had no effect on either glycogen deposition or ketogenesis. These data suggest that while adult porcine hepatocytes are indeed sensitive to hormonal manipulation, leptin has no direct influence on hepatic energy metabolism in swine. Topics: Animals; Body Weight; Carnitine; Cells, Cultured; Culture Media, Serum-Free; Dexamethasone; Glucagon; Glucocorticoids; Glycogen; Hepatocytes; Humans; Insulin; Ketone Bodies; Leptin; Linoleic Acid; Recombinant Proteins; Swine | 2004 |
Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity.
Ghrelin plays a key role in the regulation of growth hormone secretion and energy homeostasis. Adiponectin is exclusively secreted by adipose tissue and is abundantly present in the circulation, with important effects on metabolism. We studied five lean and five obese young men [ages: 24.2 +/- 1.0 (lean) and 21.8 +/- 1.6 (obese) years (difference not significant); body mass indexes: 35.0 +/- 1.3 and 23.0 +/- 0.3 kg/m2 (P = 0.01)], sampled blood every 7 min over 24 h, and measured ghrelin, adiponectin, and leptin in 2,070 samples for a total of 6,210 data points. Circulating 24-h ghrelin showed significant ultradian fluctuations and an orderly pattern of release in lean and obese subjects with similar pulsatility characteristics. Plasma adiponectin concentrations were significantly lower in the obese group, with lower pulse height. In contrast to leptin, which is secreted in an orderly manner, the 24-h patterns of adiponectin were not significantly different from random in both the lean and obese groups. We show here that adipocytes can simultaneously secrete certain hormones, such as leptin, in patterns that are orderly, whereas other hormones, such as adiponectin, are secreted in patterns that appear to be random. The cross-approximate entropy statistic revealed pattern synchrony among ghrelin-leptin, ghrelin-adiponectin, and leptin-adiponectin hormone time series in the lean and obese subjects. Plasma ghrelin concentrations showed a nocturnal rise that exceeded the meal-associated increases in lean subjects, and this newly identified nocturnal rise was blunted in the obese. We suggest that the blunting of the nocturnal rise of ghrelin is a biological feature of human obesity. Topics: Adipocytes; Adiponectin; Adult; Body Weight; Circadian Rhythm; Energy Metabolism; Ghrelin; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Obesity; Peptide Hormones; Proteins; Pulsatile Flow | 2004 |
Effects of lipopolysaccharide on leptin transport across the blood-brain barrier.
Leptin is a 16-kDa protein secreted by fat cells and transported into the brain where it decreases appetite and increases body temperature. Leptin transport is saturable and regulated by epinephrine, triglycerides, and starvation. Lipopolysaccharide (LPS) is derived from bacterial cell walls and also decreases appetite and increases body temperature. LPS is known to increase leptin levels in serum and to affect the passage of other regulatory proteins across the blood-brain barrier (BBB). Here, we examined the ability of LPS, at doses which induce weight loss, to modify the BBB transport of radioactive leptin (I-Lep). The transport rate of intravenously injected I-Lep was decreased by 50-60% from 8 to 12 h after a single i.p. injection of LPS (3 mg/kg). The effect of LPS was dose-dependent. In comparison to the brain/serum ratio, the baseline cerebrospinal fluid (CSF)/serum ratio for I-Lep was much lower and not inhibited by LPS. LPS did not affect I-Lep transport when studied by the brain perfusion method nor was Ob-Ra mRNA expression in isolated brain microvessels altered, demonstrating that a circulating factor rather than altered BBB function was responsible for inhibition. Brain perfusion showed that LPS was not this factor. Serum leptin was doubled and serum triglycerides increased by 44% after LPS administration, suggesting these to be the circulating inhibitory factors. In conclusion, a single dose of LPS has long-lasting effects on the transport of serum leptin across the BBB that are likely mediated through self-inhibition and triglycerides. Topics: Analysis of Variance; Animals; Blood-Brain Barrier; Body Weight; Brain; Brain Chemistry; Dose-Response Relationship, Drug; Gene Expression Regulation; In Vitro Techniques; Leptin; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Permeability; Protein Transport; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Triglycerides | 2004 |
Hormonal and body composition predictors of soluble leptin receptor, leptin, and free leptin index in adolescent girls with anorexia nervosa and controls and relation to insulin sensitivity.
Anorexia nervosa (AN) is associated with very low levels of leptin, a cytokine secreted by adipose tissue and known to suppress appetite. Leptin may play a permissive role in onset of puberty and in resumption of gonadal function in conditions of undernutrition. The soluble leptin receptor (sOB-R) is the main leptin binding protein, and the ratio of serum leptin to sOB-R provides a measure of the free leptin index (FLI), which may be a more accurate determinant of leptin function. Determinants of sOB-R and FLI have not been examined in an adolescent population. We examined levels of sOB-R, leptin, and FLI, and body composition and hormonal determinants of these variables in 23 adolescent girls with AN and 21 healthy adolescent girls of comparable maturity prospectively over 1 yr. Measures of insulin resistance and adiponectin were also examined. We determined changes in levels of sOB-R, leptin, and FLI with weight recovery (defined as an increase in body mass index of >/=10%, n = 11), and with resumption of menstrual cycles (n = 13). Girls with AN had significantly higher levels of sOB-R (P = 0.0008) and significantly lower levels of leptin and FLI (P < 0.0001 for both) than healthy controls, and levels of FLI were reduced more than levels of leptin in girls with AN compared with controls. An inverse correlation was noted between levels of leptin and sOB-R for the group as a whole (r = -0.64, P < 0.0001) but not in girls with AN considered alone. The most important predictor of levels of sOB-R was cortisol in the group as a whole (r = 0.61, P < 0.0001) and in girls with AN considered alone (r = 0.66, P = 0.0008). Other independent predictors of sOB-R levels for the entire group were percent body fat (r = -0.44, P = 0.003) and levels of IGF-I (r = -0.37, P = 0.01). The most important predictors of leptin and FLI were body mass index and percent body fat. An inverse relationship was noted between measures of insulin resistance and sOB-R levels, whereas a positive association was noted between these measures and leptin and FLI. Adiponectin values did not differ in girls with AN compared with healthy controls and did not correlate with sOB-R, leptin, or FLI. Weight recovery resulted in significant decreases in levels of the sOB-R (24.7 +/- 1.7 to 17.6 +/- 1.2 U/ml, P = 0.004), and increases in levels of leptin (4.4 +/- 1.0 to 13.7 +/- 2.9 microg/liter, P = 0.02). Resumption of menstrual function, but not weight recovery alone, was associated with significant Topics: Adipose Tissue; Adolescent; Anorexia Nervosa; Body Composition; Body Mass Index; Body Weight; Case-Control Studies; Female; Humans; Hydrocortisone; Insulin Resistance; Leptin; Menstrual Cycle; Receptors, Cell Surface; Receptors, Leptin; Recovery of Function; Solubility | 2004 |
Development of intestinal inflammation in double IL-10- and leptin-deficient mice.
Leptin-deficient (ob/ob) mice are resistant in different models of autoimmunity and inflammation, suggesting that leptin regulates immunity and inflammation. To investigate whether leptin deficiency modulates the spontaneous intestinal inflammation observed in interleukin (IL)-10-deficient mice, double IL-10- and leptin-deficient [IL-10 knockout (KO) ob/ob] mice were generated and compared with single IL-10 KO mice for colitis severity. Body weight in IL-10 KO ob/ob mice was significantly reduced compared with that of ob/ob mice. However, when compared with wild-type or IL-10 KO mice, IL-10 KO ob/ob mice were still markedly obese. IL-10 KO and IL-10 KO ob/ob mice developed colitis with a comparable time-course and severity in terms of macroscopic and histologic scores. Likewise, production of interferon-gamma, IL-6, and IL-13 from colon cultures and splenocytes did not differ among these two groups. Conversely, rates of apoptosis were higher in lamina propria lymphocytes obtained from the colon of IL-10 KO ob/ob compared with IL-10 KO mice. In conclusion, although leptin deficiency has been associated with resistance in models of autoimmunity and inflammation induced by exogenous stimuli, leptin appears not to play a significant role in the spontaneous colitis of IL-10 KO mice, although it modulates survival of intestinal lymphocytes. Topics: Animals; Apoptosis; Body Weight; Cell Division; Cells, Cultured; Colitis; Colon; Female; Interferon-gamma; Interleukin-10; Interleukin-13; Interleukin-6; Intestinal Mucosa; Leptin; Lymphocytes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Spleen | 2004 |
Effect of exogenous leptin administration on high fat diet induced oxidative stress.
The objective of the present study was to explore the tissue lipid peroxidation and antioxidant status in mice receiving exogenous leptin along with high fat diet for a period of 6 weeks. Significantly elevated levels of tissue thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and significantly lowered levels of glutathione and its related enzymes were observed in the liver, heart and kidney of mice fed with a high fat diet as compared with the control mice fed with a standard pellet diet. Subsequent to the treatment with high fat diet (ie., after the initial period of 30 days) exogenous leptin (230 microg kg(-1) body weight) was simultaneously administered along with the regular high fat diet every alternate day for 15 days. Leptin administration significantly lowered the tissue levels of TBARS, CD and elevated the activities of reduced glutathione (GSH), glutathione peroxidase (GPx) and glutathione S-transferase (GST) in both the control and high fat diet fed mice. Thus leptin supplementation was found to be effective in attenuating high fat diet induced oxidative stress. Topics: Animals; Antioxidants; Body Weight; Diet; Dietary Fats; Eating; Glutathione Peroxidase; Glutathione Transferase; Histocytochemistry; Leptin; Lipid Peroxidation; Liver; Mice; Oxidative Stress; Recombinant Proteins; Thiobarbituric Acid Reactive Substances | 2004 |
Ghrelin gene polymorphisms and ghrelin, insulin, IGF-I, leptin and anthropometric data in children and adolescents.
Previous investigations on the ghrelin gene reported three common polymorphisms (Arg51Gln, Leu72Met, and Gln90Leu), but their role in overweight and obese individuals remains to be clarified.. To ascertain whether these genetic variants could influence ghrelin secretion and play a part in predisposing to earlier onset of obesity or in modulating the overweight phenotype in childhood.. Mutational analysis of the entire ghrelin gene and total and acylated plasma determinations were performed in 81 obese or overweight children and adolescents (46 were obese and 35 overweight: Ob/Ow). We also recruited 168 normal-weight healthy controls (72 young adults and 96 children) for mutational or plasma ghrelin analysis.. Median total and acylated plasma ghrelin concentrations were significantly lower in Ob/Ow individuals than in controls (175 pg/ml compared with 345 pg/ml, P<0.0001, and 95 pg/ml compared with 114 pg/ml, P<0.0001, respectively). The ghrelin gene variants showed similar allele frequencies in the Ob/Ow individuals and in controls; in the former, they were not associated with any change in total and acylated circulating ghrelin concentrations or anthropometric data. The Leu72Met status was associated with a positive family history for obesity (75% for Leu72Met compared with 39% for Leu72Leu, P=0.03) and with a greater percentage of newborns born 'large for gestational age' (33% for Leu72Met compared with 5% for Leu72Leu, P=0.03), but in the control group it was related to a lower mean body mass index z-score (-0.03 for Leu72Met and -0.47 for Leu72Leu, P=0.04).. Our present findings do not support the hypothesis that the ghrelin gene polymorphisms have a relevant impact in the secretion of total and acylated ghrelin. Topics: Adolescent; Adult; Body Height; Body Weight; Child; Child, Preschool; Female; Genotype; Ghrelin; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Obesity; Peptide Hormones; Phenotype; Polymorphism, Genetic | 2004 |
Metabolic adaptations to fasting and chronic caloric restriction in heart, muscle, and liver do not include changes in AMPK activity.
Activation of adenosine monophosphate-activated protein kinase (AMPK) plays a central role in allowing cells to adapt to nutrient deprivation in vitro. This link between AMPK activity and nutritional status has raised the possibility that AMPK plays a role in the metabolic adaptation to acute and chronic nutritional stress. However, the effects of nutritional stress on AMPK activity in vivo have not been systematically evaluated. To address this, we measured the effects of 24 h of fasting and 4 mo of caloric restriction (CR) on AMPK alpha 1 and -alpha 2 activities in heart, skeletal muscle, and liver in mice. Although fasting caused the expected changes in body weight, plasma leptin, and free fatty acids, it did not increase AMPK activity in heart or skeletal muscle and only increased liver AMPK activity by approximately 20% (P = 0.10). Likewise, CR caused the expected changes in body weight, plasma leptin, and free fatty acids but did not alter AMPK activity in any of the three tissues. Although CR did not alter liver AMPK activity, it dramatically decreased the amount of phosphorylated acetyl-CoA carboxylase, and this was found to be due to decreased protein expression. Plasma leptin, a putative activator of AMPK, varied eightfold across the four groups of mice in the absence of changes in AMPK activity in any tissue. We conclude that, although the metabolic adaptations to fasting and CR include changes in plasma leptin concentration and phosphorylated acetyl-CoA carboxylase, these effects occur without changes in AMPK activity. Topics: Acetyl Coenzyme A; Adaptation, Physiological; AMP-Activated Protein Kinases; Analysis of Variance; Animals; Body Weight; Caloric Restriction; Enzyme Activation; Fasting; Fatty Acids, Nonesterified; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Multienzyme Complexes; Muscle, Skeletal; Myocardium; Nutritional Status; Protein Serine-Threonine Kinases | 2004 |
CART peptide: central mediator of leptin-induced adipose tissue apoptosis?
Because of connections between CART peptide containing neurons and the sympathetic nervous system (SNS) and the possible role of the SNS in leptin-induced adipose apoptosis, CART may act as a downstream effector of leptin-induced adipose apoptosis. Male Sprague-Dawley rats received continuous intracerebroventricular (i.c.v.) infusion for 4 days of either artificial cerebrospinal fluid (aCSF, 12 microl/day), leptin (15 microg/day), or CART55-102 at 2.4 microg/day (CART2.4) or 9.6 microg/day (CART9.6). Food intake (FI) was decreased 10.8% for CART2.4, 41.9% for CART9.6 and 33.4% for leptin (p<0.05). CART9.6 and leptin reduced meal size and meal number. Body weight (BW) was reduced by CART9.6 (14.6%) and leptin (11.6%) (p<0.05), but not by CART2.4. CART9.6 and CART2.4, but not leptin, caused hypothermia, and CART9.6 inhibited physical activity (p<0.05). Epididymal, inguinal and retroperitoneal fat pad weights were reduced (p<0.05) by both CART treatments and leptin; CART9.6 also reduced gastrocnemius muscle weight (18.1%, p<0.05). Leptin, but not CART, increased serum free fatty acid concentrations by 31.1% (p<0.05) and increased adipose apoptosis by 48% (p<0.05). These data show that although leptin and CART55-102 have some similar actions, CART55-102 is probably not a mediator for leptin-induced adipose apoptosis in the brain. Topics: Adipose Tissue; Animals; Apoptosis; Body Temperature; Body Weight; Drinking; Eating; Fatty Acids, Nonesterified; Feeding Behavior; Insulin; Leptin; Male; Motor Activity; Nerve Tissue Proteins; Organ Size; Rats | 2004 |
Leptin action is modified by an interaction between dietary fat content and ambient temperature.
Mice adapted to a high-fat diet are reported to be leptin resistant; however, we previously reported that mice fed a high-fat (HF) diet and housed at 23 degrees C remained sensitive to peripheral leptin and specifically lost body fat. This study tested whether leptin action was impaired by a combination of elevated environmental temperature and a HF diet. Male C57BL/6 mice were adapted to low-fat (LF) or HF diet from 10 days of age and were housed at 27 degrees C from 28 days of age. From 35 days of age, baseline food intake and body weight were recorded for 1 wk and then mice on each diet were infused with 10 microg leptin/day or PBS from an intraperitoneal miniosmotic pump for 13 days. HF-fed mice had a higher energy intake than LF-fed mice and were heavier but not fatter. Serum leptin was lower in PBS-infused HF- than LF-fed mice. Leptin significantly inhibited energy intake of both LF-fed and HF-fed mice, and this was associated with a significant increase in hypothalamic long-form leptin receptors with no change in short-form leptin receptor or brown fat uncoupling protein-1 mRNA expression. Leptin significantly inhibited weight gain in both LF- and HF-fed mice but reduced the percentage of body fat mass only in LF-fed mice. The percentage of lean and fat tissue in HF-fed mice did not change, implying that overall growth had been inhibited. These results suggest that dietary fat modifies the mechanisms responsible for leptin-induced changes in body fat content and that those in HF-fed mice are sensitive to environmental temperature. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Diet; Dietary Fats; Energy Intake; Environment; Epididymis; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Temperature; Thermogenesis | 2004 |
Region-specific leptin resistance within the hypothalamus of diet-induced obese mice.
Leptin resistance in diet-induced obese (DIO) mice is characterized by elevated serum leptin and a decreased response to exogenous leptin and is caused by unknown defects in the central nervous system. Leptin normally acts on several brain nuclei, but a detailed description of leptin resistance within individual brain regions has not been reported. We first mapped leptin-responsive cells in brains from DIO mice using phospho-signal transducer and activator of transcription (P-STAT3) immunohistochemistry. After 16 wk of high-fat-diet feeding, leptin-activated P-STAT3 staining within the arcuate nucleus (ARC) was dramatically decreased. In contrast, other hypothalamic and extrahypothalamic nuclei remained leptin sensitive. Reduced leptin-induced P-STAT3 in the ARC could also be detected after 4 wk and as early as 6 d of a high-fat diet. To examine potential mechanisms for leptin-resistant STAT3 activation in the ARC of DIO mice, we measured mRNA levels of candidate signaling molecules in the leptin receptor-STAT3 pathway. We found that the level of suppressor of cytokine signaling 3 (SOCS-3), an inhibitor of leptin signaling, is specifically increased in the ARC of DIO mice. The study suggests that the ARC is selectively leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus. Defects in leptin action in the ARC may play a role in the pathogenesis of leptin-resistant obesity. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Dietary Fats; Dorsomedial Hypothalamic Nucleus; Eating; Hyperphagia; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Repressor Proteins; RNA, Messenger; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors; Ventromedial Hypothalamic Nucleus | 2004 |
Chronic central administration of ghrelin reverses the effects of leptin.
To determine whether chronic central administration of ghrelin can block the effects of leptin on food intake, adiposity, and plasma concentrations of metabolic parameters and hormones.. Intracerebroventricular (ICV) infusions of leptin (5 microg/day) for 7 days, with or without ghrelin (1.2 microg/day), in rats. Rats administered leptin plus ghrelin were divided into ad lib-fed and food-restricted groups.. Body weight and food intake were monitored daily. Following killing on day 8, epididymal fat weight and fasting plasma concentrations of glucose, insulin, leptin, ghrelin, IGF-1, and adiponectin were determined.. ICV infusion of leptin decreased food intake by 39% and fat weight by 41%. Leptin decreased plasma concentrations of glucose, insulin, and leptin and increased plasma ghrelin levels. Central coadministration of ghrelin blocked the effects of leptin. Most of the effects of ghrelin were diminished by food restriction but ghrelin effect on adiposity and plasma insulin concentrations remained in food-restricted rats.. Chronic central administration of ghrelin reversed the effects of leptin, primarily by altering food intake, but ghrelin may have regulatory effects on adiposity and plasma insulin levels independent of feeding effect. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Drug Administration Schedule; Eating; Ghrelin; Insulin; Leptin; Male; Obesity; Peptide Hormones; Rats; Rats, Sprague-Dawley | 2004 |
Effects of diet and time of the day on serum and CSF leptin levels in Osborne-Mendel and S5B/Pl rats.
To characterize the effects of dietary fat on the diurnal variation in serum and cerebrospinal fluid (CSF) leptin levels in Osborne-Mendel (OM) and S5B/Pl rats and quantitate the dose response to lower doses of leptin administered into the third cerebral ventricle.. Rats were fitted with implanted vascular ports or third ventricular cannulas and fed either laboratory chow or one of two semipurified high-fat or low-fat diets. Leptin and insulin were measured by immunoassay.. Serum leptin and insulin levels were positively correlated and had similar patterns of diurnal change. CSF leptin and insulin also had diurnal rhythms, with a peak at 7:00 am, but the diurnal oscillations of leptin and insulin were significantly lower in the S5B/Pl rats than the OM rats. Thus, the ratio of CSF to serum leptin was significantly higher in the S5B/Pl rats than in the OM rats. Dietary fat had no effect on these diurnal patterns. There was a right shift in the dose response to leptin in the OM rats compared with the S5B/P1 rats. S5B/P1 rats treated with leptin had higher signal transduction and translation (STAT-3) mRNA levels compared with pair-fed or saline injected S5B/P1 rats. Hypothalamic suppressors of cytokine signaling mRNA levels were not statistically different between the groups.. The higher CSF-to-serum leptin ratio in the S5B/P1 rats, the enhanced suppression of food intake and body weight with leptin injections, and the higher STAT-3 activity in these animals suggest that S5B/P1 rats are more sensitive to leptin than OM rats. Topics: Animals; Body Weight; Circadian Rhythm; Corticosterone; Diet; Dietary Fats; DNA-Binding Proteins; Dose-Response Relationship, Drug; Drug Resistance; Eating; Insulin; Leptin; Male; Obesity; Rats; Rats, Mutant Strains; Repressor Proteins; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Trans-Activators; Transcription Factors | 2004 |
Triiodothyronine stimulates food intake via the hypothalamic ventromedial nucleus independent of changes in energy expenditure.
Increased food intake is characteristic of hyperthyroidism, although this is presumed to compensate for a state of negative energy balance. However, here we show that the thyroid hormone T(3) directly stimulates feeding at the level of the hypothalamus. Peripheral administration of T(3) doubled food intake in ad libitum-fed rats over 2 h and induced expression of the immediate early gene, early growth response-1, in the hypothalamic ventromedial nucleus (VMN), whereas maintaining plasma-free T(3) levels within the normal range. T(3)-induced feeding occurred without altering energy expenditure or locomotion. Injection of T(3) directly into the VMN produced a 4-fold increase in food intake in the first hour. The majority of T(3) in the brain is reported to be produced by tissue-specific conversion of T(4) to T(3) by the enzyme type 2 iodothyronine deiodinase (D2). Hypothalamic D2 mRNA expression showed a diurnal variation, with a peak in the nocturnal feeding phase. Hypothalamic D2 mRNA levels also increased after a 12- and 24-h fast, suggesting that local production of T(3) may play a role in this T(3) feeding circuit. Thus, we propose a novel hypothalamic feeding circuit in which T(3), from the peripheral circulation or produced by local conversion, stimulates food intake via the VMN. Topics: Adipose Tissue; Animals; Body Weight; Circadian Rhythm; Eating; Energy Metabolism; Fasting; Gene Expression Regulation, Enzymologic; Hyperthyroidism; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Leptin; Male; Rats; Rats, Wistar; RNA, Messenger; Thyroxine; Triiodothyronine; Ventromedial Hypothalamic Nucleus | 2004 |
Inhibition of hepatic gluconeogenesis and enhanced glucose uptake contribute to the development of hypoglycemia in mice bearing interleukin-1beta- secreting tumor.
Mice bearing IL-1beta-secreting tumor were used to study the chronic effect of IL-1beta on glucose metabolism. Mice were injected with syngeneic tumor cells transduced with the human IL-1beta gene. Serum IL-1beta levels increased exponentially with time. Secretion of IL-1beta from the developed tumors was associated with decreased food consumption, reduced body weight, and reduced blood glucose levels. Body composition analysis revealed that IL-1beta caused a significant loss in fat tissue without affecting lean body mass and water content. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities and mRNA levels of these enzymes were reduced, and 2-deoxy-glucose uptake by peripheral tissues was enhanced. mRNA levels of glucose transporters (Gluts) in the liver were determined by real-time PCR analysis. Glut-3 mRNA levels were up-regulated by IL-1beta. Glut-1 and Glut-4 mRNA levels in IL-1beta mice were similar to mRNA levels in pair-fed mice bearing nonsecreting tumor. mRNA level of Glut-2, the major Glut of the liver, was down-regulated by IL-1beta. We concluded that both decreased glucose production by the liver and enhanced glucose disposal lead to the development of hypoglycemia in mice bearing IL-1beta-secreting tumor. The observed changes in expression of hepatic Gluts that are not dependent on insulin may contribute to the increased glucose uptake. Topics: Animals; Anorexia; Blood Glucose; Body Composition; Body Weight; C-Peptide; Cell Line, Tumor; Eating; Female; Fibrosarcoma; Gluconeogenesis; Glucose; Glucose-6-Phosphatase; Glycogen; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Interleukin-1; Leptin; Liver; Mice; Mice, Inbred C57BL; Monosaccharide Transport Proteins; Neoplasm Transplantation; Protein Serine-Threonine Kinases; RNA, Messenger | 2004 |
Gallbladder myocytes are short and cholecystokinin-resistant in obese diabetic mice.
Obesity is associated with diabetes and gallstone formation. Obese leptin-deficient (Lepob) and leptin-resistant (Lepdb) mice are hyperglycemic and have enlarged gallbladders with diminished response in vitro to cholecystokinin (CCK) and acetylcholine (ACh). Whether this phenomenon is secondary to hyperosmolar myocytes and/or decreased neuromuscular transmission remains unclear. We hypothesize that myocytes from Lepob and Lepdb obese mice would not respond normally to neurotransmitters.. Cholecystectomy was performed on 39 lean, 19 Lepob, and 20 Lepdb 12-week-old female mice. The gallbladder was divided and enzymatically digested. Half of each gallbladder's myocytes had contraction induced by CCK (10(-8) mol/L, n = 38) or ACh (10(-5) mol/L, n = 40).. Body weights, gallbladder volumes, and serum glucoses were greater for Lep(ob) and Lepdb mice compared to controls (P < .001). Resting myocyte lengths from Lepob and Lepdb mice were 93% and 91% of the length of controls (P < .001). In response to CCK, lean myocytes shortened 6% (P < .01), while myocytes from obese mice demonstrated no shortening. None of the myocytes demonstrated significant shortening with ACh.. These data suggest that gallbladder myocytes from obese mice are (1) foreshortened and (2) have a diminished response to cholecystokinin. We conclude that altered leptin and/or increased glucose may foreshorten myocytes and decrease response to cholecystokinin. Topics: Acetylcholine; Animals; Blood Glucose; Body Weight; Cholecystokinin; Diabetes Mellitus; Female; Gallbladder; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle Contraction; Myocytes, Smooth Muscle; Obesity | 2004 |
The relationship among serum cytokines, chemokine, nitric oxide, and leptin in children with type 1 diabetes mellitus.
The aim of this study was to investigate the relationship between cytokines, leptin and vascular tone-related chemokine and nitric oxide (NO) in type 1 diabetic children.. Serum samples were collected from 58 children with type 1 diabetes and 33 of their healthy siblings.. Serum interleukin (IL)-8 was significantly higher and serum nitric oxide was significantly lower in the children with diabetes than in their healthy siblings. Stepwise regression analysis showed that there were significantly positive correlations between IL-1beta and IL-6, IL-1beta and nitric oxide, IL-4 and tumor-necrosis factor (TNF)-alpha, IL-4 and leptin, IL-8 and IL-2, and interferon (IFN)-gamma and IL-6, as well as significantly inversed correlations between IL-6 and IL-2, IL-8 and interferon-gamma, and leptin and TNF-alpha in siblings, not in the children with diabetes. However, there were significantly positive correlations between IL-2 and IL-4, IL-2 and leptin, IL-4 and IL-6, and TNF-alpha and IL-6 in children with diabetes.. Our results suggest that the alterations of circulating IL-8 and nitric oxide levels and cytokine network in children with diabetes may be associated with the cardiovascular disease in their adulthood. Topics: Adolescent; Adult; Body Mass Index; Body Weight; Chemokines; Child; Child, Preschool; Cytokines; Diabetes Mellitus, Type 1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant; Interferon-gamma; Interleukin-1; Interleukin-2; Interleukin-6; Interleukin-8; Leptin; Male; Nitric Oxide; Regression Analysis | 2004 |
Physiological regulation of hypothalamic IL-1beta gene expression by leptin and glucocorticoids: implications for energy homeostasis.
Interleukin-1beta (IL-1beta) is synthesized in a variety of tissues, including the hypothalamus, where it is implicated in the control of food intake. The current studies were undertaken to investigate whether hypothalamic IL-1beta gene expression is subject to physiological regulation by leptin and glucocorticoids (GCs), key hormones involved in energy homeostasis. Adrenalectomy (ADX) increased hypothalamic IL-1beta mRNA levels twofold, measured by real-time PCR (P < 0.05 vs. sham-operated controls), and this effect was blocked by subcutaneous infusion of a physiological dose of corticosterone. Conversely, hypothalamic IL-1beta mRNA levels were reduced by 30% in fa/fa (Zucker) rats, a model of genetic obesity caused by leptin receptor mutation (P = 0.01 vs. lean littermates), and the effect of ADX to increase hypothalamic IL-1beta mRNA levels in fa/fa rats (P = 0.02) is similar to that seen in normal animals. Moreover, fasting for 48 h (which lowers leptin and raises corticosterone levels) reduced hypothalamic IL-1beta mRNA levels by 30% (P = 0.02), and this decrease was fully reversed by refeeding for 12 h. Thus leptin and GCs exert opposing effects on hypothalamic IL-1beta gene expression, and corticosterone plays a physiological role to limit expression of this cytokine in both the presence and absence of intact leptin signaling. Consistent with this hypothesis, systemic leptin administration to normal rats (2 mg/kg ip) increased hypothalamic IL-1beta mRNA levels twofold (P < 0.05 vs. vehicle), an effect similar to that of ADX. These data support a model in which expression of hypothalamic IL-1beta is subject to opposing physiological regulation by corticosterone and leptin. Topics: Adrenalectomy; Animal Feed; Animals; Body Weight; Corticosterone; Eating; Energy Metabolism; Fasting; Gene Expression; Hypothalamus; Interleukin-1; Leptin; Male; Obesity; Rats; Rats, Wistar; Rats, Zucker; RNA, Messenger | 2004 |
Light/dark cycle-dependent metabolic changes in adipose tissue of pinealectomized rats.
We investigated the effects of pinealectomy on adipose tissue metabolism at different times of day. Adult male Wistar rats were divided into two groups: pinealectomized and control (sham-operated). Eight weeks after surgery, the animals were killed at three different times (at 8.00 a.m., at 4.00 p.m. and 11.00 p.m.). We collected blood samples for glucose, insulin, corticosterone, and leptin determinations, and periepididymal adipocytes for in vitro insulin-stimulated glucose uptake, oxidation, and incorporation into lipids. Pinealectomy caused insulin resistance as measured by 2-deoxyglucose uptake (a fall of approximately 40 % in the maximally insulin-stimulated rates) accompanied by hypercorticosteronemia at the three time points investigated without changes in plasma insulin an or leptin levels. Furthermore, pinealectomy increased the insulin-induced glucose incorporation into lipids (77 %) at 4.00 p.m. and insulin-induced glucose oxidation in the morning and in the afternoon, while higher rates were observed in the evening and in the morning in control rats. In conclusion, cell responsiveness to insulin was differentially affected by pineal ablation and time of day, and persistent insulin resistance was obtained in pinealectomized rats. We hypothesize that pinealectomy exposes the animal to an inadequate match between energy requirements and fuel mobilization. Topics: Adipocytes; Adipose Tissue; Analysis of Variance; Animals; Blood Glucose; Body Weight; Circadian Rhythm; Corticosterone; Energy Metabolism; Insulin; Insulin Resistance; Leptin; Light; Lipid Metabolism; Male; Melatonin; Photoperiod; Pineal Gland; Rats; Rats, Wistar; Receptor, Insulin | 2004 |
[Role of leptin in development of peripubertal boys].
To study the role of leptin in the development boys during their puberty and its relationship with insulin (INS), growth hormone (GH), estradiol (E2) and testosterone (T).. One hundred and fifty boys with simple obese aged 7 to 17 years, 150 normal healthy boys and 150 boys with malnutrition matched for age (+/- 3 months) and height (+/- 2 cm) were selected. Serum levels of leptin, INS, GH, E2 and T were measured for them.. Serum level of leptin in obese group was significantly higher than that in normal group, and that in normal group was significantly higher than that in malnourished group. In the all three groups, serum level of leptin increased with age first until peak value, then began to decrease, with peak value of 6.96 microg/L at ages of 10-11 y in obese group, 10.25 microg/L at ages of 11-12 y in normal group and 5.08 microg/L at ages of 11-12 y in malnourished group. Serum level of leptin increased steadily from Tanner stages G1 to G2, then began to decrease steadily in G2 to G4. Serum level of leptin increased again in stage G5. Serum level of INS in boys increased steadily with age from 7 to 17 years old. Serum levels of GH, T and E2 in boys began to increase since 10-11 years old. Serum level of leptin positively correlated with serum level of INS and negatively correlated with serum levels of GH and T, but not correlated with serum level of E2.. Leptin may promote pubertal development of boys, but not the determinant factor in triggering and maintaining their pubertal development. Re-increase in level of leptin during stage G5 could inhibit secretion of GH, and signalize the end of puberty in boys. Topics: Adolescent; Body Height; Body Mass Index; Body Weight; Child; Estradiol; Growth Hormone; Humans; Leptin; Male; Puberty; Testosterone | 2004 |
Reduced brain CRH and GR mRNA expression precedes obesity in juvenile rats bred for diet-induced obesity.
To assess the role of endogenous peptides involved in stress responsivity in the development of diet-induced obesity (DIO), selectively bred DIO and diet-resistant (DR) male were weaned onto a low fat (4.5%) chow diet at 3 weeks of age and then fed either chow or a 31% fat by energy content (high energy (HE)) diet for 9 days beginning at 4 weeks of age. Regardless of diet, DIO rats gained more weight than DR rats but did not show the selective DIO weight gain trait characteristic of older DIO rats fed HE diet. At this early age, both DR and DIO rats on HE diet ate more and had higher leptin levels but gained less body weight and had lower feed efficiency (body weight gain (g)/food intake (kcal)) than their chow-fed controls. HE diet also prevented the decline in 24h urine corticosterone levels from the third to fifth week observed in chow-fed rats. Terminally, DIO rats had lower hippocampal glucocorticoid receptor (GR) and amygdalar central nucleus corticotrophin-releasing hormone (CRH) mRNA than DR rats, regardless of their diets. Taken together with prior studies in these rats, there appears to be a critical period between 3 and 5 weeks of age when DIO and DR rats are not phenotypically different and hypothalamo-pituitary-adrenal (HPA) function is rapidly changing. The reduced expression of brain GR and CRH expression at the end of this period might contribute to the propensity of DIO rats to become obese selectively on HE diet after 5 weeks of age. Topics: Age Factors; Analysis of Variance; Animals; Body Weight; Brain Chemistry; Corticotropin-Releasing Hormone; Dietary Fats; Eating; Gene Expression Regulation; In Situ Hybridization; Leptin; Male; Obesity; Oligoribonucleotides, Antisense; Rats; Receptors, Glucocorticoid; RNA, Complementary; RNA, Messenger; Time Factors; Weight Gain | 2004 |
Ciliary neurotrophic factor injected icv induces adipose tissue apoptosis in rats.
Recent findings show that ciliary neurotrophic factor (CNTF) and leptin have similar effects on food intake and body weight, suggesting possible overlapping mechanisms. Intracerebroventricular (icv) injection of leptin results in adipose tissue apoptosis. To determine if CNTF has similar activity, male Sprague Dawley rats implanted with lateral cerebroventricular cannulas were randomly assigned to four treatment groups ( N = 8), including control (aCSF), 10 microg/day leptin, 1 microg/day CNTF, and 5 microg/day CNTF. Rats received daily icv injections for 4 successive days. Both leptin and CNTF (5 microg) decreased BW (8.6% and 11.77%, respectively, p <.05) and cumulative food intake was decreased 43% by leptin ( p <.05). Leptin and CNTF (5 microg) reduced adipose tissue mass in epididymal adipose (Epi) by 30 and 33.5%, ( p <.05), in inguinal adipose (Ing) by 51 and 55% ( p <.05), in retroperitoneal adipose (Rp) by 65 and 64% ( p <.05), and in intrascapular brown adipose (iBAT) by 34 and 25% ( p <.05), respectively. Gastrocnemius muscle was not affected. Leptin and CNTF (5 microg) increased apoptosis in Epi by 84 and 150%, respectively ( p <.05) and in Rp by 121 and 146%, respectively ( p <.05). Loss of adipocytes by apoptosis may provide an explanation for the unexpected delay in return to initial energy status following CNTF treatments. Topics: Adipose Tissue; Animals; Apoptosis; Body Weight; Cerebral Ventricles; Ciliary Neurotrophic Factor; Injections, Intraventricular; Leptin; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins | 2004 |
Impacts of dietary protein level and feed restriction during prepuberty on mammogenesis in gilts.
The possible roles of dietary protein level and feed restriction in regulating mammary development of prepubertal gilts were investigated. Cross-bred gilts were fed a commercial diet until 90 d of age and then divided into four nutritional regimens based on two pelleted diets (as-fed basis): a high-protein diet (HP = 13.8 MJ of ME, 1.0% total lysine, 18.7% CP) and a low-protein diet (LP = 13.8 MJ of ME, 0.7% total lysine, 14.4% CP). Nutritional regimens were as follows: 1) HP ad libitum until slaughter (n = 22, T1); 2) HP ad libitum until 150 d of age followed by LP until slaughter (n = 20, T2); 3) LP ad libitum until slaughter (n = 21, T3); and 4) HP with a 20% feed restriction until slaughter (n = 19, T4). Gilts were weighed, their backfat thickness was measured, and jugular blood samples were obtained on d 90, 150, and at slaughter to determine concentrations of prolactin, IGF-I, leptin, and glucose. Gilts were slaughtered 8+/-1 d after their first or second estrus (202.7+/-14.5 d of age). Mammary glands were excised, parenchymal and extraparenchymal tissues were dissected, and composition of parenchymal tissue (protein, fat, DM, DNA, protein/DNA) was determined. The T4 gilts weighed less (P < 0.01) and had less backfat (P < 0.01) than did gilts on other treatments on d 150 and at slaughter. Treatments had no significant effects on prolactin, IGF-I, or glucose concentrations, but there was a treatment x day interaction (P < 0.01) for leptin, with concentrations being lower at slaughter in restricted-fed (T4) vs. LP (T3) gilts (P < 0.05). There was less extraparenchymal mammary tissue (P < 0.01) in T4 gilts than in gilts from the other groups and a tendency (P = 0.13) for the amount of parenchymal tissue to be lower in T4 gilts. In conclusion, a lower lysine intake during prepuberty did not hinder mammary development of gilts, but a 20% feed restriction decreased mass of parenchymal and extraparenchymal tissues. The effect of feed restriction on extraparenchymal tissue is most likely associated with the lower fat deposition. Topics: Adipose Tissue; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Body Weight; Dietary Proteins; Dose-Response Relationship, Drug; Female; Food Deprivation; Insulin-Like Growth Factor I; Leptin; Mammary Glands, Animal; Nutritional Requirements; Prolactin; Random Allocation; Sexual Maturation; Swine | 2004 |
Modulation of adipoinsular axis in prediabetic zucker diabetic fatty rats by diazoxide.
Dysregulation of the adipoinsular axis in male obese Zucker diabetic fatty (ZDF; fa/fa) rats, a model of type 2 diabetes, results in chronic hyperinsulinemia and increased de novo lipogenesis in islets, leading to beta-cell failure and diabetes. Diazoxide (DZ; 150 mg/kg.d), an inhibitor of insulin secretion, was administered to prediabetic ZDF animals for 8 wk as a strategy for prevention of diabetes. DZ reduced food intake (P < 0.02) and rate of weight gain only in ZDF rats (P < 0.01). Plasma insulin response to glucose load was attenuated in DZ-Zucker lean rats (ZL; P < 0.01), whereas DZ-ZDF had higher insulin response to glucose than controls (P < 0.001). DZ improved hemoglobin A1c (P < 0.001) and glucose tolerance in ZDF (P < 0.001), but deteriorated hemoglobin A1c in ZL rats (P < 0.02) despite normal tolerance in the fasted state. DZ lowered plasma leptin (P < 0.001), free fatty acid, and triglyceride (P < 0.001) levels, but increased adiponectin levels (P < 0.02) only in ZDF rats. DZ enhanced beta3-adrenoreceptor mRNA (P < 0.005) and adenylate cyclase activity (P < 0.01) in adipose tissue from ZDF rats only, whereas it enhanced islet beta3- adrenergic receptor mRNA (P < 0.005) but paradoxically decreased islet adenylate cyclase activity (P < 0.005) in these animals. Islet fatty acid synthase mRNA (P < 0.03), acyl coenzyme A carboxylase mRNA (P < 0.01), uncoupling protein-2 mRNA (P < 0.01), and triglyceride content (P < 0.005) were only decreased in DZ-ZDF rats, whereas islet insulin mRNA and insulin content were increased in DZ-ZDF (P < 0.01) and DZ-ZL rats (P < 0.03). DZ-induced beta-cell rest improved the lipid profile, enhanced the metabolic efficiency of insulin, and prevented beta-cell dysfunction and diabetes in diabetes-prone animals. This therapeutic strategy may be beneficial in preventing beta-cell failure and progression to diabetes in humans. Topics: Adenylyl Cyclases; Adiponectin; Adipose Tissue; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diazoxide; Eating; Fasting; Glucose Intolerance; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Islets of Langerhans; Leptin; Male; Obesity; Rats; Rats, Zucker; Receptors, Adrenergic, beta-3; RNA, Messenger; Triglycerides | 2004 |
Bone turnover during inpatient nutritional therapy and outpatient follow-up in patients with anorexia nervosa compared with that in healthy control subjects.
Osteopenia and osteoporosis are among the most frequent and severe complications in adolescents with anorexia nervosa.. The aim of this study was to assess the influence of nutritional therapy on bone metabolism during adolescent anorexia nervosa.. We studied 19 anorectic patients aged 14.1 +/- 1.4 y (x +/- SD) with a body mass index (BMI; in kg/m(2)) of 14.2 +/- 1.4 and 19 age-matched control subjects aged 15.1 +/- 2.3 y with a BMI of 20.8 +/- 1.9 for 1 y. Blood samples were taken for the measurement of bone markers, insulin-like growth factor I (IGF-I), and leptin.. BMI rose significantly from 14.2 +/- 1.4 at baseline to 17.4 +/- 0.6 (P < 0.0001) at week 15. Compared with concentrations in the control subjects, concentrations of the bone formation markers procollagen type I propeptide (PICP) and bone alkaline phosphatase (bAP) in the anorectic patients were lower at baseline (PICP: P = 0.0071; bAP: P = 0.0012), increased with nutritional therapy (PICP: P = 0.0060, bAP: P = 0.0147), and were no longer significantly different (P > 0.05) during the follow-up period. Concentrations of IGF-I and leptin were significantly lower (P < 0.0001 for both) in the anorectic patients than in the control subjects at baseline. IGF-I increased with nutritional therapy but was still significantly lower (P = 0.0036) than that in the control group and decreased again during the follow-up period (P = 0.0126). In contrast, serum C-telopeptide decreased with nutritional therapy (P = 0.0446).. Nutritional therapy improves concentrations of bone formation markers in adolescent patients with anorexia nervosa. Topics: Adolescent; Adolescent Nutritional Physiological Phenomena; Alkaline Phosphatase; Anorexia Nervosa; Biomarkers; Body Mass Index; Body Weight; Bone and Bones; Case-Control Studies; Collagen Type I; Female; Follow-Up Studies; Humans; Inpatients; Insulin-Like Growth Factor I; Leptin; Nutrition Therapy; Nutritional Status; Osteogenesis; Treatment Outcome | 2004 |
Selenium deficiency impairs corticosterone and leptin responses to adrenocorticotropin in the rat.
Selenium deficiency causes oxidative stress and impairs steroidogenesis in vitro. Leptin is closely related to the hypothalamo-pituitary-adrenal (HPA) axis. Leptin inhibits the HPA axis at the central level while corticosteroids have been shown to stimulate leptin secretion in most studies. We hypothesized that oxidative stress impairs adrenal steroidogenesis and decreases leptin production in vivo. The goal of this study was to investigate in rats the effects of selenium deficiency and oxidative stress on adrenal function and on leptin concentrations. Weanling rats were fed a selenium-deficient (Se-) or selenium-sufficient (Se+) diet for 4-10 weeks. Selenium deficiency caused a marked decrease in liver (> or = 99%) and adrenal (> or = 81%) glutathione peroxidase (GPx) activities. Selenium deficiency did not affect basal and short-term adrenocorticotropin (ACTH) stimulated corticosterone or leptin concentrations. In contrast, after long-term ACTH stimulation, selenium deficiency caused a doubling in adrenal isoprostane content and blunted the increase in corticosterone and leptin concentrations observed in Se+ animals. Plasma leptin concentrations were 50% lower in Se- compared to Se+ animals following long-term ACTH. Our results suggest that oxidative stress causes a decrease in circulating corticosterone in response to ACTH, and, as a consequence, a decrease in plasma leptin concentrations. Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; Body Weight; Corticosterone; Glutathione Peroxidase; Isoprostanes; Leptin; Liver; Male; Organ Size; Oxidative Stress; Rats; Rats, Sprague-Dawley; Selenium; Thyroxine; Weaning | 2004 |
Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity.
Histamine H(1) receptors (H(1)-Rs) are found in peripheral tissues and in regions of the hypothalamus that are concerned with regulating body composition. In the present study, we investigated the detailed mechanisms of histamine H(1)-Rs in the development of obesity. Histamine H(1)-R knockout (H1KO) mice gradually developed mature-onset obesity, which was accompanied by hyperphagia and decreased expression of uncoupling protein-1 (UCP-1) mRNA. Both younger nonobese (12-week-old) and older obese (48-week-old) H1KO mice exhibited impairment of the responsiveness to the leptin. In addition, disruption of the diurnal rhythm of feeding occurred before the onset of obesity in H1KO mice. Correction of these abnormal feeding rhythms by means of scheduled feeding caused a reduction in obesity and associated metabolic disorders in H1KO mice. Furthermore, central administration of a histamine H(1)-R agonist affected feeding behavior, body weight, and c-fos-like immunoreactivity in the hypothalamus. Taken together, these findings suggest that histamine H(1)-Rs are crucial for the regulation of feeding rhythm and in mediating the effects of leptin. Early disruption of H(1)-R-mediated functions in H1KO mice may lead to hyperphagia and decreased expression of UCP-1 mRNA, which may contribute to the development of obesity in these animals. In addition, centrally acting histamine H(1)-R may be a novel therapeutic target for the treatment of obesity and related metabolic disorders. Topics: Adipose Tissue, Brown; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Carrier Proteins; Dorsomedial Hypothalamic Nucleus; Fatty Acids, Nonesterified; Feeding Behavior; Gene Expression; Histamine; Histamine Agonists; Hypothalamic Area, Lateral; Hypothalamus; Insulin; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Obesity; Proto-Oncogene Proteins c-fos; Pyridines; Receptors, Histamine H1; RNA, Messenger; Suprachiasmatic Nucleus; Triglycerides; Uncoupling Protein 1 | 2004 |
Increased serum leptin protects from adiposity despite the increased glucose uptake in white adipose tissue in mice lacking p85alpha phosphoinositide 3-kinase.
Mice lacking the p85alpha regulatory subunit of phosphoinositide (PI) 3-kinase (Pik3r1(-/-)) showed increased glucose uptake in white adipose tissue (WAT) and skeletal muscle due to increased phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P3] production and on a normal diet had a body weight and fat mass similar to wild-type mice. After 3 months on a high-fat diet, Pik3r1(-/-) mice still had increased insulin sensitivity and better glucose tolerance than wild-type mice, but showed markedly greater increases in body weight and WAT mass than wild-type mice. On the normal diet, serum leptin levels of Pik3r1(-/-) mice were significantly higher than in wild-type mice as a result of increased leptin secretion from adipocytes, presumably due to the increased PtdIns(3,4,5)P3 production in adipocytes. Leptin (5 microg/g body wt per day) caused a reduction in food intake and decrease in body weight by the wild-type mice as well as Pik3r1(-/-) mice, suggesting Pik3r1(-/-) mice having leptin sensitivity similar to wild-type mice. The slightly increased serum leptin compensated for the increased glucose uptake by adipocytes in Pik3r1(-/-) mice, thereby preventing adiposity on the normal diet. On the high-fat diet, leptin (5 microg/g body wt per day) failed to decrease food intake or body weight in either genotype, indicating that both genotypes had indeed become severely leptin resistant. Consequently, leptin secretion was unable to sufficiently compensate for the severe leptin resistance caused by the high-fat diet, thereby failing to prevent obesity in Pik3r1(-/-) mice. Our findings suggest that primary increase in serum leptin on the normal diet play a role in the protection from adiposity in Pik3r1(-/-) mice. Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Body Weight; Dietary Fats; Female; Glucose; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Mutant Strains; Obesity; Phosphatidylinositol 3-Kinases; Proteins; Uridine Diphosphate N-Acetylgalactosamine | 2004 |
The yellow agouti mutation alters some but not all responses to diet and exercise.
Effects of ectopic expression of the agouti signaling protein were studied on responses to diet restriction and exercise in C57BL/6J (B6) mice and obese B6 mice congenic for the yellow agouti mutation [B6.Cg-Ay (Ay)].. Adult male Ay mice were either kept sedentary or exercised on a running wheel and fed ad libitum or diet restricted until weight matched to ad libitum-fed B6 control mice. Body composition, plasma lipids, leptin, and adiponectin were measured. mRNA levels for leptin, adiponectin, lipoprotein lipase, and pyruvate dehydrogenase kinase 4 were measured in a visceral (epididymal) and a subcutaneous (femoral) fat depot by real-time polymerase chain reaction.. Correlations among traits exhibited one of three patterns: similar lines for B6 and Ay mice, different slopes for B6 and Ay mice, and/or different intercepts for B6 and Ay mice. Correlations involving plasma leptin, mesenteric and epididymal adipose weights, or low-density lipoprotein-cholesterol were most likely to have different slopes and/or intercepts in B6 and Ay mice. mRNA levels for leptin, Acrp30, pyruvate dehydrogenase kinase 4, and lipoprotein lipase in epididymal adipose tissue were not correlated with corresponding levels in femoral adipose tissue.. The agouti protein interferes with leptin signaling at melanocortin receptors in the hypothalamus of Ay mice. Our results are consistent with the hypothesis that the melanocortin portion of the leptin-signaling pathway mediates effects primarily on certain fat depots and on some, but not all, components of cholesterol homeostasis. Topics: Adiponectin; Adipose Tissue; Agouti Signaling Protein; Animals; Body Composition; Body Weight; Cholesterol; Diet; Eating; Food Deprivation; Intercellular Signaling Peptides and Proteins; Leptin; Lipids; Lipoprotein Lipase; Male; Mice; Mice, Inbred C57BL; Mutation; Obesity; Organ Size; Physical Exertion; Protein Kinases; Proteins; RNA, Messenger; Signal Transduction | 2004 |
Diet-induced changes in stearoyl-CoA desaturase 1 expression in obesity-prone and -resistant mice.
To investigate stearoyl-coenzyme A desaturase (SCD) 1 expression in obesity-prone C57BL/6 mice and in obesity-resistant FVB mice to explore the relationship of SCD1 expression and susceptibility to diet-induced obesity.. Nine-week-old C57BL/6 and FVB mice were fed either a high- or low-fat diet for 8 weeks. Body weight and body composition were measured before and at weeks 4 and 8 of the study. Energy expenditure was measured at weeks 1 and 5 of the study. Hepatic SCD1 mRNA was measured at 72 hours and at the end of study. Plasma leptin and insulin concentrations were measured at the end of study.. When C57BL/6 mice were switched to a calorie-dense high-fat diet, animals gained significantly more body weight than those maintained on a low-calorie density diet primarily due to increased fat mass accretion. Fat mass continued to accrue throughout 8 weeks of study. Increased calorie intake did not account for all weight gain. On the high-fat diet, C57BL/6 mice decreased their energy expenditure when compared with mice fed a low-fat diet. In response to 8 weeks of a high-fat diet, SCD1 gene expression in liver increased >2-fold. In contrast, feeding a high-fat diet did not change body weight, energy expenditure, or SCD1 expression in FVB mice.. Our study showed that a high-fat hypercaloric diet increased body adiposity first by producing hyperphagia and then by decreasing energy expenditure of mice susceptible to diet-induced obesity. Consumption of a high-fat diet in species predisposed to obesity selectively increased SCD1 gene expression in liver. Topics: Animals; Body Composition; Body Weight; Calorimetry, Indirect; Dietary Fats; Eating; Energy Intake; Energy Metabolism; Gene Expression; Genetic Predisposition to Disease; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stearoyl-CoA Desaturase | 2004 |
Body fat, leptin, and hypothalamic amenorrhea.
Topics: Adipose Tissue; Age of Onset; Amenorrhea; Anorexia Nervosa; Body Composition; Body Weight; Diagnosis, Differential; Exercise; Female; Humans; Hypothalamic Diseases; Leptin; Obesity; Thinness | 2004 |
Leptin modulates fertility under the influence of elevated growth hormone as modeled in oMt1a-oGH transgenic mice.
Elevated growth hormone (GH) concentrations suppress reproductive function in a variety of species, although it is unclear whether GH directly suppresses reproductive performance, or whether GH activates other pathways to achieve these effects. The ovine metallothionein 1a-ovine GH (oMt1a-oGH) transgenic mouse has been used to model the effects of GH on both body composition and reproductive function. A recent report has documented increased leptin levels in obese oMt1a-oGH mice. Given the importance of leptin in modulation of the reproductive endocrine axis, as well as the reports documenting reduced leptin signal transduction in animals with elevated leptin levels, we hypothesized that high leptin concentrations in response to elevated GH would reduce fertility. To determine the effects of high circulating leptin levels on the reproductive endocrine axis, we assessed hypothalamic neuropeptide Y (NPY) and GnRH expression. At weaning, oMt1a-oGH transgenic (TG) and wild-type (WT) female mice were allocated to one of four treatment groups: oMt1a-oGH females chronically expressing the transgene (TG ON); oMt1a-oGH females expressing the transgene from 3 to 8 weeks of age (TG ON/OFF); WT females receiving the transgene stimulus from 3 to 8 weeks of age (WT ON/OFF); and WT females never receiving the transgene stimulus (WT OFF). Eight-week-old females were housed with males for a 2-week period, after which females were isolated from males and allowed to carry pregnancies to term. Body and gonadal fat pad (GFP) weights, along with plasma leptin concentrations, estrous cyclicity, pregnancy rate and litter characteristics, were recorded for each female. Chronic expression of the oMt1a-oGH transgene resulted in larger leaner mice, and inactivation of the transgene produced obese females. Pregnancy rate was reduced in TG ON females when compared with all other groups, and infertility was associated with elevated leptin levels. In addition, high leptin levels were associated with increased NPY expression, suggesting reduced leptin-signaling capacity, which may contribute to suppression of the reproductive axis in oGH animals. Topics: Animals; Body Composition; Body Weight; Estrous Cycle; Female; Fertility; Gonadotropin-Releasing Hormone; Growth Hormone; Hypothalamus; In Situ Hybridization; Leptin; Litter Size; Metallothionein; Mice; Mice, Transgenic; Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction | 2004 |
Independence of hyperleptinemia-induced fat disappearance from thyroid hormone.
Sustained hyperleptinemia induced in normal rats causes the rapid disappearance of body fat. This is attributed to a marked increase in uncoupled fatty acid oxidation in the white adipocytes, which also occurs in hyperthyroidism. Because hyperleptinemic rats have normal plasma T3 or T4 levels, we tested the possibility of "localized hyperthyroidism" due to increased conversion of T4 to T3 in the adipose tissue. We therefore induced sustained hyperleptinemia in normal rats by intravenous injection of recombinant adenovirus containing the leptin cDNA (AdCMV-leptin) and measured the mRNA and the activity of enzymes involved in T4 metabolism in the disappearing fat. The epididymal fat pad remnants exhibited a decrease in mRNA of deiodinase 1 and a doubling of deiodinase 2 mRNA (p<0.05), but their enzyme activities did not differ from normoleptinemic controls. To determine if thyroid hormone was required for the fat-wasting action of hyperleptinemia, we infused AdCMV-leptin into rats made athyroid by total thyroidectomy or by methimazole therapy. The fat loss in hyperleptinemic athyroid rats was as great as in euthyroid controls. We conclude that the fat-wasting effect of sustained hyperleptinemia does not involve "local hyperthyroidism" in white adipose tissue and does not require thyroid hormone. Topics: Adipose Tissue; Animals; Body Weight; DNA, Complementary; Fats; Fatty Acids; Iodide Peroxidase; Leptin; Male; Methimazole; Oxygen; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroid Hormones; Thyroxine; Triiodothyronine | 2004 |
A novel IKKbeta inhibitor stimulates adiponectin levels and ameliorates obesity-linked insulin resistance.
Adiponectin is an anti-diabetic and anti-atherogenic hormone that is exclusively secreted from fat cells. Serum adiponectin levels are reduced in obese patients and obese model mice, despite increased adipose tissue mass. Elucidation of the mechanism(s) by which plasma adiponectin levels are decreased in obese and diabetic patients would provide insight into the cause of obesity-induced diabetes and the development of therapeutic advances. In the present study, the regulation of adiponectin secretion was investigated using 3T3-L1 adipocytes and a diabetic-/obese-mouse model. A novel insulin sensitizer, IkappaB kinase beta (IKKbeta) inhibitor, ameliorated insulin resistance and up-regulated plasma levels of adiponectin without producing a significant change in body weight in KKAy mice that were fed a high-fat diet. The IKKbeta inhibitor cancelled the TNFalpha-mediated down-regulation of adiponectin secretion and simultaneously up-regulated the phosphorylation of Akt in 3T3-L1 adipocytes. Using dominant-negative mutants of Akt or PKClambda (downstream effectors of phosphoinositide 3-kinase), insulin-stimulated Akt activity was found to be important in the regulation of adiponectin secretion by insulin in 3T3-L1 adipocytes. These observations suggest that "insulin-stimulated Akt activity in adipocytes" may play an important role in the regulation of adiponectin secretion. Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Animals; Benzamides; Blood Glucose; Body Weight; Chromones; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Inhibitors; Gene Expression Regulation; Genes, Dominant; Glucose; I-kappa B Kinase; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Obese; Models, Biological; Morpholines; Obesity; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Time Factors; Up-Regulation | 2004 |
Bezafibrate-induced changes over time in the expression of uncoupling protein (UCP) mRNA in the tissues: a study in spontaneously type 2 diabetic rats with visceral obesity.
The effect of short-term bezafibrate (BF) administration over time on the expression of UCP mRNA in the tissues was examined in Otsuka Long Evans Tokushima Fatty (OLETF) rats. Eight-week-old rats were divided into a high-dose (100 mg/kg) BF group (n = 15), a low-dose (10 mg/kg) BF group (n = 15) and a control group (n = 15), and followed for 14 days. Feed intake by the high-dose BF group increased significantly between days 10 and 14 of administration. Triglyceride, free fatty acid, and T(4) levels decreased significantly in a dose-dependent manner in the high-dose BF group. Leptin and insulin levels significantly decreased on days 3 and 7. Throughout the study period, liver UCP2 mRNA increased in the high-dose BF group. On day 3 of BF administration, the levels of UCP2 mRNA expression in the skeletal muscles as well as UCP3 mRNA expression in the WAT were significantly increased in the high-dose BF group. PPAR-alpha mRNA significantly increased in the liver on day 3 of BF administration. We thus conclude that the PPAR-alpha-mediated effects of BF on the expression of liver UCP2 may be one of the factors that helped to decrease insulin levels. Topics: Animals; Bezafibrate; Blood Glucose; Body Weight; Carrier Proteins; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Eating; Fatty Acids; Gene Expression Regulation; Hypolipidemic Agents; Insulin; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mitochondrial Proteins; Obesity; PPAR alpha; PPAR delta; Rats; Rats, Inbred Strains; RNA, Messenger; Thyroid Hormones; Uncoupling Agents; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3; Viscera | 2004 |
The carboxypeptidase E knockout mouse exhibits endocrinological and behavioral deficits.
A carboxypeptidase E (CPE) knockout (KO) mouse was generated by deletion of exons 4 and 5 from the CPE gene, and its phenotype was characterized. KO mice became obese by 10-12 wk of age and reached 60-80 g by 40 wk. At this age, body fat content was more than double that in the wild-type (WT) controls. The null animals consumed more food overall, were less physically active during the light phase of the light-dark cycle, and burned fewer calories as fat than WT littermates. Fasting levels of glucose and insulin-like immunoreactivity in plasma were elevated in both male and female KO mice at approximately 20 wk; males recovered fully and females partially from this state by 32 wk. At this time, insulin-like immunoreactivity in the plasma, identified as proinsulin, was 50-100 times higher than that of the WT animals. The KO mice showed impaired glucose clearance and were insulin resistant. High levels of leptin and no circulating fully processed cocaine- and amphetamine-related transcript, a peptide that is responsive to leptin-induced feedback inhibition of feeding, were found in serum. The KO mice were subfertile and showed deficits in GnRH processing in the hypothalamus. Behavioral analyses revealed that KO animals showed diminished reactivity to stimuli and had reduced muscle strength and coordination, as well as visual placing and toe-pinch reflexes. These data demonstrate that CPE KO mice display a wide range of neural and endocrine abnormalities and suggest that CPE may have additional physiological roles beyond those ascribed to peptide processing and sorting of prohormones in cells. Topics: Adipose Tissue; Animals; Behavior, Animal; Body Size; Body Weight; Calorimetry, Indirect; Carboxypeptidase H; Chromatography, High Pressure Liquid; Drinking; Eating; Endocrine System Diseases; Female; Fertility; Glucose Intolerance; Insulin Resistance; Leptin; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Obesity; Phenotype; Proinsulin | 2004 |
Increases in melanin-concentrating hormone and MCH receptor levels in the hypothalamus of dietary-obese rats.
Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that stimulates feeding and increases body weight in rodents. We studied the role of the system in energy homeostasis and its regulation by the satiety signals, leptin and insulin. We used real-time PCR to measure the hypothalamic expression of MCH and its receptor (MCHR1) in two contrasting models of altered nutritional status, namely, obesity induced by 8 weeks' voluntary overeating and food restriction for 10 days. Diet-fed rats were stratified according to final total fat-pad mass into a 'high fat gain' group (HG) and 'low fat gain' group (LG). MCH mRNA levels were increased by 31% (p>0.05) and 49% (p<0.05) in the LG and HG, respectively, compared with controls. MCHR1 mRNA levels rose by 118% in the LG (p<0.01) and 85% in the HG (p<0.01). There were significant positive correlations (p<0.05) between plasma leptin concentration and both MCH and MCHR1 mRNA levels, and between plasma insulin and MCHR1 expression. A positive correlation was also observed between MCH and MCHR1 mRNA levels (p<0.05). Food-restricted rats showed no significant alterations in the levels of either MCH mRNA or MCHR1 mRNA. In a second experiment, we measured MCH peptide levels in five discrete hypothalamic areas of dietary-obese rats. MCH concentrations were significantly increased in the arcuate nuclei of the HG (p<0.05) and the paraventricular nuclei of both the LG (p<0.05) and HG (p<0.05), compared with their lean counterparts. These results suggest that the MCH system becomes more active in dietary obesity and could be involved in enhancing appetite for palatable food. The possibility that MCH and MCHR1 expression are positively regulated by leptin and insulin, which normally inhibit feeding, is a putative explanation for how appetite for palatable food is able to override mechanisms that prevent the development of obesity. Topics: Animals; Blood Glucose; Body Mass Index; Body Weight; Diet; Hypothalamic Hormones; Hypothalamus; Insulin; Leptin; Male; Melanins; Obesity; Pituitary Hormones; Radioimmunoassay; Rats; Receptors, Pituitary Hormone; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2004 |
A high carbohydrate diet induces insulin resistance through decreased glucose utilization in ovariectomized rats.
Recent research has reported that high sugar diets increase insulin resistance, without abdominal obesity, in male, but not female Wistar rats. Whether a high sucrose (SU) diet increased insulin resistance in ovariectomized (OVX) rats was determined.. Female Sprague Dawley rats, weighing 273 +/- 20 g, had either an ovariectomy or a sham operation (sham). OVX and sham rats were divided into two groups: one group had a 68 En% SU diet and the other a 68 En% starch (ST) diet for 8 weeks.. The body weight was higher in the OVX than the sham rats, regardless of dietary carbohydrate subtype. The fasting serum glucose levels did not differ according to diet and ovariectomy. However, the fasting serum insulin levels were higher in the OVX than the sham rats, and in the OVX rats, a high SU diet increased the serum insulin levels more than a high ST diet. The whole body glucose disposal rates, which referred to the state of insulin sensitivity, were lower in the OVX rats fed both the high SU and ST diets, compared to sham rats. Glycogen deposits in the soleus and quadriceps muscles were lower in the OVX rats fed high SU and ST diets than in sham rats. The glucose transporter 4 content and fraction velocity of glycogen synthase in muscles showed similar glucose disposal rates. However, the triacylglycerol content in the muscles were higher in the OVX rats with a high SU diet than those with a high ST diet.. These results suggested that an OVX increased the weight gain due to higher food intakes, regardless of dietary carbohydrate subtypes. OVX-induced obesity may be involved in the induction of insulin resistance from an increased triacylglycerol content, decreased glucose uptake and glycogen synthesis in skeletal muscles, regardless of dietary carbohydrate subtypes. Topics: Animals; Blood Glucose; Body Weight; Dietary Carbohydrates; Energy Intake; Estradiol; Female; Glucose Clamp Technique; Glucose Transporter Type 4; Glycogen; Glycogen Synthase; Insulin; Insulin Resistance; Leptin; Models, Animal; Muscle, Skeletal; Ovariectomy; Rats; Rats, Sprague-Dawley; Time Factors; Triglycerides | 2004 |
Effects of fenofibrate on high-fat diet-induced body weight gain and adiposity in female C57BL/6J mice.
Our previous study suggested that fenofibrate affects obesity and lipid metabolism in a sexually dimorphic manner in part through the differential activation of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) in male and female C57BL/6J mice. To determine whether fenofibrate reduces body weight gain and adiposity in female sham-operated (Sham) and ovariectomized (OVX) C57BL/6J mice, the effects of fenofibrate on not only body weight, white adipose tissue (WAT) mass, and food intake, but also the expression of both leptin and PPARalpha target genes were measured. Compared to their respective low-fat diet-fed controls, both Sham and OVX mice exhibited increases in body weight and WAT mass when fed a high-fat diet. Fenofibrate treatment decreased body weight gain and WAT mass in OVX, but not in Sham mice. Furthermore, fenofibrate increased the mRNA levels of PPARalpha target genes encoding peroxisomal enzymes involved in fatty acid beta-oxidation, and reduced apolipoprotein C-III (apo C-III) mRNA, all of which were expressed at higher levels in OVX compared to Sham mice. However, leptin mRNA levels were found to positively correlate with WAT mass, and food intake was not changed in either OVX or Sham mice following fenofibrate treatment. These results suggest that fenofibrate differentially regulates body weight and adiposity due in part to differences in PPARalpha activation, but not to differences in leptin production, between female OVX and Sham mice. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Dietary Fats; Eating; Fatty Acids; Female; Fenofibrate; Gene Expression Regulation; Hypolipidemic Agents; Leptin; Liver; Mice; Mice, Inbred C57BL; Ovariectomy; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Transcription Factors; Weight Gain | 2004 |
Circulating leptin mediates lipopolysaccharide-induced anorexia and fever in rats.
Anorexia and fever are important features of the host's response to inflammation that can be triggered by the bacterial endotoxin lipopolysaccharide (LPS) and the appetite suppressant leptin. Previous studies have demonstrated that LPS induces leptin synthesis and secretion in the periphery, and that the action of leptin on appetite suppression and fever are dependent on brain interleukin (IL)-1beta. However, the role of leptin as a neuroimmune mediator of LPS-induced inflammation has not been fully elucidated. To address this issue, we neutralized circulating leptin using a leptin antiserum (LAS) and determined how this neutralization affected LPS-induced anorexia, fever and hypothalamic IL-1beta. Adult male rats were separated into four treatment groups, namely LPS + normal sheep serum (NSS), LPS + LAS, saline + LAS and saline + NSS. Intraperitoneal injection of LPS (100 microg kg(-1)) induced a significant reduction in food intake and body weight, which were significantly reversed in the presence of LAS (1 ml kg(-1)), 8 and 24 h after treatment. In addition, LPS-induced fever was significantly attenuated by LAS over the duration of the fever response (8 h). Lipopolysaccharide induced an increase of circulating IL-6, another potential circulating pyrogen, which was not affected by neutralization of leptin at 2 h. Interleukin-1beta mRNA at 1 and 8 h, and IL-1 receptor antagonist (ra) at 2 h were significantly upregulated in the hypothalamus of LPS-treated animals. The induction of these cytokines was attenuated in the presence of LAS. These results are the first to demonstrate that leptin is a circulating mediator of LPS-induced anorexia and fever, probably through a hypothalamic IL-1beta-dependent mechanism. Topics: Animals; Anorexia; Antibodies; Body Weight; Eating; Fever; Hypothalamus; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-6; Leptin; Lipopolysaccharides; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sialoglycoproteins | 2004 |
Neuromedin U has a novel anorexigenic effect independent of the leptin signaling pathway.
Neuromedin U (NMU) is a hypothalamic neuropeptide that regulates body weight and composition. Here we show that mice lacking the gene encoding NMU (Nmu(-/-) mice) develop obesity. Nmu(-/-) mice showed increased body weight and adiposity, hyperphagia, and decreased locomotor activity and energy expenditure. Obese Nmu(-/-) mice developed hyperleptinemia, hyperinsulinemia, late-onset hyperglycemia and hyperlipidemia. Notably, however, treatment with exogenous leptin was effective in reducing body weight in obese Nmu(-/-) mice. In addition, central leptin administration did not affect NMU gene expression in the hypothalamus of rats. These results indicate that NMU plays an important role in the regulation of feeding behavior and energy metabolism independent of the leptin signaling pathway. These characteristic functions of NMU may provide new insight for understanding the pathophysiological basis of obesity. Topics: Adipose Tissue; Analysis of Variance; Animals; Blood Chemical Analysis; Blotting, Northern; Body Composition; Body Temperature Regulation; Body Weight; Carrier Proteins; Energy Metabolism; Feeding Behavior; Gene Expression Regulation; Histological Techniques; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Ion Channels; Leptin; Liver; Membrane Proteins; Mice; Mice, Mutant Strains; Mitochondrial Proteins; Neuropeptides; Obesity; Signal Transduction; Uncoupling Protein 1 | 2004 |
Cytochemical analysis of pancreatic islet hypercytolipidemia following diabetes (db/db) and obese (ob/ob) mutation expression: influence of genomic background.
Both diabetes (db/db) and obese (ob/ob) genotype mutations induce a hyperglycemic-hyperinsulinemic endometabolic state in C57BL mice, manifesting a type II NIDDM diabetes-obesity syndrome (DOS) in these leptin ligand/receptor-deficient models. The severity of the DOS induced by these single gene, homozygous-recessive mutations may be moderated by the background genome on which the mutation is expressed. The current studies define the phenotypic, systemic, cytochemical and cellular metabolic responses to db/db and ob/ob mutation expression when modified by /KsJ (severe DOS expression) or /6 (modified DOS expression) background strain influences as compared to littermate control (+/?) indices. Both db/db and ob/ob mutations induced dramatic increases in body weights, blood glucose and serum insulin concentrations relative to +/? indices when expressed on either the C57BL/KsJ (-/KsJ) or C57BL/6 (-/6) backgrounds. However, the -/KsJ background enhanced the severity of expression of these DOS indices relative to the -/6 strain. Similarly, the -/KsJ genome suppressed cellular glucose uptake rates, pancreatic tissue weights and insulin concentrations in both db/db and ob/ob mutants relative to /6 background strain influences or +/? indices. Concurrent enhancement of tissue and cellular lipogenic metabolism and islet cytolipid depositions were exaggerated when the mutations were expressed on the -/KsJ background relative to the -/6 genome. Pancreatic islet B-cell lipodeposition was markedly enhanced in ob/ob and db/db mutants expressed on either the -/KsJ or -/6 background. In both ob/ob and db/db models, B-cell insulin granulation was prominent in mildly hypertrophic pancreatic islets when the mutations were expressed on the -/6 background. In contrast, the severity of the DOS state expressed on the -/KsJ background resulted in pronounced B-cell atrophy, characterized by insulin degranulation, cellular hypertrophy and hypercytolipidemia associated with tissue involution, in both ob/ob and db/db mutants. Dramatic alterations in tissue norephinephrine (NE) and alpha-1-receptor populations in ob/ob and db/db mutants were exaggerated by the -/KsJ genome as compared to -/6 or control indices. The influences of the -/KsJ genome on the progressive expression of tissue NE counter-regulatory responses to enhanced cytolipidemic indices were inversely related, with cytochemical lipodeposition occurring under conditions of diminished adrenergic responses to the DOS indices. Topics: Animals; Atrophy; Blood Glucose; Body Weight; Cell Size; Diabetes Mellitus, Type 2; Female; Genotype; Hyperinsulinism; Hypertrophy; Insulin; Islets of Langerhans; Leptin; Lipid Metabolism; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Norepinephrine; Obesity; Organ Size; Oxidative Stress; Phenotype; Receptors, Cell Surface; Receptors, Leptin; Species Specificity | 2004 |
Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus.
We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory beta cell hyperplasia, and leptin resistance. To more precisely determine the roles of Irs2 in beta cells and the hypothalamus, we generated beta cell-specific Irs2 KO and hypothalamus-specific Irs2 knockdown (betaHT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of betaHT-IRS2 mice was indistinguishable from that of control mice. The betaHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the betaHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the betaHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. beta Cell mass and beta cell proliferation in the betaHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 days. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the betaHT-IRS2 mice. We conclude that, in beta cells and the hypothalamus, Irs2 is crucially involved in the regulation of beta cell mass and leptin sensitivity. Topics: Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Caloric Restriction; Cell Division; Diet; Female; Glucose Intolerance; Hyperlipidemias; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Phosphoproteins; RNA, Messenger; Signal Transduction; Tissue Distribution; Transcription Factors | 2004 |
Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy.
Congenital leptin deficiency is a rare, but treatable, cause of severe early-onset obesity. To date, two United Kingdom families of Pakistani origin carrying a frameshift/premature stop mutation, c.398delG (Delta133G), and one Turkish family carrying a missense mutation, c.313C>T (Arg(105)Trp), have been described. Affected subjects are homozygotes and manifest severe obesity and hyperphagia accompanied by metabolic, neuroendocrine, and immune dysfunction. The effects of recombinant leptin therapy have been reported in three children with the Delta133G mutation, and in all cases this has led to a dramatic resolution of clinical and biochemical abnormalities. We now report a Canadian child, of Pakistani origin but unrelated to the previously reported subjects, presenting with severe hyperphagia and obesity, who was found to be homozygous for the Delta133G mutation. In this child, 4 yr of therapy with sc injections of recombinant leptin provided additional evidence for the sustained beneficial effects of leptin replacement on fat mass, hyperinsulinemia, and hyperlipidemia. In addition, leptin administration corrected abnormal thyroid biochemistry and allowed the withdrawal of T(4) treatment, providing additional support for the role of leptin in the regulation of the human hypothalamic-pituitary-thyroid axis. Topics: Body Composition; Body Weight; Bone Development; Child; Child, Preschool; Female; Follicle Stimulating Hormone; Homozygote; Humans; Hypothyroidism; Insulin; Leptin; Leukocyte Count; Lipids; Luteinizing Hormone; Obesity; Point Mutation | 2004 |
Metabolic and behavioral characteristics of metabolically obese but normal-weight women.
A unique subset of individuals termed metabolically obese but normal weight (MONW) has been identified. These young women are potentially at increased risk for development of the metabolic syndrome despite their young age and normal body mass index. We seek to determine metabolic and behavioral factors that could potentially distinguish MONW women from young women with a normal metabolic profile.Ninety-six women were classified as MONW (n = 12) or non-MONW (n = 84) based on a cut point of insulin sensitivity (as estimated by the homeostasis model assessment). Potentially distinguishing phenotypes between groups measured included serum lipids, ghrelin, leptin, adiponectin, body composition and body fat distribution, resting and physical activity energy expenditure, peak oxygen uptake, dietary intake, dietary behavior, and family history and lifestyle variables. Despite a similar body mass index between groups, MONW women showed higher percent body fat, lower fat-free mass, lower physical activity energy expenditure, and lower peak oxygen uptake than non-MONW women. Plasma cholesterol level was higher in MONW women, whereas no differences were noted for other blood lipids, ghrelin, leptin, adiponectin, and resting energy expenditure. MONW women had lower dietary restraint scores than non-MONW women, but no differences were noted in disinhibition, hunger, and dietary intake. Stepwise regression analysis performed on all subjects showed that 33.5% of the unique variance of the homeostasis model assessment was explained with the variables of percentage of body fat (17.1%), level of dietary restraint (10.4%), and age (6%). Both metabolic and dietary behavioral variables contribute to the deleterious metabolic profile of MONW women. They display lower insulin sensitivity due potentially to a cluster of sedentary behavior patterns that contribute to their higher adiposity. Furthermore, cognitive attitudes toward food (i.e. dietary restraint) and concomitant lifestyle behaviors may play a role in regulating insulin sensitivity in MONW women. Topics: Adiponectin; Adolescent; Adult; Body Mass Index; Body Weight; Cholesterol; Cohort Studies; Energy Intake; Energy Metabolism; Female; Ghrelin; Health Behavior; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Multivariate Analysis; Obesity; Peptide Hormones; Risk Factors; Risk Reduction Behavior | 2004 |
Circulating and cerebrospinal fluid ghrelin and leptin: potential role in altered body weight in Huntington's disease.
In addition to neurological impairment, weight loss is a prominent characteristic of Huntington's disease (HD). Neuropathologically, the disease affects the caudate nucleus and the cerebral cortex, and also the hypothalamus. The recently discovered orexigenic hormone of gastric origin, ghrelin and the adipocyte hormone leptin, are two peripherally produced hormones exerting opposite effects on specific populations of hypothalamic neurons that play a key role in regulating energy intake and energy output. The aim of this study was to investigate the possible involvement of cerebrospinal fluid (CSF) and circulating ghrelin and leptin in the regulation of energy balance in patients with HD.. Twenty healthy normal-weight subjects undergoing orthopedic surgery, and fifteen patients with genetically verified HD, were enrolled in this study. The unified Huntington's disease rating scale (UHDRS) was used to assess clinical course of the disease. Blood samples for hormonal measurements were obtained by venipuncture and in-parallel CSF samples for leptin/ghrelin determination were obtained by lumbar puncture.. Patients with HD had increased concentrations of ghrelin in plasma compared with healthy subjects (4523.7+/-563.9 vs 2781.1+/-306.2 pg/ml, P<0.01). On the other hand, patients with HD had decreased concentrations of leptin in plasma compared with healthy subjects (4.8+/-1.6 vs 10.9+/-2.4 ng/ml, P<0.01). The concentrations of CSF ghrelin and CSF leptin were equivalent to values in healthy subjects. No correlation was found between disease duration--and other clinical features of HD--and plasma or CSF leptin/ghrelin levels. In patients with HD, baseline levels of GH, IGF-I, insulin and glucose did not differ from those in healthy subjects.. High circulating ghrelin and low leptin levels in patients with HD suggest a state of negative energy balance. Early nutritional support of patients with HD is advocated since patients with HD and higher body mass index at presentation have slower progression of the disease. Topics: Adult; Body Mass Index; Body Weight; Energy Metabolism; Female; Ghrelin; Humans; Huntington Disease; Leptin; Male; Middle Aged; Peptide Hormones | 2004 |
The M16 mouse: an outbred animal model of early onset polygenic obesity and diabesity.
To characterize the phenotypic consequences of long-term selective breeding for rapid weight gain, with an emphasis on obesity and obesity-induced diabetes (diabesity).. M16 is the result of long-term selection for 3- to 6-week weight gain from an ICR base population. Experiment 1 characterized males from both lines for body weights (3, 6, and 8 weeks), feed (4 to 8 weeks) and H(2)O (6 to 8 weeks) consumption, and heat loss, body composition, and levels of several plasma proteins at 8 weeks of age. Experiment 2 characterized differences between lines for both sexes at three ages (6, 8, and 16 weeks) and fed two diets (high and normal fat). Body weight, composition, blood glucose, and plasma insulin and leptin levels were evaluated after an 8-hour fast.. At all ages measured, M16 mice were heavier, fatter, hyperphagic, hyperinsulinemic, and hyperleptinemic relative to ICR. M16 males and females were hyperglycemic relative to ICR, with 56% and 22% higher fasted blood glucose levels at 8 weeks of age.. M16 mice represent an outbred animal model to facilitate gene discovery and pathway regulation controlling early onset polygenic obesity and type 2 diabetic phenotypes. Phenotypes prevalent in the M16 model, with obesity and diabesity exhibited at a young age, closely mirror current trends in human populations. Topics: Animals; Blood Glucose; Body Composition; Body Temperature Regulation; Body Weight; Breeding; Diabetes Complications; Disease Models, Animal; Drinking; Eating; Female; Hyperphagia; Insulin; Leptin; Male; Mice; Mice, Inbred ICR; Obesity; Selection, Genetic | 2004 |
Absence of anorectic effect to acute peripheral leptin treatment in adult rats whose mothers were malnourished during lactation.
Diets with restricted energy or protein during lactation programs body weight in the adult offspring. We have investigated the hypothesis that protein or energy-restricted diets during lactation alter the feeding response to peripheral leptin treatment of the adult offspring. Five Wistar rats were randomly assigned to one of the following groups on the day that the offspring were born: C, control diet with 23% protein; PR, protein restricted diet with 8% protein; and ER, energy-restricted, receiving the control diet in restricted quantities, which were calculated according to the mean ingestion of the PR group. After weaning (day 21), two animals from each litter (10 pups in each group) were randomly selected and placed together in the cage with free access to water and standard diet until 150 days of age, when they were tested for its response to either leptin (0.5 mg/kg body wt ip) for groups Clep, PRlep and ERlep or saline vehicle for groups Csal, PRsal and ERsal on food intake. In the control groups, food intake was reduced two hours (36%), four hours (41%) and six hours (25%) after leptin treatment. In contrast, no response was observed to leptin treatment in the PRlep and ERlep groups, suggesting leptin resistance. We demonstrated the development of resistance to the anorectic leptin effect and its program in a critical life period associated to nutritional and hormonal factors. Topics: Aging; Animals; Animals, Newborn; Body Weight; Drug Resistance; Eating; Female; Injections, Intraperitoneal; Lactation; Leptin; Malnutrition; Mothers; Rats; Rats, Wistar | 2004 |
Effects of life-long exercise on circulating free fatty acids and muscle triglyceride content in ageing rats.
Regular physical exercise has emerged, together with dietary restriction, as an effective intervention in delaying degenerative diseases and augmenting life span in rodents. The mechanisms involved remain largely unknown, although a beneficial influence on the age-related alteration of insulin sensitivity has been hypothesized. As muscle triglyceride (TG) accumulation is considered a reliable index of muscle insulin resistance, in this study we explored muscle TG content in 23-month-old male Sprague-Dawley rats subjected to life-long training. Plasma glucose, insulin, free fatty acid (FFA) and leptin levels were also measured. Both voluntary running in wheels (RW) and forced training in treadmill (TM) were studied. As RW rats weighed less than controls, a cohort of untrained animals, fed to pair weight (PW) with RW, was added to discriminate the effect of exercise from that of food restriction. Sedentary ad libitum fed rats served as controls. In 23-month-old RW rats, muscle TG content was reduced by 50% with respect to age-matched sedentary controls, while in TM group this reduction was smaller but still highly significant, and occurred independently on the changes in body fat mass. In both the trained rat groups, there was a significant decrease in circulating FFA levels and a trend to reduced insulin levels. In PW rats, muscle TG levels decreased similarly to RW rats, while plasma parameters were less modified. In particular, RW training was more effective than PW in preventing the age-related increase in circulating leptin levels. Our results suggest that voluntary exercise effectively counteracts the development of insulin resistance in the muscles of ageing rats as well as other related changes such as hyperlipacidaemia and compensatory hyperleptinaemia. Forced training or moderate food restriction appear slightly less effective than voluntary exercise in preventing age-dependent alterations in nutrient distribution and/or utilization. Topics: Adipose Tissue; Aging; Animals; Blood Glucose; Body Weight; Fatty Acids, Nonesterified; Insulin; Leptin; Male; Motor Activity; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Triglycerides | 2004 |
Molecular and morphometric description of adipose tissue during weight changes: a quantitative tool for assessment of tissue texture.
The aim of this study was to evaluate the morphometric changes of adipose tissue of lean and obese rats as assessed by computerized image analysis (IA) system in experimental conditions, with different degrees of adiposity. Moreover, to validate measures obtained by image analysis by correlation with direct measures of adiposity (body weight, epididimal fat, mean fat cell size and serum leptin). Finally to correlate these changes to expression of genes involved in lipid deposition and mobilization in adipose tissue. Lean (Fa/?) and genetically obese (fa/fa) Zucker rats were studied. Obese rats were food-restricted or treated with retinoic acid (ATRA) in order to reduce body weight and fat content. Moreover, gene expression of two key enzymes involved in fat metabolism (HSL and DGAT) were assessed in adipose tissue by RT-PCR. Our results show that HSL expression in adipose tissue was lower in obese compared to lean rats (1.47+/-0.02 vs 0.35+/-0.03, p<0.005) and was upregulated during food restriction in obese rats. DGAT expression was similar in lean and obese rats and was reduced by treatment with ATRA in obese rats. Tissue texture assessed by IA was significantly higher in lean compared to obese rats (23.2+/-0.6 vs 11.6+/-2.4%; p=0.01). Tissue structure highly correlated with adiposity in obese rats with different amount of body fat (area fraction vs epididimal fat depot: p=0.001). Distribution of measures for each sample, an index of spread of adipose tissue texture, as expressed by the standard deviation, correlated with adiposity (standard deviation vs epididimal fat depot: p=0.002) thus suggesting that adipose tissue texture increases its heterogeneity when adiposity is lower. This observation is in agreement with the hypothesis that the process of lipid mobilization from adipose tissue is not uniform, but a subpopulation of slimming adipocytes undergoes a complete release of their fat content while the rest of the tissue is much less affected. Moreover, image analysis system seems a reliable quantitative tool for assessment of adipose tissue texture. Topics: Adipose Tissue; Animals; Body Weight; Fatty Acids, Nonesterified; Leptin; Male; Obesity; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Weight Gain; Weight Loss | 2004 |
Characterization of diabetes-related traits in MSM and JF1 mice on high-fat diet.
We examined the effect of a high-fat diet on the diabetes-related traits of the Japanese Fancy mouse 1 (JF1), MSM, and C57BL/6J (B6J) mice. MSM and JF1 mice were derived from Mus musculus molossinus. B6J is a commonly used laboratory strain, with the vast majority of genome segments derived from Mus musculus domesticus and Mus musculus musculus, and is susceptible to high-fat diet-induced type 2 diabetes. None of the strains showed symptoms of diabetes or obesity when fed a laboratory chow diet. Under a high-fat diet, JF1 mice developed impaired glucose tolerance, hyperglycemia, hyperinsulinemia, and obesity. B6J mice fed a high-fat diet mildly developed these diabetes-related traits compared to JF1 mice fed a high-fat diet. JF1 mice fed a high-fat diet were classified as having type 2 diabetes and were susceptible to high-fat diet-induced diabetes and obesity. On the other hand, MSM mice were resistant to high-fat diet-induced diabetes. These results indicate that the JF1 strain, with its unique genetic origin, is a useful new animal model of high-fat diet-induced diabetes and obesity. Further investigations using JF1 mice will help to clarify the role of the high-fat diet on human diabetes and obesity. Topics: Animals; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Eating; Genetic Predisposition to Disease; Glucose Intolerance; Hyperglycemia; Insulin; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Organ Size; Triglycerides | 2004 |
Leptin-resistant obese mice do not form biliary crystals on a high cholesterol diet.
Human obesity is associated with leptin resistance and cholesterol gallstone formation. Previously, we demonstrated that leptin-resistant (Lep(db)) obese mice fed a low cholesterol diet have enlarged gallbladders, but a decreased cholesterol saturation index, despite elevated serum cholesterol. Obese humans, however, consume a high cholesterol diet. Therefore, we hypothesized that on a high cholesterol diet, leptin-resistant mice would have cholesterol saturated bile and would form biliary crystals.. Eight-week old female lean control (n = 70) and leptin-resistant (n = 72) mice were fed a 1% cholesterol diet for 4 weeks. All animals then had cholecystectomies. Bile was collected, grouped into pools to determine cholesterol saturation index (CSI), and examined for cholesterol crystals. Serum cholesterol and leptin were also measured.. Gallbladder volumes for Lep(db) mice were enlarged compared with the lean mice (35.8 microl versus 19.1 microl, P < 0.001), but the CSI for the Lep(db) mice was lower than for the lean animals (0.91 versus 1.15, P < 0.03). The obese animals did not form cholesterol crystals, whereas the lean animals averaged 2.2 crystals per high-powered field (hpf) (P < 0.001). Serum cholesterol and leptin were also elevated (P < 0.001) in the obese animals.. These data suggest that Lep(db) obese mice fed a high cholesterol diet have increased gallbladder volume and decreased biliary cholesterol saturation and crystal formation despite elevated serum cholesterol compared with lean control mice. We conclude that the link among obesity, diet, and gallstone formation may not require hypersecretion of biliary cholesterol and may be related to the effects of diabetes, hyperlipidemia, or both on gallbladder motility. Topics: Animals; Body Weight; Cholelithiasis; Cholesterol; Cholesterol, Dietary; Crystallization; Dose-Response Relationship, Drug; Drug Resistance; Female; Gallbladder; Leptin; Liver; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity | 2004 |
LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin.
Secretion of leptin from adipose tissue communicates body energy status to the neuroendocrine system by activating the long form of the leptin receptor (LRb). Lack of leptin or LRb (as in db/db mice) results in obesity that stems from the combined effects of hyperphagia and decreased energy expenditure. We have previously generated mice in which LRb is replaced with a mutant LRb (LRbS1138) that specifically disrupts LRb-->STAT3 (signal transducer and activator of transcription-3) signaling; mice homozygous for this mutant (s/s) display increased feeding and are obese. We have now examined energy expenditure in s/s and db/db mice. Consistent with the increased lean body mass of s/s animals, locomotor activity and acute cold tolerance (partly a measure of shivering thermogenesis) in s/s mice were modestly but significantly improved compared with db/db mice, although they were decreased compared with wild-type mice. Total and resting metabolic rates were similarly depressed in s/s and db/db mice, however. Indeed, s/s and db/db mice display similar reductions in thyroid function and brown adipose tissue expression of uncoupling protein-1, which is regulated by sympathetic nervous system (SNS) tone. Thus, the LRb-->STAT3 signal is central to both the control of energy expenditure by leptin and the neuroendocrine regulation of the SNS and the thyroid axis. Topics: Animals; Basal Metabolism; Body Composition; Body Temperature Regulation; Body Weight; Calorimetry, Indirect; Carrier Proteins; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Energy Metabolism; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mitochondrial Proteins; Motor Activity; Mutagenesis; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Thyroxine; Trans-Activators; Uncoupling Protein 1 | 2004 |
Partial leptin restoration increases hypothalamic-pituitary-adrenal activity while diminishing weight loss and hyperphagia in streptozotocin diabetic rats.
Chronic leptin administration at pharmacologic doses normalizes food intake and body weight in streptozotocin (STZ)-diabetic rats. We examined the metabolic effects of acute partial physiological leptin restoration in STZ-diabetic rats by using subcutaneous osmotic mini pumps. Groups: (1) Rats infused with vehicle (DV); (2) rats infused with recombinant murine methionine leptin (DL) at 4.5 microg . (kg body weight . d)(-1); (3)pair-fed rats (DP) given a food ration matching that consumed by the DL group. A fourth group of nondiabetic, normal (N) rats was also studied to assess normal metabolic efficiency, hypothalamic-pituitary-adrenal (HPA) activity and sympathoadrenal activity. Following leptin infusion, food consumption by DL rats was significantly lower than in DV rats. Paradoxically, despite a similar food intake to that of the DP group, which demonstrated a 40% reduction in body mass, DL rats increased their initial body weight by approximately 20% (P < .05). Plasma corticosterone and ACTH concentrations were elevated by 2-fold to 3-fold in DL versus N, DP, and DV rats. In the pars distalis, glucocorticoid receptor (GR) mRNA levels were significantly higher in DL and DP rats compared with N and DV rats. Our results suggest that partial restoration of physiologic leptin: (1) successfully reduces hyperphagia while allowing body weight gain in STZ-diabetic rats; (2) increases corticosterone levels in STZ-diabetic rats, which may in turn counteract the anorexic effects of diabetes; and (3) is associated with increased pituitary GR mRNA levels, despite elevated corticosterone levels, suggesting that leptin may interfere with the negative feedback regulation of the HPA axis. Topics: Adrenocorticotropic Hormone; Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Experimental; Eating; Epinephrine; Hyperphagia; Hypothalamo-Hypophyseal System; Insulin; Leptin; Male; Mice; Norepinephrine; Pituitary-Adrenal System; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Recombinant Proteins; RNA, Messenger | 2004 |
Endocrine response to fasting in the overwintering captive raccoon dog (Nyctereutes procyonoides).
The raccoon dog (Nyctereutes procyonoides) is an omnivorous canid utilizing the passive wintering strategy in the boreal climate. Farmed raccoon dogs (n=12) were randomly assigned into two study groups on 26 November 2003. Between 3 December 2003 and 27 January 2004, half of the animals were fasted for 8 weeks and plasma weight-regulatory hormone concentrations determined on 26 November and 30 December 2003 and on 27 January 2004. The plasma peptide YY, ghrelin, and growth hormone (GH) concentrations increased due to food deprivation, while the T4 and Acrp30 concentrations decreased. Furthermore, the plasma GH concentrations were higher in the fasted raccoon dogs than in the fed animals, which had higher plasma insulin, glucagon, and T4 concentrations. However, fasting had no effect on the plasma leptin concentrations. The results confirm previous findings with unchanged leptin levels in fasting carnivores. Increased GH levels probably contribute to increased lipolysis and mobilization of fat stores. Ghrelin can also enhance lipolysis by increasing the GH levels. The decreased levels of T4 may reduce the metabolic rate. The plasma dopamine concentrations decreased due to fasting unlike observed previously in rats. Together with the unaffected adrenaline, noradrenaline, and cortisol concentrations, this suggests that food deprivation in winter does not cause stress to the raccoon dog but is an integral part of its natural life history. Topics: Adaptation, Physiological; Adiponectin; Adipose Tissue; Analysis of Variance; Animals; Body Weight; Catecholamines; Dopamine; Fasting; Female; Ghrelin; Glucagon; Growth Hormone; Hydrocortisone; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Peptide Hormones; Peptide YY; Raccoon Dogs; Random Allocation; Seasons; Thyroxine | 2004 |
Leptin concentration during different trimesters of pregnancy and its relation to other pregnancy hormones.
To determine the levels of leptin and other pregnancy hormones (progesterone, estradiol, folliculi stimulating hormone, luteinizing hormone and beta human chorionic gonadotropin) in pregnant females during different stages of pregnancy and to correlate these levels to maternal weight, body mass index (BMI), babies weight and babies BMI.. Leptin level and other pregnancy hormones were measured in 36 pregnant females and 30 non-pregnant females followed at King Khaled University Hospital, Riyadh, Kingdom of Saudi Arabia in the year 2001 in a prospective study. Blood samples were collected at the first, 2nd and 3rd trimester and after delivery. Correlation analysis between leptin level and pregnancy hormones, in addition to maternal weight, BMI, babies weight and BMI.. The mean leptin levels during pregnancy and postnatally were significantly higher in pregnant females compared to the non-pregnant controls. Serum concentration of leptin increased significantly (p=0.01) in the pregnant females from 21.24 +/- 9 ng/ml during the first trimester to 26.3 +/- 8.69 ng/ml during the 2nd trimester, but insignificantly decreased to 23.29 +/- 8.62 ng/ml during the 3rd trimester (p=0.073). After delivery leptin concentration significantly decreased to 17.36 +/- 7.95 ng/ml (p=0.0025). The changes in levels of leptin during pregnancy were independent to other pregnancy hormones which showed a different pattern of variation.. The changes in levels of leptin during pregnancy were independent to other pregnancy hormones which showed a different pattern of variation. Topics: Adult; Birth Weight; Body Mass Index; Body Weight; Chorionic Gonadotropin, beta Subunit, Human; Estradiol; Female; Gonadal Steroid Hormones; Humans; Leptin; Pregnancy; Pregnancy Trimesters; Progesterone; Prospective Studies; Reference Values; Saudi Arabia | 2004 |
Comparative effects of the antipsychotics sulpiride and risperidone in female rats on energy balance, body composition, fat morphology and macronutrient selection.
Previous studies showed that the antipsychotic drugs (APDs) sulpiride (SUL) and risperidone (RIS) induced body weight gain (BWG), hyperphagia, and increased serum levels of leptin, prolactin and corticosterone in female rats. Neither SUL nor RIS increased BWG or food intake (FI) in male rats. To further develop the animal model of APD-induced obesity, SUL (20 mg/kg/sc), RIS (0.5 mg/kg/sc) or vehicle (1 cm(3)/kg/sc) were administered to female Wistar rats for 10 or 12 days. Body composition, fat tissue morphology, energy expenditure and food efficiency were assessed in animals fed a high-fat diet. In another experiment, macronutrient selection was evaluated in animals fed with pure diets. SUL and RIS significantly increased BWG and FI, with a stronger effect of SUL. Both drugs increased fat gain and food efficiency, and did not modify energy expenditure. Obesity was due to adipocyte hyperplasia. SUL-treated rats significantly decreased fat intake (p = 0.039), showed a tendency to increase protein intake and did not modify carbohydrate consumption. No differences were observed between the RIS and the vehicle group. The macronutrient selection pattern differs from that observed in obese people undergoing APD treatment and in most animal models of obesity. Those findings suggest that SUL administration does not properly model APD treatment in humans. Results on macronutient selection in RIS-treated rats must be considered as preliminary, since in this experiment the animals did not gain weight significantly. Other diet protocols and lower APD doses must be tested to further characterize the RIS model. Topics: Adipocytes; Adipose Tissue; Animals; Antipsychotic Agents; Body Composition; Body Weight; Cell Count; Corticosterone; Dietary Fats; Eating; Energy Metabolism; Female; Leptin; Prolactin; Proteins; Rats; Rats, Wistar; Risperidone; Sulpiride | 2004 |
Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index.
Sleep duration may be an important regulator of body weight and metabolism. An association between short habitual sleep time and increased body mass index (BMI) has been reported in large population samples. The potential role of metabolic hormones in this association is unknown.. Study participants were 1,024 volunteers from the Wisconsin Sleep Cohort Study, a population-based longitudinal study of sleep disorders. Participants underwent nocturnal polysomnography and reported on their sleep habits through questionnaires and sleep diaries. Following polysomnography, morning, fasted blood samples were evaluated for serum leptin and ghrelin (two key opposing hormones in appetite regulation), adiponectin, insulin, glucose, and lipid profile. Relationships among these measures, BMI, and sleep duration (habitual and immediately prior to blood sampling) were examined using multiple variable regressions with control for confounding factors. A U-shaped curvilinear association between sleep duration and BMI was observed. In persons sleeping less than 8 h (74.4% of the sample), increased BMI was proportional to decreased sleep. Short sleep was associated with low leptin (p for slope = 0.01), with a predicted 15.5% lower leptin for habitual sleep of 5 h versus 8 h, and high ghrelin (p for slope = 0.008), with a predicted 14.9% higher ghrelin for nocturnal (polysomnographic) sleep of 5 h versus 8 h, independent of BMI.. Participants with short sleep had reduced leptin and elevated ghrelin. These differences in leptin and ghrelin are likely to increase appetite, possibly explaining the increased BMI observed with short sleep duration. In Western societies, where chronic sleep restriction is common and food is widely available, changes in appetite regulatory hormones with sleep curtailment may contribute to obesity. Topics: Adult; Appetite; Body Mass Index; Body Weight; Female; Ghrelin; Humans; Leptin; Longitudinal Studies; Male; Middle Aged; Obesity; Peptide Hormones; Sleep; Sleep Wake Disorders | 2004 |
Serum leptin level and the risk of nontraumatic fracture.
Topics: Aged; Biomarkers; Body Weight; Bone Remodeling; Collagen; Female; Fractures, Bone; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Osteocalcin; Peptide Fragments; Regression Analysis; Risk Assessment | 2004 |
Anti-obesity actions of green tea: possible involvements in modulation of the glucose uptake system and suppression of the adipogenesis-related transcription factors.
To investigate mechanisms of the anti-obesity actions of green tea in vivo, rats were given green tea instead of drinking water for 3 weeks. It was confirmed that green tea reduced adipose tissue weight without any change in body weight, other tissue weights, and food and water intakes. Green tea also significantly reduced the plasma levels of cholesterols and free fatty acids. Certain catechins existed in the plasma at 0.24 microM under our experimental conditions, though most of them existed as conjugated forms. For mechanisms of the anti-obesity actions, green tea significantly reduced glucose uptake accompanied by a decrease in translocation of glucose transporter 4 (GLUT4) in adipose tissue, while it significantly stimulated the glucose uptake with GLUT4 translocation in skeletal muscle. Moreover, green tea suppressed the expression of peroxisome proliferator-activated receptor gamma and the activation of sterol regulatory element binding protein-1 in adipose tissue. In conclusion, green tea modulates the glucose uptake system in adipose tissue and skeletal muscle and suppresses the expression and/or activation of adipogenesis-related transcription factors, as the possible mechanisms of its anti-obesity actions. Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Biological Transport; Body Weight; Glucose; Leptin; Lipids; Male; Organ Size; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Tea; Transcription Factors | 2004 |
Effect of leptin administration versus re-feeding on hypothalamic neuropeptide gene expression in fasted male rats.
Adipocytes are the primary source of circulating leptin. Leptin inhibits eating, increases metabolism, and stimulates the reproductive axis. Numerous hypothalamic neuropeptides have been implicated in leptin's behavioral and neuroendocrine effects, including neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART). The aim of this study was to investigate the physiological relevance of leptin's signaling of nutritional status by comparing the effects of leptin with the effects of re-feeding on fasting-induced changes in the expression of the long form of the leptin receptor (Ob-Rb), NPY, and CART. Adult male rats were fasted for 48 h and treated with either intracerebroventricular (i.c.v.) or subcutaneous (s.c.) leptin throughout the fast, or fed ad libitum for 24 h after terminating the fast. Expression of NPY, Ob-Rb, and CART mRNA in the arcuate nucleus (ARC) was determined by in situ hybridization histochemistry and compared with vehicle-treated fed or fasted controls. Fasting increased NPY and Ob-Rb expression and decreased CART expression in the ARC. Leptin (regardless of route) and re-feeding were equally effective in normalizing CART mRNA expression. A similar trend was observed with Ob-Rb expression. In contrast, neither re-feeding nor s.c. leptin reversed the increased expression of NPY that was induced by fasting. Only i.c.v. leptin was effective in this regard. Our results indicate leptin and re-feeding are equally effective in normalizing fasting-induced changes in CART and Ob-Rb expression, but less effective in normalizing NPY expression. These results suggest that leptin is the primary nutritional signal regulating CART and Ob-Rb expression in the ARC, and highlight potential differences between CART and NPY neuron sensitivity to leptin signaling. Topics: Animals; Appetite; Body Weight; Cell Count; Eating; Fasting; Gene Expression; Hypothalamus; In Situ Hybridization; Lateral Ventricles; Leptin; Male; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Perfusion; Rats; RNA, Complementary | 2004 |
Delayed age-associated decrease in growth hormone pulsatile secretion and increased orexigenic peptide expression in the Lou C/JaLL rat.
Since modifications in the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis and/or caloric restriction are involved in the ageing process, GH secretory profiles, total IGF-1, ghrelin, and leptin plasma levels and expression of genes implicated in somatotrope axis and food intake regulation in hypothalamus and pituitary were compared in 3-, 12-, and 24-month-old male Lou C/Jall rats and their parent strain, the Wistar rats. The Lou C/Jall strain may appear as a healthy ageing model, since it does not become obese with age and maintains its caloric intake at 2 years of age. The GH pulsatile secretion decreased from 3 months in Wistar, but only after 12 months in Lou C/Jall rats. The IGF-1 levels were lower in Lou C/Jall rats and decreased more steeply with ageing as compared with Wistar rats. The total ghrelin levels were higher in young Lou C/Jall rats than in Wistar rats, but increased similarly with age in both strains. The leptin concentrations increased with ageing only in Wistar rats. By semiquantitative reverse-transcription polymerase chain reaction, pituitary GH secretagogue receptors and GH mRNA levels were more abundant in Lou C/Jall rats, and the latter decreased with ageing in Wistar rats only. Hypothalamic growth-hormone-releasing hormone and GH secretagogue receptor mRNA levels were similar in both strains and transiently increased only in middle-aged Wistar rats. Agouti-related peptide, neuropeptide Y, and orexin mRNA levels were more abundant in the Lou C/Jall rat hypothalamus, and the two former tended to further increase with age only in this strain. Conversely, the hypothalamic pro-opiomelanocortin mRNA levels were higher in old Wistar rats. In conclusion, ageing in Lou C/Jall rats is associated with a delayed decrease in pulsatile GH secretion in the presence of a lower IGF-1 tone and an increase in the expression of orexigenic neuropeptides in the hypothalamus. Topics: Aging; Agouti-Related Protein; Animals; Body Weight; Eating; Gene Expression; Ghrelin; Growth Hormone; Hypothalamus; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Leptin; Neuropeptide Y; Neuropeptides; Orexins; Peptide Fragments; Peptide Hormones; Pituitary Gland; Pro-Opiomelanocortin; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2004 |
Gonadotropin response to clomiphene and plasma leptin levels in weight recovered but amenorrhoeic patients with anorexia nervosa.
Anorexia nervosa (AN) is a state of leptin and gonadotropin deficiency. Leptin levels are decreased in normal weight women with hypothalamic amenorrhea and leptin may be a sensitive marker of overall nutritional status. The aim of the study is to provide additional information on plasma leptin levels and on gonadotropin responses after clomiphene testing in patients with AN who recovered weight but were still amenorrheic. We evaluated 17 patients with AN, female age 20+/-1.2 yr who reached goal weight [body mass index (BMI) 14.9+/-0.5 to 19.3+/-0.4 kg/m2]. At diagnosis serum leptin levels were 2.2+/-0.1 microg/l while after behavioural therapy and hypercaloric diet for 6-12 months serum leptin levels rose to 6.4+/-1.4 microg/l significantly lower compared with those in the control (no.=10, age 28+/-6.2 yr, BMI 21.1+/-0.3 kg/m2, leptin 9.3+/-0.7 pg/l; p<0.05). None of the patients resumed spontaneous menstrual cycles after weight gain. They were tested with a 10-day administration of clomiphene citrate. All had a significant rise in LH secretion (from 1.7+/-0.3 IU/l to 8.3+/-0.9 IU/l, p<0.01) and serum estradiol levels (from 19.0+/-5.4 to 937.7+/-241.2 pg/ml, p<0.03). Nine out of 17 patients menstruated after clomiphene. Serum leptin levels were not different in those who menstruated from those who did not (6.4+/-1.4 to 6.8+/-1.4 microg/l, p>0.05). Body compositon was studied in 12 additional carefully matched patients with AN who recovered weight. Six of them resumed spontaneous menstrual cycles. Neither BMI, body fat, nor leptin appeared as significant determinants of menstrual status. In conclusion, relative hypoleptinemia persists, independent of fat mass, in weight recovered patients with AN. A normal response to clomiphene in weight-recovered yet still amenorrhoeic patients with AN, offers reassurance that the axis is intact and that the problem lies in the hypothalamus. It is reasonable to believe that nutritional disturbances, fat intake and persisting psychological factors still affect plasma leptin levels and reproductive functions in weight-recovered patients with amenorrhea. Topics: Adolescent; Adult; Amenorrhea; Anorexia Nervosa; Body Mass Index; Body Weight; Case-Control Studies; Clomiphene; Estrogen Antagonists; Female; Gonadotropins; Humans; Hypothalamus; Leptin; Nutritional Status; Weight Gain | 2004 |
Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice.
Because the CB1 receptor antagonist SR141716 was previously reported to modulate food intake in rodents, we studied its efficacy in reducing obesity in a diet-induced obesity (DIO) model widely used for research on the human obesity syndrome. During a 5-wk treatment, SR141716 (10 mg. kg(-1). day(-1) orally) induced a transient reduction of food intake (-48% on week 1) and a marked but sustained reduction of body weight (-20%) and adiposity (-50%) of DIO mice. Furthermore, SR141716 corrected the insulin resistance and lowered plasma leptin, insulin, and free fatty acid levels. Most of these effects were present, but less pronounced at 3 mg. kg(-1). day(-1). In addition to its hypophagic action, SR141716 may influence metabolic processes as the body weight loss of SR141716-treated mice was significantly higher during 24-h fasting compared with vehicle-treated animals, and when a 3-day treatment was compared with a pair feeding. SR141716 had no effect in CB1 receptor knockout mice, which confirmed the implication of CB1 receptors in the activity of the compound. These findings suggest that SR141716 has a potential as a novel anti-obesity treatment. Topics: Animals; Binding Sites; Body Weight; Diet; Dietary Fats; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Time Factors | 2003 |
AMPK expression and phosphorylation are increased in rodent muscle after chronic leptin treatment.
We have previously reported that chronic leptin administration (2 wk) increases fatty acid (FA) oxidation and triacylglycerol hydrolysis in rodent soleus muscle. Acute stimulation of AMP-activated protein kinase (AMPK) results in a repartitioning of FA toward oxidation and away from esterification in rodent soleus muscle and has recently been shown to be responsible, at least in part, for the acute stimulatory effect of leptin on FA oxidation. Therefore, we hypothesized that the effects of chronic leptin treatment on muscle FA metabolism are mediated in part through an increased expression and/or activation of AMPK and a subsequent phosphorylation of acetyl-CoA carboxylase and a decrease in malonyl-CoA content. Female Sprague-Dawley rats were infused for 2 wk with leptin (0.5 mg x kg(-1) x day(-1)) using subcutaneously implanted mini-osmotic pumps. Control and pair-fed animals received saline-filled implants. Leptin levels were elevated approximately fourfold (P < 0.001) in treated animals, relative to controls. Chronic leptin treatment resulted in an approximately 2- to 3-fold greater protein expression of AMPK catalytic (alpha(2)) and regulatory (beta(2)) units as well as a 1.5- to 2-fold increase in Thr(172) phosphorylation of AMPK in both soleus and white gastrocnemius muscles. The increased expression/phosphorylation of AMPK was not the result of an altered energy status of the muscle. Correspondingly, there was also a 1.5- to 2-fold increase in acetyl-CoA carboxylase (ACC) phosphorylation after leptin treatment in soleus and white gastrocnemius. In spite of the measured increase in ACC phosphorylation after leptin treatment, we were unable to detect a decrease in resting malonyl-CoA content in either muscle. However, taken as a whole, our data support recent evidence in rodent muscle that leptin stimulates FA oxidation through stimulation of AMPK and a subsequent downregulation of ACC activity. Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Body Weight; Drug Administration Schedule; Energy Metabolism; Female; Leptin; Malonyl Coenzyme A; Multienzyme Complexes; Muscle Fibers, Skeletal; Muscle, Skeletal; Phosphorylation; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley | 2003 |
Chronic intracerebroventricular infusion of MCH causes obesity in mice. Melanin-concentrating hormone.
Melanin-concentrating hormone (MCH) is a cyclic amino acid neuropeptide localized in the lateral hypothalamus. Although MCH is thought to be an important regulator of feeding behavior, the involvement of this peptide in body weight control has been unclear. To examine the role of MCH in the development of obesity, we assessed the effect of chronic intracerebroventricular infusion of MCH in C57BL/6J mice that were fed with regular or moderately high-fat (MHF) diets. Intracerebroventricular infusion of MCH (10 microg/day for 14 days) caused a slight but significant increase in body weight in mice maintained on the regular diet. In the MHF diet-fed mice, MCH more clearly increased the body weight accompanied by a sustained hyperphagia and significant increase in fat and liver weights. Plasma glucose, insulin, and leptin levels were also increased in the MCH-treated mice fed the MHF diet. These results suggest that chronic stimulation of the brain MCH system causes obesity in mice and imply that MCH may have a major role in energy homeostasis. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Dietary Fats; Drug Administration Schedule; Hyperphagia; Hypothalamic Hormones; Injections, Intraventricular; Insulin; Leptin; Liver; Male; Melanins; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Pituitary Hormones | 2003 |
Method of leptin dosing, strain, and group housing influence leptin sensitivity in high-fat-fed weanling mice.
High-fat diets are reported to induce resistance to peripherally administered leptin. In an attempt to develop a model of juvenile diet-induced obesity, mice were weaned onto high-fat diet. Male and female, 35-day-old, C57BL/6J high-fat (45% kcal fat) diet-fed mice housed individually on grid floors did not decrease food intake or body weight in response to intraperitoneal (30 microg), lateral ventricle (5 microg), or third ventricle (0.5 microg) injections of leptin. Body weight and fat were significantly reduced by 13-day intraperitoneal infusions of 10 microg leptin/day, which doubled circulating leptin. Leptin infusion also reduced body fat in weanling, high-fat diet-fed NIH Swiss mice. Group housing mice on bedding prevented loss of fat in high-fat diet-fed male and female NIH Swiss and female C57BL/6J mice. These results indicate that peripherally infused leptin reduces fat in part by increasing thermogenesis and that inhibition of food intake in high-fat diet-fed mice requires either chronic activation of central leptin receptors or is independent of receptors that inhibit feeding in response to an acute central injection of leptin. Topics: Animals; Body Composition; Body Weight; Dietary Fats; Drug Administration Routes; Drug Resistance; Energy Intake; Energy Metabolism; Feeding Behavior; Female; Housing, Animal; Leptin; Male; Mice; Mice, Inbred C57BL; Organ Size; Species Specificity; Weaning | 2003 |
Leptin-induced changes in body composition in high fat-fed mice.
Female C57BL/6J mice were adapted to 10% or 45% kcal fat diets for 8 weeks. Continuous intraperitoneal infusion of 10 micro g of leptin/day from a miniosmotic pump transiently inhibited food intake in low fat-fed but not high fat-fed mice. In contrast, both low and high fat-fed leptin-infused mice were less fat than their phosphate-buffered saline (PBS) controls after 13 days. Leptin infusion inhibited insulin release but did not change glucose clearance in low fat-fed mice during a glucose tolerance test. A single intraperitoneal injection of 30 micro g of leptin inhibited 24-hr energy intake and inhibited weight gain in both low and high fat-fed mice. Insulin responsiveness was improved in high fat-fed mice during an insulin sensitivity test due to an exaggerated elevation of circulating insulin concentrations. Thus, leptin infusion reduced adiposity independently of energy intake in high fat-fed mice and improved insulin sensitivity in low fat-fed mice, whereas leptin injections, which produced much greater, but transient, increases in serum leptin concentration, inhibited energy intake in both low and high fat-fed mice. Topics: Animals; Body Composition; Body Weight; Dietary Fats; Feeding Behavior; Female; Glucose Tolerance Test; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL | 2003 |
Reductions in adipose tissue and skeletal growth in rat adult offspring after prenatal leptin exposure.
Leptin is involved in regulating food intake, energy balance and bone formation. Increasing evidence suggests that leptin is also involved in fetal growth and development. The aim of this study was to determine if increased maternal leptin is followed by changes in body composition, skeletal growth or hormonal regulation in the adult rat offspring. Pregnant rats were given injections of either human recombinant leptin (3.5 mg/kg, i.p.) or vehicle on days 8, 10 and 12 of gestation. Both genders of leptin-exposed offspring showed significantly reduced adipose tIssue weight at adult age. Skeletal growth and cortical bone dimensions were significantly reduced. Circulating testosterone levels were significantly increased in female leptin-exposed offspring, and male leptin-exposed offspring had significant testicular enlargement. No significant effects were seen on circulating leptin levels or hypothalamic protein levels of the leptin receptor. The results demonstrate that maternally administered leptin is involved in fetal growth and development, leading to lean offspring with reduced skeletal growth. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Bone Density; Bone Development; Eating; Female; Gestational Age; Gonadal Steroid Hormones; Leptin; Male; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Recombinant Proteins | 2003 |
The intricate interplay among body weight, stress, and the immune response to friend or foe.
Topics: Autoimmunity; Body Weight; Corticotropin-Releasing Hormone; Humans; Leptin; Stress, Physiological; Th1 Cells | 2003 |
Influence of phytostanol phosphoryl ascorbate (FM-VP4) on insulin resistance, hyperglycemia, plasma lipid levels, and gastrointestinal absorption of exogenous cholesterol in Zucker (fa/fa) fatty and lean rats.
The purpose of this investigation was to determine the effects of Phytostanol Phosphoryl Ascorbate (FM-VP4) on insulin resistance, hyperglycemia, plasma lipid levels, body weight, and gastrointestinal absorption of exogenous cholesterol in Zucker (fa/fa) fatty and lean rats. A group of 12 age-matched male obese (n = 6) and lean (n = 6) Zucker rats were administered 250 mg/kg twice a day (as 2% FM-VP4 in drinking water) for 30 consecutive days. Fasted blood samples prior to and following treatment were taken from all rats for glucose, lipid, insulin, and leptin determination. An oral glucose tolerance test was also carried out at the end of the treatment protocol. In addition, male obese (n = 7) and lean (n = 8) Zucker rats were coadministered a single oral gavage of [(3)H]cholesterol plus cold cholesterol with or without FM-VP4 (20 mg/kg) dissolved in Intralipid and the plasma concentration of the radiolabel was determined 10 h following the dose. FM-VP4 30-day treatment did not alter body weight, morning glucose, insulin, lipids, and leptin concentrations. There was no alteration in glucose tolerance in the nondiabetic, normoglycemic lean group; however, there was a highly significant improvement in glucose tolerance in the fatty group following FM-VP4 treatment. In addition, the insulin response to oral glucose showed no significant change in nondiabetic lean rats, whereas there was a change in the insulin secretory profile in the fatty group following FM-VP4 treatment. Furthermore, following a single oral gavage of FM-VP4 resulted in a significant decrease in the percentage of radiolabeled cholesterol absorbed. These findings suggest that FM-VP4 treatment to fatty Zucker rats could result in increased glucose responsiveness of the insulin secreting pancreatic beta cells. Furthermore, our findings suggest that FM-VP4 may only be effective presystemically. Systemic administration of FM-VP4 is warranted to determine the therapeutic potential of this effect. Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Cholesterol, Dietary; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Intestinal Absorption; Leptin; Lipids; Male; Obesity; Phytosterols; Rats; Rats, Zucker | 2003 |
Orexin-A immunoreactivity and prepro-orexin mRNA expression in hyperphagic rats induced by hypothalamic lesions and lactation.
Orexins are endogenous neuropeptides that potently facilitate appetite and food consumption. In the present study, we examined orexin immunoreactivity and prepro-orexin mRNA expression in the lateral hypothalamus by immunohistochemistry and competitive reverse transcription-polymerase chain reaction (RT-PCR) methods in different models of hyperphagia in rats. Hyperphagia was induced by lesions of either the ventromedial hypothalamus (VMHL) or the paraventricular nucleus (PVNL), and we also compared lactating rats to nonlactating controls. Both VMHL and PVNL increased food intake and body weight compared to shams. On day 7 post lesion, serum leptin and insulin concentrations exhibited 3.2- and 2.8-fold increases in VMHL rats, and nonsignificant 1.8- and 1.8-fold increases in PVNL rats; there were significant decreases (48% and 33%) in lactating rats on day 12 postpartum compared to controls, respectively. Serum glucose concentrations were not significantly changed compared to controls in these rats. Quantification by image analysis suggests that VMHL significantly decreased the number and mean staining intensity of orexin-A immunoreactive neurones compared to those in the sham-lesioned group; while PVNL did not change orexin-A immunoreactivity. Competitive RT-PCR analysis showed that VMHL significantly decreased the prepro-orexin mRNA expression compared to those in the sham-lesioned group, and PVNL did not change it. Lactating rats on days 11-12 of lactation had significantly greater number and mean staining intensity of orexin-A immunoreactive neurones, prepro-orexin mRNA expression food intake and body weight than nonlactating postpartum rats. Thus, changes in orexin-A immunoreactivity and prepro-orexin mRNA expression were not consistent between the hyperphagia models. These results suggest that the hyperphagia from VMHL or PVNL and lactating rats differ in their involvement of orexin-A, and the change in circulating leptin and insulin concentrations may be involved in the change of orexin-A immunoreactivity in these rats. Topics: Animals; Blood Glucose; Body Weight; Carrier Proteins; Eating; Gene Expression; Hyperphagia; Insulin; Intracellular Signaling Peptides and Proteins; Lactation; Leptin; Male; Neurons; Neuropeptides; Orexins; Paraventricular Hypothalamic Nucleus; Protein Precursors; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Ventromedial Hypothalamic Nucleus | 2003 |
Suppression of pulsatile luteinizing hormone secretion but not luteinizing hormone surge in leptin resistant obese Zucker rats.
The adipose tissue-derived hormone leptin may be a primary mediator linking nutritional status and reproduction. The present study used the leptin-resistant obese female Zucker rat to investigate whether leptin signalling is required for normal pulsatile luteinizing hormone (LH) secretion and/or generation of the LH surge. For the pulsatile LH secretion study, an indwelling atrial catheter was implanted and a low dose of oestrogen given as a subcutaneous implant to lean and obese ovariectomized (OVX) Zucker rats. One week following OVX, blood samples were collected every 10 min for 3 h during the morning. Plasma LH concentrations were measured by radioimmunoassay. For the LH surge study, lean and obese OVX rats were given a high dose of oestrogen as a subcutaneous implant. Two days later, rats were given progesterone at 09.00 h to induce a proestrus-like LH surge. Blood samples were collected from an indwelling atrial catheter throughout that and the following day and plasma LH concentrations were measured by radioimmunoassay. LH pulse amplitude and mean LH secretion were profoundly attenuated in obese Zucker rats compared with lean littermates, whereas LH pulse frequency was not significantly different between phenotypes. The opioid receptor antagonist naloxone did not affect the pattern of pulsatile LH secretion in obese rats, suggesting that leptin does not exert its facilitatory effects on LH secretion through an opioidergic pathway. Both lean and obese rats showed characteristic steroid-induced LH surges. It therefore appears that a leptin signal is required for generation of a normal pattern of pulsatile LH secretion, but is not a necessary component of the steroid-induced LH surge. Topics: Animals; Body Weight; Estrogens; Female; Leptin; Luteinizing Hormone; Naloxone; Narcotic Antagonists; Obesity; Opioid Peptides; Pulsatile Flow; Rats; Rats, Zucker | 2003 |
Glucose intolerance and resistin expression in rat offspring exposed to ethanol in utero: modulation by postnatal high-fat diet.
High-fat diet and intrauterine growth retardation may predispose to obesity, insulin resistance, and type 2 diabetes. Because prenatal ethanol (ETOH) exposure causes intrauterine growth retardation, we investigated its interactions with postnatal high-fat diet on glucose tolerance and adipocyte-derived hormones in the rat offspring. High-fat-fed offspring had increased adiposity, serum leptin, and muscle uncoupling protein-3, but decreased adiponectin mRNA, compared with corresponding chow-fed groups. ETOH-exposed offspring had normal adiponectin, but increased resistin mRNA and protein, compared with controls, regardless of postnatal diet. Skeletal muscle glucose transporter-4 content was decreased after both ETOH exposure and high-fat feeding. Glycemic and insulin responses to an ip glucose challenge were equally increased in non-ETOH-exposed high-fat-fed offspring and in ETOH-exposed chow-fed offspring, with additive effects of ETOH and high-fat diet. Pancreatic insulin content was elevated only in non-ETOH-exposed high-fat-fed offspring. The data suggest that high-fat diet worsens glucose intolerance in offspring of rats exposed to ETOH. Prenatal ETOH exposure and postnatal high-fat diet might cause insulin resistance through separate mechanisms, involving resistin and adiponectin, respectively. Topics: Adiponectin; Adipose Tissue; Animals; Body Weight; Carrier Proteins; Central Nervous System Depressants; Dietary Fats; Eating; Ethanol; Fatty Acids, Nonesterified; Female; Gene Expression; Glucose Intolerance; Glucose Transporter Type 4; Hormones, Ectopic; Hyperinsulinism; Insulin; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Mitochondrial Proteins; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Nerve Growth Factor; Organ Size; Pancreas; Pregnancy; Prenatal Exposure Delayed Effects; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Resistin; Uncoupling Protein 3 | 2003 |
Hepatocyte retinoid X receptor-alpha-deficient mice have reduced food intake, increased body weight, and improved glucose tolerance.
Hepatocyte retinoid X receptor (RXR)alpha-deficient mice and wild-type mice were fed either a regular or a high-saturated-fat diet for 12 wk to study the functional role of hepatocyte RXRalpha in fatty acid and carbohydrate metabolism. Food intake was significantly reduced in hepatocyte RXRalpha-deficient mice when either diet was used. The amount of food intake was negatively associated with serum leptin level. Although mutant mice ate less, body weight and fat content were significantly higher in mutant than wild-type mice. Examination of the expression of peroxisome proliferator-activated receptor-alpha target genes indicated that the peroxisome proliferator-activated receptor-alpha-mediated pathway was compromised in the mutant mice, which, in turn, might affect fatty-acid metabolism and result in increased body weight and fat content. Although mutant mice were obese, they demonstrated the same degree of insulin sensitivity and the same level of serum insulin as the wild-type mice. However, these mutant mice have improved glucose tolerance. To explore a mechanism that may be responsible for the improved glucose tolerance, serum IGF-I level was examined. Serum IGF-1 level was significantly increased in mutant mice compared with wild-type mice. Taken together, hepatocyte RXRalpha deficiency increases leptin level and reduces food intake. Those mice also develop obesity, with an unexpected improvement of glucose tolerance. The result also suggests that an increase in serum IGF-I level might be one of the mechanisms leading to improved glucose tolerance in hepatocyte RXRalpha-deficient mice. Topics: Animals; Body Weight; Dietary Fats; Eating; Glucose Intolerance; Hepatocytes; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Obese; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors | 2003 |
Regulation of serum leptin and its role in the hyperphagia of lactation in the rat.
The factors regulating serum leptin concentration and its relationship to the hyperphagia of lactation have been investigated in rats. Lactation results in hypoleptinaemia and loss, or at least marked attenuation, of the nocturnal rise in serum leptin. Litter removal resulted in a fall in food intake and restoration of the nocturnal rise in serum leptin. Returning the litter to the mother after a 48-h absence increased food intake and began to reinitiate milk production, but the nocturnal serum leptin levels were still increased at 48 h after litter restoration. Adjusting litter size to four, eight, ten or fourteen pups at parturition resulted in different rates of litter growth and food intake during the subsequent lactation, but had no effect on the degree of hypoleptinaemia. Reducing litter size from ten to four pups at mid-lactation resulted in a transient increase in both serum leptin and pup growth rate, while food intake fell to a level found in rats suckling four pups throughout lactation. Reducing milk production by injection of bromocriptine increased serum leptin, but did not restore the nocturnal rise in serum leptin; food intake decreased, but remained much higher than in non-lactating rats. Feeding a varied, high-energy diet resulted in a decrease in the weight of food ingested, but no change in calorie intake, and had no effect on the hypoleptinaemia. These studies suggested that the hypoleptinaemia of lactating rats is due to negative energy balance, but the loss of the nocturnal rise in serum leptin is due to the suckling stimulus. The negative energy balance of lactation does not appear to be caused by a physical constraint on food intake. While the hypoleptinaemia should facilitate the hyperphagia of lactation, other orexigenic signals must also be involved. Topics: Animals; Body Weight; Bromocriptine; Circadian Rhythm; Diet; Female; Hormone Antagonists; Hyperphagia; Insulin; Lactation; Leptin; Litter Size; Prolactin; Rats; Rats, Wistar; Thyroxine | 2003 |
P27 knockout mice: reduced myostatin in muscle and altered adipogenesis.
Knockout of the P27(kip) gene, which encodes a cyclin-dependent kinase inhibitor involved in cell proliferation regulation, results in growth enhancement in mice. To investigate how p27 deficiency affected adipogenesis and myogenesis, levels of PPARgamma, C/EBPalpha, and the myogenesis inhibitor, myostatin, were measured in p27(-/-) (n=14), p27(+/-) (n=18), and p27(+/+) mice (n=11). Body weight and gastrocnemius muscle (GC) mass were increased in p27(-/-) mice (P<0.05), but there were no differences in fat depot weights, percent body fat or serum leptin concentrations among genotypes. PPARgamma, but not C/EBPalpha, was markedly increased in p27(-/-) mice (P<0.05). There was also a higher incidence of inguinal fat apoptosis (P<0.01) in p27(-/-) mice. Myostatin levels were reduced in GC muscle of p27(-/-) mice (P<0.05). These findings suggest that in p27 deficient mice, increased skeletal muscle mass is mediated in part through decreased myostatin. Although total adiposity was not changed, increased PPARgamma levels suggest an alteration in adipogenesis. Topics: Adipose Tissue; Animals; Body Weight; CCAAT-Enhancer-Binding Protein-alpha; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p27; Genotype; Leptin; Mice; Mice, Knockout; Muscle, Skeletal; Myostatin; Organ Size; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Transforming Growth Factor beta; Tumor Suppressor Proteins | 2003 |
Peptides that regulate food intake: orexin gene expression is increased during states of hypertriglyceridemia.
Previous reports implicate the orexins in eating and body weight regulation. This study investigated possible functional relationships between hypothalamic orexins and circulating hormones or metabolites. In situ hybridization and quantitative PCR were used to examine orexin expression in the perifornical hypothalamus (PF) of rats and mice on diets varying in fat content and with differential propensity toward obesity. The results showed that orexin gene expression was stimulated by a high-fat diet in close association with elevated triglyceride levels, suggesting a functional relationship between these measures. Results obtained in obesity-prone rats and mice revealed a similar increase in orexin in close relation to triglycerides. A direct test of this orexin-triglyceride link was performed with Intralipid, which increased PF orexin expression along with circulating triglycerides. Whereas PF galanin is similarly stimulated by dietary fat, double-labeling immunofluorescence studies showed that orexin and galanin neurons are anatomically distinct. This evidence suggests that the orexins, like galanin, are "fat-responsive" peptides that respond to circulating lipids. Topics: Animals; Blood Glucose; Body Weight; Carrier Proteins; Colchicine; Dietary Fats; Galanin; Gene Expression Regulation; Hypertriglyceridemia; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred Strains; Neuropeptides; Obesity; Orexins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Triglycerides | 2003 |
Leptin administration normalizes insulin secretion from islets of Lep(ob)/Lep(ob) mice by food intake-dependent and -independent mechanisms.
Leptin-deficient Lep(ob)/Lep(ob) mice exhibit elevations in plasma insulin early in development. The present study tested the hypothesis that absence of leptin during neonatal development permanently programs islets from these mice to hypersecrete insulin. Administration of leptin for 8 days to young adult Lep(ob)/Lep(ob) mice normalized their food intake, plasma insulin concentration, and insulin secretion in response to glucose, acetylcholine, and leptin. Restriction of food intake per se of Lep(ob)/Lep(ob) mice lowered, but did not normalize, plasma insulin concentrations. Food-restricted Lep(ob)/Lep(ob) mice continued to hypersecrete insulin in response to glucose, but islets from these mice did not hyperrespond to acetylcholine or respond to leptin as occurs in ad libitum-fed Lep(ob)/Lep(ob) mice. We conclude that neonatal leptin deficiency does not permanently program islets from mice to hypersecrete insulin. The hyperphagia associated with leptin deficiency contributes substantially to the hypersecretion of insulin, but leptin also appears to have more direct effects on regulation of insulin secretion. Topics: Acetylcholine; Androstadienes; Animals; Body Weight; Cells, Cultured; Diet; Eating; Enzyme Inhibitors; Glucose; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Wortmannin | 2003 |
Anti-cachectic effect of ghrelin in nude mice bearing human melanoma cells.
Ghrelin is a novel brain-gut peptide that stimulates food intake and body weight gain. We studied the anabolic effect of ghrelin in a cancer cachexia mouse model. SEKI, a human melanoma cell line, was inoculated into nude mice to examine the effects of ghrelin on food intake and body weight. The intraperitoneal administration of ghrelin twice a day (6 nmol/mice/day) for 6 days suppressed weight loss in SEKI-inoculated mice and increased the rate of weight gain in vehicle-treated nude mice. Ghrelin administration also increased food intake in both SEKI- and vehicle-treated mice. Both the weight of white adipose tissue and the plasma leptin concentration were reduced in tumor-inoculated mice compared with vehicle-treated mice; these factors increased following ghrelin administration. The levels of both ghrelin peptide and mRNA in the stomach were upregulated in tumor-inoculated mice. The anabolic effect of ghrelin efficiently reverses the cachexia in mice bearing SEKI human melanoma. Ghrelin therefore may have a therapeutic ability to ameliorate cancer cachexia. Topics: Animals; Body Weight; Cachexia; Cell Transplantation; Female; Gastric Mucosa; Ghrelin; Growth Inhibitors; Humans; Injections, Intraperitoneal; Interleukin-6; Leptin; Leukemia Inhibitory Factor; Lymphokines; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Peptide Hormones; Tumor Cells, Cultured | 2003 |
Leptin suppresses food intake and body weight in corticosterone-replaced adrenalectomized rats.
Intracerebroventricular (ICV) injections of leptin decrease food intake and body weight while increasing energy expenditure. Some of these effects are reportedly enhanced in bilaterally adrenalectomized (ADX) rats. The purpose of the present experiment was to establish the time course of the suppression in body weight and food intake after an ICV injection of leptin. We wanted to establish the effect of varying doses of corticosterone (CORT) on body weight and food intake suppression by using separate groups of ADX, ADX and corticosterone-treated and sham-operated Sprague-Dawley rats. All rats were implanted with cholesterol pellets that varied in CORT content. During the same surgical session, all rats were fitted with a cannula in the lateral ventricle. After recovering from surgery, each rat was administered a 5- micro g ICV injection of leptin. ADX rats that were treated with CORT replacement lost more (P < 0.05) weight and took longer (P < 0.05) to return to baseline body weight than sham-operated controls. Leptin injection decreased food consumption to a greater extent (P < 0.05) in the ADX groups treated with CORT than in the sham-operated controls. Plasma insulin increased in a dose-dependent manner in the ADX rats as a function of CORT replacement. The higher of the two CORT replacement doses used in this experiment restored circulating CORT to levels observed in sham-operated controls. Contrary to earlier reports, physiological doses of CORT appear to enhance leptin-induced weight loss. Topics: Adrenalectomy; Animals; Body Weight; Corticosterone; Eating; Injections, Intraventricular; Insulin; Leptin; Male; Rats; Rats, Sprague-Dawley | 2003 |
Diabetes-induced neuroendocrine changes in rats: role of brain monoamines, insulin and leptin.
Diabetes is characterized by hyperphagia, polydypsia and activation of the HPA axis. However, the mechanisms by which diabetes produces these effects are not clear. This study was conducted to examine the effects of diabetes on the neuroendocrine system and to see if treatment with insulin and/or leptin is capable of reversing these effects. Streptozotocin-induced diabetic adult male rats were subjected to the following treatments: vehicle, insulin (2 U/day, s.c.), leptin (100 microg/kg BW) or leptin+insulin every day for 2 weeks. Food intake, water intake, and body weight were monitored daily. We measured changes in monoamine concentrations in discrete nuclei of the hypothalamus at the end of treatment. Diabetes produced a marked increase in food intake and water intake and this effect was completely reversed by insulin treatment and partially reversed by leptin treatment (P<0.05). Diabetes caused an increase in norepinephrine (NE) concentrations in the paraventricular nucleus with a concurrent increase in serum corticosterone. Treatment with insulin and leptin completely reversed these effects. Induction of diabetes also increased the concentrations of NE, dopamine and serotonin in the arcuate nucleus and NE concentrations in the lateral hypothalamus, ventromedial hypothalamus (VMH) and suprachiasmatic nucleus (P<0.05). Although insulin treatment was capable of reversing all these changes, leptin treatment was unable to decrease diabetes-induced increase in NE concentrations in the VMH. These data provide evidence that hypothalamic monoamines could mediate the neuroendocrine effects of diabetes and that insulin and leptin act as important signals in this process. Topics: Animals; Biogenic Monoamines; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Experimental; Drinking; Drug Interactions; Eating; Hyperphagia; Hypothalamo-Hypophyseal System; Hypothalamus; Insulin; Leptin; Male; Norepinephrine; Rats; Rats, Sprague-Dawley; Signal Transduction | 2003 |
A new nonisotopic, highly sensitive assay for the measurement of human placental growth hormone: development and clinical implications.
Human placental GH (hGH-V) is a variant of pituitary hGH (hGH-N) synthesized and secreted by syncytiotrophoblasts during pregnancy. It differs from hGH-V by only 13 amino acid residues, which makes difficult a specific measurement of hGH-V without interference from hGH-N. To overcome the analytical difficulties, we produced new high affinity monoclonal antibodies specific for hGH-V. Precise screening and epitope mapping allowed identification of a pair of monoclonal antibodies suitable to establish a highly sensitive assay for hGH-V measurement. In a prospective, longitudinal study involving 84 normal pregnancies, we measured maternal concentrations of hGH-V, leptin, IGF-I, and cord blood IGF-I. hGH-V was detectable as early as gestational week (GW) 7. Mean concentrations of hGH-V increased from 0.9 +/- 0.5 microg/liter (GW 7-13) to 2.8 +/- 0.9 microg/liter (GW 18-22), 7.3 +/- 2.6 microg/liter (GW 28-32), and 13.0 +/- 9.6 (GW 37-41). A negative correlation was found between prepregnancy body mass index and hGH-V concentrations from GW 28 onward. Peak hGH-V levels occurred at wk 36.5 +/- 2.6 and were significantly lower in obese (P = 0.029) and higher in underweight (P = 0.035) mothers compared with those in mothers of normal weight. The increase in hGH-V between GW 18-22 and GW 28-32 was negatively correlated to the increase in maternal leptin during this period (P = 0.027). Maternal IGF-I concentrations were correlated to those of hGH-V from GW 18 onward (P = 0.039). The strongest correlation was found at GW 28-32 (P = 0.001). Furthermore, maternal hGH-V concentrations in late pregnancy correlated with cord blood IGF-I (P = 0.025) and size of the newborn (P = 0.017). These results, obtained by a new, highly sensitive hGH-V-specific immunoassay, highlight the importance of maternal hGH-V in the regulation of maternal and fetal IGF-I. In addition, the results indicate that maternal weight has a major impact on circulating concentrations of hGH-V. Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Body Weight; Epitope Mapping; Female; Fetal Blood; Fibroblasts; Gene Expression; Growth Hormone; Humans; Immunoassay; Insulin-Like Growth Factor I; Leptin; Longitudinal Studies; Mice; Mice, Inbred BALB C; Placental Hormones; Pregnancy; Prospective Studies; Reagent Kits, Diagnostic; Recombinant Proteins; Sensitivity and Specificity | 2003 |
Cellular warriors at the battle of the bulge.
Topics: Agouti-Related Protein; alpha-MSH; Animals; Anti-Obesity Agents; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Brain; Caloric Restriction; Fatty Acids; Ghrelin; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Longevity; Mice; Neurons; Neuropeptide Y; Obesity; Peptide Hormones; Peptide YY; Pro-Opiomelanocortin; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Proteins; Receptor, Insulin; Receptors, Pituitary Hormone; Stearoyl-CoA Desaturase | 2003 |
A war on obesity, not the obese.
In their efforts to lose weight, obese individuals may be fighting a powerful set of evolutionary forces honed in an environment drastically different from that of today. Topics: Adipose Tissue; Body Mass Index; Body Weight; Diet; Energy Intake; Energy Metabolism; Feeding Behavior; Female; Genes; Homeostasis; Humans; Hunger; Incidence; Leptin; Life Style; Male; Obesity; Public Health; Selection, Genetic; United States; Weight Loss | 2003 |
Deficiency of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) impairs nutritionally induced obesity in mice.
Tissue inhibitor of matrix metalloproteinase-1 deficient (TIMP-1(-/-)) mice and wild-type (TIMP-1(+/+)) controls were kept on a standard (SFD) or a high fat diet (HFD) for 15 weeks. At the time of sacrifice, TIMP-1(-/-) mice on HFD had a significantly lower body weight (29 +/- 1.5 versus 41 +/- 1.8 g, p <0.005), and significantly less subcutaneous (0.81 +/- 0.19 versus 1.78 +/- 0.21 g, p <0.05) and gonadal (0.87 +/- 0.17 versus 1.85 +/- 0.18 g, p <0.005) fat mass. These differences were much less pronounced for mice on SFD. On HFD but not on SFD, adipocyte diameters were significantly lower in the adipose tissue of TIMP-1(-/-) mice. Plasma leptin levels in TIMP-1(-/-) mice on HFD were significantly lower as compared to TIMP-1(+/-) mice, and strongly correlated with adipose tissue mass for both genotypes. Staining with an endothelial cell specific lectin revealed a significantly higher blood vessel density, larger stained area and vessel size in adipose tissue of TIMP-1(-/-) mice on HFD. This difference disappeared after normalization to the adipocyte number, suggesting that it does not represent a true enhancement of angiogenesis. Thus, in a murine model of nutritionally induced obesity, TIMP-1 promotes adipose tissue development. Topics: Adipocytes; Adipose Tissue; Animals; Blood Glucose; Body Weight; Cell Size; Cholesterol; Crosses, Genetic; Dietary Fats; Endothelium, Vascular; Gelatinases; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic; Obesity; Tissue Inhibitor of Metalloproteinase-1; Triglycerides | 2003 |
DNA microarray analysis of genes differentially expressed in diet-induced (cafeteria) obese rats.
To better understand the molecular basis of dietary obesity, we examined adipose tissue genes differentially expressed in an obesity model using DNA microarray analysis.. We assessed the expression level of over 12,500 transcripts in epididymal fat pads from (cafeteria) obese and control rats with the aid of the array technology.. Cafeteria (obese) rats weighed 50% more and had 2.5-fold higher levels of epididymal fat and elevated levels of circulating leptin. Adipose genes differentially expressed in obese and control rats were categorized into five groups: macronutrient metabolism, transcription factors, hormone receptor and signal transduction, redox and stress proteins, and cellular cytoskeleton. Interestingly, the expression levels of a number of genes involved in lipid metabolism such as glycerol-3-phosphate dehydrogenase, stearoyl coenzyme A desaturase, together with the transcription factors implicated in adipocyte differentiation (CAAT/enhancer binding protein-alpha and peroxisome proliferator-activated receptor-gamma), were significantly increased in obese animals compared with control. The most up-regulated transcripts were the ob (49.2-fold change) and the fatty acid-binding protein genes (15.7- fold change). In contrast, genes related to redox and stress protein were generally down-regulated in obese animals compared with the control.. Our study showed that in diet-induced obesity, the expression levels of some important genes implicated in lipid metabolism were up-regulated, whereas those related to redox and stress protein were down-regulated in obese animals compared with control. This pattern of gene expression may occur in human obesity cases after high-fat intake. Topics: Adipocytes; Adipose Tissue; Animals; Blotting, Northern; Body Weight; Carrier Proteins; CCAAT-Enhancer-Binding Proteins; Cell Differentiation; Diet; Epididymis; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Gene Expression; Glycerolphosphate Dehydrogenase; Leptin; Lipid Metabolism; Male; Neoplasm Proteins; Nerve Tissue Proteins; Obesity; Oligonucleotide Array Sequence Analysis; Oxidation-Reduction; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Stearoyl-CoA Desaturase; Transcription Factors | 2003 |
A role for galanin-like peptide in the integration of feeding, body weight regulation, and reproduction in the mouse.
Galanin-like peptide (GALP) shares sequence homology with galanin and binds to galanin receptors in vitro. GALP neurons in the arcuate nucleus coexpress leptin receptors, and GALP mRNA expression is up-regulated by leptin. Based on these observations, we postulated that GALP plays a role in mediating leptin's inhibitory effects on food intake (FI) and body weight (BW), as well as its stimulatory effect on the reproductive axis. To test these hypotheses, we performed several studies in which mice received intracerebroventricular injections of either GALP or vehicle. Acute GALP treatment elicited a dose-dependent suppression of FI and BW. Long-term treatment with GALP caused only transient reductions in FI and BW, demonstrating that the mice became refractory to continued exposure to GALP. GALP inhibited FI as early as 1 h post injection. Central injection of GALP suppressed locomotor activity and elicited the formation of a conditioned taste aversion. In male mice, serum levels of LH and testosterone were increased by GALP administration. Although we cannot rule out possible nonspecific effects of GALP on FI, the present observations are consistent with the argument that GALP is a downstream effector of leptin's actions within the central nervous system. Topics: Animals; Body Weight; Conditioning, Psychological; Dose-Response Relationship, Drug; Eating; Follicle Stimulating Hormone; Galanin-Like Peptide; Injections, Intraventricular; Kinetics; Leptin; Luteinizing Hormone; Male; Mice; Mice, Inbred C57BL; Motor Activity; Nerve Tissue Proteins; Rats; Rats, Sprague-Dawley; Reproduction; Taste; Testosterone | 2003 |
Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice.
We determined the effect of a cannabinoid CB1 receptor antagonist (AM-251; N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) on food intake, body weight and adipose tissue mass in Western diet-induced obese (DIO) mice using a chronic, interrupted, oral dosing paradigm. The dosing paradigm was 2 weeks on treatment (treatment 1), 2 weeks off-treatment, followed by 2 weeks on treatment (treatment 2). During treatment 1 and treatment 2, food intake and body weight were reduced after a single dose. At 30 mg/kg/day, anorectic efficacy was maintained through 12 days (treatment 1) and 7 days (treatment 2). Body weight of AM-251-treated mice remained less than vehicle-treated mice throughout treatment 1 and treatment 2. Administration of AM-251 reduced inguinal subcutaneous, retroperitoneal and mesenteric adipose tissue mass. Antiobesity effects of AM-251 were lost during the off-treatment period, and hyperphagia was observed in treated animals. With re-initiation of AM-251 treatment, mice again responded to the effects of the compound. These results support the hypothesis that chronic treatment of obese individuals with cannabinoid CB1 receptor antagonists is a viable pharmacologic approach to sustained weight loss. Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Dietary Fats; Dose-Response Relationship, Drug; Eating; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Triglycerides | 2003 |
STAT3 signalling is required for leptin regulation of energy balance but not reproduction.
Secretion of leptin from adipocytes communicates body energy status to the brain by activating the leptin receptor long form (LRb). LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes. Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin action. To investigate the contribution of STAT3 signalling to leptin action in vivo, we replaced the gene encoding the leptin receptor (lepr) in mice with an allele coding for a replacement of Tyr 1138 in LRb with a serine residue (lepr(S1138)) that specifically disrupts the LRb-STAT3 signal. Here we show that, like db/db mice, lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short and diabetic, s/s mice are fertile, long and less hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. LRb-STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis. Topics: Alleles; alpha-MSH; Animals; Blood Glucose; Body Weight; Cell Line; Diabetes Mellitus; DNA-Binding Proteins; Energy Metabolism; Estrous Cycle; Female; Homeostasis; Humans; Infertility; Leptin; Male; Mice; Neuropeptide Y; Obesity; Phenotype; Receptors, Cell Surface; Receptors, Leptin; Reproduction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Trans-Activators | 2003 |
Genetically obese MMTV-TGF-alpha/Lep(ob)Lep(ob) female mice do not develop mammary tumors.
Elevated body weight is a risk factor for postmenopausal breast cancer and is associated with increased incidence of spontaneous and chemically induced mammary tumors (MTs) in rodents. In this study, genetically obese Lep(ob)Lep(ob) female mice that overexpress human TGF-alpha (transforming growth factor-alpha) were used to assess the role of body weight on oncogene-induced MT development in comparison to lean counterparts. MMTV (mouse mammary tumor virus)-TGF-alpha and Lep strain mice were crossed to produce TGF-alpha/Lep(+)Lep(+) (homozygous lean), TGF-alpha/Lep(+)Lep(ob) (heterozygous lean) and TGF-alpha/Lep(ob)Lep(ob) (homozygous obese) genotypes. Body weights were determined weekly and mice palpated for the presence of MTs until 104 weeks of age. Despite their significantly higher body weight, obese TGF-alpha/Lep(ob)Lep(ob) mice failed to develop MTs. MTs were detected between 48 and 104 weeks of age for 26/39 TGF-alpha/Lep(+)Lep(ob) mice and for 19/38 TGF-alpha/Lep(+)Lep(+) mice between 67 and 104 weeks of age. Although MT incidence was not statistically different between the lean groups, age of MT detection tended to be younger for TGF-alpha/Lep(+)Lep(ob) mice (p < 0.09). There were significant effects of both genotype and MTs on final body weight, that is, TGF-alpha/Lep(+)Lep(ob) mice weighed more than homozygous lean mice, and mice with MTs weighed more than those without MTs. TGF-alpha/Lep(ob)Lep(ob) mice are not a good model to evaluate the effect of body weight on MT development possibly due to leptin deficiency. However, the finding that increased body weight is associated with increased oncogene-induced MT development within the normal weight range provides experimental support for the role of body weight in breast cancer. Topics: Animals; Body Weight; Disease Models, Animal; DNA Primers; Female; Leptin; Mammary Neoplasms, Experimental; Mammary Tumor Virus, Mouse; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Polymerase Chain Reaction; Survival Analysis; Transforming Growth Factor alpha | 2003 |
Does leptin mediate the effect of photoperiod on immune function in mice?
Seasonal fluctuations in immune status have been documented for avian and mammalian populations. During the late summer and early fall, immune function is bolstered to help animals cope with the more physiologically demanding winter. The environmental cue for these seasonal changes is apparently decreasing photoperiod. In the present study, we determined the potential role of leptin in mediating the effect of photoperiod on cell-mediated immune responses in male mice. Leptin-deficient (ob/ob) and littermate control mice were housed for 10 wk in either a short (8L:16D) or a long (16L:8D) photoperiod beginning at 6 wk of age. After the mice were killed, immune and reproductive organs were weighed and splenocytes isolated. The proliferative and cytokine responses (interleukin [IL]-2 and IL-4) of splenocytes to the T-cell mitogen, concanavalin A (Con A; 0-40 microg/ml), were determined. Body weights were elevated and both testes and seminal vesicle weights subnormal in ob/ob mice (by ANOVA, main effect of leptin deficiency), but thymuses and spleens were of normal size. Serum leptin levels were at minimum detection limits in ob/ob mice, but leptin levels in control mice housed at 8L:16D were higher than in control mice housed at 16L:8D. The proliferative response of splenocytes from ob/ob mice to Con A was subnormal (by ANOVA, main effect of leptin deficiency), but photoperiod had no effect on this response. Production of IL-2 in splenocytes of ob/ob mice was subnormal (by ANOVA, main effect of leptin deficiency) irrespective of photoperiod, but cells from mice housed at 8L:16D (by ANOVA, main effect of photoperiod) produced more IL-2 than cells from animals housed at 16L:8D. In contrast, a leptin deficiency did not alter IL-4 production, but cells from animals (ob/ob and controls) housed at 16L:8D produced less IL-4 than cells from animals housed at 8L:16D (by ANOVA, main effect of photoperiod). The present study suggests that both photoperiod and leptin have mutually independent effects on the proliferation of lymphocytes and cytokine production profiles. The data do not provide definitive support for the hypothesis that photoperiod-induced changes in leptin secretion mediate the effects of season on immune status. Topics: Animals; Body Weight; Cell Division; Cytokines; Immunity; In Vitro Techniques; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Models, Immunological; Organ Size; Photoperiod; Seasons; T-Lymphocytes; Testis; Testosterone | 2003 |
Differential sensitivity to central leptin and insulin in male and female rats.
The distribution of fat in the body differs between the male and female sexes and is associated with the relative secretion of the two "adiposity" hormones leptin and insulin. We now report that the brains of male and female rats are differentially sensitive to the catabolic actions of small doses of these two hormones. Leptin (1 or 3.5 microg/2 microl) or saline (2 microl) was administered into the third cerebral ventricle of age- and weight-matched male and female rats. Leptin significantly reduced food intake in female and male rats over 4 h; however, leptin reduced 24-h intake in female but not in male rats. When the same rats were administered insulin (1 or 4 mU/2 microl) or saline (2 microl), male but not female rats had a robust reduction in food intake over 24 h. Previous research demonstrates the melanocortins are a central mediator of the effects of both leptin and insulin. However, we found no sex differences in sensitivity to the melanocortin agonist MTII (0.01, 0.1, 0.3, and 1.0 nmol/2 microl). These results suggest that the sex differences in sensitivity to leptin and insulin at the doses that we injected occur upstream of the melanocortin receptors. Because insulin and leptin reflect different fat beds and are differentially distributed in the male and female sexes, the implication is that the male and female sexes regulate adiposity-relevant parameters differently. Topics: alpha-MSH; Animals; Body Composition; Body Weight; Brain; Eating; Female; Injections, Intraventricular; Insulin; Leptin; Male; Rats; Rats, Long-Evans; Receptors, Corticotropin; Receptors, Melanocortin; Sex Characteristics | 2003 |
Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible.
Leptin resistance is a major cause of obesity in humans. A major component of this resistance is likely an impaired transport of leptin across the blood-brain barrier (BBB). The fattest subgroup of otherwise normal 12-mo-old CD-1 mice have severely impaired transport of leptin across the BBB. However, it is unknown whether these mice are born with a BBB impairment or acquire it with aging and obesity. Here, we found within an otherwise normal population of CD-1 mice that the 10% fattest mice gained weight throughout a 12-mo-life span, whereas the 10% thinnest mice gained little weight after 3 mo of age. The fattest mice acquired a progressive impairment in their ability to transport leptin across the BBB, whereas the thinnest mice had a rate of transport that did not change with age. Fasting fat mice for 24 h or treating them with leptin resulted in modest weight reduction and development of transport rates for leptin across the BBB similar to those of thin mice. These results show that, in obese CD-1 mice, the impaired transport of leptin across the BBB develops in tandem with obesity and is reversible with even modest weight reduction. Topics: Aging; Algorithms; Animals; Biological Transport, Active; Blood-Brain Barrier; Body Weight; Capillaries; Fasting; Leptin; Male; Mice; Obesity; Weight Loss | 2003 |
Increased salt sensitivity secondary to leptin resistance in SHHF rats is mediated by endothelin.
A link between leptin resistance, obesity, and salt sensitivity has been suggested. SHHF/Mcc-fa(cp) rats (SHHF) were used to study the effect of gene dosage of a null mutation of the leptin receptor (cp) on salt sensitivity and response to a combined endothelin A and B receptor antagonist (bosentan). Obese (cp/cp), heterozygous (+/cp), and homozygous lean (+/+) male SHHF were fed a low salt diet (0.3% NaCl) for 7 days, followed by a high salt diet (8.0% NaCl) for 7 days. There were no significant differences in systolic blood pressure between genotypes on low salt. In response to high salt, cp/cp had significantly greater systolic pressure than +/cp and +/+. On high salt diet, cp/cp showed a significant increase in 24 h urinary endothelin excretion and increased renal expression of preproendothelin mRNA. There was no effect of high salt diet on renal excretion of nitric oxide (NOx) or on gene expression of endothelial, neuronal, or cytokine-induced nitric oxide synthase isoforms (eNOS, nNOS, iNOS, respectively). Treatment with bosentan prevented the high salt-induced increment in systolic blood pressure in cp/cp. This was associated with a doubling of renal NOx excretion, but without changes in eNOS, nNOS, or iNOS expression. Endothelin receptor antagonism did not normalize systolic pressure in any of the genotypes. Our studies indicate that obesity secondary to leptin resistance (cp/cp) results in increased salt sensitivity that is mediated by endothelin in the SHHF rat. Topics: Animals; Blood Pressure; Body Weight; Disease Models, Animal; Endothelins; Hypertension; Kidney; Leptin; Male; Obesity; Rats; Rats, Inbred SHR; Receptors, Endothelin; RNA, Messenger; Sodium Chloride, Dietary | 2003 |
Chemical sympathectomy alters regulation of body weight during prolonged ICV leptin infusion.
To assess the importance of the sympathetic nervous system in regulating body weight during prolonged leptin infusion, we evaluated food intake, body weight, and physical activity in conscious, unrestrained rats. Initial studies illustrated that prolonged intracerebroventricular (ICV) infusion of leptin enhanced substrate oxidation so that adipose tissue lipid stores were completely ablated, and muscle triglyceride and liver glycogen stores were depleted. After neonatal chemical sympathectomy, changes in weight and food intake were compared in groups of sympathectomized (SYM) and control (CON) adult animals during ICV infusion of leptin. CON animals lost 60 +/- 9 g over 10 days vs. 25 +/- 3 g in the SYM animals when food intake was matched between the two groups. Greater weight loss despite similar energy intake points to an important role of the sympathetic nervous system in stimulating energy expenditure during ICV leptin infusion by increasing the resting metabolic rate, since no differences in physical activity were observed between CON and SYM groups. In conclusion, activation of the SNS by leptin increases energy expenditure by augmenting the resting metabolic rate. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Energy Metabolism; Fatty Acids, Nonesterified; Injections, Intraventricular; Insulin; Leptin; Male; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Sympathectomy, Chemical; Sympathetic Nervous System; Triglycerides | 2003 |
Serum leptin levels as a marker for a syndrome X-like condition in wild baboons.
We measured serum leptin levels in two groupings of wild male baboons, one with access to abundant quantities of food from gardens and garbage dumps near human habitations (Garbage; n = 11) and one without access (No Garbage; n = 10). A Garbage subgroup had high leptin levels (Garbage HL), whereas the rest of the Garbage group had low leptin levels (Garbage LL) similar to those in the No Garbage group. The Garbage HL individuals were obese, with higher mass, body mass index, and leptin to mass ratios; were insulin to resistant, with elevations in serum insulin, glucose, and insulin to glucose ratios; and were hyperlipidemic. This syndrome X-like condition occurred only in the Garbage HL subset. The Garbage LL subset did not differ from the No Garbage individuals in mass, body mass index, leptin to mass ratio, insulin, glucose, or insulin to glucose ratios. The highest cholesterol levels, however, occurred in the Garbage LL individuals, suggesting that susceptibility to hyperlipidemia is distinguishable from susceptibility to obesity and insulin resistance. The differences were not explained by age or social status. These results show that a subgroup of wild baboons is susceptible to developing obesity and insulin resistance and that this susceptibility is not related to age or social rank. Topics: Age Factors; Animals; Biomarkers; Body Mass Index; Body Weight; Insulin Resistance; Leptin; Microvascular Angina; Obesity; Papio | 2003 |
Leptin influences cellular differentiation and progression in prostate cancer.
Several studies have shown a positive association of dietary fat with prostate cancer. Leptin, a peptide hormone that has a role in the regulation of body weight, currently serves as a more accurate biomarker for total body fat. We designed a study to determine whether leptin influences cellular differentiation and the progression of prostate cancer.. In this study we investigated serum leptin in 21 patients with prostate cancer, 50 with benign prostatic obstruction and 50 healthy individuals matched for sex, body mass index and age. Patients with cancer were stratified into 2 groups by the disease spread, including groups 1--organ confined and 2--advanced disease, and into 3 groups by the differentiation degree, including groups 3--Gleason sum 2 to 4 or well differentiated, 4--Gleason sum 5 to 7 or moderately differentiated and 5--Gleason sum 8 to 10 or poorly differentiated.. We noted significant differences in serum leptin in the cancer versus control and cancer versus benign prostatic obstruction groups. In addition, in the prostate cancer group serum leptin correlated with prostate specific antigen and biopsy Gleason score. We also observed significant differences in serum leptin in groups 1 versus 2, 3 versus 5 and 4 versus 5.. Leptin may have roles in the development of prostate cancer through testosterone and factors related to obesity. It influences cellular differentiation and the progression of prostate cancer. Topics: Adult; Aged; Aged, 80 and over; Biopsy; Body Weight; Cell Transformation, Neoplastic; Disease Progression; Female; Humans; Leptin; Male; Middle Aged; Neoplasm Staging; Prognosis; Prostatic Hyperplasia; Prostatic Neoplasms; Risk Factors; Testosterone; Urinary Bladder Neck Obstruction | 2003 |
Adipose tissue cellularity and apoptosis after intracerebroventricular injections of leptin and 21 days of recovery in rats.
To determine the effect of leptin and post-treatment recovery on adipose tissue cellularity and apoptosis. In addition, to investigate whether Bcl-2 and/or Bax is involved in the mechanism of leptin-induced adipose tissue apoptosis.. A total of 24 adult male Sprague-Dawley rats were injected i.c.v. with either 10 microg mouse leptin or 10 microl vehicle once per day for 4 days. At 24 h after the last injection, one group was killed while the other was monitored for 21 days.. DNA fragmentation and Bcl-2 and Bax protein levels were determined in inguinal (ING), epididymal (EPI) and retroperitoneal (RP) white adipose tissues and the interscapular brown adipose tissue (BAT). Cellularity was determined in ING and EPI.. Leptin significantly reduced the masses of all white fat pads [RPINGEPI] but not BAT. Cell volume was significantly reduced in EPI and ING. Only ING had a significantly reduced cell number from leptin treatment plus exhibited apoptosis by increased DNA fragmentation and DNA laddering, and upregulation of pro-apoptosis Bax protein. The other fat pads exhibited a general trend to increase the Bcl-2/Bax ratio. Recovery allowed for normalization of white fat pad mass, cell number and cell volume; however, BAT mass increased 42% over control. After recovery, apoptosis was not detected, Bcl-2 protein had increased in ING, and the Bcl-2/Bax ratio had risen overall.. Central administration of mouse leptin in the rat targets white fat depots individually to reduce mass by a reduction in cell volume plus adipocyte deletion in, at least, the ING fat pad by Bax-mediated apoptosis. Even after a dramatic loss in adipose tissue mass and change in cellularity, the rat demonstrates a resilient return to control levels together with an increase in factors that prevent adipocyte loss. Topics: Adipocytes; Adipose Tissue; Animals; Apoptosis; bcl-2-Associated X Protein; Body Weight; Cell Count; Cell Size; DNA Fragmentation; Injections, Intraventricular; Leptin; Male; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley | 2003 |
Body composition, leptin, and the leptin receptor and their relationship to the growth hormone (GH) axis in growing wethers treated with zeranol.
Age-related changes in body composition, leptin, and hypothalamic-pituitary expression of the leptin receptor and associative relationships of these factors to constituents of the growth hormone (GH) axis were evaluated. Seventy wethers were randomly assigned at birth to one of four treatment groups: control; treatment 1 implanted with the estrogenic compound zeranol (12 mg, Ralgro on days 0, 45, and 90; treatment 2 received zeranol on days 45 and 90; and treatment 3 received zeranol on day 90. Serum and tissues were collected from wethers (n > or = 5) from each group on days 28, 73, 118, and 135. Percent body fat and leptin increased linearly (P < 0.01) with age, but were not influenced (P > or = 0.14) by zeranol. The leptin receptor in the pituitary appeared to be differentially (P = 0.097) expressed across days 73-135, but no differences (P > or = 0.43) were detected in expression of this receptor in the hypothalamus among treatments and ages. Leptin and % body fat were negatively correlated (r > or = -0.52, P < 0.05) to mRNA levels of factors involved in pituitary synthesis and secretion of GH. Serum leptin increased with age as did percent body fat, but zeranol did not influence body composition, serum leptin, or expression of the leptin receptor in the hypothalamus or pituitary; however, the leptin receptor appeared to be differentially expressed among the hypothalamus and pituitary with level of body fat and leptin being inversely associated to transcriptional-factors involved in somatotrope synthesis and secretion of GH. Topics: Adipose Tissue; Aging; Animals; Body Composition; Body Weight; Drug Implants; Estrogens, Non-Steroidal; Gene Expression; Growth Hormone; Leptin; Male; Pituitary Gland; Random Allocation; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Sheep; Zeranol | 2003 |
Decreased serum leptin levels in women with uterine leiomyomas.
To analyze the possible involvement of leptin in uterine leiomyomas.. Serum leptin levels, determined by radioimmunoassay, were compared in myomatic (n = 50) and the normal (n = 50) women.. A significant correlation was found between serum leptin levels and body mass index in both the myomatic women (r = 0.76, p < 0.001) and the normal women (r = 0.56, p < 0.001). Serum leptin levels in the myomatic women (9.3 +/- 0.6 ng/mL) were significantly lower (p < 0.001) than those in the normal women (13.6 +/- 1.2 ng/mL). In addition, the ratios of serum leptin levels/body mass index in the myomatic women (0.38 +/- 0.02) were significantly lower than those in the normal women (0.57 +/- 0.04) (p < 0.001). A significant correlation was found between the ratios of serum leptin levels/body mass index and body mass index (r = 0.59, p < 0.001) in the normal women, but not in the myomatic women (r = 0.27, p = 0.061).. The lower plasma leptin levels observed in the women with myomas were independent of body mass index, and unlike the normal women there was no significant up-regulation of leptin production in response to increased adiposity. Topics: Adult; Body Mass Index; Body Weight; Female; Humans; Leiomyoma; Leptin; Middle Aged; Radioimmunoassay; Uterine Neoplasms | 2003 |
Longitudinal study of nutritional status, body composition, and physical function in hemodialysis patients.
Cross-sectional studies have shown an association between the duration (y) of dialysis and nutritional status, providing evidence of wasting.. The aim was to determine the extent, pace, determinants, and optimal methods of assessing wasting in patients undergoing hemodialysis.. Laboratory variables, body composition, and physical activity, function, and performance were tested 4 times over 1 y in 54 hemodialysis patients. Changes in repeated measures were evaluated, with adjustment for baseline differences by age, sex, race, diabetes status, and dialysis vintage (ie, time since initiation of dialysis).. No significant changes in body weight, fat mass, lean body mass, or laboratory variables were observed. Phase angle, a bioelectrical impedance analysis-derived variable related to body cell mass, decreased significantly (linear estimate: -0.043 degrees /mo, or approximately 0.5 degrees/y; P = 0.001). Physical activity measured by accelerometry declined 3.4%/mo (P = 0.01). The Maximum Activity Score of the Human Activity Profile (HAP) also declined significantly (linear estimate: -0.50/mo, or approximately 6 points/y; P = 0.025). Higher interleukin 1beta (IL-1beta) concentrations were associated with a narrower phase angle (P = 0.004) and with a more rapid decline in phase angle with time (time x IL-1beta interaction, P = 0.01); similar effects of IL-1beta on physical activity were observed. Dietary protein and energy intakes were associated with changes in the HAP.. Evidence of adverse changes in body composition and physical activity, function, and performance and of a modest influence of inflammation and dietary intake on these changes was observed in this cohort. Tools such as bioelectrical impedance analysis, accelerometry, and the HAP may be required to identify subtle changes. Topics: Activities of Daily Living; Adipose Tissue; Adult; Aged; Aged, 80 and over; Body Composition; Body Weight; C-Reactive Protein; Dietary Proteins; Electric Impedance; Energy Intake; Exercise; Female; Humans; Interleukin-1; Karnofsky Performance Status; Leptin; Longitudinal Studies; Male; Middle Aged; Nutritional Status; Renal Dialysis; Serum Albumin | 2003 |
Enhanced nutritionally induced adipose tissue development in mice with stromelysin-1 gene inactivation.
To investigate a potential role of stromelysin-1 (MMP-3) in development of adipose tissue, 5 week old male MMP-3 deficient mice (MMP-3(-/-)) and wild-type (MMP-3(+/+)) controls were kept on a high fat diet (HFD) for 15 weeks. MMP-3(-/-) mice were hyperphagic and gained more weight than the MMP-3(+/+) mice. At the time of sacrifice, the body weight of the MMP-3(-/-) mice was significantly higher than that of the MMP-3(+/+) mice, as was the weight of the isolated subcutaneous (SC) and gonadal (GON) fat deposits. Significant adipocyte hypertrophy was observed in the GON but not in the SC adipose tissue of MMP-3(-/-) mice. Fasting plasma glucose and cholesterol levels were comparable in both genotypes, whereas triglyceride levels were significantly lower in MMP-3(-/-) mice. Staining with an endothelial cell specific lectin revealed a significantly higher blood vessel density and larger total stained area in the GON adipose tissues of MMP-3(-/-) mice. Thus, in a murine model of nutritionally induced obesity, MMP-3 impairs adipose tissue development, possibly by affecting food intake and/or adipose tissue-related angiogenesis. Topics: Adipocytes; Adipose Tissue; Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Blotting, Western; Body Weight; Cholesterol; Disease Models, Animal; DNA; Enzyme-Linked Immunosorbent Assay; Genotype; Immunohistochemistry; Leptin; Male; Matrix Metalloproteinase 3; Mice; Neovascularization, Physiologic; Obesity; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Triglycerides | 2003 |
A controlled high-fat diet induces an obese syndrome in rats.
The prevalence of obesity is increasing. Although the etiology of obesity is complex, dietary factors, particularly the consumption of a high-fat (HF) diet, is considered a risk factor for its development. Nonetheless, a causal role of dietary fat has never been definitively documented, in part because of inadequate animal models. We developed a rat model of diet-induced obesity that will be a powerful tool for assessment of this issue. In four experiments, Long-Evans rats ate ad libitum a synthetic semipurified diet containing 20 g (HF) or 4 g [low-fat (LF)] of fat/100 g of diet or a nonpurified diet. Other rats ate ad libitum the HF diet in amounts matched to the energy intake of the LF rats. When compared over 10 wk of free feeding, HF rats weighed 10% more (P < 0.01) than LF rats and had 50% more body fat (P < 0.01), as well as significant hyperleptinemia and insulin resistance. Compared with rats fed the nonpurified diet, the HF rats had even more marked differences in these variables. The rats fed the HF diet to match the rats fed the LF diet had similar body weights but significantly more adipose tissue than LF rats, suggesting that diet composition and/or energy density of the diet affects fat deposition. This dietary regimen has reproducible effects on body size and composition, and these are similar in male and female rats. This model of diet-induced obesity will be a useful tool for studying the mechanisms by which dietary fat influences the regulation of energy balance. Topics: Animals; Body Composition; Body Weight; Dietary Fats; Energy Intake; Female; Glucose Tolerance Test; Insulin; Leptin; Male; Obesity; Rats; Rats, Long-Evans | 2003 |
Effect of in ovo leptin administration on the development of Japanese quail.
Potential changes in the activity of endocrine axes related to growth as a result of leptin administration during embryonic development of birds were evaluated in the Japanese quail as a model bird with fast growth and development. On day 5 of incubation, 0.1 microg or 1 microg of recombinant mice leptin in 50 microl of phosphate buffered saline were injected into the albumen of eggs. Animals from each group were killed by decapitation on day 0, 2, 5, 7, 14, 21, 28, 35, 42, 49 and 56 of life. Plasma concentrations of triiodothyronine (T(3)), thyroxin (T(4)), corticosterone, testosterone, total lipids, triacylglycerols, cholesterol, glucose and alkaline phosphatase activity were measured. Quail treated by leptin hatched earlier (5-24 hours) and had a higher body weight than the control group (P<0.05-0.001). Mean body weight across the whole observed period was higher in both treated groups as compared to the control group (P<0.05). Leptin in ovo administration was accompanied by changes of endocrine and metabolic parameters during postembryonic development. The most prominent changes appeared immediately after hatching (T(3), T(4), total lipids, triacylglycerols) and before sexual maturity. It is suggested that leptin acts as a general signal of low energy status to neuroendocrine systems in birds which improves utilization of nutrients. Topics: Aging; Animals; Body Weight; Coturnix; Dose-Response Relationship, Drug; Female; Humans; Leptin; Lipids; Male; Mice; Organ Size; Recombinant Proteins; Testis; Testosterone; Thyroid Hormones; Zygote | 2003 |
Effects of prenatal alcohol exposure on glucose tolerance in the rat offspring.
Low birth weight in humans predisposes to obesity, cardiovascular diseases, and type 2 diabetes in adult life. Alcohol exposure during pregnancy has been associated with fetal growth restriction. We investigated the effects of prenatal exposure to alcohol on glucose metabolism later in the offspring. Female Sprague Dawley rats were given ethanol (ETOH), 4 g/kg/day by gavage throughout pregnancy. Compared with controls, newborn ETOH rats had decreased body size (5.1 +/- 0.1 v 6.3 +/- 0.1 g, P <.001), plasma insulin (0.44 +/- 0.4 v 0.67 +/- 0.1 ng/mL, P <.05), and leptin mRNA (P <.05), but they had normal beta-cell mass and elevated adipose resistin mRNA and plasma glucose (5.0 +/- 0.5 v 3.6 +/- 0.3 mmol/L, P <.01). Food intake was decreased in ETOH rats during the fourth week of life, and body weight remained decreased compared with controls until a catch-up growth occurred by 7 weeks of life. At 13 weeks of age, body weight and beta-cell mass of ETOH offspring were normal, but plasma glucose and insulin after a glucose challenge were increased compared with controls (P <.05). Adipose leptin and hypothalamic Ob-R mRNA were not different from controls, but resistin was increased (P <.05), and muscle GLUT4 content was decreased (P <.05) in ETOH offspring compared with controls. The data suggest that prenatal alcohol exposure impairs glucose tolerance in the offspring by both inducing insulin resistance and beta-cell dysfunction. The prevailing mechanism in 3-month-old rat offspring appears to be insulin resistance, manifested by glucose intolerance and decreased GLUT4 despite hyperinsulinemia. Topics: Animals; Body Weight; Central Nervous System Depressants; Eating; Ethanol; Female; Fetal Growth Retardation; Glucose Intolerance; Glucose Transporter Type 4; Hormones, Ectopic; Insulin; Leptin; Monosaccharide Transport Proteins; Muscle Proteins; Nerve Growth Factor; Pancreas; Pregnancy; Prenatal Exposure Delayed Effects; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Resistin | 2003 |
Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms.
We evaluated the effects of diet on intestinal tumorigenesis in male Apc(Min) mice by comparing AIN-76A diet fed ad libitum (CON); calorie intake restricted by 40% of the CON (CR); diet high in olive oil and supplemented with freeze-dried fruit and vegetable extracts (OFV); and diet high in total fat (HF). Compared with CON, the frequency of intestinal polyps was reduced by 57% by CR (P < 0.001) and by 33% OFV diet (P = 0.04). Both effective interventions reduced total body weight, lean mass, and fat mass and increased daily urinary corticosterone output, but only CR reduced serum insulin-like growth factor I and leptin. We conclude that dietary interventions can partially offset genetic susceptibility to intestinal carcinogenesis. Topics: Animals; Body Composition; Body Weight; Corticosterone; Diet; Energy Intake; Genes, APC; Genetic Predisposition to Disease; Insulin-Like Growth Factor I; Intestinal Neoplasms; Intestinal Polyps; Leptin; Male; Mice; Mice, Inbred C57BL | 2003 |
Leptin concentrations in relation to energy balance, milk yield, intake, live weight, and estrus in dairy cows.
The objective of this study was to describe fluctuations in leptin concentrations during late pregnancy and lactation and to investigate how those fluctuations are related to energy balance, milk yield, milk components, dry matter intake, live weight, first postpartum luteal activity, and first observed estrus during lactation. Live weight, dry matter intake, energy balance, and milk yield were measured weekly on 304 primiparous Holstein cows for the first 80 d of lactation. The first postpartum luteal activity was determined by measuring milk progesterone, and independently, first observed estrus. For measuring leptin concentrations from 30 d before until 80 d after calving, blood samples were taken at 2-wk intervals at a fixed time of the day after milking but before feeding. Leptin concentrations were high during pregnancy and declined to a nadir at parturition. It seems that leptin concentrations reflect the state of energy balance during lactation; plasma leptin concentrations were lower in cows with a mean negative energy balance during lactation. Those cows usually produced more milk, consumed less feed, and had a lower live weight compared with cows having a mean positive energy balance. The recovery of leptin concentrations from the leptin nadir at parturition seemed to depend on the extent and duration of the negative energy balance, thus probably on the amount of fat that was re-accumulated. Although there was lack of a relationship between leptin and first postpartum luteal activity, higher leptin concentrations associated with shorter intervals to first observed estrus might indicate a relationship between leptin and expression of estrus. Topics: Animals; Body Weight; Cattle; Corpus Luteum; Eating; Energy Metabolism; Estrus; Female; Lactation; Leptin; Milk; Postpartum Period; Pregnancy; Progesterone | 2003 |
Leptin and insulin responses to a four-day energy-deficient diet in men with different weight history.
To assess the leptin responses to a 4-day energy-restricted diet in men with different weight history; high retrospective weight gain was expected to be associated with a small decline in leptin.. Changes in fasting leptin and insulin were measured during a 4-day controlled intervention, in which men with high retrospective weight gain and men who had stable weight consumed 35% of their estimated energy needs.. A total of 44 healthy men (age: 31-52 y, BMI: 22.7-39.8 kg/m(2)) were recruited from a cohort study: 22 men who had gained weight (weight change >1 kg/y) and 22 men whose weight had remained stable (weight change +/-0.3 kg/y) between the first (1987-1991) and the second measurement (1993-1997) of the cohort study. The intervention study was carried out in 2001.. After intervention, changes in fasting leptin levels were similar for both groups of retrospective weight gain: -2.2 microlU/ml (95% CI: -2.8; -1.7) and -2.4 microlU/ml (95% CI: -3.2; -1.7) respectively (P=0.69). Proportional changes in fasting leptin levels were different: -43.3% (95% CI: -47.8; -38.4) in the participants whose weight had remained stable (n=22) and -35.2% (95% CI: -42.4; -27.1) in those who had gained weight (n=22)(P<0.05). Analyses in a subgroup of men (n=18), in which the contrast in weight history was more pronounced than in the total group, did not show this difference. A higher proportional decrease in insulin levels was seen in men whose weight remained stable than in those who had gained weight: -35.4% (95% CI: -46.9; -21.3) and -12.8% (95% CI: -28.1; 5.7), respectively. The proportional decrease in leptin was positively associated with the proportional decrease in insulin (r=0.52; P<0.05). The decrease in leptin was positively associated with preintervention body weight (r=0.36; P<0.05), BMI (r=0.44; P<0.05), and waist-circumference (r=0.46; P<0.05).. Although we found that the 4-day energy restriction had a smaller effect on the decrease in leptin in men with retrospective weight gain, our study does not show convincing evidence that men who gained weight are less leptin responsive to changes in energy balance than those who were weight stable. Topics: Adult; Blood Glucose; Body Weight; Cohort Studies; Diet, Reducing; Energy Metabolism; Fasting; Humans; Insulin; Leptin; Male; Middle Aged; Retrospective Studies; Weight Gain | 2003 |
Involvement of plasma leptin, insulin and free tryptophan in cytokine-induced anorexia.
Hypothalamic serotonin, the synthesis of which parallels plasma free tryptophan, contributes to satiety. Plasma free tryptophan, insulin and leptin, all of which can also decrease food intake partly via the hypothalamic serotonergic system, are modulated by cytokines, which decrease food intake. The mechanisms of anorexia induced by cytokines, as related to plasma tryptophan, leptin and insulin, have not been fully determined.. We determined the plasma concentrations of free as well as total tryptophan, leptin and insulin, and correlations to those of food intake and body weight change after cytokines or tryptophan injection.. Interleukin-1alpha and/or tumor necrosis factor-alpha, or tryptophan was injected subcutaneously into male rats for 2 days. Daily food intake, body weight, carcass adiposity, plasma total as well as free tryptophan, plasma leptin and insulin were measured.. Interleukin-1alpha injection decreased food intake, body weight, carcass adiposity and plasma leptin, but increased plasma free tryptophan and insulin. Tryptophan injection increased both free and total tryptophan, but did not change food intake, body weight, carcass adiposity or leptin. Plasma free tryptophan, but not total tryptophan, was significantly negatively correlated with food intake. There was a negative correlation between plasma insulin and food intake.. Increased plasma free tryptophan may contribute to synthesis of brain serotonin but anorexia may be due to stimulation of its release induced by interleukin-1alpha. Plasma insulin, but not leptin, may partly contribute to anorexia of cytokines. Topics: Adipose Tissue; Animals; Anorexia; Body Weight; Brain; Cytokines; Energy Intake; Injections, Subcutaneous; Insulin; Interleukin-1; Leptin; Male; Random Allocation; Rats; Rats, Inbred F344; Satiety Response; Serotonin; Tryptophan; Tumor Necrosis Factor-alpha | 2003 |
A role for suppressed thermogenesis favoring catch-up fat in the pathophysiology of catch-up growth.
Catch-up growth is a risk factor for later obesity, type 2 diabetes, and cardiovascular diseases. We show here that after growth arrest by semistarvation, rats refed the same amount of a low-fat diet as controls show 1) lower energy expenditure due to diminished thermogenesis that favors accelerated fat deposition or catch-up fat and 2) normal glucose tolerance but higher plasma insulin after a glucose load at a time point when their body fat and plasma free fatty acids (FFAs) have not exceeded those of controls. Isocaloric refeeding on a high-fat diet resulted in even lower energy expenditure and thermogenesis and increased fat deposition and led to even higher plasma insulin and elevated plasma glucose after a glucose load. Stepwise regression analysis showed that plasma insulin and insulin-to-glucose ratio after the glucose load are predicted by variations in efficiency of energy use (i.e., in thermogenesis) rather than by the absolute amount of body fat or plasma FFAs. These studies suggest that suppression of thermogenesis per se may have a primary role in the development of hyperinsulinemia and insulin resistance during catch-up growth and underscore a role for suppressed thermogenesis directed specifically at catch-up fat in the link between catch-up growth and chronic metabolic diseases. Topics: Adipose Tissue; Aging; Analysis of Variance; Animals; Blood Glucose; Body Weight; Diet, Fat-Restricted; Energy Metabolism; Fatty Acids, Nonesterified; Glucose Tolerance Test; Growth; Growth Disorders; Insulin; Leptin; Male; Rats; Rats, Sprague-Dawley; Regression Analysis; Thermogenesis | 2003 |
Serum copper levels and not zinc are positively associated with serum leptin concentrations in the healthy adult population.
Leptin, the obesity gene protein product, is a hormone with multiple physiological functions in the human. However, there are few reports in the literature on its role in trace element metabolism in the normal population. Therefore, we investigated the association among serum leptin, zinc, copper, and zinc/copper ratio in 570 healthy men and women aged 15 yr and older. Serum leptin assay was done with a commercial enzymelinked immunosorbent assay kit; serum zinc and copper levels were measured by an atomic absorption spectrophotometer. Serum leptin was found to be positively associated with age (r=0.254, p<0.001), sex (r=0.406, p<0.001), body mass index (BMI) (r=0.553, p<0.001), and serum copper (r=0.419, p<0.001), but negatively associated with the zinc/copper ratio (r=-0.423, p<0.001). There was no significant association between serum leptin and zinc (r= -0.131, p>0.05). When the confounding effects of age, sex, and BMI were removed, serum leptin was still positively associated with serum copper (r=0.197, p=0.02) and the serum zinc/copper ratio (r=-0.182, p=0.03). These results suggest that copper and not zinc has an effect on serum leptin levels. Topics: Adult; Aged; Body Height; Body Weight; Copper; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Male; Middle Aged; Nutritional Status; Reference Values; Trace Elements; Zinc | 2003 |
Uterine artery function in pregnant rats fed a diet supplemented with animal lard.
We hypothesised that maternal uterine artery vascular dysfunction could contribute to cardiovascular dysfunction in offspring of rats fed a diet rich in fat. Sprague-Dawley rats were fed for 10 days prior to pregnancy and throughout gestation either: (a) a control breeding diet, or (b) the same diet supplemented with 20 % w/w lard, vitamins, essential micronutrients and protein to control values. At 20 days gestation vascular function was assessed in uterine arteries and third-order mesenteric arteries. Vascular reactivity in response to application of potassium, noradrenaline, the thromboxane analogue U46619, acetylcholine and nitric oxide was assessed. Maternal plasma concentrations of factors likely to contribute to endothelial dysfunction were measured. Maximum acetylcholine-induced relaxation was impaired in the mesenteric arteries of the lard-fed dams (max % relaxation: lard-fed, 69.7 +/- 6.48; control, 85.37 +/- 2.69, P = 0.03). Uterine artery vascular function was similar in the two groups (max % acetylcholine-induced relaxation: lard-fed, 73.7 +/- 4.01; control, 77.5 +/- 4.72, P = 0.98). Concentrations of plasma lipids, 8-epi-PGF(2alpha) and leptin were normal, whereas insulin and corticosterone concentrations were raised in the lard-fed group (insulin (ng ml(-1)): lard-fed, 8.04 +/- 0.47; control, 1.35 +/- 0.37, P < 0.0001; corticosterone (ng ml(-1)): lard-fed, 1164.0 +/- 170.9; control, 541.9 +/- 96.3, P = 0.005). Fetal and placental weights were reduced in lard-fed dams (fetus (g): lard-fed, 4.27 +/- 0.38; control, 2.96 +/- 0.40, P = 0.025; placenta (g): lard-fed, 0.72 +/- 0.06; control, 0.57 +/- 0.04, P = 0.05). Cardiovascular dysfunction in offspring is not associated with reduced uterine artery endothelial function but is associated with activation of the hypothalamic-pituitary-adrenal axis, hyperinsulinaemia and fetoplacental growth retardation. Topics: Animal Feed; Animals; Arteries; Body Weight; Cholesterol; Corticosterone; Diet; Dietary Fats; Dinoprost; Eating; Endothelium, Vascular; Energy Metabolism; F2-Isoprostanes; Female; Insulin; Leptin; Lipid Peroxidation; Litter Size; Mesenteric Arteries; Pregnancy; Rats; Rats, Sprague-Dawley; Reproduction; Uterus; Vasoconstriction; Vasodilation | 2003 |
Inverse correlation between serum leptin concentration and vertebral bone density in postmenopausal women.
Although the protective effect of obesity on bone mass has been ascribed to high body fat content, this is still controversial. The present study of 215 postmenopausal Japanese women investigated whether circulating leptin concentration was correlated with per cent fat mass or age-adjusted bone mineral density (Z-score). In this study population, the mean circulating leptin concentration was 10.15 +/- 5.42 (range 1.7-29.6) ng/ml. Significant correlations were found between circulating leptin concentrations and per cent fat mass (r = 0.514, p < 0.0001) and Z-score (r = -0.516, p < 0.0001), confirming the existence of an inverse relationship between leptin concentration and postmenopausal bone density. By contrast, no significant correlation was found between per cent abdominal fat mass and vertebral bone mineral density (r = -0.071). Serum leptin concentration reflects fat mass and postmenopausal bone mass in human subjects. Increased serum leptin levels might cause bone loss in postmenopausal Japanese women, and our results do not support the hypothesis that leptin induces or mediates the bone-protective effects of obesity. Topics: Abdomen; Adipose Tissue; Aging; Alkaline Phosphatase; Body Composition; Body Mass Index; Body Weight; Bone Density; Female; Humans; Japan; Leptin; Middle Aged; Postmenopause; Regression Analysis; Spine | 2003 |
Reproduction and plasma concentrations of leptin, insulin and insulin-like growth factor 1 in growth-hormone-transgenic female sheep before and after artificial insemination.
The transgenic sheep used in this study expressed an additional copy of the gene for ovine growth hormone (GH), so they had continuously high plasma concentrations of GH. They were used to test whether the GH transgene affected plasma concentrations of the metabolic hormones leptin, insulin-like growth factor 1 (IGF-1) and insulin, and whether these effects were associated with changes in conception, pregnancy or parturition following artificial insemination. Compared with control animals, the GH-transgenic sheep had higher bodyweight, lower body condition score and less subcutaneous fat (P < 0.05). These sheep also had lower plasma concentrations of leptin, higher plasma concentrations of insulin, and higher plasma concentrations of IGF-1 (P < 0.001). A similar proportion of GH-transgenic and control ewes came into oestrus, but the conception rate to artificial insemination was lower in GH-transgenic ewes than in the controls. Only four live lambs were recovered from 12 GH-transgenic ewes (33%) compared with 38 lambs from 43 controls (88%). This outcome was not associated with any difference in plasma progesterone profile in the period leading up to artificial insemination (Day 0). The GH-transgenic ewes had lower concentrations of FSH at all times measured (Day -19, Day -2 and Day 19). These results indicate that appropriate regulation of GH secretion from pituitary or peripheral tissues is necessary for normal reproduction and normal levels of metabolic hormones. Chronically high concentrations of GH were associated with increased levels of IGF-1 and insulin, and decreased levels of leptin. Topics: Animals; Animals, Genetically Modified; Body Composition; Body Weight; Female; Follicle Stimulating Hormone; Growth Hormone; Insemination, Artificial; Insulin; Insulin-Like Growth Factor I; Leptin; Pregnancy; Pregnancy Outcome; Progesterone; Reproduction; Sheep | 2003 |
Hyperleptinemia prevents increased plasma ghrelin concentration during short-term moderate caloric restriction in rats.
Ghrelin is an orexigenic hormone secreted by the stomach. Increased plasma ghrelin concentration was reported during diet-induced weight loss in obese humans, suggesting that ghrelin contributes to adaptive increment in appetite associated with caloric restriction. Leptin reduces spontaneous food intake and body weight in rodents. The current study tested the hypothesis that increased plasma leptin prevents the potential increase in plasma ghrelin concentration during moderate caloric restriction in lean rats.. Six-month-old male rats (body weight, 367 +/- 9 grams) were randomly assigned to one of the following treatments (8 rats each) for 1 week: (1) leptin subcutaneous infusion to induce moderate hyperleptinemia and moderate caloric restriction (-26% of ad libitum), (2) vehicle infusion and pair feeding, and (3) vehicle infusion and ad libitum feeding.. Leptin-treated (-19 +/- 5 grams) and pair-fed (-19 +/- 2) rats lost weight compared with ad libitum-fed rats (-3 +/- 1, P < 0.05). Compared with control (6.8 +/- 0.7 ng/mL), plasma leptin was higher in leptin-treated (18.6 +/- 0.9 ng/mL, P < 0.01) rats and lower in pair-fed rats (4.3 +/- 0.4 ng/mL, P < 0.05). Plasma ghrelin was substantially higher in calorie-restricted than control rats (2505 +/- 132 pg/mL vs. 1790 +/- 134 pg/mL, P < 0.01), and leptin treatment (1625 +/- 117 pg/mL) completely prevented this change. Plasma ghrelin concentration was negatively correlated with body weight changes in calorie-restricted and control (r = -0.75, P < 0.01) but not in leptin-treated rats (P > 0.8).. Moderate hyperleptinemia prevents an increase of plasma ghrelin during moderate short-term caloric restriction. Satiety-inducing effects of leptin include suppression of gastric orexigenic signals and disruption of a potential feedback mechanism between body weight changes and plasma ghrelin in lean adult rats. Topics: Animals; Body Weight; Caloric Restriction; Eating; Feedback, Physiological; Ghrelin; Insulin; Leptin; Male; Peptide Hormones; Rats; Rats, Inbred F344; Satiation | 2003 |
Hormonal reactions during heavy training stress and following tapering in highly trained male rowers.
The purpose of this study was to determine whether fasting plasma leptin, cortisol, testosterone and growth hormone concentrations were altered with a heavy increase in training stress followed by a reduced stress in highly trained male rowers. Twelve male national standard rowers (age 20.5 +/- 3.0 years, height 187.9 +/- 6.1 cm, body mass 87.1 +/- 8.3 kg, percent body fat 10.4 +/- 3.2 %) underwent a three-week period of maximally increased training stress followed by a two-week tapering period. The fasting blood samples were obtained every week after the rest day. In addition, the maximal 2000-meter rowing ergometer performance time was assessed before and immediately after the exhaustive training period as well as after the tapering period. A 22 % increase in training stress caused a significant decrease (by 8 %) and increase (by 9 %) in leptin and testosterone, respectively. A further increase in training volume by 25 % significantly reduced leptin further by 35 %. At the same time, no changes were observed in testosterone. Growth hormone was significantly elevated only after the first week of heavy training stress compared to the pretraining level. In the first tapering week, where the physical stress was reduced by 50 %, leptin only significantly increased by 29 %. Testosterone and growth hormone were significantly reduced to almost pretraining levels by the end of the second tapering week. Leptin was further significantly increased during the second tapering week. Cortisol remained relatively constant during the whole study period. Similarly, rowing performance was not significantly changed. We conclude that leptin is more sensitive to the rapid and pronounced changes in training stress compared to measured stress hormones in athletes. In addition, fasting plasma leptin could be regarded as a key signal for metabolic adaptation to exhaustive training stress in highly trained male rowers. Topics: Adult; Body Height; Body Weight; Human Growth Hormone; Humans; Leptin; Male; Physical Endurance; Sports; Stress, Physiological; Testosterone; Time Factors | 2003 |
Exogenous leptin controls the development of the small intestine in neonatal piglets.
Leptin, a hormone produced and secreted by adipose tIssue, muscles and stomach, is involved in the regulation of adipose tIssue mass, food intake and body weight in neonatal animals. It is also produced in the mammary glands and secreted into the colostrum and milk. Since leptin receptors are widely distributed in the small intestine mucosa, the aim of the present study was to investigate the effect of exogenous leptin on the development of the small intestine in neonatal piglets. Male neonatal piglets were fed with sow's milk or artificial milk formula. Every 8 h the latter received either vehicle or leptin (2 or 10 microg/kg body weight). The animals were either killed after 6 days of treatment and the small intestine sampled for histology and brush border enzyme activities or were tested for marker molecule (Na-fluorescein and BSA) absorption in vivo. Feeding milk formula slowed the maturation of small intestinal mucosa compared with feeding sow's milk. However, after leptin treatment the length of the small intestine was increased, and intestinal villi length, but not crypt size, was reduced compared with controls. The mitotic index was increased and the percentage of vacuolated enterocytes was reduced in the entire small intestine. Enterocyte brush border protease and lactase activities were reduced in the jejunum. Na-fluorescein marker molecule absorption did not change but that of BSA was reduced 3.8-fold. In conclusion, exogenous leptin administered in physiological doses reversed the maturation of the small intestinal mucosa to the range found in sow-reared piglets. Topics: alpha-Glucosidases; Aminopeptidases; Animals; Animals, Newborn; beta-Galactosidase; Body Weight; CD13 Antigens; Endopeptidases; Intestinal Absorption; Intestinal Mucosa; Intestine, Small; Lactase; Leptin; Male; Mitotic Index; Organ Size; Serum Albumin, Bovine; Sodium; Sucrase; Swine | 2003 |
Regional fat pad growth and cellularity in obese zucker rats: modulation by caloric restriction.
To investigate, in young obese male Zucker rats, the effects of chronic food restriction and subsequent refeeding on: 1). parameters of nonadipose and adipose growth, 2). regional adipose depot cellularity [fat cell volume (FCV) and number], and 3). circulating leptin levels.. Obese (fa/fa) and lean (Fa/?) male Zucker rats were studied from age 5 to 19 weeks. After baseline food intake monitoring, 10 obese rats were subjected to 58 days of marked caloric restriction from ad libitum levels [obese-restricted (OR)], followed by a return to ad libitum feeding for 22 days. Ten lean control rats and 10 obese control rats were fed ad libitum for the entire experiment. All rats were fed using a computer-driven automated feeding system designed to mimic natural eating patterns.. After food restriction, OR rats weighed significantly less than did lean and obese rats and showed a significant diminution in body and adipose growth as compared with obese rats. Relative adiposity was not different between obese and OR rats and was significantly higher than that of lean rats. The limitation in growth of the adipose tissue mass in OR rats was due mostly to suppression of fat cell proliferation because the mean FCV in each of the four depots was not affected. Serum leptin levels of OR and obese rats were not different from each other but were significantly higher than those of lean rats.. Marked caloric restriction affects obese male Zucker rats in a manner different from that of nongenetic rodent models (i.e., Wistar rats). In comparison with the response to caloric deprivation of Wistar rats, these calorically restricted obese male Zucker rats appeared to defend their relative adiposity and mean FCV at the expense of fat cell number. These findings indicate that genetic and/or tissue-specific controls override the general consequences of food restriction in this genetic model of obesity. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Caloric Restriction; Eating; Food Deprivation; Leptin; Male; Obesity; Organ Size; Rats; Rats, Zucker | 2003 |
Neuronal histamine regulates food intake, adiposity, and uncoupling protein expression in agouti yellow (A(y)/a) obese mice.
Hypothalamic neuronal histamine and its H(1) receptor (H(1)-R) form a part of the leptin-signaling pathway in the brain and have been shown to regulate body weight and adiposity in diabetic (db/db) and diet-induced obese mice by affecting food intake and uncoupling protein mRNA expression. The proopiomelanocortin (POMC) melanocortin-4 receptor (MC-4R) is also important for leptin signaling. The present study had two aims: first, to clarify the antiobesity action of neuronal histamine in agouti yellow (A(y)/a) obese mice, a model of obesity in which POMC/MC-4R signaling is disrupted by blockade of MC-4R and second, to investigate the functional relationship between neuronal histamine and POMC/MC-4R signaling. Central administration of histamine into the lateral cerebroventricle decreased cumulative food intake and body weight in A(y)/a obese mice. Histamine treatment also decreased mRNA expression of ob gene in epididymal white adipose tissue and up-regulated uncoupling protein 1 mRNA expression in brown adipose tissue. These effects were attenuated in A(y)/a obese mice with histamine H(1)-receptor (H(1)-R) knockout. Histamine treatment induced c-Fos-like immunoreactivity in both paraventricular and arcuate nucleus. There was no significant difference in histamine-induced c-Fos-like immunoreactivity in the hypothalamus between A(y)/a obese mice and lean littermates, indicating histamine signaling was not disrupted at the hypothalamic level in A(y)/a obese mice. These results suggest that neuronal histamine have an antiobese action, even in A(y)/a obese mice despite a deficiency in POMC/MC-4R signaling. In addition, it appears that the histamine H(1)-R signaling pathway may be independent or downstream of the POMC/MC-4R signaling. Topics: Adipose Tissue, Brown; Animals; Body Weight; Carrier Proteins; Eating; Energy Metabolism; Gene Expression; Histamine; Hypothalamus; Injections, Intraventricular; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Mitochondrial Proteins; Neurons; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-fos; Receptors, Histamine H1; RNA, Messenger; Signal Transduction; Triglycerides; Uncoupling Protein 1 | 2003 |
[Roles of leptin in the development during girls'puberty].
To study the roles of leptin in the development during puberty in girls and the its relationship with insulin (INS), growth hormone (GH), estradiol (E(2)) and testosterone (T).. One hundred and fifty girls with simple obese aged 7 to 17 years, and 150 normal healthy girls and 150 girls with malnutrition matched for age (+/- 3 months) and height (+/- 2 cm) were selected. Serum levels of leptin, INS, GH, E(2) and T were measured for them.. Their serum level of leptin positively correlated with body mass index (BMI) and age. Serum level of leptin in girls increased steadily from Tanner stage B(1) to stage B(5). At Tanner stage B(2), serum level of leptin in the normal groups (7.72 microg/L) was not significantly different from that in those with malnutrition (7.36 microg/L), but significantly lower than that in the obese groups (12.85 microg/L). At other Tanner stages, there was significant difference in serum level of leptin among obese, normal and malnutrition groups. Serum level of leptin correlated negatively with serum GH and positively with serum INS, but not correlated with E(2) and T.. Leptin may play a role in triggering development during puberty in girls. Serum level of leptin at Tanner stage B(2) may be the threshold dose to trigger the onset of puberty in girls. Quickly increasing level of leptin at Tanner stage B(5) may inhibit the increase of GH, which ushered the end of puberty in girls. Topics: Adolescent; Body Height; Body Mass Index; Body Weight; Child; Female; Growth Hormone; Humans; Leptin; Puberty; Testosterone | 2003 |
Insulin resistance and lipodystrophy in mice lacking ribosomal S6 kinase 2.
The p90 ribosomal S6 kinase 2 (RSK2) is a serine/threonine kinase with high expression levels in adipose tissue. Numerous in vitro studies show that RSK2 is activated by a broad number of cellular stimuli and suggest that RSK2 is involved in the regulation of a variety of cellular processes. However, the physiological role of RSK2 still remains elusive. We therefore generated rsk2 knockout (KO) mice to better understand the function of RSK2 in vivo. Birth weights of RSK2 KO mice are normal, but the body weight is reduced with age, as compared with wild-type littermates. We found that the difference in body weight was largely caused by a specific loss of white adipose tissue that is accompanied by reduced serum levels of the adipocyte-derived peptide, leptin. KO mice also have impaired glucose tolerance and elevated fasting insulin and glucose levels that are restored following administration of low amounts of leptin, which do not affect food intake. We conclude that RSK2 plays a novel and an important role in regulation of adipose mass in mice and speculate that the reduction in fat tissue may negatively affect insulin sensitivity, as observed in human lipodystrophy, through reduced levels of adipocyte-derived factors, such as leptin. Topics: Adipose Tissue; Aging; Animals; Blood Glucose; Body Weight; Dietary Fats; Glucose Intolerance; Insulin; Insulin Resistance; Leptin; Lipodystrophy; MAP Kinase Signaling System; Mice; Mice, Knockout; Ribosomal Protein S6 Kinases, 90-kDa | 2003 |
Leptin activation of corticosterone production in hepatocytes may contribute to the reversal of obesity and hyperglycemia in leptin-deficient ob/ob mice.
Glucocorticoids have been implicated as pathophysiological mediators of obesity and insulin resistance and are regulated by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). This enzyme regenerates active corticosterone from inactive 11-keto forms. To assess the role of 11beta-HSD1-mediated synthesis of active corticosterone in leptin-related obesity and diabetes, we examined the peripheral effect of leptin on 11beta-HSD1 activity and gene expression in vivo and in vitro in hepatocytes from ob/ob mice and in liver of streptozotocin (STZ)-treated ob/ob mice. We observed an inverse relationship between hepatic 11beta-HSD1 expression and body weight in ob/ob mice and lean littermates. Leptin treatment of ob/ob mice markedly increased hepatic 11beta-HSD1 activity and mRNA expression. This induction of 11beta-HSD1 expression corresponded to reduced levels of circulating corticosterone and weight loss in ob/ob mice treated with leptin, indicating that impaired hepatic 11beta-HSD1 expression may contribute to the pathogenesis of obesity in ob/ob mice. In addition, leptin treatment of STZ-treated ob/ob mice caused marked increases in hepatic 11beta-HSD1 levels associated with decreased body weight and a significant reduction in hyperglycemia due to pancreatic beta-cell damage. Addition of leptin to ob/ob mouse primary hepatocytes led to a dose-dependent increase in 11beta-HSD1 mRNA expression. In contrast, leptin did not influence 11beta-HSD1 expression in primary hepatocytes from db/db mice, indicating that leptin regulation of 11beta-HSD1 expression is probably mediated by the functional leptin receptor. Thus, leptin appears to be an important metabolic signal that directly activates intrahepatic corticosterone production. These findings suggest that the liver-specific interaction of leptin with 11beta-HSD1 is involved in the development of obesity and insulin resistance in ob/ob mice. Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Experimental; Female; Hepatocytes; Hydroxysteroid Dehydrogenases; Hyperglycemia; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Recombinant Proteins | 2003 |
Weight gain in gonadectomized normal and lipoprotein lipase-deficient male domestic cats results from increased food intake and not decreased energy expenditure.
Gonadectomy predisposes domestic cats to undesired body weight gain and obesity. The disturbance responsible for this disregulation of energy balance has not been clearly identified. Energy intake and expenditure, body composition and plasma concentrations of leptin, insulin, glucose and triacylglycerol were determined during a 36-wk period in adult male (2-5 y) gonadectomized (n = 8) and intact (n = 8) normal cats and gonadectomized (n = 8) and intact (n = 8) lipoprotein lipase (LPL)-deficient cats. Cats were housed individually in temperature- and light-controlled rooms and continuously provided a commercial dry-type diet. In normal and LPL-deficient cats, body weight increased (P < 0.05) after gonadectomy by 27 to 29%, mostly as a result of fat accretion. There was a rapid increase (P < 0.05) in food intake of approximately 12% after gonadectomy of normal and LPL-deficient cats. The metabolic rate (kJ.kg(-1).d(-1)), determined in normal intact (319 +/- 20, n = 5) and gonadectomized (332 +/- 36, n = 5) cats, did not differ after gonadectomy. After gonadectomy, plasma concentrations of glucose and triacylglycerol did not change, whereas plasma insulin and leptin concentrations increased (P < 0.05), but not coincidentally with body weight gain. A stair-step increase in energy intake, and not decreased energy expenditure, appears to drive the weight gain associated with gonadectomy. Body fat mass appears to increase until the energy intake supports no further expansion. Adiposity signaling through insulin or leptin does not appear to mediate the energy intake effect. LPL deficiency did not preclude development of the overweight body condition. Therefore, gonadectomy-induced weight gain in cats is not a result of changed adipose LPL activity, as previously suggested. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Cats; Eating; Energy Metabolism; Insulin; Leptin; Lipoprotein Lipase; Male; Orchiectomy; Osmolar Concentration; Triglycerides; Weight Gain | 2003 |
Oligofructose protects against the hypertriglyceridemic and pro-oxidative effects of a high fructose diet in rats.
Recent findings indicate that in addition to its hyperlipemic effect, a high fructose diet has a pro-oxidant effect in rats compared with a starch-based diet. Oligofructose (OFS) has already been shown to decrease plasma lipids in rats. We assessed the impact of fructose on oxidative stress by supplementing a high fructose diet with OFS. Rats were fed either a high fructose diet or a starch-based diet, with or without supplementation of 10 g/100 g oligofructose for 4 wk. Regardless of the type of carbohydrate, OFS in the diet produced an enlargement of the cecum and led to a significant increase in the SCFA cecum pool. Fructose feeding was associated with significantly higher insulin plasma concentrations (+63%) in the control groups, whereas insulin plasma concentrations did not differ in rats fed the fructose diet supplemented with OFS. Plasma leptin concentration was significantly lower (approximately 50%) in the OFS-supplemented fructose group compared with the other three groups. Fructose feeding in rats also significantly increased plasma (P < 0.001) and liver (P < 0.001) triglyceride (TG) concentrations and the addition of OFS prevented the TG accumulation induced by fructose in the liver (P < 0.05) and hyperlipemia (P < 0.05). OFS consumption prevented (P < 0.05) the lower plasma vitamin E/TG ratio in rats fed the fructose diet. Control rats fed the fructose diet had high plasma TBARS values compared with rats fed the starch diet, whereas TBARS values remained unchanged when rats were supplemented with OFS. Control rats fed the fructose diet had higher TBARS urine values and higher heart tissue susceptibility to peroxidation compared with rats fed the starch diet, and this effect was significantly reduced by OFS consumption. Further studies are required to identify the mechanisms underlying the protective effect of OFS against the pro-oxidant effect of fructose. However, the potential nutritional benefits of OFS supplementation in fructose-rich diets are suggested. Topics: Animals; Blood Glucose; Body Weight; Cecum; Copper; Diet; Dose-Response Relationship, Drug; Fermentation; Fructose; Hypertriglyceridemia; Insulin; Leptin; Liver; Male; Oligosaccharides; Organ Size; Oxidation-Reduction; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Triglycerides; Vitamin E | 2003 |
Effect of two modes of antiandrogen treatment on insulin sensitivity and serum leptin in women with PCOS.
Androgens are suggested to interact with leptin production and with insulin sensitivity in both polycystic ovary syndrome (PCOS) and obesity. The aim of the study was to follow these interactions along with two forms of antiandrogen treatment. Twenty women with PCOS were treated with ethinylestradiol and high dose of cyproteroneacetate (EE-CA) and 8 with the gonadotrophin-releasing hormone (GnRH) analogue goserelin for 6 months. The patients were divided into a low and a high body weight group and compared with a group of overweight women without PCOS. Both treatments resulted in a significant reduction of free testosterone but the concentration of leptin remained unchanged. EECA treatment resulted in deterioration and GnRH in improvement of insulin sensitivity. Serum leptin correlated only with body weight and body fat. It is concluded that leptin levels do not adequately reflect changes in insulin sensitivity or androgen levels after short-term antiandrogen or antigonadotropin treatment. Topics: Adipose Tissue; Adult; Androgen Antagonists; Apolipoproteins A; Apolipoproteins B; Blood Glucose; Body Composition; Body Constitution; Body Mass Index; Body Weight; C-Peptide; Cyproterone Acetate; Dehydroepiandrosterone Sulfate; Ethinyl Estradiol; Female; Gonadotropin-Releasing Hormone; Goserelin; Humans; Insulin; Insulin Resistance; Leptin; Lipoprotein(a); Obesity; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Testosterone; Triglycerides | 2003 |
Concentrate feeding strategy in lactating dairy cows: metabolic and endocrine changes with emphasis on leptin.
This study aimed to evaluate metabolic and endocrine adaptations to energy intake in multiparous Holstein cows (n = 90; mean 9434 kg energy-corrected milk yield/305 d) over the first 20 wk postpartum and to assess the association of leptin with metabolic, endocrine, and zootechnical traits. Concentrates were fed automatically for 24 h at 30% (C30) or 50% (C50) of total dry matter intake (DMI) from wk 1 to 10 postpartum and at linearly reduced amounts thereafter. Roughage was fed for ad libitum intake. The DMI was measured over 24 h; milk yield and body weight (BW), twice/d; milk composition, 4 times/wk; and milk acetone, weekly. Blood samples for determination of metabolite, hormone, and electrolyte concentrations and enzyme activities were obtained at wk 2 prepartum, and at wk 1 to 16 and at wk 20 postpartum from 0730 to 0900. Body condition scores (BCS) and backfat thickness were measured postpartum and during wk 1, 4, 8, 12, 16, and 20. Energy balance (EB) was considerably lower, but milk yield only slightly lower, in C30 than C50. Metabolic stress was more marked in C30 than C50, expressed by lower, glucose, insulin, insulin-like growth factor-1 (IGF-1), triiodothyronine, milk protein, and lactose concentrations, higher nonesterified fatty acid, beta-hydroxybutyrate, growth hormone, and milk acetone concentrations, and an accelerated decrease in BCS and backfat thickness. Nevertheless, C30 adapted successfully and thus maintained high milk yields despite negative EB. Leptin concentrations were lower in C30 than in C50 over the first 20 wk postpartum and were positively associated with BCS, EB, BW, cholesterol, albumin, insulin, and IGF-1; negatively associated with DMI and triiodothyronine; and were higher in cows calving in spring than in fall. Leptin is one among several factors involved in the regulation of energy metabolism and may be important for overall homeostatic and homeorhetic control of metabolism and thus for maintenance of performance. Topics: 3-Hydroxybutyric Acid; Acetone; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Body Composition; Body Weight; Cattle; Cholesterol; Eating; Energy Intake; Fatty Acids, Nonesterified; Female; Insulin; Insulin-Like Growth Factor I; Lactation; Lactose; Leptin; Milk; Milk Proteins; Postpartum Period; Serum Albumin; Triiodothyronine | 2003 |
Leptin resistance in mice is determined by gender and duration of exposure to high-fat diet.
Mice fed a high-fat diet are reported to be resistant to peripheral injections of leptin. We previously failed to induce leptin resistance in female mice fed a high-fat diet for 15 weeks. Therefore, we measured the responsiveness to peripheral infusions (10 microg/day) of leptin, and the responsiveness to third ventricle injections of leptin (1 microg) in male and female NIH Swiss mice fed low-fat (10% kcal) or high-fat (45% kcal) diets. Male and female 15-week-old mice that had been fed low- or high-fat diet from 10 days of age lost fat during a 13-day intraperitoneal infusion of leptin and lost weight in response to a single central injection of leptin. Fifteen-week-old male mice fed a high-fat diet for 5 weeks did not lose body fat during a peripheral infusion of leptin and did not lose weight in response to a central injection of leptin. Female mice fed high-fat diet for 5 weeks remained leptin-responsive. Weight loss was achieved without a significant voluntary decrease in food intake, suggesting that both peripherally and centrally administered leptin increases energy expenditure. These results demonstrate that the development of leptin resistance in NIH Swiss mice fed a high-fat diet is dependent upon the gender of the mice and either the duration of exposure to high-fat diet or the age at which the mice are first exposed to the diet. Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Weight; Diet; Dietary Fats; Drug Resistance; Eating; Energy Metabolism; Female; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Mice; Obesity; Sex Characteristics; Time Factors | 2003 |
Activation of the hypothalamic arcuate nucleus predicts the anorectic actions of ciliary neurotrophic factor and leptin in intact and gold thioglucose-lesioned mice.
Similar to leptin, ciliary neurotrophic factor (CNTF) suppresses appetite and selectively reduces body fat in leptin-deficient ob/ob mice. To assess the relative importance of specific regions of the hypothalamus in mediating these effects, we administered a CNTF analogue (CNTFAx15) or leptin to mice made obese by administration of gold thioglucose (GTG), which destroys a well-defined portion of the medial basal hypothalamus. CNTFAx15 treatment reduced appetite and body weight in obese GTG-lesioned C57BL/6 mice, whereas leptin failed to effect similar changes regardless of whether treatment was initiated before or after the lesioned mice had become obese. Because leptin does not reduce food intake or body weight in most forms of obesity (a condition termed 'leptin resistance'), we also investigated the actions of leptin in GTG-lesioned leptin-deficient (ob/ob) mice. By contrast to C57BL/6 mice, leptin treatment reduced food intake and body weight in GTG-lesioned ob/ob mice, although the effect was attenuated. To further compare the neural substrates mediating the anorectic actions of leptin and CNTF, we determined the patterns of neurone activation induced by these proteins in the hypothalamus of intact and GTG-lesioned mice by staining for phosphorylated signal transducer and activator of transcription 3 (pSTAT3). CNTFAx15 stimulated robust pSTAT3 signalling in neurones of the medial arcuate nucleus in both intact and lesioned C57BL/6 and ob/ob mice. Leptin administration stimulated pSTAT3 signalling in only a few neurones of the medial arcuate nucleus in intact or lesioned C57BL/6 mice, but elicited a robust response in intact or lesioned ob/ob mice. By contrast to CNTFAx15, leptin treatment also resulted in prominent activation of STAT3 in several areas of the hypothalamus outside the medial arcuate nucleus. This leptin-induced pSTAT3 signal was at least as prominent in intact and GTG-lesioned C57BL/6 mice as it was in ob/ob mice, and thus was not correlated with appetite suppression or weight loss. These results indicate that the medial arcuate nucleus is a key mediator of appetite suppression and weight loss produced by CNTF and leptin, whereas GTG-vulnerable regions play a role only in leptin-induced weight loss. Other regions of hypothalamus in which pSTAT3 signal is induced by leptin may regulate energy metabolism through mechanisms other than appetite reduction. Topics: Animals; Appetite; Arcuate Nucleus of Hypothalamus; Aurothioglucose; Body Weight; Ciliary Neurotrophic Factor; DNA-Binding Proteins; Drug Resistance; Eating; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neurons; Obesity; Phosphorylation; Signal Transduction; STAT3 Transcription Factor; Trans-Activators; Weight Gain | 2003 |
Maternal protein restriction increases hepatic glycogen storage in young rats.
This study aimed to determine whether maternal protein restriction alters hepatic glycogen metabolism. Mated female rats were fed diets containing 20% protein throughout pregnancy and lactation (CONT), 8% protein throughout pregnancy and lactation (LP), or 8% protein during the last week of pregnancy only and lactation (LLP). Weights and lengths were reduced in the LLP and LP offspring compared with the CONT offspring. The LLP and LP offspring demonstrated reduced insulin concentrations at both 10 and 26 d and also failed to show the increase in insulin seen with time in the CONT offspring. Serum glucose and leptin levels increased with time but were not different among the groups; however, in relation to adiposity leptin levels were greater in the LLP and LP offspring at 26 d. The LLP and LP offspring had increased hepatic glycogen at day 10 (CONT, 75.1 +/- 9.8; LLP, 103.4 +/- 11.0; LP, 116.0 +/- 18.4 glucose residues/g tissue) and d 26 (CONT, 183.1 +/- 38.9; LLP, 395.3 +/- 16.8; LP, 396.6 +/- 15.1 glucose residues/g tissue). Glycogen synthase expression was increased in the LLP and LP offspring at 10 d but not 26 d; glucose transporter 2 and glycogen phosphorylase expressions were not different at either time. At 26 d glycogen synthase activity was not different; however, glycogen phosphorylase a activity was reduced. The enhanced capacity to store glycogen despite reductions in insulin secretion suggests increased insulin sensitivity possibly acting with an alternative non-insulin-dependent glycogen storage mechanism. Topics: Adipose Tissue; Animals; Animals, Newborn; Animals, Suckling; Blood Glucose; Body Weight; Diet, Protein-Restricted; Female; Glucose Transporter Type 2; Glycogen Phosphorylase; Glycogen Synthase; Insulin; Lactation; Leptin; Liver; Liver Glycogen; Male; Monosaccharide Transport Proteins; Pregnancy; Rats; Rats, Wistar | 2003 |
Soluble leptin receptor levels in patients with chronic renal failure.
Soluble leptin receptor (SLR) is the extracellular part of the leptin receptor. This protein is released into circulation and constitutes the main circulating leptin-binding protein. The aim of our study was to measure SLR concentrations in patients with chronic renal failure (CRF) and healthy subjects and to explore the relationship of SLR to other hormones and cytokines. The patients with CRF had significantly higher serum leptin, TNF-alpha and insulin levels than healthy subjects (25.1+/-23.5 vs. 9.4+/-7.6 ng.ml(-1) (S.D.); 14.2+/-4.2 vs. 4.55+/-2.5 ng.ml(-1); 39.8+/-36.1 vs. 20.3+/-11.1 mU.l(-1)). Serum soluble leptin receptor levels did not differ between these groups (19.1+/-11.3 vs. 19.6+/-6.1 U.ml(-1)). An inverse relationship between serum SLR and leptin levels was found in both groups. In patients with CRF the inverse relationship between SLR and insulin, body fat content and total protein levels were also found, while in healthy subjects only inverse relationship of SLR with insulin and albumin concentrations were detected. We conclude that soluble leptin receptor levels in patients with chronic renal failure do not differ from those of healthy subjects despite higher serum leptin levels in CRF patients. The physiological consequences of this finding require further investigation. Topics: Blood Proteins; Body Composition; Body Weight; Data Interpretation, Statistical; Humans; Insulin; Kidney Failure, Chronic; Leptin; Receptors, Cell Surface; Receptors, Leptin; Serum Albumin; Skinfold Thickness; Tumor Necrosis Factor-alpha | 2003 |
Responses to ozone are increased in obese mice.
Epidemiological data indicate an increased incidence of asthma in overweight adults and children. Ozone (O3) is a common trigger for asthma. Accordingly, the purpose of this study was to compare O3-induced airway hyperresponsiveness and airway inflammation in lean, wild-type (C57BL/6J) mice and mice that are obese as a consequence of a genetic defect in the gene encoding the satiety hormone leptin (ob/ob mice). The ob/ob mice eat excessively and weighed more than twice as much as age- and gender-matched wild-type mice. Airway responsiveness to intravenous methacholine was measured by forced oscillation. In air-exposed controls, baseline pulmonary resistance was greater, and the dose of methacholine required to double pulmonary resistance was lower in ob/ob than wild-type mice. Exposure to O3 (2 parts/million for 3 h) caused AHR and airway inflammation in both groups of mice, but responses to O3 were enhanced in ob/ob compared with wild-type mice. Administration of exogenous leptin did not reverse the enhanced inflammatory response observed in ob/ob mice, but augmented airway inflammation in wild-type mice. The inhaled dose of O3 per gram of lung tissue was greater in ob/ob than wild-type mice. Our results indicate that O3-induced airway responses are enhanced in ob/ob mice and suggest that inhaled O3 dose may be one factor contributing to this difference, but other aspects of the obese phenotype may also contribute. Our results also indicate that the hormone leptin, which is increased in the obese, has the capacity to increase airway inflammation. Topics: Animals; Body Weight; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Cytokines; Female; Leptin; Male; Methacholine Chloride; Mice; Mice, Obese; Neutrophils; Obesity; Oxidants, Photochemical; Ozone; Phenotype; Respiratory Mechanics | 2003 |
Effect of salt on hypertension and oxidative stress in a rat model of diet-induced obesity.
High-salt diet is known to induce or aggravate hypertension in animal models of hypertension and in humans. When Sprague-Dawley rats (n = 60) are fed a moderately high-fat diet (32% kcal fat, 0.8% NaCl) for 10 wk, about one-half develop obesity [obesity prone (OP)] and mild hypertension, whereas the other half [obesity resistant (OR)] maintain body weight equivalent to a low-fat control (C) and are normotensive. The aim of this study was to test the effect of high-NaCl diets (2 and 4% NaCl) on the development of hypertension and obesity, oxidative stress, and renal function. Both 2 and 4% NaCl induced an early increase in systolic blood pressure of OP but not OR or C rats. High-salt intake induced an increase in the size and reduction in number of adipocytes, concomitant to a twofold increase in circulating leptin in OP rats. Aortic superoxide generation indicated a 2.8-fold increase in the OP high-salt vs. normal-salt groups, whereas urine isoprostanes were not significantly increased. Also, hydroxynonenal protein adducts in the kidney were highly increased in OP rats on 2 and 4% NaCl, indicating oxidative stress in the renal tissue. Urine albumin was increased threefold in the OP on 2% NaCl and fourfold in the same group on 4% NaCl vs. 0.8% NaCl. Kidney histology indicated a higher degree of glomerulosclerosis in OP rats on high-salt diets. In summary, high-salt diet accelerated the development but did not increase the severity of hypertension; high salt increased oxidative stress in the vasculature and kidney and induced kidney glomerulosclerosis and microalbuminuria. Also, the OP rats on high salt displayed adipocyte hypertrophy and increased leptin production. Topics: Adipocytes; Adipose Tissue; Animals; Aorta; Blood Pressure; Body Weight; Diet; Disease Susceptibility; Diuresis; Hypertension; Hypertrophy; Kidney; Leptin; Male; Obesity; Oxidative Stress; Rats; Rats, Sprague-Dawley; Renin; Sclerosis; Sodium Chloride, Dietary | 2003 |
Hyperleptinemia precipitates diet-induced obesity in transgenic mice overexpressing leptin.
Transgenic mice overexpressing leptin backcrossed to the C57BL/6J genetic background (LepTg) have a lean phenotype, characterized by a 95% reduction in adipose mass; reduced plasma levels of glucose, triglycerides, insulin, and IGF-1; and a 75% decrease in adipocyte size. High-fat diet treatment for 20 wk revealed that, compared with normal mice, the LepTg mice had an increased susceptibility to diet-induced obesity, as demonstrated by their rate of weight gain, higher accumulation of sc white adipose tissue mass, hypertrophy of adipocytes, and normalization of their reduced metabolic parameters. The stromal vascular fraction of white adipose tissue from the LepTg mice was highly cellular and contained cells capable of rapid lipid accumulation in primary cultures. The precipitous diet-induced obesity of the LepTg mice was accompanied with 10-fold and 1.6-fold elevations in insulin and IGF-1, respectively, suggesting that the trophic action of insulin and IGF-1 on the preadipocytes and small adipocytes may have caused them to rapidly differentiate and accumulate triacylglycerol stores. Other contributing factors may involve a shift in insulin sensitivity triggered by hyperleptinemia and a decrease in energy expenditure. These studies demonstrate that a chronic response to hyperleptinemia as in the LepTg mice is a predisposing factor to diet-induced obesity and suggest that individuals who are particularly lean because of increased leptin secretion may develop rapid obesity under conditions of a high-fat diet. Topics: Adipocytes; Adipose Tissue; Animals; Blood Glucose; Body Weight; Cells, Cultured; Dietary Fats; DNA; Insulin; Insulin-Like Growth Factor I; Leptin; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Obesity; Triglycerides | 2003 |
Increased dietary fat attenuates the anorexic effects of intracerebroventricular injections of MTII.
The hypothalamic melanocortin (MC) system provides a critical inhibitory control on food intake and body weight. Because access to high-fat (HF) diets is associated with the development of obesity, we hypothesized that increased dietary fat attenuates signaling through the MC system. To evaluate this hypothesis, we compared the efficacy of the MC3/4 receptor agonist, MTII, to reduce food intake in rats fed carefully matched HF or low-fat (LF) diets for 12 wk. Rats given the HF diet ad libitum were significantly more obese than rats given the LF diet, and had significantly higher plasma insulin and leptin levels. MTII given into the third cerebral ventricle in doses of 0.1, 0.3, and 1.0 nmol was less effective at reducing food intake in HF rats than in LF rats. Whole-hypothalamic expression of the MC agonist precursor gene, proopiomelanocortin, the MC antagonist agouti-related protein, and the MC4 receptor, were not different between the HF and LF groups. These results indicate that consumption of a HF diet decreases signaling through the melanocortin system, an abnormality that could contribute to diet-induced obesity. Topics: Agouti-Related Protein; alpha-MSH; Animals; Anorexia; Body Weight; Dietary Fats; Eating; Gene Expression; Injections, Intraventricular; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Obesity; Oligopeptides; Pro-Opiomelanocortin; Proteins; Rats; Rats, Long-Evans; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; RNA, Messenger; Signal Transduction | 2003 |
Leptin-induced leptin resistant rats exhibit enhanced responses to the melanocortin agonist MT II.
The purpose of this study was to determine if leptin could induce a leptin resistance in young rats and if leptin-induced leptin resistant rats are responsive to the melanocortin agonist, melanotan II (MT II). Recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control viral vector were administered into young, lean rats for 300 days, and food consumption, body weight, oxygen consumption, serum leptin, and leptin signal transduction were measured. In the rAAV-leptin rats, the anorexic response attenuated by day 140, and the increase in energy expenditure attenuated prior to day 223. At day 300, the rats were challenged with centrally administered recombinant leptin to test leptin responsiveness. Whilst the control responded with a decrease in food intake, the rAAV-leptin rats were unresponsive. The same rats were administered MT II subsequently, and both the leptin-resistant and leptin-responsive groups displayed reduced food intake. Notably, the anorexic response persisted longer in the leptin-resistant group. These data demonstrate that leptin induces leptin resistance in young rats and that these leptin-resistant rats have an enhanced anorexic response to exogenous melanocortin activation. We suggest that defective endogenous melanocortin activation may represent one element of leptin resistance, leading to compensatory hypersensitivity of the melanocortin pathway. Topics: alpha-MSH; Animals; Body Weight; Drug Resistance; Eating; Leptin; Male; Peptides, Cyclic; Rats; Rats, Inbred BN; Rats, Inbred F344; Receptors, Corticotropin; Receptors, Melanocortin | 2003 |
Acute food deprivation and chronic food restriction differentially affect hypothalamic NPY mRNA expression.
Although acute food deprivation and chronic food restriction both result in body weight loss, they produce different metabolic states. To evaluate how these two treatments affect hypothalamic peptide systems involved in energy homeostasis, we compared patterns of hypothalamic neuropeptide Y (NPY), agouti-related protein (AgRP), proopiomelanocotin (POMC), and leptin receptor gene expression in acutely food-deprived and chronically food-restricted rats. Both acute food deprivation and chronic food restriction reduced body weight and circulating leptin levels and resulted in increased arcuate NPY and decreased arcuate POMC gene expression. Arcuate AgRP mRNA levels were only elevated in acutely deprived rats. NPY gene expression was increased in the compact subregion of the dorsomedial hypothalamus (DMH) in response to chronic food restriction, but not in response to acute food deprivation. Leptin receptor expression was not affected by either treatment. Double in situ hybridization histochemistry revealed that, in contrast to the situation in the arcuate nucleus, NPY and leptin receptor mRNA-expressing neurons were not colocalized in the DMH. Together, these data suggest that arcuate and DMH NPY gene expression are differentially regulated. DMH NPY-expressing neurons do not appear to be under the direct control of leptin signaling. Topics: Agouti-Related Protein; Animals; Blood Glucose; Body Weight; Dorsomedial Hypothalamic Nucleus; Energy Intake; Food Deprivation; Gene Expression; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Pro-Opiomelanocortin; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger | 2003 |
Neuroendocrine profiles in galanin-overexpressing and knockout mice.
The peptide galanin has been implicated in the neuroendocrine regulation of reproduction and energy balance. To gain more insight into the functional significance of galanin in these processes, we studied the phenotype of mice that either overexpress galanin in the brain under the control of the dopamine beta-hydroxylase promoter (GALTG) or have a complete absence of galanin expression (GALKO). Both GALTGs and GALKOs had body weights and feeding patterns that were indistinguishable from wild-type (WT) control animals, and both genotypes were reproductively competent. Serum levels of follicle-stimulating hormone were significantly higher in GALKOs and slightly lower in GALTGs than in their respective WT controls. Both GALTGs and GALKOs showed a normal response to fasting, but when GALKO mice were treated with leptin during fasting, levels of corticosterone and testosterone were altered compared to WT mice. In addition, GALKOs were more sensitive than WT controls to the effects of chronic leptin treatment on body weight and fat pad mass, whereas GALTGs showed responses to this metabolic challenge that were indistinguishable from their controls. When galanin was administered centrally, GALKOs had lower testosterone and corticosterone levels than did WT mice. These results suggest that the complete loss of galanin leads to significant alterations in neuroendocrine homeostasis, whereas targeted overexpression of galanin in the brain does not interfere with normal neuroendocrine function. Topics: Animals; Body Weight; Corticosterone; Dopamine beta-Hydroxylase; Eating; Fasting; Fluoroimmunoassay; Follicle Stimulating Hormone; Galanin; Immunoenzyme Techniques; Leptin; Luteinizing Hormone; Mice; Mice, Inbred Strains; Mice, Knockout; Neuropeptide Y; Phenotype; Promoter Regions, Genetic; Temperature; Testosterone; Time Factors; Up-Regulation | 2003 |
Knockout studies defining different roles for melanocortin receptors in energy homeostasis.
Proopiomelanocortin (POMC) is expressed in the arcuate nucleus of the hypothalamus (ARC) and the commissural nucleus of the solitary tract (cNTS). Post-translational processing of POMC produces two melanocortin receptor ligands, alpha- and gamma-melanocyte-stimulating hormone (MSH). Two melanocortin receptors (MC3R, MC4R) are expressed in brain regions receiving projections of POMC fibers, most of which also receive projections from a population of ARC neurons that co-express neuropeptide Y (NPY) and the MC3R/MC4R antagonist agouti-related peptide (AgRP). MC4R haploinsufficient humans and MC4R knockout (MC4RKO) mice exhibit increased adiposity and linear growth. MC4RKO mice exhibit hyperleptinemia and hyperinsulinemia and sometimes, but not always, develop type 2 diabetes (T2D). Individually housed MC4RKO mice fed low-fat diets are not hyperphagic when food intake is corrected for lean mass, whereas hyperphagia is observed after the introduction of diets with increased fat content. POMC knockout (POMCKO) mice are similar in that the severity of hyperphagia increases with the introduction of high-fat diets. By contrast, targeted deletion of the MC3R in the mouse results in increased adiposity despite the absence of hyperphagia. MC3RKO mice also exhibit reduced linear growth and lean mass; while MC3RKO mice are hyperleptinemic and hyperinsulinemic, the development of T2D has not been reported. The MC4R, but not the MC3R, is required for the stimulation of energy expenditure in response to melanocortin agonists and voluntary hyperphagia. Evidence for altered physical activity has also been reported for both knockout models. Analysis of MC4RKO mice indicates that this receptor is involved in rapidly coordinating energy consumption with energy expenditure through diet-induced thermogenesis and activity. Topics: Animals; Body Weight; Diet; Eating; Energy Metabolism; Homeostasis; Humans; Leptin; Male; Mice; Mice, Knockout; Oxygen; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Thermogenesis | 2003 |
Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulin.
Central melanocortin signaling plays an important role in regulation of energy homeostasis by leptin and insulin. We investigated the interaction between leptin, insulin, and melanocortin-4 receptors (MC-4Rs) in the control of renal sympathetic nerve activity (RSNA) in mice. We compared the effects of intracerebroventricular (ICV) administration of leptin, insulin, MC-3/4R agonist (MTII), and corticotrophin-releasing factor (CRF) on RSNA in leptin receptor-deficient (db/db) mice, MC-4R knock-out mice, and their wild-type controls. ICV administration of leptin and MTII caused a significant and dose-dependent increase in RSNA in control mice. As expected, leptin had no significant effect on RSNA in the db/db mice. Interestingly, db/db mice exhibited markedly attenuated RSNA responses to ICV administration of MTII. However, the increase in RSNA induced by insulin and CRF was comparable between db/db and control mice. In the heterozygous and homozygous MC-4R knock-out mice, the RSNA response to MTII was attenuated and abolished, respectively. The RSNA response to ICV leptin and insulin was also attenuated and abolished in the heterozygous and homozygous MC-4R knock-out mice, respectively. In contrast, CRF induced a similar increase in RSNA in the MC-4R knock-out and wild-type mice. Our data demonstrate that in the absence of leptin receptors, the sympathoexcitatory effects of melanocortin system stimulation are attenuated. In addition, the renal sympathoexcitatory responses to leptin and insulin are dependent on the MC-4R, demonstrating an important role for the MC-4R in the regulation of renal sympathetic nerve outflow by leptin and insulin. Topics: Action Potentials; alpha-MSH; Animals; Body Weight; Corticotropin-Releasing Hormone; Hemodynamics; Injections, Intraventricular; Insulin; Kidney; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptor, Melanocortin, Type 4; Receptors, Cell Surface; Receptors, Corticotropin; Receptors, Leptin; Sympathetic Nervous System | 2003 |
Maternal weight and leptin in breast milk and in breastfed infants.
Topics: Body Weight; Breast Feeding; Female; Humans; Infant, Newborn; Leptin; Milk, Human | 2003 |
Effects of angiotensin II receptor antagonists on insulin resistance syndrome and leptin in sucrose-fed spontaneously hypertensive rats.
In order to investigate the usefulness of angiotensin II type 1 receptor (AT1) antagonists (ARA) in the treatment of hypertension with insulin resistance syndrome, we studied the effects of a high dose sucrose diet and ARA on insulin sensitivity, plasma lipids, and leptin in spontaneous hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). SHR and WKY were divided into three groups and treated for 12 weeks: those fed a standard chow, those given a sucrose-rich chow or those given a sucrose-rich chow and ARA. While in SHR the weight of both subcutaneous and mesenteric adipose tissue was greater in the sucrose-rich chow fed animals than in the standard chow fed animals, ARA treatment significantly decreased the weights of both subcutaneous and mesenteric adipose tissue. ARA treatment decreased free fatty acid and triglyceride in SHR, and increased high density lipoprotein cholesterol in SHR and WKY. Homeostasis model assessment-insulin resistance (HOMA-IR) index, plasma levels of leptin, and leptin mRNA in mesenteric adipose tissue were significantly greater in the sucrose-rich chow fed animals than in the standard chow fed animals, and significantly lower in the ARA-treated sucrose-rich chow fed animals than in the sucrose-rich chow fed animals in both SHR and WKY. ARA improved insulin resistance, and reduced plasma leptin and leptin mRNA in adipose tissue. These results suggest that the improvement of insulin resistance by ARA may be attributed, at least in part, to the reduction of adipose tissue weight. It is concluded that ARA is useful in the treatment of patients with hypertension and concomitant insulin resistance syndrome. Topics: Adipose Tissue; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Glucose; Body Weight; Cholesterol; Cholesterol, LDL; Diet; Fatty Acids, Nonesterified; Homeostasis; Hypertension; Insulin Resistance; Leptin; Male; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sucrose; Triglycerides | 2003 |
Abnormalities of leptin and ghrelin regulation in obesity-prone juvenile rats.
Rats selectively bred to develop diet-induced obesity (DIO) spontaneously gain more body weight between 5 and 7 wk of age than do those bred to be diet resistant (DR). Here, chow-fed DIO rats ate 9% more and gained 19% more body weight from 5 to 6 wk of age than did DR rats but had comparable leptin and insulin levels. However, 6-wk-old DIO rats had 29% lower plasma ghrelin levels at dark onset but equivalent levels 6 h later compared with DR rats. When subsequently fed a high-energy (HE; 31% fat) diet for 10 days, DIO rats ate 70% more, gained more body and adipose depot weight, had higher leptin and insulin levels, and had 22% lower feed efficiency than DR rats fed HE diet. In DIO rats on HE diet, leptin levels increased significantly at 3 days followed by increased insulin levels at 7 days. These altered DIO leptin and ghrelin responses were associated with 10% lower leptin receptor mRNA expression in the arcuate (ARC), dorsomedial (DMN), and ventromedial hypothalamic nuclei and 13 and 15% lower ghrelin receptor (GHS-R) mRNA expression in the ARC and DMN than in the DR rats. These data suggest that increased ghrelin signaling is not a proximate cause of DIO, whereas reduced leptin sensitivity might play a causal role. Topics: Adipose Tissue; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Diet; Dietary Fats; Dorsomedial Hypothalamic Nucleus; Eating; Energy Intake; Ghrelin; Insulin; Leptin; Male; Obesity; Organ Size; Peptide Hormones; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Receptors, Leptin; RNA, Messenger; Signal Transduction; Ventromedial Hypothalamic Nucleus | 2003 |
Maternal endocrine adaptation throughout pregnancy to nutritional manipulation: consequences for maternal plasma leptin and cortisol and the programming of fetal adipose tissue development.
Maternal nutrient restriction at specific stages of gestation has differential effects on fetal development such that the offspring are programmed to be at increased risk of adult disease. We investigated the effect of gestational age and maternal nutrition on the maternal plasma concentration of leptin and cortisol together with effects on fetal adipose tissue deposition plus leptin, IGF-I, IGF-II ligand, and receptor mRNA abundance near to term. Singleton bearing ewes were either nutrient restricted (NR; consuming 3.2-3.8 MJ/d of metabolizable energy) or fed to appetite (consuming 8.7-9.9 MJ/d) over the period of maximal placental growth, i.e. between 28 and 80 d gestation. After 80 d gestation, ewes were either fed to calculated requirements, consuming 6.7-7.5 MJ/d, or were fed to appetite and consumed 8.0-10.9 MJ/d. Pregnancy resulted in a rise in plasma leptin concentration by 28 d gestation, which continued up to 80 d gestation when fed to appetite but not with nutrient restriction. Plasma cortisol was also lower in NR ewes up to 80 d gestation, a difference no longer apparent when food intake was increased. At term, irrespective of maternal nutrition in late gestation, fetuses sampled from ewes NR in early gestation possessed more adipose tissue, whereas when ewes were fed to appetite throughout gestation, fetal adipose tissue deposition and leptin mRNA abundance were both reduced. These changes may result in the offspring of NR mothers being at increased risk of obesity in later life. Topics: Adaptation, Physiological; Adipose Tissue; Animals; Body Composition; Body Weight; Eating; Energy Intake; Female; Food Deprivation; Gestational Age; Hydrocortisone; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Nutritional Physiological Phenomena; Organ Size; Placenta; Pregnancy; Pregnancy, Animal; Prolactin; Receptor, IGF Type 2; RNA, Messenger; Sheep; Thyroxine | 2003 |
A thyroid hormone receptor alpha gene mutation (P398H) is associated with visceral adiposity and impaired catecholamine-stimulated lipolysis in mice.
Thyroid hormone has profound effects on metabolic homeostasis, regulating both lipogenesis and lipolysis, primarily by modulating adrenergic activity. We generated mice with a point mutation in the thyroid hormone receptor alpha (TRalpha) gene producing a dominant-negative TRalpha mutant receptor with a proline to histidine substitution (P398H). The heterozygous P398H mutant mice had a 3.4-fold (p < 0.02) increase in serum thyrotropin (TSH) levels. Serum triiodothyronine (T3) and thyroxine (T4) concentrations were slightly elevated compared with wild-type mice. The P398H mice had a 4.4-fold increase in body fat (as a fraction of total body weight) (p < 0.001) and a 5-fold increase in serum leptin levels (p < 0.005) compared with wild-type mice. A 3-fold increase in serum fasting insulin levels (p < 0.002) and a 55% increase in fasting glucose levels (p < 0.01) were observed in P398H compared with wild-type mice. There was a marked reduction in norepinephrine-induced lipolysis, as reflected in reduced glycerol release from white adipose tissue isolated from P398H mice. Heart rate and cold-induced adaptive thermogenesis, mediated by thyroid hormone-catecholamine interaction, were also reduced in P398H mice. In conclusion, the TRalpha P398H mutation is associated with visceral adiposity and insulin resistance primarily due to a marked reduction in catecholamine-stimulated lipolysis. The observed phenotype in the TRalpha P398H mouse is likely due to interference with TRalpha action as well as influence on other metabolic signaling pathways. The physiologic significance of these findings will ultimately depend on understanding the full range of actions of this mutation. Topics: Adipose Tissue; Animals; Blotting, Western; Body Weight; Carrier Proteins; Catecholamines; Cold Temperature; Dose-Response Relationship, Drug; Electrocardiography; Female; Genes, Dominant; Glucose; Glycerolphosphate Dehydrogenase; Heterozygote; Histidine; Insulin; Ion Channels; Leptin; Lipolysis; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Mutation; Norepinephrine; Phenotype; Point Mutation; Proline; Receptors, Adrenergic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Temperature; Thyroid Hormone Receptors alpha; Thyroid Hormones; Thyrotropin; Thyroxine; Time Factors; Triiodothyronine; Uncoupling Protein 1 | 2003 |
Differential effects of fatty acids and exercise on body weight regulation and metabolism in female Wistar rats.
High-fat diets made with different fats may have distinct effects on body weight regulation and metabolism. In the present study, the metabolic effects of high-fat (HF) diets made with fish oil, palm oil, and soybean oil were compared with a low-fat diet in female Wistar rats that were either exercised (EX, swimming) or that remained sedentary as controls. Each adult rat was exposed to the same diet that their dams consumed during pregnancy and lactation. When they were 9 weeks old, rats began an EX regimen that lasted for 6 weeks. Twenty-four hours after the last EX bout, rats were sacrificed in a fasted state. It was observed that HF feeding of soybean oil induced more body weight and fat gain, as well as insulin resistance, as indicated by insulin/glucose ratios, than other oils. Female rats fed a HF diet made with fish oil had body weight and insulin sensitivity not different from that observed in low fat fed control rats. For rats fed HF diets made with soybean oil or palm oil, EX also exerted beneficial effects by reducing body fat %, blood insulin, triglyceride and leptin levels, as well as improving insulin sensitivity. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Dietary Fats; Fatty Acids; Female; Insulin; Insulin Resistance; Leptin; Liver; Organ Size; Physical Conditioning, Animal; Pregnancy; Rats; Rats, Wistar; Triglycerides | 2003 |
Intermittent hypoxia increases insulin resistance in genetically obese mice.
Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl-1 on day 0 to 138 +/- 10 mg dl-1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 +/- 0.3 vs. 1.7 +/- 0.2 ng ml-1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml-1 at baseline to 9.8 +/- 1.8 ng ml-1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Fasting; Gene Expression; Glucose Intolerance; Hypoxia; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity | 2003 |
Trans-10,cis-12 CLA increases liver and decreases adipose tissue lipids in mice: possible roles of specific lipid metabolism genes.
Although consumption of CLA mixtures has been associated with several health effects, less is known about the actions of specific CLA isomers. There is evidence that the t10,c12-CLA isomer is associated with alterations in body and organ weights in animals fed CLA, but the mechanisms leading to these changes are unclear. The purpose of this study was to determine the effects of two commonly occurring isomers of CLA on body composition and the transcription of genes associated with lipid metabolism. Eight-week-old female mice (n = 11 or 12/group) were fed either a control diet or diets supplemented with 0.5% c9,t11-CLA or t10,c12-CLA isomers or 0.2% of the peroxisome proliferator-activated receptor alpha (PPARalpha) agonist fenofibrate for 8 wk. Body and retroperitoneal adipose tissue weights were significantly lower (6-10 and 50%, respectively), and liver weights were significantly greater (100%) in the t10,c12-CLA and the fenofibrate groups compared with those in the control group; body and tissue weights in the c9,t11-CLA group did not differ from those in the control group. Livers from animals in the t10,c12-CLA group contained five times more lipids than in the control group, whereas the lipid content of the fenofibrate group did not differ from that in the control group. Although fenofibrate increased the mRNA for PPARalpha, t10,c12-CLA decreased it. These results suggest that PPARalpha did not mediate the effects of t10,c12-CLA on body composition. The CLA isomers and fenofibrate altered mRNA levels for several proteins involved in lipid metabolism, but the most striking difference was the reduction of mRNA for leptin and adiponectin in the t10,c12-CLA group. These initial results suggest that changes associated with energy homeostasis and insulin action may mediate the effects of t10,c12-CLA on lipid metabolism. Topics: Acyl-CoA Oxidase; Adiponectin; Adipose Tissue; Animals; Apolipoprotein A-I; Apolipoprotein C-III; Apolipoproteins C; Blotting, Northern; Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cytochrome P-450 Enzyme System; Female; Fenofibrate; Gene Expression Regulation; Intercellular Signaling Peptides and Proteins; Ion Channels; Isomerism; Leptin; Linoleic Acids, Conjugated; Lipids; Lipoprotein Lipase; Liver; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Muscles; Myocardium; Organ Size; Oxidoreductases; Proteins; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Triglycerides; Uncoupling Protein 2 | 2003 |
Impact of dietary FA and energy restriction on plasma leptin and ob gene expression in mice.
The aim of the present study was to elucidate whether the qualitative composition of dietary fat influences plasma leptin and adipose tissue ob gene expression differentially. Two high-fat diets and a diet rich in carbohydrate were each administered both ad libitum and with a 25% energy restriction. The high-fat diets contained 58 energy percent as either monounsaturated FA (MUFA) or saturated FA (SAFA), whereas the carbohydrate-rich diet (CH) contained 7 energy percent as fat. We aimed at obtaining the same final weight for the animals in the ad libitum group as in the energy-restricted groups. This goal was reached at the same time (days 22-24) for all groups except for the ad libitum animals fed on saturated fat (day 36). The plasma leptin concentrations on ad libitum CH and MUFA diets did not differ significantly (24.3 +/- 2.1 and 34.7 +/- 6.7 ng/mL, respectively) whereas the saturated fat diet caused a lower concentration (13.9 +/- 1.9 ng/mL; P < 0.05). Interestingly, no differences in plasma leptin levels between groups were seen in the energy-restricted groups (mean 8.0 +/- 1.0 ng/mL). The type of diet did not alter the ob gene expression in intraabdominal white adipose tissue; however, a lower expression level was found in the energy-restricted groups. The percentage of body fat in the three ad libitum fed groups did not differ (23 +/- 1%). Thus, short-term administration of a diet rich in SAFA suppresses circulating leptin levels without altering the adipose tissue ob gene expression. This indicates that saturated fat may alter protein handling by adipose tissue or the whole body clearance of leptin. Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Weight; Dietary Fats; Eating; Energy Intake; Fatty Acids; Female; Gene Expression Regulation; Leptin; Mice; Mice, Inbred Strains | 2003 |
The role of leptin in the etiopathogenesis of anorexia nervosa and bulimia.
Leptin is an adipocyte-derived signal factor (167 amino acid protein) encoded by the ob gene in chromosome 7q31 that regulates eating behaviour via central neuroendocrine mechanisms. It has been shown that serum leptin levels correlate with weight and percentage body fat in normal and obese individuals, but the exact correlation between leptin and body weight in anorexic and bulimic patients has not yet been clarified. We investigated leptin levels in the serum of 58 female subjects aged 15-36 years: 10 with bulimia nervosa (BN); 12 with anorexia nervosa (AN); 12 overweight controls (not BN); 12 weight-reduced controls (not AN); and 12 normal weight controls. The aim of the study was to evaluate the possible correlations between leptin levels and the body mass index (BMI) in all five groups. Our results showed that the serum leptin levels of the bulimic patients were similar to those of the healthy controls, with a positive correlation between leptin and BMI. Although bulimic patients have very bad nutritional behaviour, their leptin levels do not appear altered. Serum leptin was significantly (p<0.001) reduced in the anorexic patients because of the dramatic decrease in adipose mass caused by the nutritional defect, as: is further supported by the significantly (p<0.001) low level of transferrinemia. Our data suggest that, although significantly reduced, serum leptin levels in fasting anorexic patients are non-linearly related to body weight (BMI). Topics: Adolescent; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Bulimia; Female; Humans; Leptin | 2003 |
Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice.
Whether left ventricular hypertrophy (LVH) in obesity results from increased hemodynamic load or altered neurohormonal signaling remains controversial. Dysregulation of leptin, a neurohormone essential to energy homeostasis, is implicated in the pathogenesis of obesity. Because leptin has cardiovascular bioactivity, we hypothesized that disruption of leptin signaling mediates the development of obesity-associated LVH.. We measured left ventricular (LV) wall thickness and LV mass with echocardiography in mice lacking leptin (ob/ob, n=15) or functional receptor (db/db, n=10) and controls at 2, 4, and 6 months of age. None of the mice had LVH at 2 months. Progressive obesity developed in ob/ob and db/db mice. At 6 months, LVH occurred in ob/ob and db/db compared with controls. We observed corresponding myocyte hypertrophy by light microscopy. To separate the direct contribution of leptin deficiency from mechanical effects of obesity, we induced weight loss in 6- to 8-month-old ob/ob mice either by leptin infusion or caloric restriction. Mice in both groups lost similar weight compared with placebo-treated controls. Leptin infusion completely reversed the increase in wall thickness with partial resolution of myocyte hypertrophy, whereas calorie-restricted mice had no decrease in wall thickness and a lesser change in myocyte size.. Together these data show that the effect of leptin on LV remodeling is not attributable to weight loss alone, indicating that leptin has antihypertrophic effects on the heart, either directly or through a leptin-regulated neurohumoral pathway. Disruption of leptin signaling may represent a novel mechanism in LVH and related cardiovascular disorders. Topics: Animals; Body Weight; Cardiomegaly; Disease Models, Animal; Disease Progression; Heart Ventricles; Hemodynamics; Homozygote; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Myocardium; Myocytes, Cardiac; Obesity; Organ Size; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Ventricular Remodeling | 2003 |
Impaired lung function and serum leptin in men and women with normal body weight: a population based study.
Impaired lung function is a risk factor for cardiovascular morbidity. Whether circulating factors are responsible for this association is unknown. A study was undertaken to determine whether leptin, a hormone that can promote atherothrombosis, is raised in individuals with impaired lung function.. Data from non-obese participants in the Third National Health, Nutrition, and Examination Survey (n=2808) were analysed to determine the relationship between circulating leptin levels and forced expiratory volume in 1 second (FEV(1)) values divided into quintiles (quintile 1, FEV(1) predicted < or =85.2%; quintile 2, 85.3-94.3%; quintile 3, 94.4-101.4%; quintile 4, 101.5-110.0%; and quintile 5, > or =110.1%).. Serum leptin levels changed along the FEV(1) gradient. The highest leptin levels were found in quintile 1 (geometric mean (GM) 5.42; interquartile range (IQR) 3.00-9.60 fg/l) and the lowest in quintile 5 (GM 4.94; IQR 2.80-9.10 fg/l). Adjustments for age, body mass index, and other confounders strengthened this relationship. Compared with quintile 5, the odds of having an increased serum leptin level in quintiles 1, 2, 3, and 4 were 2.26 (95% confidence interval (CI) 1.54 to 3.31), 2.20 (95% CI 1.52 to 3.17), 1.46 (95% CI 1.01 to 2.09), and 1.28 (95% CI 0.90 to 1.83), respectively.. Individuals with impaired lung function have raised serum leptin levels. Leptin may play a role in the pathogenesis of cardiovascular morbidity and mortality related to impaired lung function. Topics: Adult; Age Distribution; Aged; Body Mass Index; Body Weight; Cardiovascular Diseases; Cohort Studies; Cross-Sectional Studies; Female; Forced Expiratory Volume; Humans; Leptin; Lung Diseases; Male; Middle Aged; Multivariate Analysis; Risk Factors; Vital Capacity | 2003 |
Effects of leptin gene expression in mice in vivo by electroporation and hydrodynamics-based gene delivery.
In vivo electroporation and hydrodynamics-based gene delivery were utilized to test the effect of leptin gene transfer on food intake, and body and fat weights of mice. Gene transfer of pVRmob by electroporation caused a significant reduction in body weight compared with the control counterpart (p<0.05), although a lesser effect was found in food intake, and the weights of interscapular brown and epididymal fat by electroporation. As might be expected, the hydrodynamics-based transfection method significantly reduced body weight over 1 week post-transfection (p<0.05). Furthermore, epididymal fat was decreased by 50% at 1 week after gene transfer (p<0.001). These results suggest that both electroporation and hydrodynamics-based gene delivery may be effective approaches for systemic delivery of recombinant leptin to the central nervous system, and that the efficiency of gene transfer in hydrodynamics-based gene delivery was markedly higher than that in electroporation at least within the first week after transfection. Topics: Adipose Tissue; Animals; Body Weight; Eating; Electroporation; Gene Expression; Green Fluorescent Proteins; Leptin; Luminescent Proteins; Male; Mice; Mice, Inbred ICR; Muscle, Skeletal; RNA, Messenger; Transfection; Water | 2003 |
Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype.
Energy homeostasis is regulated by a complex network involving peripheral and central signals that determine food intake and energy expenditure. Melanin-concentrating hormone (MCH) plays an essential role in this process. Animals treated with MCH develop hyperphagia and obesity. Ablation of the prepro-MCH gene leads to a lean phenotype, as does ablation of the rodent MCH receptor, MCHR-1. MCH is overexpressed in the leptin-deficient ob/ob mouse, and we hypothesized that ablation of MCH in this animal would lead to attenuation of its obese phenotype. Compared with ob/ob animals, mice lacking both leptin and MCH (double null) had a dramatic reduction in body fat. Surprisingly, the hyperphagia of the ob/ob mouse was unaffected. Instead, leanness was secondary to a marked increase in energy expenditure resulting from both increased resting energy expenditure and locomotor activity. Furthermore, double-null mice showed improvements in other parameters impaired in ob/ob mice. Compared with ob/ob mice, double-null animals had increased basal body temperature, improved response to cold exposure, lower plasma glucocorticoid levels, improved glucose tolerance, and reduced expression of stearoyl-CoA desaturase 1 (SCD-1). These results highlight the importance of MCH in integration of energy homeostasis downstream of leptin and, in particular, the role of MCH in regulation of energy expenditure. Topics: Adipose Tissue, Brown; Animals; Base Sequence; Body Composition; Body Temperature Regulation; Body Weight; Carrier Proteins; Corticosterone; DNA; Eating; Energy Metabolism; Hypothalamic Hormones; Ion Channels; Leptin; Liver; Male; Melanins; Membrane Proteins; Mice; Mice, Knockout; Mice, Obese; Mitochondrial Proteins; Motor Activity; Obesity; Phenotype; Pituitary Hormones; Stearoyl-CoA Desaturase; Triglycerides; Uncoupling Protein 1 | 2003 |
Melatonin effects on metabolism independent of gonad function.
We previously demonstrated that daily melatonin administration to middle-aged rats, restoring nocturnal plasma melatonin to young adult levels, decreased body weight and suppressed visceral fat and plasma leptin. In some species, metabolic and some neuronal responses to melatonin are mediated or dependent at least in part on gonadal steroid levels. Thus, melatonin-induced changes in gonadal steroid secretion may have mediated the aging-dependent melatonin-induced metabolic responses in our previous studies. To address this issue, melatonin (0.4 micro g/mL) or vehicle (0.01% ethanol) was administered for 10 wk in the drinking water of both castrate and sham-operated Sprague-Dawley male rats, starting 1 mo after surgery at 9 mo of age. Melatonin treatment decreased (p < 0.05) body weight in sham-operated rats by 7 +/- 2% relative to control (n = 7/treatment), comparable to our previous results; melatonin likewise decreased (p < 0.05) body weight in castrate rats by 6 +/- 2% relative to control (n = 7/treatment). Melatonin treatment also decreased both intraabdominal fat and plasma leptin levels in both intact and castrate rats, with no significant differences of percentage suppression in the intact versus castrate rats. These results demonstrate that suppression of body weight, visceral adiposity, and plasma leptin levels by daily melatonin administration to middle-aged rats was independent of gonadal function. Topics: Adipose Tissue; Age Factors; Animals; Body Composition; Body Weight; Castration; Circadian Rhythm; Eating; Energy Metabolism; Fasting; Insulin; Leptin; Male; Melatonin; Rats; Rats, Sprague-Dawley; Testis; Testosterone | 2003 |
Effect of clozapine on serum leptin, insulin levels, and body weight and composition in patients with schizophrenia.
Weight gain frequently occurs during treatment with clozapine. However, the pathophysiology of clozapine-induced weight gain remains unclear. The aim of this study was to investigate the influence of clozapine on hormones leptin and insulin in relation to body weight and composition measures to determine their contribution to clozapine-induced weight gain.. Data are reported on 19 patients with schizophrenia (11 women and 8 men) who completed 10 weeks of treatment with clozapine. Insulin levels, weight measurements, body mass index (BMI), and body composition measurements were evaluated at baseline and at the end of treatment. Leptin levels were assessed at baseline and after 4 and 10 weeks of treatment. Analysis of variance with repeated measures was used to evaluate changes in weight, body composition measures, leptin, and insulin. The Pearson correlations were used to assess the relationships between changes in hormone levels and weight along with body composition measurements. The correlations of change in Positive and Negative Syndrome Scale (PANSS) score with changes in hormone levels, weight gain and body composition measures were evaluated with Pearson correlations.. Leptin and insulin levels did not show any significant alterations across time. The use of clozapine was associated with significant increases in BMI (F=19.8, P<.001), lean muscle mass (F=8.2, P=.01), and fat mass (F=15.4, P=.001), while total body fluid percentage (F=4.1, P=.05) significantly decreased. Improvement in PANSS scores was not correlated to change in leptin, insulin, weight, BMI, or body composition measurements. The change in leptin levels was correlated to change in body fat mass.. The role of leptin in weight gain induced by clozapine might be a regulatory mechanism rather than being etiologic. Topics: Adult; Analysis of Variance; Body Composition; Body Weight; Clozapine; Female; Humans; Insulin; Leptin; Male; Middle Aged; Schizophrenia | 2003 |
Leptin signaling in the hypothalamus during chronic central leptin infusion.
Using a rat model of chronic central leptin infusion in which neuropeptide Y neurons develop leptin resistance, we examined whether leptin signal transduction mechanism in the hypothalamus is altered during central leptin infusion. Adult male rats were infused chronically into the lateral cerebroventricle with leptin (160 ng/h) or vehicle via Alzet pumps for 16 d. In the leptin-infused group, the initial decrease in food intake was followed by a recovery to their preleptin levels by d 16, although food intake remained significantly lower than in artificial cerebrospinal fluid controls; and body weight gradually decreased reaching a nadir at d 11 and remained stabilized at lower level thereafter. Phosphorylated leptin receptor and phosphorylated signal transducer and activator of transcription-3 (p-STAT3) remained elevated in association with a sustained elevation in DNA-binding activity of STAT3 in the hypothalamus throughout 16-d period of leptin infusion. However, phosphorylated Janus kinase-2 was increased during the early part of leptin infusion but remained unaltered on d 16. Although hypothalamic suppressors of cytokine signaling-3 (SOCS3) mRNA levels were increased throughout leptin infusion, SOCS3 protein levels were increased only on d 16. This study demonstrates a sustained elevation in hypothalamic leptin receptor signaling through Janus kinase-STAT pathway despite an increased expression of SOCS3 during chronic central leptin infusion. We propose that an alteration in leptin signaling in the hypothalamus through pathways other than STAT3 and/or a defect in downstream of STAT3 signaling may be involved in food intake recovery seen after an initial decrease during chronic central leptin infusion. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Disease Models, Animal; DNA-Binding Proteins; Eating; Epididymis; Gene Expression; Hypothalamus; Injections, Intraventricular; Insulin; Janus Kinase 2; Leptin; Male; Neurons; Obesity; Phosphorylation; Protein-Tyrosine Kinases; Proteins; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Repressor Proteins; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Trans-Activators; Transcription Factors | 2003 |
Changes in cerebral endothelial barrier antigen, without alteration of permeability for intravenously injected leptin in diet-induced obesity in rats.
Leptin, a potent anorectic, 16-kDa, adipose tissue-derived protein, predominantly acts in hypothalamic nuclei, signaling obesity and modulating ingestive behavior. To reach this brain area, leptin, probably has to cross the blood-brain barrier (BBB). In some cases of obesity, enhanced leptin levels in the blood do not result in anorectic effects, probably due to an altered leptin transport across the BBB. Therefore, we investigated the BBB in lean and diet-induced obese Lewis rats. To obtain information about the presence of microvessels with barrier dysfunction we examined three brain areas (hypothalamus, cortex, hippocampus) using a monoclonal antibody which detects intact microvessels of the BBB (anti-endothelial barrier antigen, anti-EBA). The results showed a significantly reduced EBA staining in the brain sections of the obese animals, except the hippocampus, compared to the control group. In a second step we injected I125-labeled leptin intravenously (i.v.) in permanent i.v.-cannulated, unrestrained Lewis rats (lean and obese). We measured the radioactivity in the cerebrospinal fluid after puncture of the cisterna magna, in the blood and brain tissue 90 min after injection. The leptin content in the cerebrospinal fluid and brain was not reduced in obese compared to lean rats, thus showing a similar transport capacity of the BBB in both experimental groups. Therefore, the results of the in vivo investigations do not indicate an impairment of the BBB in diet-induced obesity, despite the immunohistological findings. Further functional and morphological studies are necessary to evaluate the specific role of other organs and distinct forms of leptin (free and protein-bound) in the pathogenesis of diet-induced obesity. Topics: Animals; Antigens, Surface; Blood-Brain Barrier; Body Weight; Brain; Dietary Fats; Disease Models, Animal; Endothelium, Vascular; Immunoenzyme Techniques; Injections, Intravenous; Iodine Radioisotopes; Leptin; Male; Microcirculation; Obesity; Rats; Rats, Inbred Lew; Specific Pathogen-Free Organisms | 2003 |
Leptin and insulin modulate nutrient partitioning and weight loss in ob/ob mice through regulation of long-chain fatty acid uptake by adipocytes.
Leptin treatment of ob/ob mice leads to weight loss appreciably greater than that in pair-fed mice. To test whether this "extra" weight loss is mediated by leptin-induced alterations in nutrient partitioning, the effects in ob/ob mice of subcutaneous leptin infusion (500 ng/h for Topics: Adipocytes; Animal Nutritional Physiological Phenomena; Animals; Aspartate Aminotransferases; Body Weight; CD36 Antigens; Cell Size; Eating; Fatty Acids; Insulin; Kinetics; Leptin; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mitochondria; Obesity; Organic Anion Transporters; Osmolar Concentration; Receptors, Leptin; RNA, Messenger; Weight Loss | 2003 |
Effect of oral oleoyl-estrone on the energy balance of diabetic rats.
We studied the effects of a 10-day oral 10 micromol/kg oleoyl-estrone (OE) treatment on streptozotocin-diabetic Wistar, Goto-Kakizaki and control Wistar rats. Streptozotocin rats lost more than half the energy ingested as urine glucose. Oleoyl-estrone induced the loss of body weight (mainly body fat) in all groups. Energy expenditure was similar in the three groups of rats studied. Water turnover was deranged in streptozotocin rats, which spent 14% of energy available heating the water drunk. Body lipids were highest in Goto-Kakizaki; lipid levels in streptozotocin rats were very low. Oleoyl-estrone decreased body lipid content in Wistar and Goto-Kakizaki; oleoyl-estrone decreased triacylglycerols (44% in Wistar and Goto-Kakizaki and 22% in streptozotocin rats) and phospholipids but did not affect body cholesterol. Oleoyl-estrone decreased insulin and leptin, did not affect blood glucose but decreased plasma glucose in all groups. There were no changes in plasma triacylglycerols or fatty acids, but HDL, LDL and cholesterol decreased in all groups. The same effects of OE on insulin, plasma (but not blood) glucose and leptin were observed in both models, but the presence of insulin seems to be needed for OE to normalise glycaemia and to facilitate the uptake and utilisation of glucose by tissues. This different handling of glucose and triacylglycerol energy accounts for the disparate effects of OE on energy balance. The main conclusion of this study is that OE function as a lipid-mobilising hormone is dependent on the mass of reserves available, which in turn is closely related to insulin status. Lack of insulin thus results in limited OE effects, and insulin resistance does not prevent or limit the effects of OE on energy homeostasis or the mobilisation of fat. Topics: Administration, Oral; Animals; Anti-Obesity Agents; Blood Glucose; Body Water; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Drinking; Energy Metabolism; Estrone; Glucose; Insulin; Leptin; Lipid Metabolism; Lipids; Oleic Acids; Rats; Rats, Inbred Strains; Rats, Wistar; Streptozocin; Urea | 2003 |
Response to acute food deprivation in OLETF rats lacking CCK-A receptors.
Otsuka Long-Evans Tokushima Fatty (OLETF) rats lacking cholecystokinin (CCK)-A receptors are hyperphagic and obese, and exhibit deficits in meal size control and in neuropeptide Y (NPY) gene expression in the dorsomedial hypothalamus (DMH). The present study was intended to determine whether these deficits would affect OLETF rat's response to an acute 24-h period of food deprivation. OLETF rats lost more body weight in response to deprivation but recovered their weight more quickly during refeeding than did lean Long-Evans Tokushima Otsuka (LETO) rats. Food deprivation decreased plasma glucose and leptin levels to a similar degree in both strains. Both groups increased intake during refeeding but the magnitude of increase was significantly greater in OLETF rats. Deprivation resulted in a significant elevation in arcuate NPY gene expression (approximately 47%) in LETO rats but only produced a small nonsignificant increase in the already decreased level of expression in OLETF rats (approximately 24%, P>.05). DMH NPY gene expression was not changed by deprivation in either OLETF or LETO rats. Although paraventricular corticotropin-releasing factor (CRF) expression was decreased by deprivation in LETO rats, CRF expression was not affected in OLETF rats. Together, these data suggested that OLETF rats lacking CCK-A receptors are not only capable of increasing their food intake in response to food deprivation, but also exhibit differential sensitivity to the effects of deprivation during both the food deprivation and refeeding periods. Topics: Analysis of Variance; Animals; Appetite Regulation; Blood Glucose; Body Weight; Corticotropin-Releasing Hormone; Eating; Feeding Behavior; Food Deprivation; Leptin; Male; Matched-Pair Analysis; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred OLETF; Receptor, Cholecystokinin A; RNA, Messenger | 2003 |
Melanocortin receptors mediate leptin effects on feeding and body weight but not adipose apoptosis.
The melanocortin (MC) system is a known downstream mediator of leptin signaling in the brain; thus, activation of MC receptors by melanotan II (MTII), a MC3/4 receptor agonist, was hypothesized to increase adipose apoptosis, a phenomenon seen after leptin treatments. To test this hypothesis, male Sprague-Dawley rats received pretreatments of intracerebroventricular injections of artificial cerebrospinal fluid (aCSF, 5 microl) or SHU9119 (1.0 nmol/5 microl), an MC3/4 receptor antagonist. One hour later, aCSF (5 microl), leptin (10 microg/5 microl), or MTII (0.1 nmol/5 microl) was injected intracerebroventricularly in the aCSF-pretreated groups, and either leptin (10 microg/5 microl) or MTII (0.1 nmol/5 microl) was injected intracerebroventricularly in SHU9119-pretreated groups. Each pair of treatments was given once daily for four successive days. Body weight (BW), food intake (FI), and body temperature (BT) were measured daily at 4- and 24-h intervals. SHU9119 completely prevented the decrease in FI and BW caused by either MTII or leptin. Muscle mass remained unchanged regardless of treatment, but both leptin and MTII significantly reduced mass of inguinal (iWAT), retroperitoneal (rWAT), and epididymal (eWAT) white adipose tissues (P<.05). SHU9119 prevented the decrease in mass of intrascapular brown fat, iWAT, and rWAT (P<.05). Leptin, but not MTII, increased DNA fragmentation in eWAT (P<.05), but SHU9119 pretreatment had no effect on leptin-induced apoptosis. Thus, although the MC receptors in the brain are involved in mediating actions of leptin on FI, fat mass, and BW, leptin-induced adipose apoptosis is regulated independently of MC receptors. Topics: Adipose Tissue; alpha-MSH; Animals; Apoptosis; Body Composition; Body Weight; Feeding Behavior; Injections, Intraventricular; Leptin; Male; Melanocyte-Stimulating Hormones; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptors, Melanocortin; Signal Transduction | 2003 |
Activation of the sympathetic nervous system by galanin-like peptide--a possible link between leptin and metabolism.
The effects of leptin upon body weight (BW) cannot be explained by its anorectic actions alone. Part of the metabolic changes elicited by leptin includes sympathetic nervous system activation leading to increased energy expenditure. Galanin-like peptide (GALP), a recently described hypothalamic neuropeptide, is up-regulated by leptin and has anorectic effects in the mouse. We postulated that GALP mediates effects of leptin upon metabolism. To test this hypothesis, we administered GALP centrally to the leptin-deficient ob/ob mouse. Acutely, GALP induced a decrease in food intake and BW, both of which remained significant relative to controls for 4 d. Chronic GALP administration resulted in a sustained decrease in BW and an increase in core body temperature, despite significant recovery of food intake. In a pair-fed model, chronic GALP treatment resulted in a greater decrease in BW than that seen in controls. Furthermore, GALP treatment resulted in increased body temperature and uncoupling protein 1 mRNA and protein in brown adipose tissue compared with controls. The expression of pro-opiomelanocortin (POMC) mRNA in the arcuate nucleus was decreased after chronic GALP treatment. These observations suggest that leptin's activation of the sympathetic nervous system, and ultimately thermogenesis, may be partially mediated by GALP through a melanocortin-independent mechanism. Topics: Adipose Tissue, Brown; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Carrier Proteins; Drug Administration Schedule; Eating; Galanin-Like Peptide; Injections, Intraventricular; Ion Channels; Leptin; Male; Membrane Proteins; Metabolism; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Obesity; Pro-Opiomelanocortin; Rats; RNA, Messenger; Sympathetic Nervous System; Uncoupling Protein 1 | 2003 |
Hyperleptinemia, visceral adiposity, and decreased glucose tolerance in mice with a targeted disruption of the histidine decarboxylase gene.
Histamine has been referred to as an anorexic factor that decreases appetite and fat accumulation and affects feeding behavior. Tuberomammillary histaminergic neurons have been implicated in central mediation of peripheral metabolic signals such as leptin, and centrally released histamine inhibits ob gene expression. Here we have characterized the metabolic phenotype of mice that completely lack the ability to produce histamine because of targeted disruption of the key enzyme in histamine biosynthesis (histidine decarboxylase, HDC). Histochemical analyses confirmed the lack of HDC mRNA, histamine immunoreactivity, and histaminergic innervation throughout the brain of gene knockout mouse. Aged histamine-deficient (HDC-/-) mice are characterized by visceral adiposity, increased amount of brown adipose tissue, impaired glucose tolerance, hyperinsulinemia, and hyperleptinemia. Histamine-deficient animals are not hyperphagic but gain more weight and are calorically more efficient than wild-type controls. These metabolic changes presumably are due to the impaired regulatory loop between leptin and hypothalamic histamine that results in orexigenic dominance through decreased energy expenditure, attenuated ability to induce uncoupling protein-1 mRNA in the brown adipose tissue and defect in mobilizing energy stores. Our results further support the role of histamine in regulation of energy homeostasis. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Blood Glucose; Body Weight; Brain; Carrier Proteins; Energy Metabolism; Glucose Intolerance; Histamine; Histidine; Histidine Decarboxylase; Hormones; Insulin; Insulin Secretion; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Knockout; Mitochondrial Proteins; Neurons; RNA, Messenger; Uncoupling Protein 1; Viscera | 2003 |
Study of the alteration of gene expression in adipose tissue of diet-induced obese mice by microarray and reverse transcription-polymerase chain reaction analyses.
In the present study we developed a model of diet-induced obesity (DIO) in male C57 BL/6J mice using an 8-wk high fat diet. This model should better reflect the physiology of the majority of the human obese patients than mouse genetic models of obesity with defects in leptin or leptin signaling. At the end of the diet, DIO mice displayed an increased weight (20%) and higher leptin, insulin, glucose, and corticosterone plasma levels compared with mice fed a standard diet during the same period. Moreover, they became resistant to the central effect of peripheral administration of leptin. Oligonucleotide microarray studies were conducted in adipose tissue. They showed that a great number of genes are differentially expressed. The majority of these genes (69%) are down-regulated in DIO mice. Among those are genes encoding enzymes of the lipid metabolism or markers of adipocyte differentiation, enzymes involved in detoxification processes, as well as structural components of the cytoskeleton. Some other groups of genes displayed increased expression, such as those encoding inflammatory markers. The results of the microarray analysis were confirmed by semiquantitative RT-PCR studies run on a selected number of genes that were differentially expressed or not modified. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Corticosterone; Dietary Fats; Gene Expression; Gene Expression Profiling; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation | 2003 |
Systemic 5-hydroxy-L-tryptophan down-regulates the arcuate CART mRNA level in rats.
This study was conducted to determine if serotonin (5-hydroxytryptamine; 5-HT) system correlates with the hypothalamic expression of cocaine-amphetamine-regulated transcript (CART) gene. Rats received intraperitoneal 5-hydroxy-L-tryptophan (5-HTP; a single or three daily injections at a dose of 100 mg/kg/10 ml), and CART mRNA level in the hypothalamus was examined by in situ hybridization at different time points. The 5-HT contents of the hypothalamus as well as the brainstem was increased persistently by 5-HTP injections, and food intake and body weight gain reduced. CART mRNA level decreased significantly in the hypothalamic arcuate nucleus by three daily 5-HTP, but not by a single injection. The pair-fed group of the chronic 5-HTP did not show a decrease in the arcuate CART mRNA level. The plasma leptin level markedly decreased in the chronic 5-HTP group, compared to the saline group, however, still higher than the pair-fed group with a statistical significance. These results suggest that 5-HT may suppress CART mRNA expression in the arcuate nucleus, not only by leptin signaling via its anorectic effect on the control of food intake, but also by some non-leptin mediated pathway. Topics: 5-Hydroxytryptophan; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Brain Stem; Down-Regulation; In Situ Hybridization; Leptin; Male; Nerve Tissue Proteins; Neurotransmitter Agents; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2003 |
IL-1 plays an important role in lipid metabolism by regulating insulin levels under physiological conditions.
IL-1 is a proinflammatory cytokine that plays important roles in inflammation. However, the role of this cytokine under physiological conditions is not known completely. In this paper, we analyzed the role of IL-1 in maintaining body weight because IL-1 receptor antagonist-deficient (IL-1Ra-/-) mice, in which excess IL-1 signaling may be induced, show a lean phenotype. Body fat accumulation was impaired in IL-1Ra-/- mice, but feeding behavior, expression of hypothalamic factors involved in feeding control, energy expenditure, and heat production were normal. When IL-1Ra-/- mice were treated with monosodium glutamate (MSG), which causes obesity in wild-type mice by ablating cells in the hypothalamic arcuate nucleus, they were resistant to obesity, indicating that excess IL-1 signaling antagonizes the effect of MSG-sensitive neuron deficiency. IL-1Ra-/- mice showed decreased weight gain when they were fed the same amount of food as wild-type mice, and lipid accumulation remained impaired even when they were fed a high-fat diet. Interestingly, serum insulin levels and lipase activity were low in IL-1Ra-/- mice, and the insulin levels were low in contrast to wild-type mice after MSG treatment. These observations suggest that IL-1 plays an important role in lipid metabolism by regulating insulin levels and lipase activity under physiological conditions. Topics: Adipose Tissue; Animals; Body Weight; Cytokines; Eating; Energy Metabolism; Female; Homeostasis; Hypothalamic Hormones; Insulin; Interleukin-1; Leptin; Lipase; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Interleukin-1; Triglycerides | 2003 |
The maternal endocrine environment in the low-protein model of intra-uterine growth restriction.
Many adult diseases, including type 2 diabetes, hypertension and cardiovascular disease, are related to low birth weight. The mechanistic basis of this relationship is not known. To investigate the role of fetal undernutrition, we used a rat model of maternal protein restriction in which dams were fed a diet containing 80 g protein/kg (v. 200 g/kg in the control group) throughout gestation and lactation. Offspring were born smaller than controls and in adulthood developed diabetes, hyperinsulinaemia and tissue insulin resistance. To determine possible mechanisms of fetal programming, circulating levels of several hormones were measured in maternal plasma at gestational days 14, 17 and 21 and fetal plasma at gestational day 21. Several differences were noted at day 14, when glucose concentrations in maternal and feto-placental blood were raised significantly (P=0.04 and P=0.0001 respectively); insulin levels in the low-protein (LP) dams were raised (P=0.04), prolactin levels were raised (P=0.047) and progesterone levels were reduced (P=0.02). Circulating 17beta-oestradiol in the LP dams was raised by 35 % over those of the controls from day 17 to day 21 (P=0.008). A significant decrease in maternal leptin levels (P=0.004) was observed at gestation on day 21. Neither oestradiol nor leptin levels were altered in the fetal circulation at day 21. Maternal and fetal corticosterone levels were comparable with control levels, suggesting that they do not initiate the programming effects in this model. Our present results suggest that maternal protein restriction imposes changes in maternal levels of glucose, insulin, prolactin, progesterone, oestradiol and leptin; these changes could influence the programming of eventual adult disease in the developing fetus. Topics: Animals; Blood Glucose; Body Weight; Corticosterone; Diet, Protein-Restricted; Disease Models, Animal; Eating; Estradiol; Fatty Acids, Nonesterified; Female; Fetal Growth Retardation; Insulin; Leptin; Organ Size; Placenta; Pregnancy; Progesterone; Prolactin; Rats; Rats, Wistar; Triglycerides; Weight Gain | 2003 |
Influence of dietary and genetic factors on metabolic status in obese and lean postmenopausal women.
This preliminary study addressed the possible associations between dietary, genetic and hormonal factors that are involved in the development of menopausal obesity and its metabolic consequences. We performed anthropometrical, hormonal and biochemical measurements and used a nutritional questionnaire on 43 postmenopausal women who were non-HRT-users (14 obese and 29 non-obese subjects, mean age +/- SD of 52.8 +/- 4.6 years, mean body mass 74.6 +/- 4.6 kg). All of the women also had fat mass assessed by DPX-Lunar. From the 24-h dietary recall, the nutrient intake in daily food rations was calculated using a computer program (Nutritionist IV, San Bruno, CA, USA) based on our own database. Restriction fragment length polymorphism of the estrogen-receptor-alpha gene was determined with the PvuII restriction enzyme. Obese women widely under-reported their daily food intake. The analysis of body fat distribution showed that the total body weight and the percentage of total fat mass were significantly increased in the obese group (p = 0.001). We observed significantly higher leptin (20.56 +/- 11.9 vs. 9.02 +/- 2.8 ng/ml) and total cholesterol (but lower cholesterol HDL), triglycerides levels in the obese subjects (261.89 +/- 48.8 vs. 248.23 +/- 55.9; 52.17 +/- 13.6 vs. 60.92 +/- 13.04; 142.82 +/- 61.02 vs. 106.61 +/- 27.7 mg/dl). Except for diastolic blood pressure, clinical variables were not significantly different between subjects with and without the PvuII ERalpha polymorphism. Allele frequencies of the ERalpha polymorphism did not differ from those previously reported (P-0.48, p-0.52) in our study. In this preliminary study we failed to find dietary and genetic factors involved in the pathogenesis of menopausal obesity. However, our results provide support for the notion that the perimenopausal increase in visceral fat is a significant factor involved in the increased cardiovascular risk in postmenopausal women. Topics: Blood Glucose; Body Composition; Body Mass Index; Body Weight; Cholesterol; Eating; Estradiol; Estrogen Receptor alpha; Female; Humans; Insulin; Leptin; Middle Aged; Obesity; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Postmenopause; Receptors, Estrogen; Testosterone; Triglycerides | 2003 |
Serum leptin concentrations in children with mild-to-moderate protein-energy malnutrition.
The aim of the present study was to clarify the relationship between nutritional anthropometric parameters and serum leptin concentrations in otherwise healthy children with mild-to-moderate protein-energy malnutrition (PEM) secondary to inadequate energy intake.. Eighty-one otherwise healthy children with poor appetite and inadequate energy intake were enrolled in the study. The anthropometric values were evaluated in all subjects. Fasting serum leptin concentrations were assessed.. Of the 81 otherwise healthy children, 30 were found to have mild-to-moderate PEM. The control group consisted of 51 healthy children who had normal anthropometric values, even though they had inadequate energy intake. There was a significant difference in serum leptin concentrations between the two groups (P < 0.01). Furthermore, there was a positive correlation between mean serum leptin concentrations and percentage of standard weight for height in the patient and the control group (P < 0.05). Multiple linear regression analysis indicated that percentage of standard BMI was the best predictor for serum leptin concentrations (P < 0.05).. In addition to BMI, percentage of standard weight for height is a valuable nutritional anthropometric parameter for serum leptin concentrations in PEM and inadequate energy intake. However in the present study, percentage of standard BMI was the best predictor for serum leptin concentrations. Serum leptin concentrations are low not only in severe PEM, but also in children with mild-to-moderate PEM without chronic disease. Topics: Body Height; Body Weight; Case-Control Studies; Child; Child, Preschool; Female; Humans; Infant; Leptin; Male; Protein-Energy Malnutrition; Skinfold Thickness | 2003 |
Exercise and intestinal polyp development in APCMin mice.
Epidemiological evidence suggests that physical activity protects against colon cancer. We previously used a mouse predisposed to intestinal polyps (APCMin) to evaluate this association and found the suggestion of fewer polyps in exercised males but not females. The present study was designed to further explore the potential exercise x sex interaction on polyp development and to begin to look at potential mechanisms.. Six-week-old APCMin mice (N = 60 males; 60 females) were randomly assigned to one of two groups by sex: treadmill running at 20 m.min-1, 5% grade, 45 min.d-1, 5 d.wk-1 (EX) or nonrunning controls (CON) (N = 30 per group). EX mice ran in running wheels while in quarantine (weeks 0-3), followed by treadmill running weeks 3-8. Body weights were measured weekly. Urine was collected at 5 wk and fasting blood at 7.5 wk. Body composition was measured, serum was frozen, and polyp number and size were measured at sacrifice.. EX resulted in lower body weights (P < 0.01) and reduced fat mass (P < 0.01). Fasting glucose was lower in EX (P < 0.01), and leptin was lower in EX (P = 0.05) compared with CON. EX did not affect serum insulin-like growth factor-1 or urinary corticosterone. Total polyp number and size were not statistically different between groups; however, there were fewer jejunal polyps in EX (3.6 +/- 0.7, mean +/- SE) versus CON males (5.2 +/- 0.8; P = 0.04) and an even larger difference when only the consistent runners were kept in the analysis (2.7 +/- 0.5 in EX; P = 0.01).. Despite favorable changes in body composition, blood glucose, and leptin, 8 wk of running resulted in only minor changes related to polyp development in male but not female APCMin mice. Topics: Animals; Body Composition; Body Weight; Disease Models, Animal; Female; Hormones; Intestinal Polyps; Leptin; Male; Mice; Running; Sex Characteristics | 2003 |
Genetic modulation of PPARgamma phosphorylation regulates insulin sensitivity.
Obesity-associated diabetes is epidemic in industrialized societies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in adipose tissue and the presumed molecular target for antidiabetic thiazolidinedione drugs that reverse insulin resistance but also promote weight gain. Phosphorylation reduces the activity of PPARgamma in vitro, but physiological relevance has not been demonstrated. We have studied mice homozygous for a mutation (S112A) that prevents PPARgamma phosphorylation. Surprisingly, the weights and adipose mass of PPARgamma-S112A mice are not greater than wild-type. Remarkably, however, genetic prevention of PPARgamma phosphorylation preserves insulin sensitivity in the setting of diet-induced obesity. Underlying this protection are smaller fat cells, elevated serum adiponectin, and reduced free fatty acid levels. Thus, the phosphorylation state of PPARgamma modulates insulin sensitivity. Compounds that prevent PPARgamma phosphorylation or ligands that induce the conformation of nonphosphorylated PPARgamma may selectively enhance insulin sensitivity without increasing body weight. Topics: Adiponectin; Adipose Tissue; Adipose Tissue, Brown; Alanine; Amino Acid Substitution; Animals; Blood Glucose; Blotting, Southern; Body Weight; Cell Size; Cells, Cultured; Culture Media, Conditioned; Dose-Response Relationship, Drug; Embryo, Mammalian; Fatty Acids, Nonesterified; Female; Gene Expression; Glucose; Glucose Tolerance Test; Immunoblotting; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Obesity; Phosphorylation; Proteins; Receptors, Cytoplasmic and Nuclear; Serine; Time Factors; Transcription Factors | 2003 |
Central leptin gene therapy fails to overcome leptin resistance associated with diet-induced obesity.
The objective of this study was to determine if central overexpression of leptin could overcome the leptin resistance caused by 100 days of high-fat feeding. Three-month old-F344XBN male rats were fed either control low fat chow (Chow), which provides 15% of energy as fat, or a high-fat/high-sucrose diet (HF), which provides 59% of energy as fat. Over several weeks, the HF-fed animals spontaneously split into two groups of animals: those that became obese on the HF diet (DIO) and those that did not gain extra weight on the HF diet [diet resistant (DR)]. After 100 days of HF feeding, animals were given a single intracerebroventricular injection containing 5.75E10 particles of rAAV encoding leptin (rAAV-leptin) or control virus (rAAV-con). Chow animals responded robustly to rAAV-leptin, including significant anorexia, weight loss, and lipopenia. In contrast, DIO were completely unresponsive to rAAV-leptin. DR rats responded to rAAV-leptin, but in a more variable fashion than Chow. Unlike what was observed in Chow, the anorectic response to rAAV-leptin rapidly attenuated and was no longer significant by day 14 postvector delivery. Both DIO and DR animals were found to have reduced long-form leptin receptor expression and enhanced basal P-STAT-3 in the hypothalamus with respect to Chow. rAAV-leptin caused an increase in STAT3 phosphorylation and proopiomelanocortin expression in the hypothalamus and an increase in uncoupling protein-1 in brown adipose tissue in both Chow and DR animals, but failed to do so in DIO. This suggests that central overexpression of leptin is not a viable strategy to reverse diet-induced obesity. Topics: Adipose Tissue, Brown; Animals; Body Weight; Carrier Proteins; Dietary Fats; DNA-Binding Proteins; Eating; Fatty Acids, Nonesterified; Gene Expression; Genetic Therapy; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Neuropeptide Y; Obesity; Oxygen Consumption; Pro-Opiomelanocortin; Rats; Rats, Inbred BN; Rats, Inbred F344; Receptors, Cell Surface; Receptors, Leptin; STAT3 Transcription Factor; Trans-Activators; Transgenes; Treatment Failure; Uncoupling Protein 1 | 2003 |
Bound leptin and sympathetic outflow in nonobese men.
Leptin exists in a free form and a receptor-bound form. Protein-bound rather than free leptin levels may be associated with regulation of muscle sympathetic nerve activity (MSNA). We determined MSNA and bound leptin concentrations in 25 men [age, 29 +/- 6 yr, body mass index (BMI), 24 +/- 3 kg/m(2)]. Baroreflex sensitivity was measured using phenylephrine and nitroprusside infusions. We measured bound leptin in patients with central (multiple system atrophy, n = 8; age, 59 +/- 8 yr; BMI, 23 +/- 2 kg/m(2)) and peripheral autonomic failure (pure autonomic failure, n = 4; age, 71 +/- 10 yr; BMI, 25 +/- 3 kg/m(2)). MSNA was correlated with protein-bound leptin concentrations (r(2) = 0.35; P < 0.01) but not with free leptin levels (r(2) = 0.09). MSNA at baseline was 15 +/- 2 bursts x minutes(-1) in subjects with lower and 24 +/- 3 bursts x minutes(-1) in subjects with higher bound leptin concentrations (P < 0.05). Blood pressure as well as baroreflex regulation of heart rate and MSNA was similar in both groups. Phenylephrine and nitroprusside responses were similar. Patients with multiple system atrophy and autonomic failure featured similar bound leptin levels. We conclude that protein-bound rather than free leptin levels are correlated with basal sympathetic outflow in normotensive, nonobese men. This relationship cannot be explained by a direct central nervous effect of protein-bound leptin. Instead, protein-bound leptin may increase sympathetic vasomotor tone indirectly via a baroreflex mechanism. Topics: Adult; Autonomic Nervous System Diseases; Baroreflex; Blood Pressure; Body Mass Index; Body Weight; Humans; Leptin; Male; Multiple System Atrophy; Obesity; Parasympathetic Nervous System; Regression Analysis; Sympathetic Nervous System | 2003 |
The potential beneficial effect of leptin on an experimental model of hyperlipidemia, induced by chronic ethanol treatment.
Obesity is known to predispose individuals to liver disease by increasing hepatic sensitivity to endotoxin. The aim of the present study was to determine the effect of mouse recombinant leptin on food intake, body weight, hepatic and plasma lipids and lipoproteins in alcohol-induced liver injury.. Male Swiss mice weighing 28-32 g were administered ethanol (6.32 g x kg(-1) body weight, p.o.) for the first 30 days. Subsequently, ethanol-fed mice were given intraperitoneal injections of exogenous leptin (230 microg x kg(-1) body weight, i.p.) every alternate day for 15 days. At the end of the total experimental period of 45 days, plasma concentrations of total cholesterol, free fatty acids, triglycerides, lipoprotein lipase and lipoproteins were measured.. Exogenous leptin injections to alcohol-fed mice significantly (P<0.05) inhibited the rise in hepatic and plasma lipid and lipoprotein concentrations as compared with those of the unsupplemented ethanol fed mice. Food intake and average body weight at the end of the experimental period was significantly decreased on leptin administration.. Chronic administration of exogenous mouse recombinant leptin prevents the rise in lipids and lipoprotein concentrations significantly in an animal model of alcohol-induced hyperlipidemia. Topics: Administration, Oral; Alcohol-Induced Disorders; Animals; Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Disease Models, Animal; Eating; Ethanol; Fatty Acids, Nonesterified; Hyperlipidemias; Injections, Intraperitoneal; Leptin; Lipoprotein Lipase; Liver; Male; Mice; Triglycerides | 2003 |
Effect of nicotine on the expression of leptin and forebrain leptin receptors in the rat.
We have previously reported that chronic nicotine administration (4.0 mg/kg/day by i.p. injection over 14 days) up-regulates orexin/hypocretin and neuropeptide Y (NPY) mRNA expression and peptide levels within the hypothalamus. Since there exists a coregulation between these neuropeptides and the protein leptin, the present study was undertaken to determine whether nicotine has a regulatory effect on leptin signaling. Under the same experimental regimen used previously, we found that nicotine down-regulates plasma leptin concentration by 48.8% (P<0.001) and leptin RNA level by 11.4% and 12.4%, respectively, in the perirenal and epididymal white adipose tissue (PWAT, EWAT) compared to the saline controls. We also measured an approximately 20% decrease in white and brown adipose tissue (BAT) by weight in nicotine-treated animals relative to saline controls (P<0.05). On the other hand, we found that chronic nicotine administration increased the expression levels of OB-Rb mRNA by 12% and OB-R mRNA by 25% in the medial basal hypothalamus compared to control rats. Subsequent radioligand binding assays indicated that nicotine also significantly increased leptin binding in ventromedial hypothalamic area (VMA), medial basal hypothalamic area (MBA), arcuate nucleus/median eminence, paraventricular nuclei and piriform cortex. Taken together, our results revealed that nicotine is involved in the regulation of leptin signaling, suggesting that leptin and its receptor play a role in the anorectic effects of nicotine on food intake and body weight in rats. Topics: Adipose Tissue; Animals; Body Weight; Down-Regulation; Feeding Behavior; Ganglionic Stimulants; Leptin; Male; Nicotine; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors | 2003 |
Increased insulin sensitivity and hypoinsulinemia in APS knockout mice.
A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS(-/-)) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. APS(-/-) mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS(-/-) mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes. Topics: 3T3 Cells; Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Adipocytes; Adiponectin; Animals; Blood Glucose; Body Weight; Energy Intake; Glucagon; Glucose; Glucose Clamp Technique; Hyperinsulinism; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Knockout; Proteins; Receptor, Insulin; Triglycerides | 2003 |
Transgenic neuronal expression of proopiomelanocortin attenuates hyperphagic response to fasting and reverses metabolic impairments in leptin-deficient obese mice.
Hypothalamic proopiomelanocortin (POMC) gene expression is reduced in many forms of obesity and diabetes, particularly in those attributable to deficiencies in leptin or its receptor. To assess the functional significance of POMC in mediating metabolic phenotypes associated with leptin deficiency, leptin-deficient mice bearing a transgene expressing the POMC gene under control of the neuron-specific enolase promoter were produced. The POMC transgene attenuated fasting-induced hyperphagia in wild-type mice. Furthermore, the POMC transgene partially reversed obesity, hyperphagia, and hypothermia and effectively normalized hyperglycemia, glucosuria, glucose intolerance, and insulin resistance in leptin-deficient mice. Effects of the POMC transgene on glucose homeostasis were independent of the partial correction of hyperphagia and obesity. Furthermore, the POMC transgene normalized the profile of hepatic and adipose gene expression associated with gluconeogenesis, glucose output, and insulin sensitivity. These results indicate that central POMC is a key modulator of glucose homeostasis and that agonists of POMC products may provide effective therapy in treating impairments in glucose homeostasis when hypothalamic POMC expression is reduced, as occurs with leptin deficiency, hypothalamic damage, and aging. Topics: Adipose Tissue; Animals; Base Sequence; Body Weight; Cloning, Molecular; DNA Primers; Fasting; Glucose Tolerance Test; Hyperphagia; Insulin; Leptin; Mice; Mice, Transgenic; Neurons; Obesity; Phosphopyruvate Hydratase; Pro-Opiomelanocortin | 2003 |
Relationship of leptin and insulin-like growth factor I to nutritional status in hemodialyzed children.
Malnutrition is prevalent in patients with end-stage renal disease (ESRD). Elevated serum leptin levels were thought to contribute to the anorexia and poor nutrition in renal failure. However, studies of the relationship between nutritional status and leptin concentration in chronic renal failure have yielded conflicting results. Plasma insulin-like growth factor I (IGF-I) level has been used as an indicator of nutritional status in patients with renal failure. The relationship between leptin and IGF-I is controversial. The present study was conducted with the aim of assessing the relationship between nutritional status, hyperleptinemia, and serum IGF-I. Seventeen ESRD patients (8 male, 9 female), aged 8-18 years (mean 15.3+/-3.3 years) and undergoing standard hemodialysis for 58.8+/-23.1 months were enrolled. Nine age-matched healthy children served as controls. In all patients, energy and protein intakes were 40-70 kcal/kg per day and 1-1.54 g/kg per day, respectively. Predialysis serum leptin and IGF-I levels were measured by radioimmunoassay. Body mass index was decreased in 13 (76%) patients. Triceps skinfold thickness (TST) was reduced (below the 5th percentile) in 7 (41%), whereas mid arm circumference and mid arm muscle circumference were reduced in 14 (82.5%) and 13 (76.5%), respectively. The median serum leptin level was significantly higher in patients than in controls [13.7 interquartile range (IQR) 30.50 pg/ml vs. 6.50 IQR 8.65 pg/ml, P=0.01]. The median serum IGF-I level was lower in the patients (205.1 ng/ml IQR 194.4 ng/l) than controls (418.0 ng/l IQR 310.5 ng/ml) ( P=0.01). IGF-I levels were more decreased in patients with severe malnutrition, defined according to TST (145.0 ng/ml IQR 125.5 ng/l) than patients without malnutrition (301.2 ng/l IQR 218.8 ng/ml) ( P=0.03) and healthy children ( P=0.002). Although statistically not significant, IGF-I levels tended to be decreased, while leptin levels were increased. The median plasma insulin concentration was 15 microU/ml (1.63-45.80) and did not correlate with leptin and IGF-I levels. In conclusion, the results of this study confirm the presence of high circulating plasma leptin levels, which may be one of the many factors involved in the pathogenesis of the malnutrition in children on hemodialysis. Topics: Adolescent; Anthropometry; Arm; Biomarkers; Blood Urea Nitrogen; Body Mass Index; Body Weight; Child; Creatinine; Female; Humans; Insulin; Insulin-Like Growth Factor I; Kidney Failure, Chronic; Leptin; Male; Nutritional Status; Protein-Energy Malnutrition; Renal Dialysis; Skinfold Thickness | 2003 |
Interaction between estradiol replacement and chronic stress on feeding behavior and on serum leptin.
Exposure to stress may cause either an increase or a decrease in food intake. Behavioral and physiological responses to stress, including alterations in feeding behavior, are sexually dimorphic. This study aimed to evaluate the interaction between estradiol levels and chronic variate stress on the intake of sweet food and on serum levels of leptin, a hormone secreted by the adipose cells with a role in the regulation of body weight. Adult female Wistar rats were used. After ovariectomy, the animals received estradiol replacement (or oil) subcutaneously. Rats were then divided in controls and stressed (submitted to 30 days of variate stress). Consumption of sweet food and of serum leptin was measured. Although animals receiving estradiol replacement presented smaller weight gain, they showed an increased consumption of sweet food. Chronic variate stress decreased sweet food intake at 30, but not at 20, days of treatment. Estradiol replacement in the stressed group prevented both the reduction observed in sweet food intake and the increase in leptin levels. These results suggest that there is an interaction between chronic stress and estradiol replacement in feeding behavior concerning sweet food consumption, and this interaction may be related to altered leptin levels. Topics: Animals; Body Weight; Chronic Disease; Estradiol; Estrogen Replacement Therapy; Feeding Behavior; Female; Food Preferences; Leptin; Ovariectomy; Rats; Rats, Wistar; Stress, Psychological; Weight Gain | 2003 |
Effect of oxalomalate on lipid metabolism and antioxidant defense system in rats.
The metabolic functions of NADP(+)-specific isocitrate dehydrogenase (ID2), which may participate in the production of NADPH and biosynthesis of fatty acids, are not yet clearly understood. Accordingly, the current study investigated the effect of oxalomalate, known as a competitive inhibitor of ID2 in vitro, on lipid metabolism and the cellular defense system in vivo. Male Sprague Dawley rats (3 weeks old) were divided into two groups, fed a pelletized AIN-76 semisynthetic diet for 8 weeks, and injected intraperioneally with either saline or oxalomalate (25 mg/kg BW) dissolved in saline every 2 days. Oxalomalate did not lower the body weight and adipose tissue weight significantly; however, it significantly lower the plasma leptin concentration (p < 0.000), plasma and hepatic triglyceride levels (p < 0.01, p < 0.05), and adipocyte lipoprotein lipase activity (p < 0.01) compared to the control group. Meanwhile, hepatic antioxidant enzyme activities, except for superoxide dismutase activity (p < 0.01), glutathione content, and thiobarbituric acid reactive substances levels were not significantly different between the groups. Therefore, the current data suggests that oxalomalate produces a triglyceride-lowering activity and play a possible inhibitory role in fat accumulation. Furthermore, it was not found to affect the most antioxidative enzyme activities, glutathione content, and thiobarbituric acid reactive substances levels in rats fed normal diet. Topics: Adipose Tissue; Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Catalase; Glutathione; Injections, Intraperitoneal; Leptin; Lipoprotein Lipase; Liver; Male; Organ Size; Oxalates; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Triglycerides | 2003 |
Long-term control of food intake and body weight by hydrodynamics-based delivery of plasmid DNA encoding leptin or CNTF.
Obesity contributes to many common diseases, including cardiovascular and metabolic disorders such as diabetes, hypertension, and stroke. Leptin and ciliary neurotrophic factor (CNTF), two members of the cytokine family, play important roles in controlling food intake and body weight in rodents. Here, we used the hydrodynamics-based gene delivery technique to introduce leptin and CNTF expression plasmids, pCAGGS-leptin and pCAGGS-CNTF, into mice and to assess whether they could induce high expression of leptin or CNTF and reduce food intake and body weight in the mice.. Plasmid DNA (50 microg) in lactated Ringer's solution (0.1 ml/g body weight) was rapidly injected into the tail vein of 4-week-old male MCH-ICR mice.. After a single injection, serum leptin peaked (at 32.0 +/- 3.1 ng/ml) 2 days after the injection, and serum CNTF peaked (at 22.0 +/- 0.8 microg/ml) 1 day after the injection. The high expression of either leptin or CNTF was sustained and dramatically reduced food intake (CNTF and leptin group vs. control group; 2.3 +/- 0.5 and 3.1 +/- 0.5 g/day vs. 4.8 +/- 0.6 g/day; p < 0.001) and body weight (3 weeks after the injection; CNTF and leptin group vs. control group; -19.5% and +3.3% vs. +33.3-47.5%; p < 0.001) in the mice, suggesting potent in vivo activities for these exogenously expressed proteins.. These results suggest that hydrodynamics-based gene delivery could have broad applications in the study of appetite regulation and metabolism. Topics: Animals; Blotting, Western; Body Weight; Ciliary Neurotrophic Factor; Disease Models, Animal; Eating; Gene Expression; Genetic Therapy; Immunoenzyme Techniques; Leptin; Male; Mice; Mice, Inbred ICR; Obesity; Plasmids; Reverse Transcriptase Polymerase Chain Reaction | 2003 |
Plasma leptin levels in children with cyanotic and acyanotic congenital heart disease and correlations with growth parameters.
Leptin has been shown to be an integral component of energy homeostasis and regulation of body weight. Leptin regulates adipose tissue mass and correlates with the fat mass, however the circulating levels are altered by energy intake. Research on the physiological function of leptin has primarily focused on its role in the pathogenesis of obesity. However, its role in the negative energy imbalance is unclear. Increased energy expenditure is a primary factor in the reduced growth in infants with cyanotic congenital heart disease. The objective of this study was to examine the possible role of leptin on growth and nutrition in children with cyanotic and acyanotic congenital heart disease.. In this study, plasma leptin levels, nutritional and growth status were evaluated in 28 cyanotic and 20 acyanotic patients with congenital heart disease. Although standard deviation (S.D.) of height (P<0.01), mid arm circumference (MAC) (P<0.001) and body mass index (BMI) (P<0.05) were significantly low in cyanotic group, plasma leptin levels were similar. Energy intake was high in cyanotic group. In both cyanotic and acyanotic group, plasma leptin levels were correlated with BMI (R: 0.388, P<0.05 and R: 0.789, P<0.001, respectively). In addition, leptin levels were significantly correlated with the height (R: 0.415, P<0.05), MAC (R: 0.482, P<0.05) and BMI (R: 0.377, P<0.05) S.D. in cyanotic subjects.. Our results suggest that the leptin regulating axis is intact in cyanotic patients and leptin does not contribute to the cachexia of cyanotic heart disease. Topics: Adolescent; Body Height; Body Mass Index; Body Weight; Cachexia; Child; Child, Preschool; Cyanosis; Energy Metabolism; Heart Defects, Congenital; Humans; Leptin; Nutritional Status | 2003 |
Changes in adipokine expression during food deprivation in the mouse and the relationship to fasting-induced insulin resistance.
We investigated the changes in insulin resistance and adipose tissue expression of the adipokines resistin, adiponectin, and leptin and the transcription factors peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and retinoid X receptor-alpha (RXR-alpha) during 48 h of food deprivation. Insulin sensitivity (SI) declined, whereas glucose effectiveness (SG) increased. Plasma adiponectin levels declined in the first 8 h and remained constant thereafter. There was no correlation between either SI or SG and adiponectin protein or mRNA levels. PPAR-gamma mRNA abundance remained constant, whereas leptin and resistin mRNAs and plasma leptin declined and RXR-alpha mRNA abundance increased in both white and brown fat. Leptin mRNA abundance was closely correlated with SI (R2 = 0.91 and 0.87 for white and brown fat, respectively). Resistin mRNA abundance correlated inversely with SG (R2 = 0.99 and 0.84 for white and brown fat, respectively). These data indicate that changes in the expression of leptin are more closely correlated with the insulin resistance of fasting than with changes in other adipokines or RXR-alpha and PPAR-gamma expression. Topics: Adiponectin; Adipose Tissue; Adipose Tissue, Brown; Animals; Blood Glucose; Body Weight; Fasting; Food Deprivation; Hormones, Ectopic; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Proteins; Receptors, Cytoplasmic and Nuclear; Resistin; RNA, Messenger; Time Factors; Transcription Factors | 2003 |
Ghrelin and body weight regulation in the obese Zucker rat in relation to feeding state and dark/light cycle.
Ghrelin is a new orexigenic peptide primarily produced by the stomach but also present in the hypothalamus. It has adipogenic effects when it is chronically injected in rodents but in obese humans, its plasma concentration is decreased. It can reverse the anorectic effects of leptin when it is co-injected with this peptide in the brain ventricles. The Zucker fa/fa rat is a genetic model of obesity related to a default in the leptin receptor. It is characterized by a large dysregulation of numerous hypothalamic peptides but the ghrelin status of this rat has not yet been determined. Through several experiments, we determine in lean and obese Zucker rats its circulating form in the plasma, its tissue levels and/or expression, and studied the influence of different feeding conditions and its light/dark variations. Ghrelin expression was higher in the obese stomach and hypothalamus (P < 0.05 and P < 0.02, respectively). The ratio of [Octanoyl-Ser3]-ghrelin (active form) to [Des-Octanoyl-Ser3]-ghrelin (inactive form) was approximately 1:1 in the stomach and 2:1 in the plasma in lean and obese rats (no differences). After fasting, plasma ghrelin concentrations increased significantly in lean (+ 64%; P < 0.001) and obese (+ 60%; P < 0.02) rats. After 24 hours of refeeding, they returned to their initial ad lib levels. Ghrelin concentrations were higher in obese rats by 69% (P < 0.005), 65% (P < 0.02), and 73% (P < 0.005) in the ad libitum, fast, and refed states respectively. These results indicate that the obese Zucker rat is characterized by increases in the stomach mRNA expression and in peptide release in the circulation. They clearly support a role for ghrelin in the development of obesity in the absence of leptin signaling. Topics: Animals; Body Weight; Darkness; Eating; Fasting; Gastric Mucosa; Gene Expression Regulation; Ghrelin; Hypothalamus; Leptin; Light; Male; Peptide Hormones; Photoperiod; Radioimmunoassay; Rats; Rats, Zucker; RNA, Messenger; Stomach | 2003 |
Ghrelin concentrations in healthy children and adolescents.
In addition to its regulation by GH releasing hormone (GHRH) and somatostatin, release of GH from the pituitary is modulated by a third factor, ghrelin, which is expressed in high concentration in the stomach and is present in the circulation. Ghrelin has also been shown to cause weight gain by increasing food intake and decreasing fat utilization. Ghrelin is a potential candidate hormone to influence nutrient intake and growth. Its role through normal childhood and adolescence has not been fully defined.. Cross-sectional study in 121 healthy children (65 male, 56 female) aged 5-18 years, in whom height, weight, body mass index (BMI), pubertal status and measurements of IGF-I, IGFBP-3, IGFBP-1 and leptin were available.. Serum ghrelin concentrations have been measured in radioimmunoassay (RIA; Phoenix, AZ, USA) that detects active and inactive human ghrelin. Relationships between ghrelin and anthropometric data and growth factors were assessed by correlation and regression analyses.. Ghrelin was detected in all samples, with a median concentration of 162 pg/ml, range 60-493 pg/ml. Prepubertal children had higher ghrelin concentrations than those in puberty [218 pg/ml (n = 42) and 157 pg/ml (n = 79), P < 0.001], with significant negative correlations between ghrelin and age (rs = -0.39, P < 0.001) and pubertal stage (rs = -0.42, P < 0.001). The decrease in ghrelin with advancing pubertal stage/age was more marked in boys than girls. In the whole group, ghrelin was negatively correlated to BMI SD (rs = -0.24, P = 0.006) and to weight SD (rs = -0.24, P = 0.008) but not height sds. Ghrelin was also negatively correlated to IGF-I (rs = -0.48, P < 0.001), IGFBP-3 (rs = -0.32, P < 0.001) and leptin (rs = -0.22, P = 0.02) but not IGF-II. It was positively related to IGFBP-1 (rs = +0.46, P < 0.001). In stepwise multiple regression, 30% of the variability in ghrelin through childhood could be accounted for by log IGF-I (24%) and log IGFBP-1 (6%).. The fall in ghrelin over childhood and with puberty does not suggest that it is a direct growth-promoting hormone. However in view of the negative relationship with IGF-I and the positive relationship with IGFBP-1, this fall in ghrelin could facilitate growth acceleration over puberty. Topics: Adolescent; Adult; Age Factors; Body Mass Index; Body Weight; Child; Child, Preschool; Cross-Sectional Studies; Female; Ghrelin; Humans; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Linear Models; Male; Peptide Hormones; Puberty; Sex Factors; Statistics, Nonparametric | 2003 |
Effects of agouti-related protein on metabolism and hypothalamic neuropeptide gene expression.
The hypothalamic melanocortin system regulates feeding in part through interaction of the appetite stimulating peptide, agouti-related protein (AGRP), and the anorectic peptide, alpha-melanocyte stimulating hormone, a peptide derived from the pro-opiomelanocortin (POMC) polyprotein. Central administration of AGRP induces hyperphagia and increased gain in body weight in rodents, but may also exert metabolic effects even when hyperphagia is prevented. In the present studies, the effects of AGRP on hypothalamic neuropeptide gene expression and metabolism were examined in the rat. Central administration of AGRP for 3- and 7-day periods resulted in hyperphagia, increased body weight and increased plasma leptin and insulin concentrations compared to saline-injected controls. Hypothalamic concentrations of Pomc mRNA were also increased by 27% and 44% (in 3- and 7-day experiments, respectively). The hypothalamic concentration of Agrp mRNA was unchanged after 3 days, but was significantly decreased by 33% after 7 days of AGRP infusion. To determine if these changes were dependent upon AGRP-induced hyperphagia, pair-fed rats with restricted food intake receiving central administration of AGRP were also studied. In the absence of hyperphagia, intracerebralventricular administration of AGRP caused significant increases in plasma leptin and insulin concentrations (two-fold and 1.5-fold, respectively) and fat pad mass. A significant increase in hypothalamic Pomc mRNA concentrations was not detected in pair-fed rats. In contrast, Agrp mRNA concentrations remained suppressed by 45% in the pair-fed group after 7 days of AGRP infusion despite equal body weight compared to saline controls. The ratio of hypothalamic Pomc to Agrp mRNA was elevated two-fold in ad libitum and pair-fed AGRP-injected rats, which is consistent with increased stimulation of central melanocortin signalling pathways. Thus, central administration of AGRP exerts changes in hypothalamic neuropeptide gene expression and metabolic effects that are independent of the effects on food intake and body weight. Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Energy Metabolism; Food Deprivation; Gene Expression; Injections, Intraperitoneal; Injections, Intraventricular; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Peptide Fragments; Pro-Opiomelanocortin; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2003 |
Monounsaturated n-9 fatty acids and adipocyte lipolysis in rats.
To investigate the role of the monounsaturated n-9 fatty acids (MUFA) in the lipolytic activity of adipocytes, a study was carried out in which an increase in MUFA was produced in the tissues by two different methods; by the dietary enrichment of oleic acid or by producing an essential fatty acid deficiency syndrome. For this, forty-five male Sprague-Dawley rats were fed with a normal-energy diet and were subdivided into three groups. The diets varied in the type of dietary fat; palmitic acid, olive oil, or soyabean oil+palmitic acid. At the end of the study measurements were taken of weight, plasma leptin, tissue concentration of fatty acids, fat-cell size in the epididymal and the omental adipose tissues, adipocyte lipolytic activity of both tissues after stimulation with adrenaline, and the capacity of insulin to inhibit lipolysis. The baseline and adrenaline-stimulated lipolytic activity were greater and the anti-lipolytic capacity of insulin lower in the animals undergoing an increase in MUFA in the tissues (palmitic-acid and olive-oil diets). The area under the curve of glycerol, used as an indicator of lipolytic activity, was positively correlated with the concentration of MUFA and negatively with polyunsaturated fatty acids in the adipose tissues. It is concluded that an increase in tissue MUFA, however obtained, induces an increase in lipolytic activity. Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Cells, Cultured; Diet; Dietary Fats, Unsaturated; Dose-Response Relationship, Drug; Epinephrine; Fatty Acids, Monounsaturated; Insulin; Leptin; Linear Models; Lipolysis; Male; Oleic Acid; Rats; Rats, Sprague-Dawley; Weight Gain | 2003 |
Overexpression of leptin in transgenic mice leads to decreased basal lipolysis, PKA activity, and perilipin levels.
Transgenic mice overexpressing leptin (LepTg) exhibit substantial reductions in adipose mass. Since the binding of leptin to its receptor activates the sympathetic nervous system, we reasoned that the lean state of the LepTg mice could be caused by chronic lipolysis. Instead, the LepTg mice exhibited a low basal lipolysis state and their lean phenotype was not dependent on the presence of beta3-adrenergic receptors. In their white adipose tissue, protein levels of protein kinase A, hormone-sensitive lipase, and ADRP were not impaired. However, compared to normal mice, perilipin, perilipin mRNA, and cAMP-stimulated PKA activity were significantly attenuated. Overall, we demonstrate that the lean phenotype of the LepTg mice does not result in a chronically elevated lipolytic state, but instead in a low basal lipolysis state characterized by a decrease in perilipin and PKA activity in white fat. Topics: Adipose Tissue; Aging; Animals; Body Weight; Carrier Proteins; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Enzyme Activation; Fatty Acids, Nonesterified; Female; Gene Expression Regulation; Glycerol; Leptin; Lipolysis; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Perilipin-1; Perilipin-2; Phosphoproteins; Receptors, Adrenergic, beta-3; Receptors, Leptin; Sex Factors; Signal Transduction | 2003 |
Modulatory effects of leptin on leydig cell function of normal and hyperleptinemic rats.
Neonatal L-monosodium glutamate (MSG) administration in rats induces several neuroendocrine and metabolic disruptions. Leptin, the adipocyte product, modulates several neuroendocrine systems including the hypothalamic-pituitary-gonadal (HPG) axis in mammals. The aim of the present study was to determine whether MSG-induced chronic hyperleptinemia could play any relevant role in the hypogonadism developed by male rats when examined in adulthood. We found that 120-day-old MSG male rats displayed significant hyperleptinemia, hypogonadism, and undisturbed basic testis structure and spermatogenesis. In vitro studies in purified Leydig cells from normal (CTR) and MSG-damaged rats revealed that basal and human chorionic gonadotropin (hCG)-stimulated 17-hydroxy-progesterone (17-HO-P(4)), Delta(4)-androstenedione (Delta(4)A) and testosterone (T) secretions were significantly lower in MSG than in CTR cells. Exposure to murine leptin (Mleptin, 10(-8)M) significantly inhibited hCG-elicited T secretion by CTR cells after 180 min incubation. While Mleptin significantly inhibited hCG-stimulated Delta(4)A output and the Delta(4)A:17-OH-P(4) ratio of secretion, conversely, it failed to modify the ratio T:Delta(4)A release by CTR Leydig cells. Interestingly, the effects of Mleptin found on CTR Leydig cells were absent in MSG Leydig cells. Finally, endogenous hyperleptinemia was associated with a significant decrease in Leydig cell expression of Ob-Rb mRNA in MSG rats. In summary, this study demonstrates that: (1) Mleptin inhibited testicular steroidogenesis in CTR rats; (2) MSG-treated rats showed lower in vitro 17-OH-P(4), Delta(4)A and T production under basal and post-hCG stimulation conditions; (3) purified Leydig cells from MSG-treated rats displayed resistance to the inhibitory action of Mleptin on T release, and (4) endogenous leptin exerts a modulatory effect on Leydig cell Ob-Rb mRNA expression. The inhibitory effect of leptin on testicular function is thus abrogated in MSG-damaged rats. The testicular leptin-resistance developed by MSG rats seems to be due to early chronic exposure of Leydig cells to high leptin circulating levels, which in turn down-regulate testicular Ob-Rb expression. It remains to be determined whether the testicular dysfunction of MSG rats can be reversed after correction of hyperleptinemia or whether it is an irreversible effect of the hypothalamic lesion. Topics: Analysis of Variance; Androstenols; Animals; Animals, Newborn; Blotting, Northern; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Follicle Stimulating Hormone; Hypogonadism; Leptin; Leydig Cells; Luteinizing Hormone; Male; Mice; Organ Size; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium Glutamate; Testis; Testosterone; Thyroxine | 2003 |
[Serum concentration of leptin and resistin in girls during puberty].
The aim of this study was to find the link, if any between leptin, resistin and amount of adipose tissue in girls during puberty.. Forty six healthy girls aged 9, 8-15, 4 took part in this study, from which 12 were after menarche. Height, weight, body mass index, arm circumference and thickness of skin-fold were assessed. Serum concentrations of estradiol, FSH, LH, insulin, leptin and resistin were estimated.. As it was expected, girls before menarche were younger, smaller, lighter, had smaller BMI, arm circumference and serum concentration of sex hormones than those after menarche. No significant differences between skinfold thickness on abdomen and at triceps site as well as between serum leptin (4, 88 +/- 4, 16 ng/ml in girls before menarche, 6.56 +/- 5.15 ng/ml), were found. The concentrations of insulin occurred to be similar, too. No correlations between serum resistin and insulin concentration as well as between serum resitin and leptin concentration were noticed, either. The existence of high positive correlations between leptin concentration and skin-fold thickness was confirmed but the correlation between resistin concentration and skinfold thickness was not proved. Interdependences between the serum concentrations of leptin, resistin and sex hormones were not found, either. Topics: Adipose Tissue; Adolescent; Body Composition; Body Constitution; Body Mass Index; Body Weight; Child; Female; Hormones, Ectopic; Humans; Insulin; Leptin; Puberty; Resistin | 2003 |
Dose- and time-dependent effects of a novel (-)-hydroxycitric acid extract on body weight, hepatic and testicular lipid peroxidation, DNA fragmentation and histopathological data over a period of 90 days.
(-)-Hydroxycitric acid (HCA), a natural extract from the dried fruit rind of Garcinia cambogia (family Guttiferae), is a popular supplement for weight management. The dried fruit rind has been used for centuries as a condiment in Southeastern Asia to make food more filling and satisfying. A significant number of studies highlight the efficacy of Super CitriMax (HCA-SX, a novel 60% calcium-potassium salt of HCA derived from Garcinia cambogia) in weight management. These studies also demonstrate that HCA-SX promotes fat oxidation, inhibits ATP-citrate lyase (a building block for fat synthesis), and lowers the level of leptin in obese subjects. Acute oral, acute dermal, primary dermal irritation and primary eye irritation toxicity studies have demonstrated the safety of HCA-SX. However, no long-term safety of HCA-SX or any other (-)-hydroxycitric acid extract has been previously assessed. In this study, we have evaluated the dose- and time-dependent effects of HCA-SX in Sprague-Dawley rats on body weight, hepatic and testicular lipid peroxidation, DNA fragmentation, liver and testis weight, expressed as such and as a % of body weight and brain weight, and histopathological changes over a period of 90 days. The animals were treated with 0, 0.2, 2.0 and 5.0% HCA-SX as feed intake and the animals were sacrificed on 30, 60 or 90 days of treatment. The feed and water intake were assessed and correlated with the reduction in body weight. HCA-SX supplementation demonstrated a reduction in body weight in both male and female rats over a period of 90 days as compared to the corresponding control animals. An advancing age-induced marginal increase in hepatic lipid peroxidation was observed in both male and female rats as compared to the corresponding control animals. However, no such difference in hepatic DNA fragmentation and testicular lipid peroxidation and DNA fragmentation was observed. Furthermore, liver and testis weight, expressed as such and as a percentage of body weight and brain weight, at 30, 60 and 90 days of treatment, exhibited no significant difference between the four groups. Taken together, these results indicate that treatment of HCA-SX over a period of 90 days results in a reduction in body weight, but did not cause any changes in hepatic and testicular lipid peroxidation, DNA fragmentation, or histopathological changes. Topics: Animals; ATP Citrate (pro-S)-Lyase; Body Weight; Citrates; DNA Fragmentation; Dose-Response Relationship, Drug; Female; Leptin; Lipid Peroxidation; Liver; Male; Rats; Rats, Sprague-Dawley; Testis; Time Factors | 2003 |
Hypothalamic neuropeptide Y/Y1 receptor pathway activated by a reduction in circulating leptin, but not by an increase in circulating ghrelin, contributes to hyperphagia associated with triiodothyronine-induced thyrotoxicosis.
Food intake is regulated by hypothalamic neuropeptides which respond to peripheral signals. Plasma ghrelin and leptin levels reflect peripheral energy balance and regulate hypothalamic neuropeptides such as neuropeptide Y (NPY), pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and orexins. Thyroid hormone stimulates food intake in humans and rodents. However, the mechanisms responsible for this stimulation have not been fully elucidated. To investigate the hyperphagic response to triiodothyronine (T(3))-induced thyrotoxicosis, adult male rats were studied 7 days after daily intraperitoneal injections of T(3) or vehicle. T(3)-treated rats were markedly hyperphagic. During this hyperphagia, plasma leptin levels were markedly decreased. However, the expression of the ghrelin gene in the stomach and the plasma ghrelin concentrations did not differ between the 2 groups. Hypothalamic NPY mRNA levels were significantly increased and associated with a marked decreased in both hypothalamic POMC and CART mRNA levels in the T(3)-treated rats. Hypothalamic MCH and orexin mRNA levels did not differ between the 2 groups. In addition, hyperphagia was partially reversed by intracerebroventricular administration of the NPY Y1 receptor antagonist BIBO3304. Therefore, the decreased plasma leptin levels could contribute to hyperphagia in T(3)-induced thyrotoxicosis. However, plasma ghrelin levels did not contribute to this hyperphagia. Topics: Animals; Arginine; Body Weight; Eating; Energy Metabolism; Gastric Mucosa; Gene Expression; Ghrelin; Hyperphagia; Hypothalamus; Leptin; Male; Nerve Tissue Proteins; Neuropeptide Y; Peptide Hormones; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Thyrotoxicosis; Triiodothyronine | 2003 |
Future directions in weight control. Molecular and genetic discoveries pave the way.
Obesity is the result of a long-standing imbalance between energy intake and energy expenditure, aided by a complex biologic system that regulates appetite and favors intake. New knowledge about substances that stimulate or inhibit appetite offers hope that drug-based solutions will be found for the current high prevalence of obesity in the United States. In this article, Dr Bessesen highlights some of the new molecular and genetic discoveries related to obesity and outlines the hypothalamic neural pathways involved in regulating food intake. Topics: Animals; Appetite; Body Weight; Energy Intake; Energy Metabolism; Humans; Leptin; Obesity | 2003 |
The effect of leptin, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) production on insulin resistance in Otsuka Long-Evans fatty rats.
Adipocytokines and nitric oxide (NO) play important roles in type 2 diabetes; however, the regulatory mechanism has not been fully clarified. To investigate the role of adipocytokines and NO production on insulin resistance in type 2 diabetes, the LETO rats and the OLETF rats were fed a control diet or a high-fat diet for 4 weeks. After 4 weeks the blood levels of leptin, tumor necrosis factor-alpha (TNF-alpha), and NO were measured. As an indicator of insulin resistance, the homeostasis model assessment for insulin resistance (HOMA-R) was applied. Food intake in high-fat diet group rats was lower than in control diet group rats. The high fat diet increased body weight (BW), but did not significantly affect the HOMA-R and blood pressure (BP). Leptin and TNF-alpha levels were significantly higher in the OLETF rats than in the LETO rats, while NO levels did not change between the two groups. The high-fat diet elevated blood leptin levels, but not TNF-alpha and NO levels. The HOMA-R in the OLETF rats was correlated with leptin, but not with BP, BW, TNF-alpha or NO. NO showed an inverse correlation with BP. In conclusion, leptin, TNF-alpha, and NO may each regulate insulin sensitivity through their own unique pathways. The elucidation of the regulatory mechanism of adipocytokines and NO may give a clue to clarify the pathophysiology of insulin resistance. Topics: Adipose Tissue; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Eating; Energy Intake; Homeostasis; Insulin; Insulin Resistance; Leptin; Male; Nitric Oxide; Organ Size; Random Allocation; Rats; Rats, Inbred OLETF; Rats, Inbred Strains; Systole; Tumor Necrosis Factor-alpha | 2003 |
Effects of exercise training on glomerular structure in fructose-fed spontaneously hypertensive rats.
A high-fructose diet (HFD) has been shown to elevate blood pressure (BP) and to decrease insulin sensitivity in rats. Although running exercise can attenuate these phenomena, its effect on target organ protection is not clear. We investigated whether exercise training has renal protective effects in this model. Nine-week-old spontaneously hypertensive rats were allocated to groups that received HFD or a control diet (control group) for 15 weeks. At the age of 10 weeks, fructose-fed rats were allocated to groups that were given vehicle (FRU group), temocapril, an angiotensin converting enzyme inhibitor (TEM group), exercise training (EX group; treadmill running), or temocapril plus exercise training (TEM+EX group). BP was higher in the FRU group than in the control group. Exercise training tended to decrease BP and temocapril treatment decreased BP significantly. Proteinuria was similar in the five groups. Plasma leptin concentration and epididymal fat weight were lower in the EX and TEM+EX groups than in the FRU group. In the soleus muscle of the FRU group, the composite ratio of type I fiber was decreased and that of type IIa fiber was increased compared with those in the control group. Both temocapril and exercise training restored these ratios. The glomerular sclerosis index (GSI) was higher in the FRU group than in the control group. GSI was decreased equally in the TEM, EX, and TEM+EX groups and was positively correlated with plasma leptin concentration. The results suggest that exercise training ameliorates glomerular sclerosis through mechanisms other than a reduction in BP. Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Composition; Body Weight; Diet; Fructose; Glomerulosclerosis, Focal Segmental; Hypertension; Kidney Glomerulus; Leptin; Male; Muscle Fibers, Skeletal; Muscle, Skeletal; Organ Size; Physical Conditioning, Animal; Proteinuria; Rats; Rats, Inbred SHR; Thiazepines | 2003 |
Effects of zinc deficiency and supplementation on the glycogen contents of liver and plasma lactate and leptin levels of rats performing acute exercise.
The aim of the present study was to investigate how zinc (Zn) deficiency and supplementation affect glycogen content of the liver and plasma lactate and leptin levels of rats performing acute swimming exercise just before the blood samples were obtained. Four sets of 10 rats each served as the (1) Zn-deficient group, (2) Zn-supplemented group, (3) swimming controls, and (4) normal controls. Plasma lactate levels of Zn-deficient animals were significantly higher than those in the other three groups (p<0.01), and those in the swimming controls (group 3) were significantly higher than in the Zn-supplemented animals, group 2 (p<0.01). The plasma glucose of the Zn-deficient group was significantly higher than all other groups (p<0.01) and that of group 2 was significantly lower than group 4 (p<0.01). Glycogen levels in liver of the Zn-deficient animals was significantly lower than groups 2 and 4 (p<0.01), and, in turn, were higher than for group 3 (p<0.01). The plasma leptin and Zn levels of group 1 were significantly lower than in all other groups (p<0.01). These results suggest that Zn deficiency exerts a negative influence in the above-mentioned parameters and that Zn supplementation has the opposite effect. Topics: Animals; Blood Glucose; Body Weight; Dietary Supplements; Glycogen; Lactic Acid; Leptin; Liver; Physical Conditioning, Animal; Plasma; Rats; Rats, Sprague-Dawley; Zinc | 2003 |
Atrophy of brown adipocytes in the adult mouse causes transformation into white adipocyte-like cells.
Adipose tissue is an important endocrine regulator of glucose metabolism and energy homeostasis. Researches have focused on this tissue not only as a target for pharmacotherapy of obesity and insulin resistance but also as an endocrine tissue with leptin secretion and high insulin sensitivity. Brown adipose tissue (BAT) additionally plays a unique role in thermoregulation through the mitochondrial uncoupling protein 1 (UCP1), which uncouples oxidative phosphorylation. As a genetic tissue ablation model of BAT, we made transgenic mice expressing herpes simplex virus thymidine kinase (HSV-TK) driven by the brown adipocyte- specific UCP1 minimal regulatory element. The HSV-TK transgene was expressed specifically in BAT and more than 35% increase of apoptosis was induced by ganciclovir (GCV) treatment. Nevertheless, the expression level was not high enough to induce BAT ablation in GCV-treated adult mice. Importantly, however, we found that brown adipocytes in the periphery of interscapular BAT were transformed into white adipocyte-like unilocular cells. These cells express white adipocyte-specific leptin protein but are different in the ultrastructure of mitochondria from classical white adipocytes. Our data indicates that atrophy of BAT causes transformation into white adipocyte-like cells in the adult mouse and also suggests that further molecular understanding of adipocyte plasticity using our transgenic mouse model might be beneficial for the development of anti-obesity/anti-diabetic therapies. Topics: Adipose Tissue; Aging; Animals; Body Weight; Carrier Proteins; Cell Differentiation; Ganciclovir; Ion Channels; Leptin; Membrane Proteins; Mice; Mice, Transgenic; Mitochondrial Proteins; Obesity; Organ Specificity; Thymidine Kinase; Uncoupling Protein 1 | 2003 |
Partial reversal of cachexia by beta-adrenergic receptor blocker therapy in patients with chronic heart failure.
Cachexia is a common problem in chronic heart failure (CHF) that may be partly mediated by activation of the sympathetic nervous system. The effects of beta-adrenergic receptor blocker (BB) therapy on body weight in cachectic and noncachectic subjects with CHF has not been previously reported.. Body weight and plasma norepinephrine, leptin, and insulin levels were measured in 27 subjects with CHF before and after 6 months of beta-adrenergic receptor blockade with carvedilol or long-acting metoprolol. Before BB therapy, baseline weight, plasma leptin, and plasma insulin levels did not differ between cachectic and noncachectic subjects. Baseline plasma norepinephrine levels were increased in cachectic subjects when compared with noncachectic subjects (930+/-248 pg/mL versus 503+/-109 pg/mL, P=.063). After 6 months of BB therapy, subjects with baseline cachexia demonstrated significantly greater weight gain (+5.2+/-9.6 versus +0.8+/-5.0 kg, P=.027), greater increase in plasma leptin levels (+3.7+/-3.9 versus +1.2+/-4.3 ng/mL, P=.030), and greater decrease in plasma norepinephrine levels (-374+/-261 versus -41+/-122 pg/mL, P=.012) when compared with noncachectic subjects.. Six months of BB therapy with carvedilol or long-acting metoprolol is associated with differential effects on body weight and hormonal levels in cachectic and noncachectic subjects with CHF. Further work is needed to determine the role the sympathetic nervous system in the pathogenesis of cachexia in patients with CHF. Topics: Adrenergic beta-Antagonists; Biomarkers; Blood Pressure; Body Weight; Cachexia; Carbazoles; Carvedilol; Chronic Disease; Female; Heart Failure; Heart Rate; Humans; Insulin; Leptin; Male; Metoprolol; Middle Aged; Norepinephrine; Propanolamines; Prospective Studies; Severity of Illness Index; Stroke Volume; Treatment Outcome | 2003 |
Effect of non-digestible gluco-oligosaccharides on glucose sensitivity in high fat diet fed mice.
Non digestible dietary carbohydrates have been reported to modify lipaemia and post-prandial glycaemia and insulinaemia. The aim of this study was to investigate the effect of a non-digestible gluco-oligosaccharides (GOS) diet on glucose, insulin, triglycerides and free fatty acid blood levels and glucose sensitivity in high fat diet fed mice (a high fat diet composed of 45% fat, 35% carbohydrate and 20% protein). Female C57B16/J mice were divided into two groups fed a high fat diet (HF) for 20 weeks supplemented or not with 1.5 g/kg/day of GOS (HF-GOS). The GOS supplementation did not change body weight nor fat pad mass, nor any of the blood parameters measured (glucose, insulin, leptin, triglycerides, and free fatty acids). However, mice which received the GOS supplemented diet showed an increased glucose utilization after a 1 g/kg load of glucose compared with the mice fed the high fat diet alone. Our results suggest a role for non-digestible GOS in the regulation of carbohydrate metabolism. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Dietary Fats; Fatty Acids, Nonesterified; Female; Glucose; Glucose Tolerance Test; Insulin; Leptin; Mice; Mice, Inbred C57BL; Oligosaccharides; Triglycerides | 2003 |
Leptin and soluble leptin receptor in follicular fluid.
Previous studies suggest that follicular fluid leptin levels predict successful assisted reproduction. The relationship between intrafollicular leptin and the soluble leptin receptor, ovarian hormones, and oocyte quality was examined to determine potential factors contributing to this finding.. Follicular fluid leptin, soluble leptin receptor, hormones, and oocyte quality were examined in 84 individual follicles from 30 women undergoing in vitro fertilization.. Follicular fluid leptin and soluble leptin receptor levels correlated inversely with each other (r = -0.354; p = 0.001). Follicular fluid leptin levels correlated with intrafollicular estradiol (r = 0.42; p < 0.001), progesterone (r = 0.48; p < 0.001), and androstenedione (r = 0.49; p < 0.001), whereas soluble leptin receptor levels correlated with activin (r = 0.38; p < 0.001) and follistatin (r = 0.35; p < 0.002). There was no relationship between follicular fluid leptin or soluble leptin receptor levels and pretreatment serum hormone levels, stimulated serum estradiol, follicle number, oocyte quality, fertilization, or embryo grade.. The data demonstrate that leptin and the soluble leptin receptor are highly interrelated with each other and with other intrafollicular hormones, but not with markers of oocyte quality, fertilization, or embryo grade. Topics: Body Mass Index; Body Weight; Female; Follicular Fluid; Humans; Leptin; Receptors, Cell Surface; Receptors, Leptin; Reproductive Techniques, Assisted | 2003 |
Plasma leptin, insulin and free tryptophan contribute to cytokine-induced anorexia.
Cytokines contribute to anorexia of diseases. Tumor Necrosis Factor (TNF) and/or interleukin-1 (IL-1) stimulate leptin release, but not insulin. Both affect hypothalamus to decrease food intake (FI). Hypothalamic serotonin (5HT) decreases FI. Its synthesis depends on brain availability of precursor, tryptophan (TRP), which depends on plasma free TRP. Purpose is to test involvement of plasma leptin, insulin, TRP, and thus hypothalamic 5HT in cytokine-induced anorexia in rats. In male rats, IL-1alpha (10 mg/kg/d; n=9), TNFalpha (30 mg/kg/d; n=9), Il-1alpha+TNFalpha (10:30 mg/kg/d; n=9), TRP (100 mg/kg/d, n=8) and saline (n=8; Control) were injected sc for 2 days. FI, BW, plasma free and total TRP, leptin and insulin, and body fat were measured. Data analyzed via ANOVA. IL-1alpha and IL-1alpha+TNFalpha vs others decreased FI and BW. TNFalpha and TRP did not change FI and BW. Plasma total TRP was higher in TRP vs IL-1alpha, TNFalpha, and IL-1alpha+TNFalpha. Plasma free TRP was higher in IL-1alpha and IL-1alpha+TNFalpha vs Control. IL-1alpha and IL-1alpha+TNFalpha decreased leptin and body fat. Insulin in Control was lower than others. Data suggest: i) IL-1alpha increases plasma free TRP, but not total TRP, thus increases hypothalamic 5HT synthesis, resulting in anorexia; ii) leptin does not mediate anorexia, but; iii) insulin may contribute to anorexia induced by cytokines. Topics: Animals; Anorexia; Body Weight; Cytokines; Eating; Insulin; Interleukin-1; Leptin; Male; Rats; Rats, Inbred F344; Tryptophan; Tumor Necrosis Factor-alpha | 2003 |
Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance.
Insulin signaling in adipose tissue plays an important role in lipid storage and regulation of glucose homeostasis. Using the Cre-loxP system, we created mice with fat-specific disruption of the insulin receptor gene (FIRKO mice). These mice have low fat mass, loss of the normal relationship between plasma leptin and body weight, and are protected against age-related and hypothalamic lesion-induced obesity, and obesity-related glucose intolerance. FIRKO mice also exhibit polarization of adipocytes into populations of large and small cells, which differ in expression of fatty acid synthase, C/EBP alpha, and SREBP-1. Thus, insulin signaling in adipocytes is critical for development of obesity and its associated metabolic abnormalities, and abrogation of insulin signaling in fat unmasks a heterogeneity in adipocyte response in terms of gene expression and triglyceride storage. Topics: Adipocytes; Adiponectin; Adipose Tissue; Animals; Aurothioglucose; Body Weight; CCAAT-Enhancer-Binding Proteins; Cell Size; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Energy Metabolism; Female; Glucose; Glucose Intolerance; Glucose Transporter Type 1; Glucose Transporter Type 4; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Knockout; Monosaccharide Transport Proteins; Muscle Proteins; Obesity; Proteins; Receptor, Insulin; Sterol Regulatory Element Binding Protein 1; Transcription Factors; Ventromedial Hypothalamic Nucleus | 2002 |
Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss.
Leptin elicits a metabolic response that cannot be explained by its anorectic effects alone. To examine the mechanism underlying leptin's metabolic actions, we used transcription profiling to identify leptin-regulated genes in ob/ob liver. Leptin was found to specifically repress RNA levels and enzymatic activity of hepatic stearoyl-CoA desaturase-1 (SCD-1), which catalyzes the biosynthesis of monounsaturated fatty acids. Mice lacking SCD-1 were lean and hypermetabolic. ob/ob mice with mutations in SCD-1 were significantly less obese than ob/ob controls and had markedly increased energy expenditure. ob/ob mice with mutations in SCD-1 had histologically normal livers with significantly reduced triglyceride storage and VLDL (very low density lipoprotein) production. These findings suggest that down-regulation of SCD-1 is an important component of leptin's metabolic actions. Topics: Animals; Body Weight; Crosses, Genetic; Down-Regulation; Eating; Energy Metabolism; Female; Gene Expression; Gene Expression Profiling; Leptin; Lipid Metabolism; Lipids; Lipoproteins, VLDL; Liver; Male; Mice; Mice, Obese; Microsomes, Liver; Mutation; Oligonucleotide Array Sequence Analysis; Oxygen Consumption; RNA, Messenger; Stearoyl-CoA Desaturase; Vacuoles; Weight Loss | 2002 |
Leptin, ghrelin, and energy metabolism of the spawning burbot (Lota lota, L.).
The aim of this study was to investigate the energy metabolism of the burbot (Lota lota, n=38) before, during, and after spawning, which represents the greatest annual metabolic demand for the species. A decrease in body mass, relative weight of the livers, and glycogen concentration of the livers was observed toward the end of spawning. The prespawning period was characterized by high rates of liver glycogenolysis and lipid mobilization. Also, plasma triiodothyronine and sex steroid levels were high before reproduction. During spawning, liver lipolysis was reduced and muscle glycogenolysis stimulated. The levels of triiodothyronine and sex steroids decreased. After reproduction, liver glycogenolysis was suppressed and the rate of gluconeogenesis increased. Thyroid hormone levels were elevated after spawning. Leptin protein and a ghrelin-immunoreactive peptide were detected in burbot plasma. Their concentrations were relatively low before and during reproduction but increased after spawning. The functions of leptin and the ghrelin-immunoreactive peptide in the physiology of the burbot are not consistent with the models of their function in mammals. Topics: Animals; Body Mass Index; Body Weight; Energy Metabolism; Female; Fishes; Ghrelin; Glycogen; Leptin; Liver; Male; Peptide Hormones; Peptides; Reproduction | 2002 |
Attenuation of hypercholesterolemia and hyperglycemia in ob/ob mice by NPY Y2 receptor ablation.
Neuropeptide Y (NPY) is a 36 amino acid peptide well known for its role in regulating food intake and energy homeostasis. It has previously been shown that the NPY Y2 receptor is required for a full biological response to leptin in the central nervous system. We have examined the impact of this receptor on plasma levels of lipid and cholesterol in wild type and obese (ob/ob) mice. The results show that an absence of Y2 in female mice has no effect on cholesterol level in normal lean mice but profoundly decreases serum cholesterol and glucose levels in ob/ob mice. We conclude that NPY, interacting with the Y2 receptor, participates in cholesterol and glucose homeostasis of obese mice. Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Crosses, Genetic; Female; Hypercholesterolemia; Hyperglycemia; Leptin; Lipids; Lipoproteins; Mice; Mice, Inbred BALB C; Mice, Obese; Mice, Transgenic; Neuropeptide Y; Receptors, Neuropeptide Y; Temperature; Time Factors | 2002 |
Leptin-induced leptin resistance reveals separate roles for the anorexic and thermogenic responses in weight maintenance.
The purpose of this study was to determine whether leptin induces leptin resistance by examining the temporal attenuation of the anorexic and energy expenditure responses to leptin. We administered recombinant adeno-associated virus encoding rat leptin cDNA or control viral vector into mildly obese rats for 138 d and compared these results with those from pair-fed rats. We measured food consumption, body weight, oxygen consumption, leptin signal transduction, and brown adipose tissue uncoupling protein 1. The anorexic response attenuated by d 25, whereas the increase in energy expenditure persisted for 83 d before attenuating. Despite attenuation of physiological responses, phosphorylated signal transducer and activator of transcription-3 remained elevated for the duration of the study. The temporal differential attenuation of the anorexic and thermogenic responses allowed us to determine the relative contributions of each response to weight maintenance. The anorexic response predominantly mediated the initial loss of body weight, but only the energy expenditure response was necessary to maintain the reduced weight. This study provides evidence that leptin induces leptin resistance. The leptin resistance was associated with persistent elevation in hypothalamic phosphorylated signal transducer and activator of transcription-3 and was characterized by a rapid attenuation of the anorexic response and slower onset for the attenuation of the energy expenditure response. We propose that both elevated leptin and obesity may be necessary for the development of leptin resistance. Topics: Adipose Tissue, Brown; Animals; Body Weight; Carrier Proteins; Dependovirus; Eating; Energy Metabolism; Hypothalamus; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Rats; Rats, Inbred BN; RNA, Messenger; Signal Transduction; Uncoupling Protein 1 | 2002 |
Photoperiodic regulation of leptin resistance in the seasonally breeding Siberian hamster (Phodopus sungorus).
Seasonal Siberian hamsters lose fat reserves, decrease body weight and leptin concentrations, and suppress reproduction on short-day photoperiod (SD). Chronic leptin infusion at physiological doses caused body weight and fat loss in SD animals but was ineffective in long-day (LD) hamsters. Using ovariectomized estrogen-treated females, we tested the hypothesis that responsiveness to leptin is regulated by photoperiod. On SD, hypothalamic neuropeptide Y, agouti-related peptide, and cocaine- and amphetamine-regulated transcript gene expression in the arcuate nucleus did not exhibit significant changes, and despite SD-induced fat loss, the catabolic peptide proopiomelanocortin was down-regulated. Food restriction of LD-housed animals caused significant reduction of fat reserves and serum leptin concentrations to SD levels, suppressed serum gonadotropins, and induced increased anabolic (neuropeptide Y, agouti-related peptide) and decreased catabolic (proopiomelanocortin, cocaine- and amphetamine-regulated transcript) gene expression in the arcuate nucleus. Leptin infusion in food-restricted animals had no effect on fat reserves or gonadotropins and did not modulate neuropeptide gene expression. Also, leptin treatment did not blunt the refeeding responses or weight and fat gain in LD-housed food-restricted animals. In conclusion, our results strongly suggest that hypothalamic responses to leptin are regulated primarily by photoperiod, rather than seasonal changes in fat reserves, sex steroids, or leptin concentrations. Topics: Adipose Tissue; Agouti-Related Protein; Animals; Body Weight; Breeding; Cricetinae; Drug Resistance; Gene Expression; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Luteinizing Hormone; Nerve Tissue Proteins; Neuropeptide Y; Photoperiod; Pro-Opiomelanocortin; Proteins; Seasons | 2002 |
In vivo effects of bisphenol A on the polecat (mustela putorius).
Bisphenol A (BPA), an environmental estrogen derived from the plastic industry, was given orally via incorporation into the food of 30 male and female polecats at 3 different doses (10, 50, or 250 mg/kg body weight/day) for 2 wk with 10 animals acting as controls. Several hormone levels in the plasma were determined as well as the activities of the phase I and II biotransformation enzymes 7-ethoxyresorufin O-deethylase (EROD), cytosolic glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UDPGT). BPA did not cause any macroscopic effects on body mass or the health of the animals. UDPGT and GST activities increased significantly in direct correlation with increasing BPA exposure in females and UDPGT increased in a dose-related manner in males. There was no change in the plasma T4 and testosterone concentrations of the males with increasing BPA exposure. Discriminant analysis indicated that the group receiving 10 mg BPA/kg body weight/d was not different from the control group but the groups receiving 50 and 250 mg/kg body weight/d were different from the control group. This suggests physiological changes in the groups receiving 50 or 250 mg BPA/kg body weight/d. Topics: Administration, Oral; Animals; Benzhydryl Compounds; Body Weight; Cytochrome P-450 CYP1A1; Discriminant Analysis; Dose-Response Relationship, Drug; Environmental Pollutants; Enzyme Activation; Estradiol; Estrogens, Non-Steroidal; Female; Ferrets; Follicle Stimulating Hormone; Glucuronosyltransferase; Glutathione Transferase; Hydrocortisone; Leptin; Liver; Male; Microsomes, Liver; Phenols; Sex Factors; Testosterone; Thyrotropin; Thyroxine; Triiodothyronine | 2002 |
Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats.
Ageing is associated with insulin and leptin resistance in mammals. These alterations might be caused by the increased adiposity associated with ageing, by ageing alone or both. We studied whether leptin resistance occurs at the central level in the Wistar rat and we aimed to discriminate between the effects of ageing from those of the increased adiposity associated with ageing.. Leptin was infused intracerebroventricularly at a constant rate in young adult, old and old Wistar rats fasted for 3 months, using osmotic pumps. The effects on body weight, daily food intake, Lee index, adiposity and serum leptin values were analysed. The effect of food restriction on the expression of the long form of leptin receptor in the hypothalamus was also studied.. Leptin decreased daily food intake and body weight in young and old Wistar rats. With a dose of 10 microg/day similar responses were obtained in young and old rats but with a dose of 0.2 microg/day, only young rats showed decreases in these parameters. Food-restriction in old rats lowered adiposity and serum leptin to values close to those of young rats, recovered responsiveness to i.c.v. administration of leptin at the dose of 0.2 microg/day and increased leptin receptor expression in the hypothalamus.. Our data show that old Wistar rats have a decreased response to leptin at the central level. Food-restriction recovers leptin responsiveness and increases leptin receptor in the hypothalamus suggesting that adiposity plays a key role in the development of leptin resistance associated with ageing. Topics: Adipose Tissue; Aging; Animals; Base Sequence; Body Weight; Caloric Restriction; Diet, Reducing; DNA Primers; Drug Resistance; Fasting; Leptin; Male; Polymerase Chain Reaction; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA | 2002 |
Opposite modifications in circulating leptin and soluble leptin receptor across the eating disorder spectrum.
Leptin is thought to modulate feeding behaviour, body weight and energy metabolism by acting through specific cellular receptors. Derangements of leptin production have been repeatedly reported in patients with anorexia nervosa (AN) or bulimia nervosa (BN), but no information has been provided on the functional status of leptin receptors in these disorders. Therefore, we measured plasma levels of leptin and its soluble receptor (Ob-Re) in a total of 130 women, including 22 patients with AN, 45 patients with BN, 18 patients with the binge-eating disorder (BED), 12 non-binge eating obese women and 33 healthy women. Circulating leptin was drastically reduced in underweight anorexics and normal-weight bulimics, but increased in overweight BED patients and non-binge-eating obese women. Conversely, plasma levels of Ob-Re were significantly increased in patients with AN or BN, but decreased in BED and non-binge-eating obese women. Significant inverse correlations were detected between plasma levels of leptin and those of Ob-Re in all the subject groups, except in non-binge-eating obese subjects. These results show, for the first time, that opposite modifications occur in circulating levels of leptin and Ob-Re across the eating-disorder spectrum. The relevance of these findings to the pathophysiology and treatment of eating disorders remains to be elucidated. Topics: Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Bulimia; Estradiol; Female; Humans; Hydrocortisone; Leptin; Prolactin; Receptors, Cell Surface; Receptors, Leptin; Reference Values | 2002 |
Associations between leptin gene polymorphisms and production, live weight, energy balance, feed intake, and fertility in Holstein heifers.
Leptin is a 16-kDa protein synthesized by adipose tissue and is involved in regulation of feed intake, energy balance, fertility, and immune functions. Since evidence of a genetic correlation between start of luteal activity and energy balance, milk yield, and live weights is present, we investigated the association of genetic differences in the bovine leptin gene with these traits. Between 1990 and 1997, a total of 613 Holstein-Friesian heifers of two genetic groups with known pedigree were followed from parturition until d 105 of lactation. During the first 15 wk of lactation live weight, feed intake, and milk yield were measured for 565 cows. The start of luteal activity was set at the first day with a progesterone concentration higher than 3 ng/ml. In addition to the interval between calving and start of luteal activity, analyses were performed for average milk yield, percentage fat, protein, and lactose in milk, dry matter intake, feed intake, energy balance, and live weight over the first 15 wk of lactation. All 613 cows were genotyped for two restricted fragment length polymorphisms and for the BM1500 microsatellite, all located at the leptin gene locus. Significances of the genotype effects were estimated using the approximated F-statistic provided by ASREML. Fixed effects were year-season, genetic group, and a quadratic polynomial for age at calving. Animal was fitted as a random effect including the additive relationship between animals to account for background genes. Firstly, each genotype effect was fitted in turn, and secondly the other restriction fragment length polymorphisms were fitted as a cofactor to take into account effects of linkage disequilibrium. Thirdly, sire x genotype interaction was investigated. Heifers with the RFLP1-AB genotype produce 1.32 kg/d more milk and consume 0.73 kg/d more food compared with the RFLP1-AA genotype. No effects were found for start of luteal activity. When linkage disequilibrium with the other markers was taken into account and DMI was included as fixed effect in the model a 0.96 kg/d higher milk yield was still found. Assuming that no pleiotropic effects on traits such as immunity and milk production in later lactations exist, future breeding programs favoring the RFLP1 B-allele can yield a higher milk production without negatively affecting energy balance and fertility. The prospects are good because in this study the frequency of the RFLP1 AB- and BB-genotypes were only 18.5 and 0.2%, respectively Topics: Animals; Body Weight; Cattle; Corpus Luteum; Eating; Energy Metabolism; Fats; Female; Fertility; Gene Frequency; Genotype; Lactation; Leptin; Linkage Disequilibrium; Microsatellite Repeats; Milk; Milk Proteins; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length | 2002 |
Inverse relationship between plasma adiponectin and leptin concentrations in normal-weight and obese women.
Adiponectin, a novel adipocyte-derived collagen-like protein, is the gene product of the adipose most-abundant gene transcript 1 (apM1), which has been considered to have anti-inflammatory and anti-atherogenic effects.. To characterize the relationship between adiponectin and leptin, the ob gene product, in normal-weight and obese women.. In this cross-sectional study, we measured fasting plasma adiponectin by ELISA, leptin concentrations by RIA, and related parameters such as blood pressure, body mass index (BMI), body fat mass, lipids, fasting blood glucose and insulin in 353 non-diabetic adult women with a wide range of BMI values.. Plasma adiponectin concentrations in women with the highest tertile of BMI (at least 25.0 kg/m(2)) were decreased compared with those in the middle (22.0-25.0 kg/m(2)) or lowest ( Topics: Adiponectin; Blood Glucose; Blood Pressure; Body Composition; Body Mass Index; Body Weight; Cholesterol, HDL; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Lipids; Middle Aged; Obesity; Proteins; Radioimmunoassay; Regression Analysis; Triglycerides | 2002 |
Correlation of maternal serum fetuin/alpha2-HS-glycoprotein concentration with maternal insulin resistance and anthropometric parameters of neonates in normal pregnancy and gestational diabetes.
Human fetuin/alpha(2)-HS-glycoprotein (AHSG) is a 49 kDa serum and tissue protein which is a natural inhibitor of insulin receptor signaling. We investigated serum AHSG levels during pregnancy and whether the protein is involved in insulin resistance observed in healthy pregnant women and patients with gestational diabetes.. One hundred and four healthy pregnant women and 23 of their neonates, 30 patients with gestational diabetes and their neonates and 30 healthy age-matched non-pregnant females as a control group were investigated in a case-control cross-sectional study.. Serum AHSG was determined by radial immunodiffusion.. We observed an increase of serum AHSG concentration in the second and third trimesters. Gestational diabetes patients had significantly higher AHSG levels than healthy pregnant women and non-pregnant controls. There was a highly significant positive correlation between serum AHSG concentration and indirect parameters of insulin resistance, i.e. tumor necrosis factor-alpha (TNF-alpha), leptin, C-peptide and C-peptide/blood glucose ratio. There was also a negative correlation between maternal AHSG, TNF-alpha, leptin levels and head circumference, body length and body weight of newborns.. AHSG, TNF-alpha and leptin may contribute to insulin resistance during normal pregnancy and gestational diabetes. AHSG along with these cytokines may also negatively regulate neonatal skeletal development. Topics: alpha-2-HS-Glycoprotein; Blood Glucose; Blood Proteins; Body Height; Body Weight; C-Peptide; Cephalometry; Diabetes, Gestational; Female; Gestational Age; Humans; Infant, Newborn; Insulin Resistance; Leptin; Pregnancy; Tumor Necrosis Factor-alpha | 2002 |
Influence of leptin levels and body weight in survival of children with sepsis.
High levels of serum leptin (LPT) were reported in adult patients with sepsis and a protective role was suggested. LPT was determined in sera from 55 children with severe sepsis at admission (0 h), 6, 24 and 48 h. LPT levels were higher at 0 h than at 24 h (2.80 vs 1.61 ng/ml; p = 0.009) and a negative correlation was found with IL-13 (p = 0.009), and granulocyte counts (p = 0.035), but not with other factors. Infants younger than 12 mo of age had higher LPT levels than older infants (5.88 vs 2.38 ng/ml; p = 0.0005). The increase in LPT levels was higher in non-survivor patients than in survivors, with a maximum difference at 24 h (5.30 vs 1.45 ng/ml; p = 0.0042). However, LPT levels were not associated with shock, multiorgan failure or the severity score. Children who died showed higher percentiles of weight than survivors (p = 0.025). A subgroup with higher LPT (> Pc75) included mainly patients with weight > Pc50 (p = 0.0065), low IL-13 levels (p = 0.007) and low granulocyte counts (p = 0.013), Neisseria meningitidis B being the most frequently isolated germ (p = 0.022).. Using a model of severe infection, mainly meningococcal, in young children (median 3 y 6 mo old), it was not possible to confirm previous results in adults. A general protective role for LPT in sepsis seems unlikely. Topics: Adolescent; Bacteremia; Biomarkers; Body Weight; Child; Child, Preschool; Critical Care; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant; Infant, Newborn; Intensive Care Units, Pediatric; Leptin; Male; Probability; Prognosis; Prospective Studies; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric; Survival Analysis | 2002 |
Fenofibrate lowers abdominal and skeletal adiposity and improves insulin sensitivity in OLETF rats.
The effect of peroxisome proliferator-activated receptor (PPAR)-alpha activators on the liver is well established, but the other effects on muscle and adipose tissue about lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-alpha activation affects adiposity of skeletal muscle as well as adipose tissue and improves insulin sensitivity in spontaneous type 2 diabetes model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Thirty-three weeks of aged, 20 male OLETF rats were divided into two groups. Control group (n=10) was fed with chow and treatment group (n=10) with chow contained fenofibrate for 7 weeks. At the age of 40 weeks, all rats were examined with MRI, intravenous glucose tolerance test, and then sacrificed for measurement of fat mass and RNA analyses. The total fat (the sum of subcutaneous, mesenteric, epididymal, and retroperitoneal fat pads) measured by dissection was significantly reduced in treatment group. The signal intensity of muscular adiposity was significantly decreased in treatment group. The mRNA levels of FAT/CD36 and mitochondrial carnitine palmitoyltransferase I (M-CPT I) in liver were remarkably increased. Fasting plasma insulin and leptin levels, insulin response after intravenous glucose loading and homeostasis model assessment insulin resistance (HOMA(IR)) index were lowered in treatment group. Fenofibrate increase mitochondrial fatty acid beta-oxidation in liver but not in skeletal muscle and lower the plasma levels of triglyceride and free fatty acid. It might result in reduction of adiposity of truncal adipose tissue and skeletal muscle. We suggest that reduction of adiposity in trunk and skeletal muscle might improve insulin sensitivity. Topics: Abdomen; Adipose Tissue; Animals; Body Weight; Carnitine O-Palmitoyltransferase; CD36 Antigens; Diabetes Mellitus, Type 2; Eating; Fenofibrate; Hypolipidemic Agents; Insulin; Leptin; Lipids; Liver; Magnetic Resonance Imaging; Male; Membrane Glycoproteins; Muscle, Skeletal; Organic Anion Transporters; Rats; Rats, Inbred OLETF; Receptors, Cytoplasmic and Nuclear; Statistics as Topic; Transcription Factors | 2002 |
Ageing increases SOCS-3 expression in rat hypothalamus: effects of food restriction.
Aged Wistar rats are characterized by leptin and insulin resistance. The expression of SOCS-3 in hypothalamus increases with ageing. Food restriction during 3 months decreases obesity Lee index in aged rats with respect to their ad libitum aged-mates and brings serum leptin concentrations to values close to those of young rats. Food restriction partially reverts the increases in SOCS-3 mRNA levels associated with ageing. These results suggest that SOCS-3 may be a mediator of hypothalamic leptin resistance in the aged Wistar rat and that the hyperleptinemia associated with ageing is, at least in part, responsible for the increase of SOCS-3 expression in hypothalamus. Topics: Aging; Animals; Body Weight; Food Deprivation; Hypothalamus; Leptin; Male; Proteins; Rats; Rats, Wistar; Repressor Proteins; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors | 2002 |
Resistin and RELM-alpha gene expression in white adipose tissue of lactating mice.
The adipose tissue-derived factor resistin has been suggested to induce insulin resistance in obesity and inhibit adipocyte differentiation. Lactation is associated with major metabolic adaptations, which cause a profound loss of adipose tissue to support milk production by the mammary gland. This study has examined the expression of the resistin and resistin-like molecule-alpha (RELM-alpha) genes in white adipose tissue of lactating mice. Lactation induced significant increases in food intake and body weight, whereas body fat was substantially decreased at peak lactation. Resistin and RELM-alpha mRNAs were both detectable in gonadal, subcutaneous, and mammary gland fat; mRNA level was highest in gonadal fat and lowest in mammary tissue. There was no difference in resistin mRNA level in gonadal fat of lactating mice compared with controls. However, RELM-alpha mRNA fell by approximately 40% in early lactation and there was a parallel fall in the leptin mRNA level proportional to the loss of fat mass. These results indicate that the substantial reduction of adiposity in lactation does not lead to any changes in resistin gene expression; however, the fall in RELM-alpha mRNA might indicate a role for RELM-alpha in the metabolic adaptations of lactation. Topics: Adipose Tissue; Animals; Body Weight; Eating; Female; Gene Expression; Hormones, Ectopic; Intercellular Signaling Peptides and Proteins; Lactation; Leptin; Mice; Nerve Growth Factor; Pregnancy; Proteins; Resistin | 2002 |
Dietary (n-3) polyunsaturated fatty acids up-regulate plasma leptin in insulin-resistant rats.
The study was designed to evaluate the chronic regulation of plasma leptin by dietary (n-3) polyunsaturated fatty acids (PUFA) in insulin-resistant, sucrose-fed rats. Male Sprague-Dawley rats were randomly assigned to consume for 3 or 6 wk a diet containing 57.5% (g/100 g) sucrose and 14% lipids as either fish oil (SF) or control oils (SC). After 3 and 6 wk of consuming the SF diet, plasma leptin was 70% (P < 0.001) and 75% (P < 0.05) greater, respectively, than in rats fed the SC diet. The same result was found when plasma leptin was adjusted by total fat mass, as measured by dual-energy X-ray absorptiometry. Despite high leptin levels, food intake of rats fed the SF diet was greater than in SC-fed rats without any difference in body weight or total fat mass. After 3 wk, accumulated leptin in epididymal and retroperitoneal adipose tissue was higher in the SF-fed rats than in the SC-fed rats. However, after 6 wk, tissue leptin in the SF-fed rats did not differ from that of the SC-fed rats. The SF diet increased adipose tissue glucose transporter-4 protein quantity and prevented the sucrose-induced elevations in plasma triglycerides and free fatty acids. When all SC- and SF-fed rats (both diets and feeding durations) were considered, plasma leptin levels were positively correlated with body weight (r = 0.5, P < 0.0001) and with total fat mass (r = 0.5, P < 0.0005). These results suggest that plasma leptin at a given time could be inappropriately high for a given fat mass in insulin-sensitive rats fed (n-3) PUFA. Topics: Absorptiometry, Photon; Adipose Tissue; Animals; Blood Glucose; Body Weight; Dietary Fats, Unsaturated; Dietary Sucrose; Energy Intake; Epididymis; Fatty Acids, Nonesterified; Fatty Acids, Omega-3; Insulin; Insulin Resistance; Leptin; Male; Rats; Rats, Sprague-Dawley; Sucrose; Triglycerides | 2002 |
Transketolase haploinsufficiency reduces adipose tissue and female fertility in mice.
Transketolase (TKT) is a ubiquitous enzyme used in multiple metabolic pathways. We show here by gene targeting that TKT-null mouse embryos are not viable and that disruption of one TKT allele can cause growth retardation ( approximately 35%) and preferential reduction of adipose tissue ( approximately 77%). Other TKT(+/-) tissues had moderate ( approximately 33%; liver, gonads) or relatively little ( approximately 7 to 18%; eye, kidney, heart, brain) reductions in mass. These mice expressed a normal level of growth hormone and reduced leptin levels. No phenotype was observed in the TKT(+/-) cornea, where TKT is especially abundant in wild-type mice. The small female TKT(+/-) mice mated infrequently and had few progeny (with a male/female ratio of 1.4:1) when pregnant. Thus, TKT in normal mice appears to be carefully balanced at a threshold level for well-being. Our data suggest that TKT deficiency may have clinical significance in humans and raise the possibility that obesity may be treated by partial inhibition of TKT in adipose tissue. Topics: Adipose Tissue; Alleles; Animals; Body Weight; Cornea; Disease Models, Animal; Embryonic and Fetal Development; Energy Metabolism; Eye Proteins; Female; Gene Targeting; Growth Disorders; Growth Hormone; Heterozygote; Infertility, Female; Introns; Leptin; Litter Size; Mice; Mice, Inbred C57BL; Mice, Knockout; Morula; Mutagenesis, Insertional; Organ Size; Phenotype; Pregnancy; Sexual Behavior, Animal; Transketolase | 2002 |
Gut hormone PYY(3-36) physiologically inhibits food intake.
Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY(3-36) (PYY(3-36)), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY(3-36) in rats inhibits food intake and reduces weight gain. PYY(3-36) also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY(3-36) increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY(3-36) inhibits food intake. PYY(3-36) also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY(3-36) significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY(3-36) may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway. Topics: Action Potentials; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Electrophysiology; Energy Intake; Feeding Behavior; Gene Deletion; Humans; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Peptide Fragments; Peptide YY; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Signal Transduction | 2002 |
Normal insulin sensitivity and IMCL content in overweight humans are associated with higher fasting lipid oxidation.
Intramyocellular lipid (IMCL) storage is considered a local marker of whole body insulin resistance; because increments of body weight are supposed to impair insulin sensitivity, this study was designed to assess IMCL content, lipid oxidation, and insulin action in individuals with a moderate increment of body fat mass and no family history of diabetes. We studied 14 young, nonobese women with body fat <30% (n = 7) or >30% (n = 7) and 14 young, nonobese men with body fat <25% (n = 7) or >25% (n = 7) by means of the euglycemic-insulin clamp to assess whole body glucose metabolism, with indirect calorimetry to assess lipid oxidation, by localized (1)H NMR spectroscopy of the calf muscles to assess IMCL content, and with dual-energy X-ray absorptiometry to assess body composition. Subjects with higher body fat had normal insulin-stimulated glucose disposal (P = 0.80), IMCL content in both soleus (P = 0.22) and tibialis anterior (P = 0.75) muscles, and plasma free fatty acid levels (P = 0.075) compared with leaner subjects in association with increased lipid oxidation (P < 0.05), resting energy expenditure (P = 0.046), resting oxygen consumption (P = 0.049), and plasma leptin levels (P < 0.01) in the postabsorptive condition. In conclusion, in overweight subjects, preservation of insulin sensitivity was combined with increased lipid oxidation and maintenance of normal IMCL content, suggesting that abnormalities of these factors may mutually determine the development of insulin resistance associated with weight gain. Topics: Adult; Anthropometry; Antigens, CD; Body Weight; C-Peptide; Energy Metabolism; Fasting; Female; Glucose; Homeostasis; Humans; Hydrocortisone; Insulin; Leptin; Lipid Metabolism; Lipids; Male; Muscle, Skeletal; Oxidation-Reduction; Postprandial Period; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type II; Reference Values | 2002 |
MSG lesions decrease body mass of suckling-age rats by attenuating circadian decreases of energy expenditure.
Suckling-age rats display endogenous circadian rhythmicity of metabolic rate (MR) with energy-saving, torpor-like decreases, which are sympathetically controlled and suppressed by leptin treatment. We investigated whether neonatal monosodium glutamate (MSG) treatment, known to cause arcuate nucleus damage and adult-age obesity, alters energy balance in the first two postnatal weeks. Continuously recorded MR and core temperatures (T(c)) show that MSG treatment disinhibits the periodic, sympathetically controlled, energy-saving drops of T(c) and MR. Increased energy expenditure thus explains reduced body fat at normal lean body mass found in MSG-treated pups artificially nourished identically to controls. In MSG-treated mother-reared pups, lean body mass is additionally reduced, suggesting that MSG also reduces suckling. Plasma leptin levels are similar in controls and MSG-treated pups but higher per unit of fat mass in the latter. We conclude that the postweaning development of MSG obesity and depressed thermogenesis are preceded by an early phase of increased energy expenditure with decreased fat deposition during suckling age and hypothesize cell damage in the arcuate nucleus to be involved in both. Topics: Animal Husbandry; Animals; Animals, Suckling; Body Composition; Body Temperature; Body Weight; Circadian Rhythm; Energy Metabolism; Female; Hypothalamus; Leptin; Metabolism; Mothers; Periodicity; Rats; Rats, Zucker; Sodium Glutamate | 2002 |
Immunomanipulation of appetite and body temperature through the functional mimicry of leptin.
Although current obesity therapies produce some benefits, there is a need for new strategies to treat obesity. A novel proposal is the use of anti-idiotypic antibodies as surrogate ligands or hormones. These anti-idiotypic antibodies carry an internal motif that imitates or mimics an epitope in the antigen (i.e., hormone or ligand). Thus, anti-idiotypic antibodies to several ligands may mimic them in transducing signals when binding to their receptors.. We developed an anti-idiotypic polyclonal antibody against the region of a leptin monoclonal antibody that competitively binds leptin, mimicking the active site structure of leptin. To test whether our anti-idiotype could also reproduce leptin functions, we examined food intake, body weight, and colonic temperature in male Wistar rats (n = 9) in response to intracerebroventricular administration of the leptin anti-idiotype.. Our leptin anti-idiotype induced a significant reduction in food intake coupled with an increase in body temperature comparable to that of leptin. That is, the intracerebroventricular administration of 8.0 microg of leptin anti-idiotype or 5.0 microg leptin significantly increased colonic temperature (Delta 1.9 +/- 0.11 degrees C and Delta 1.7 +/- 0.12 degrees C, respectively). In addition, both decreased 24-hour food intake (-26.4 +/- 2.4% and -21.9 +/- 2.2%) compared with the control. The gain in body weight was also decreased by acute administration of the anti-idiotype (-1.4 +/- 0.28%) and leptin (-1.1 +/- 0.17%) vs. the phosphate-buffered saline control (1.3 +/- 0.15%).. These studies revealed that the leptin anti-idiotype inhibited food intake and enhanced heat production, mimicking leptin's central actions. Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Appetite; Body Temperature; Body Weight; Colon; Eating; Injections, Intraventricular; Leptin; Male; Rats; Rats, Wistar | 2002 |
Long-term effects of diet on leptin, energy intake, and activity in a model of diet-induced obesity.
This study investigated the effect of long-term high-fat sucrose (HFS) or low-fat complex-carbohydrate (LFCC) diet consumption on leptin, insulin, fat cell size, energy intake, and markers of activity to ascertain the role that leptin plays in long-term energy balance in a model of diet-induced obesity. Female Fischer 344 rats were fed either a HFS or LFCC diet ad libitum for a period of 20 mo. Measurements of leptin concentration, insulin concentration, and adipocyte size were performed at 2 wk, 2 mo, 6 mo, and 20 mo. Body weight and energy intake were measured weekly for calculation of feed efficiency. Body temperature and activity levels were assessed over a 5-day period after 12 mo of the dietary intervention. Plasma leptin and insulin concentrations were significantly elevated within 2 wk of HFS diet consumption and remained elevated throughout the course of the study. After 2 mo, the adipocytes of the HFS group were significantly larger and continued to increase in size throughout the course of the study. A significant correlation was noted between leptin and adipocyte cell size (r = 0.96, P < 0.01). However, despite elevated leptin, energy intake was similar, and the HFS group weighed significantly more than the LFCC group, as a result of a higher feed efficiency. There were no significant differences in body temperature or activity levels between the groups. These results demonstrate that a HFS diet causes hyperleptinemia and hyperinsulinemia before adipocyte size is increased and suggests that leptin resistance may be present or, alternatively, that leptin does not to play a major role in the long-term regulation of energy intake or activity levels in this model. Topics: Adipocytes; Animals; Body Temperature; Body Weight; Cell Size; Diet; Energy Intake; Female; Insulin; Leptin; Motor Activity; Obesity; Rats; Rats, Inbred F344; Time Factors | 2002 |
Serum leptin and IGF-I during growth hormone treatment in chronic renal failure.
Serum leptin decreases during growth hormone (hGH) treatment and pre-treatment values have been suggested as a predictor of the response to hGH in GH deficiency (GHD) but not in non-GHD syndromes. To investigate whether this holds true in children with chronic renal failure (CRF), we evaluated changes in serum leptin, insulin-like growth factor-I (IGF-I) and height before(b) and during the 1st year (3 months, 6 months, 9 months, 12 months) of hGH treatment (1 IU/kg per week) in 11 children (median age(b) 10.1 years, mean height(b) -2.9 SDS) with CRF. Serum leptin and IGF-I were compared with values from healthy children. Each patient also served as his/her own control, with values during treatment compared with those before treatment. Growth improved in all patients during treatment (mean change(12 m) +7.2 cm, change in height SDS(12 m) +0.5, P=0.001). Weight decreased (median decrease(12 m) 0.3 SDS, P=0.02) but body mass index (BMI) and serum leptin did not change during treatment. Serum IGF-I levels were low before (mean -1.1 SDS) but increased during hGH treatment, the increment being greatest at 10 days (mean increment +1.9 SDS, P<0.0001). Serum leptin(b) did not correlate with change in serum IGF-I(10d), height(12 m) or weight(12 m). Serum IGF-I SDS(b) correlated with height SDS at 12 months ( r=0.80, P=0.006) of hGH treatment. Serum leptin(b) correlated with BMI ( r(s)=0.75, P=0.01). Levels adjusted for BMI did not differ from values in healthy children and did not change during treatment. Despite an IGF-I and growth response during hGH treatment, serum leptin did not change and pre-treatment values did not predict the growth response in these children with CRF. Topics: Adipose Tissue; Adolescent; Biomarkers; Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Female; Growth Hormone; Human Growth Hormone; Humans; Infant; Insulin-Like Growth Factor I; Kidney Failure, Chronic; Leptin; Male; Radioimmunoassay | 2002 |
Leptin and metabolic syndrome in obese and non-obese children.
Metabolic syndrome is characterized by a clustering of metabolic abnormalities: insulin resistance - hyperinsulinemia, dyslipidemia (high triglycerides and low HDL - cholesterol serum concentrations), impaired glucose tolerance and/or type 2 diabetes, and hypertension. The aim of this study was to analyse the role of different variables of metabolic syndrome, including leptin, in 74 non-obese children and 68 children with non-syndromal obesity. As metabolic syndrome variables, we have included body mass index, waist circumference, trunk-to-total skinfolds (%), systolic blood pressure, diastolic blood pressure, glucose, uric acid, fasting insulin, triglycerides and high-density lipoprotein-cholesterol (HDL-C). Factor analysis showed 4 factors in each group. In non-obese children, waist circumference, BMI, fasting insulin, triglycerides, trunk-to-total skinfolds (%), leptin and uric acid loaded positively on factor 1, and HDL-C loaded negatively on this factor; systolic and diastolic blood pressure had high positive loadings in factor 2; HDL-C and leptin showed positive loadings and triglycerides and uric acid, negative loadings in factor 3; and, finally, glucose and insulin showed positive loadings in factor 4. These four factors explained 72.16 % of the total variance in the non-obese group. In obese children, BMI, waist circumference, leptin, diastolic blood pressure and systolic blood pressure loaded positively on factor 1; diastolic blood pressure, trunk-to-total skinfolds (%), uric acid and systolic blood pressure showed high positive loadings in factor 2; fasting insulin, glucose and triglycerides showed positive loadings in factor 3; and, finally, triglycerides showed positive loadings and HDL-C negative loadings in factor 4. These four factors explained 74.18 % of the total variance in the obese group. Our results point to a different homeostatic control of metabolic syndrome characteristics in obese and non-obese children. Leptin seems to play a key underlying role in metabolic syndrome, especially in the obese group. Topics: Blood Glucose; Blood Pressure; Body Height; Body Weight; Child; Cholesterol, HDL; Factor Analysis, Statistical; Female; Humans; Insulin; Leptin; Male; Metabolic Syndrome; Obesity; Triglycerides; Uric Acid | 2002 |
Leptin treatment during the neonatal period is associated with higher food intake and adult body weight in rats.
For this study, we have determined the effects of neonatal leptin treatment on the evolution of body weight. Experiment 1: pups were divided into two groups: LepF - injected with leptin (8 micro g/100 g of body weight) for the first 10 days of lactation and control (C) - receiving saline. Experiment 2: pups were divided into two groups: LepL - injected with the same leptin concentration of experiment one for the last 10 days of lactation, and C, which received saline. Body weight and food intake were monitored until age 150 days, after which leptin concentrations were measured by ELISA. The LepF group had a significant increase in body weight (p < 0.05) from day 98 onward, in food intake (p < 0.05) from day 74 onward, and higher serum leptin concentration compared to the control (108 %, p < 0.05). The LepL group had a significant increase in body weight (p < 0.05) from day 113 onward, in food intake from day 121 onward (p < 0.001), and higher serum leptin concentration compared to controls (6.9 %, p < 0.05). These results suggest that both periods of lactation constituted a critical window for body weight and food intake programming, but the effects are more marked when the leptin is injected within the first ten days. Topics: Aging; Algorithms; Animals; Animals, Newborn; Body Weight; Eating; Female; Lactation; Leptin; Rats; Rats, Wistar | 2002 |
Nicotine treatment decreases food intake and body weight via a leptin-independent pathway in Psammomys obesus.
It has been reported previously that leptin may be involved in nicotine's ability to reduce body weight. Our aim was to investigate whether the anorexic action of nicotine is related to the actions of leptin by utilizing lean leptin-sensitive and obese leptin-resistant Psammomys obesus. Lean and obese P. obesus were assigned to receive nicotine sulphate at 6, 9 or 12 mg/day or saline (control) for 9 days (n = 6-10 in each group), administered using mini-osmotic pumps. Food intake, body weight, plasma leptin concentrations, plasma insulin and blood glucose were measured at baseline and throughout the study period. Nicotine treatment reduced food intake by up to 40% in lean and obese P. obesus. Plasma leptin levels fell significantly only in lean nicotine-treated animals, whereas no changes were observed in obese nicotine-treated animals. However, both lean and obese nicotine-treated animals had similar reductions in body weight. Our results show that nicotine has dramatic effects on food intake and body weight, however, these changes appear to be independent of the leptin signalling pathway. Topics: Animals; Blood Glucose; Body Weight; Eating; Female; Ganglionic Stimulants; Gerbillinae; Insulin; Leptin; Male; Nicotine | 2002 |
Leptin predicts bone and fat mass after accounting for the effects of diet and glucocorticoid treatment in piglets.
The role of leptin in neonatal growth and bone metabolism has been investigated, but not simultaneously. The objectives of this study were to determine if leptin relates to bone mass during rapid growth; if consumption of maternal milk is related to elevated circulating concentrations of leptin resulting in higher fat mass; and if glucocorticoids result in higher fat mass and reduced bone mass due to elevated leptin. Thirty-two piglets were randomized to either a suckling or milk substitute plus either dexamethasone (DEX) or placebo injection for 15 days beginning at 5 days of age. Milk and blood samples were obtained at baseline, and after 15 days, blood was sampled again for measurement of leptin and bone biochemistry. Weight at baseline plus weight and length after 15 days were recorded, followed by measurement of whole body bone mineral content, bone area, and fat mass using dual energy x-ray absorptiometry. At baseline, plasma leptin was elevated in suckled piglets. Piglets that suckled had elevated fat mass as did those who received DEX. However, DEX resulted in suppressed weight and length, bone mass, and bone metabolism. Leptin was similar among groups after the 15 days. After accounting for body size and treatment effects, piglet plasma leptin was predictive of bone and fat mass. Leptin circulating early postnatally is linked to body composition, specifically fat and bone mass. Elevations in fat mass and reductions in bone mass observed after 15 days of DEX treatment are not related to leptin metabolism. Both human and porcine neonates share similar characteristics with respect to relationships of leptin with fat and bone mass. Topics: Adipose Tissue; Animal Feed; Animals; Body Composition; Body Weight; Bone and Bones; Bone Density; Dexamethasone; Leptin; Male; Milk; Minerals; Models, Animal; Organ Size; Random Allocation; Species Specificity; Swine; Weight Gain | 2002 |
Comparing mRNA levels of genes encoding leptin, leptin receptor, and lipoprotein lipase between dairy and beef cattle.
Body weight and fat mass vary distinctly between German Holstein (dairy cattle) and Charolais (beef cattle). The aim of this study was to determine whether the expression of the obese (Ob) gene and lipoprotein lipase (LPL) gene in fat tissues and expression of the long isoform leptin receptor (Ob-Rb) gene in the hypothalamus were different between these two cattle breeds. Body weight and the area of longissimus muscle cross-section of German Holstein were lower (P<0.001), while body fat content, as well as the omental and perirenal fat mass were higher (P<0.001), compared to Charolais. Plasma insulin and leptin levels between two cattle breeds were determined by radioimmunoassay. Compared to Charolais, plasma insulin concentrations were significantly higher (P<0.01), and plasma leptin levels were tended to be higher (P<0.1) in German Holstein. Ob mRNA levels in subcutaneous and perirenal fat depots, but not in the omental fat depot, were significantly higher (P<0.05) in German Holstein than in Charolais. LPL mRNA expression in the perirenal fat depot of German Holstein was greater in abundance than that of Charolais. No significantly different LPL mRNA levels were found in subcutaneous and omental fat depots, and Ob-Rb mRNA levels in the hypothalamus between these two cattle breeds (P<0.05). Both Ob and LPL expression was greater in perirenal and omental fat depots than in the subcutaneous fat depot (P<0.05). Data indicated that in bovine the Ob and LPL gene expression levels in perirenal fats are an important index that is associated with body fat content, while Ob-Rb in hypothalamus is not. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Cattle; Female; Insulin; Leptin; Lipoprotein Lipase; Male; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2002 |
Serum leptin and its adipose gene expression during pubertal development, the estrous cycle, and different seasons in cattle.
Circulating concentrations of leptin and IGF-I, leptin gene expression, and serum binding of [126I]ovine leptin in cattle during pubertal development, as well as leptin gene expression and circulating concentrations of leptin during the estrous cycle and different calendar seasons, were investigated. Multivariate regression analysis was utilized to evaluate temporal changes in BW, leptin mRNA, and serum concentrations of IGF-I and leptin normalized to the week of puberty (Exp. 1). Body weight accounted for most of the variation associated with the onset of puberty in the full regression model (R2 = 0.99; P < 0.01). However, serum leptin was closely related to changes in BW (r = 0.85; P < 0.02) and in the absence of BW was most predictive of pubertal onset (r2 = 0.73; P < 0.01). Mean concentrations of leptin increased (P < 0.0001) linearly from 16 wk before until the wk of pubertal ovulation in yearling heifers reaching sexual maturation from early spring to midsummer. Leptin mRNA transformed to a percent of the value at puberty increased (P < 0.02) as puberty approached, but serum leptin and leptin mRNA values were not well correlated. We found no evidence of leptin-binding proteins in serum of developing heifers. Combined mean serum concentrations of IGF-I (ng/mL) during periods III and IV (-9 wk to wk of puberty; 216.6 +/- 9) were 21% higher (P < 0.0001) than combined mean concentrations of IGF-I during periods I and II (-19 to wk of puberty; 193 +/- 10). In mature heifers and cows (Exp. 2), serum leptin tended to decrease (P = 0.10) during the late luteal/early follicular phase of the estrous cycle, which corresponded to a reduction (P < 0.03) in adipocyte leptin gene expression. In mature ovariectomized cows, serum concentrations of leptin increased (P < 0.001) by 34% from early winter to the summer solstice and remained unchanged throughout the remainder of the year (Exp. 3). Results from these studies indicate that marked increases in both circulating leptin and leptin gene expression occur in developing heifers during pubertal development and are associated with increases in serum IGF-I and BW. Seasonal effects on circulating leptin observed in mature cows from winter to summer could also plausibly account for a portion of the prepubertal rise in serum leptin observed in heifers. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Cattle; Estrous Cycle; Estrus; Female; Gene Expression; Insulin-Like Growth Factor I; Leptin; Ovariectomy; Regression Analysis; RNA, Messenger; Seasons; Sexual Maturation | 2002 |
Evidence for competing effects of body mass, hyperinsulinemia, insulin resistance, and androgens on leptin levels among lean, overweight, and obese women with polycystic ovary syndrome.
To evaluate the relationships between leptin, body composition, insulin resistance, androgens, and reproductive indices among women with polycystic ovary syndrome (PCOS).. Matched case-control study.. Academic reproductive endocrine practice; school of public health.. Forty-six Caucasian women with PCOS and 46 population-based controls matched by age and body mass index (BMI).. None.. Leptin, insulin, androgenic hormones, body composition parameters; reproductive parameters.. Overall, leptin levels among women with PCOS did not differ significantly from those of control women (20.4 +/- 14.9 vs. 21.9 +/- 14.3 ng/mL). However, within the lowest BMI tertile, women with PCOS had significantly lower leptin levels (9.6 vs. 18.3 ng/mL), comparable insulin, and higher testosterone concentrations than controls of similar body mass. Within the overweight and obese subgroups, both insulin and testosterone levels were increased among women with PCOS; leptin levels, although higher among obese cases, were not statistically different than those in controls.. Below a certain BMI, hyperandrogenic women with PCOS have lower leptin levels than controls. Conversely, overweight and obese PCOS subjects appear to produce insufficient leptin for a given fat mass, relative to the degree of hyperinsulinemia, potentially because of the competing effects of adipocyte insulin resistance and androgens on leptin. Topics: Adult; Body Composition; Body Mass Index; Body Weight; Case-Control Studies; Female; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Obesity; Pennsylvania; Polycystic Ovary Syndrome; Reference Values; Reproduction; Thinness; White People | 2002 |
Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats.
Acute administration of leucine and norleucine activates the mammalian target of rapamycin (mTOR) cell-signaling pathway and increases rates of protein synthesis in a number of tissues in fasted rats. Although persistent stimulation of mTOR signaling is thought to increase protein synthetic capacity, little information is available concerning the effects of chronic administration of these agonists on protein synthesis, mTOR signal transduction, or leucine metabolism. Hence, we developed a model of chronic leucine/norleucine supplementation via drinking water and examined the effects of chronic (12 days) supplementation on protein synthesis in adipose tissue, kidney, heart, liver, and skeletal muscle from ad libitum-fed rats. The relative concentration of proteins involved in mTOR signaling and the two initial steps in leucine oxidation were also examined. Leucine or norleucine supplementation was accompanied by increased rates of protein synthesis in adipose tissue, liver, and skeletal muscle, but not in heart or kidney. Supplementation was not associated with increases in the anabolic hormones insulin or insulin-like growth factor I. Chronic supplementation did not cause apparent adaptation in either components of the mTOR cell-signaling pathway that respond to leucine (mTOR, ribosomal protein S6 kinase, and eukaryotic initiation factor 4E-binding protein-1) or the first two steps in leucine metabolism (the mitochondrial isoform of branched-chain amino acid transaminase, branched-chain keto acid dehydrogenase, and branched-chain keto acid dehydrogenase kinase), which may be involved in terminating the signal from leucine. These results suggest that provision of leucine or norleucine supplementation via the drinking water results in stimulation of postprandial protein synthesis in adipose tissue, skeletal muscle, and liver without notable adaptive changes in signaling proteins or metabolic enzymes. Topics: 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); Adipose Tissue; Amino Acid Sequence; Amino Acids; Animals; Body Weight; Drinking; Eating; Focal Adhesion Kinase 2; Insulin-Like Growth Factor I; Ketone Oxidoreductases; Leptin; Leucine; Liver; Male; Molecular Sequence Data; Multienzyme Complexes; Muscle, Skeletal; Norleucine; Protein Biosynthesis; Protein Kinases; Protein-Tyrosine Kinases; Rats; Rats, Sprague-Dawley; Signal Transduction; Tissue Distribution; TOR Serine-Threonine Kinases; Transaminases | 2002 |
Splenic denervation blocks leptin-induced enhancement of humoral immunity in Siberian hamsters (Phodopus sungorus).
Nontropical rodents have evolved adaptations to maximize winter survival, including alterations in reproduction, energy balance and immunity. Short-day-housed Siberian hamsters display reductions in body fat and decreases in humoral immunity compared with long-day hamsters. The hormone leptin, secreted by adipose tissue, varies in response to changes in body fat and has been implicated in photoperiodic changes in immunity. In addition, the metabolic effects of this hormone appear to be mediated by the sympathetic nervous system (SNS). Very little is known, however, regarding the role of the SNS in regulating the effects of leptin on immunity. The goal of the present study was to examine the effects of splenic denervation on leptin-induced immune enhancement of short-day Siberian hamsters. Male hamsters were housed in long (LD 16:8) or short days (LD 8:16) for 10 weeks. Half of the animals in each photoperiod received surgical denervations of the spleen; the remaining animals received sham operations. In addition, animals in each group were implanted with osmotic minipumps containing either leptin or vehicle. Hamsters were then injected with keyhole limpet hemocyanin (KLH) and serum anti-KLH antibody production was assessed. Short-day hamsters displayed decreased humoral immunity in short versus long days; leptin attenuated the short-day decrease but did not enhance immunity of long-day hamsters. Furthermore, splenic denervation blocked the leptin-induced increase in immunity in short-day hamsters. Collectively, these data suggest that leptin plays an important role in regulating seasonal changes in humoral immunity of Siberian hamsters and the effects of leptin occur, at least in part, via changes in the SNS innervation of lymphoid tissue. Topics: Adjuvants, Immunologic; Animals; Antibodies; Antibody Formation; Body Weight; Cricetinae; Denervation; Hemocyanins; Leptin; Male; Organ Size; Phodopus; Photoperiod; Spleen; Sympathetic Nervous System; Testis | 2002 |
Leptin production by the stomach is up-regulated in obese (fa/fa) Zucker rats.
Genetically obese (fa/fa) Zucker rats display markedly elevated circulating leptin levels compared with their lean counterparts; this is expected because of the lack of a LepR-mediated feedback inhibition. The aim of this study was to determine the effect of the leptin receptor mutation in the Zucker rat on gastric leptin production and on the response to 14 hours of starvation. The response to a short-term period of food intake (20 minutes) on gastric leptin release was also analyzed.. Leptin mRNA expression in the gastric mucosa and in adipose tissue depots (epididymal, retroperitoneal, mesenteric, and inguinal) was assessed by reverse transcriptase-polymerase chain reaction and serum and stomach leptin content by enzyme-linked immunosorbent assay.. Obese Zucker rats overexpressed leptin in the stomach. They overexpress leptin in the inguinal adipose tissue but not in visceral adipose tissue depots, indicating tissue-specific obesity-dependent differences. Gastric leptin expression is regulated by feeding conditions in lean but not in obese (fa/fa) rats. In lean animals, leptin mRNA levels decrease in fasting conditions and increase rapidly with a short period of food intake. Obese Zucker rats also overdisplay stomach leptin levels. Feeding acutely stimulates leptin secretion by the stomach in lean, and to a lesser extent, in obese rats.. These results indicate impaired regulation of leptin expression in the stomach of obese (fa/fa) Zucker rats. However, there is still an effect of the nutritional status on gastric leptin levels despite the lack of a functional leptin receptor. Topics: Adipose Tissue; Animals; Body Weight; Enzyme-Linked Immunosorbent Assay; Epididymis; Food; Gastric Mucosa; Gene Expression Regulation; Groin; Leptin; Male; Mesentery; Obesity; Rats; Rats, Zucker; Retroperitoneal Space; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Starvation | 2002 |
Establishment of a highly sensitive leptin radioimmunoassay and detection of increased leptin levels in hyperlipidemia and pregnancy.
The highly effective antibody has been obtained by immunizing rabbits with recombinant leptin many times. The leptin is iodinated with the chloramine-T method and purified with a Sephadex-G25 chromatography column. The reaction between antigen and antibody is carried out by a one-step balance method and cultured at 4 degrees C for 24 h; the binding and free antigen was then separated by PR reagent. The determining range of this method is about 0.5-24 ng/mL; limited detection level is 0.45 ng/mL, relative standard deviation in a group, and among groups, are less than 5.4% and 8%, respectively. The level of blood leptin in 277 samples of normal persons, in 112 samples of overweight persons (weight/hieght m2 > or = 25) and 224 samples of hyperlipidemic patients have been measured by this method. It is demonstrated that the level of blood leptin in males is much lower than that of the females, and becomes elevated with increased age. Serum leptin level in overweight persons and hyperlipidemic patients is also much higher than that of normal groups (P < 0.01). Serum leptin of 21 workers in our lab at 8:00 AM and 4:00 PM has been tested. It was found that there are no differences between the two time points. The same results are obtained within age groups. Leptin levels of pregnant women's serum is higher than those of the control group (P < 0.001). Leptin in newborn's serum is significantly lower than those of mothers (P < 0.01). There is no obvious correlation between leptin level of mother and newborns by correlation analysis (r = 0.19, P > 0.05). The body weight and body weight index of pregnant women are well correlated with their serum leptin levels (r = 0.33 and 0.35, P < 0.05). The body weight and body weight index of newborns are well correlated with their serum leptin levels (r = 0.54 and 0.49, P < 0.001). The serum leptin level of pregnant women is not correlated with newborn's body weight (r = 0.10). These results have shown that the proposed method is stable, simple, and specific, being sensitive enough to determine leptin levels in human serum or plasma. Topics: Adolescent; Adult; Age Factors; Aged; Animals; Body Weight; Case-Control Studies; Circadian Rhythm; Female; Humans; Hyperlipidemias; Immune Sera; Infant, Newborn; Leptin; Male; Middle Aged; Obesity; Pregnancy; Rabbits; Radioimmunoassay; Reproducibility of Results; Sensitivity and Specificity | 2002 |
Reduced central leptin sensitivity in rats with diet-induced obesity.
On low-fat chow diet, rats prone to diet-induced obesity (DIO) have increased arcuate nucleus neuropeptide Y (NPY) expression but similar leptin levels compared with diet-resistant (DR) rats (19). Here, body weight and leptin levels rose in DIO rats, and they defended their higher body weight after only 1 wk on a 31% fat high-energy (HE) diet. However, DIO NPY expression did not fall to DR levels until 4 wk when plasma leptin was 168% of DR levels. When switched to chow, DIO rats lost carcass fat (18). By 10 wk, leptin levels fell to 148% and NPY expression again rose to 150% of DR levels. During 4 wk of food restriction, DIO leptin fell by approximately 50% while NPY increased by 30%. While both returned to control levels by 8 wk, DIO rats still regained all lost weight when fed ad libitum. Finally, the anorexic effect of intracerebroventricular leptin (10 microg) was inversely correlated with subsequent 3-wk weight gain on HE diet. Thus NPY expression and food intake are less sensitive to the leptin's suppressive effects in DIO rats. While this may predispose them to develop DIO, it does not fully explain their defense of a higher body weight on HE diet. Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Body Weight; Brain; Dietary Fats; Energy Intake; Food Deprivation; Injections, Intraventricular; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2002 |
Metabolic characteristics of multiparous Angus and Brahman cows grazing in the Chihuahuan Desert.
Understanding metabolic differences between breeds of cattle is important when selecting for production in semiarid environments. Spring-calving multiparous Angus and Brahman cows (n = 8/breed) grazing in the Chihuahuan Desert were used to evaluate metabolic hormone status in February (i.e., 3rd trimester of pregnancy), May (i.e., early lactation), and September (i.e., late lactation) 2000. Crude protein in ruminal digesta collected from grazing companion ruminally cannulated cows during these months was 5.6, 6.0, and 10.3%, respectively. Angus cows were heavier (P < 0.01) than Brahman cows across months. Body condition scores among breed groups were 4.4, 3.6, and 4.6 in February, May, and September with Brahman cows tending (P < 0.10) to have greater body condition than Angus cows in May. Brahman cows tended to have greater fecal output per 100 kg BW than Angus cows in February (0.9 > 0.7 +/- 0.1, P < 0.10). Brahman cows had greater serum concentrations of leptin than Angus cows in September (1.8 > 0.70 +/- 0.1 ng/mL; P < 0.05), and serum concentrations of insulin were greater (P < 0.01) in Brahman than Angus cows throughout the study. Brahman cows also had greater (P < 0.01) serum concentrations of glucose during February and May than Angus cows. Serum concentrations of triiodothyronine were greatest (P < 0.01) during September and lowest during February and May in both breed groups and were greater (P < 0.01) in Brahman than in Angus cows in February, May, and September. Pregnancy rate and 205-d adjusted weaning weights were similar (P > or = 0.46) among breed groups. Results suggest that Brahman and Angus cows are sensitive to the seasonal dynamics of forage quality in the Chihuahuan Desert. Brahman cattle appear to have greater concentrations of metabolic hormones and metabolites than Angus cows in this environment, but Angus cows experience greater fluctuations in BW. Topics: Animal Feed; Animals; Blood Glucose; Blood Urea Nitrogen; Body Weight; Breeding; Cattle; Desert Climate; Diet; Fatty Acids, Nonesterified; Female; Growth Substances; Insulin; Lactation; Leptin; New Mexico; Parity; Plants, Edible; Pregnancy; Pregnancy, Animal; Seasons; Triiodothyronine | 2002 |
Leptin levels in rat offspring are modified by the ratio of linoleic to alpha-linolenic acid in the maternal diet.
The supply of polyunsaturated fatty acids (PUFA) is important for optimal fetal and postnatal development. We have previously shown that leptin levels in suckling rats are reduced by maternal PUFA deficiency. In the present study, we evaluated the effect of maternal dietary intake of (n-3) and (n-6) PUFA on the leptin content in rat milk and serum leptin levels in suckling pups. For the last 10 days of gestation and throughout lactation, the rats were fed an isocaloric diet containing 7% linseed oil (n-3 diet), sunflower oil (n-6 diet), or soybean oil (n-6/n-3 diet). Body weight, body length, inguinal fat pad weight, and adipocyte size of the pups receiving the n-3 diet were significantly lower during the whole suckling period compared with n-6/n-3 fed pups. Body and fat pad weights of the n-6 fed pups were in between the other two groups at week one, but not different from the n-6/n-3 group at week 3. Feeding dams the n-3 diet resulted in decreased serum leptin levels in the suckling pups compared with pups in the n-6/n-3 group. The mean serum leptin levels of the n-6 pups were between the other two groups but not different from either group. There were no differences in the milk leptin content between the groups. These results show that the balance between the n-6 and n-3 PUFA in the maternal diet rather than amount of n-6 or n-3 PUFA per se could be important for adipose tissue growth and for maintaining adequate serum leptin levels in the offspring. Topics: Adipocytes; Adipose Tissue; alpha-Linolenic Acid; Analysis of Variance; Animals; Animals, Suckling; Body Weight; Diet; Dietary Fats, Unsaturated; Fatty Acids; Female; Leptin; Linoleic Acid; Milk; Pregnancy; Prenatal Nutritional Physiological Phenomena; Rats; RNA, Messenger | 2002 |
Brief access to sucrose engages food-entrainable rhythms in food-deprived rats.
Two studies examined whether brief access to sucrose solutions engages food-entrainable rhythms when pitted against a light-dark cycle. In Experiment 1, 32% sucrose was given once daily for 5-6 min at Zeitgeber Time 4 (ZT 4) for 17-18 days to 8 food-deprived and 8 ad-lib-fed rats. Chow was provided at ZT 16. Temperature, wheel running, activity, and corticosterone (B) anticipated sucrose only in food-deprived rats. Ad-lib rats were similar to controls. In Experiment 2, 32% sucrose was presented at ZT 4 for 5 or 10 min for 17 days to food-deprived rats. Chow was given at ZT 12. Exogenous cues were minimized. Both groups showed anticipation of sucrose, whereas room controls did not. After a shift to 4% sucrose for 8 days, the 10-min group showed signs of damping of these rhythms, whereas the 5-min group did not. Data indicated that brief access to sucrose engages food-entrainable rhythms in food-deprived rats. Topics: Analysis of Variance; Animals; Blood Glucose; Body Weight; Circadian Rhythm; Corticosterone; Dose-Response Relationship, Drug; Eating; Energy Intake; Extinction, Psychological; Fatty Acids, Nonesterified; Feeding Behavior; Food; Food Deprivation; Insulin; Leptin; Male; Motor Activity; Rats; Rats, Sprague-Dawley; Sucrose; Temperature; Testosterone; Time Factors; Triglycerides | 2002 |
Effect of diet-induced obesity on ovalbumin-specific immune response in a murine asthma model.
Some epidemiologic surveys have demonstrated that asthma is more prevalent in obese children and adults. However, the mechanism of association between obesity and asthma has not been fully clarified. This report investigates a murine model for antigen-induced asthma and diet-induced obesity from an immunologic perspective. For the induction of obesity, C57BL/6J mice were fed a high-fat diet supplemented with lard or soybean oil. Mice were then sensitized and challenged with ovalbumin (OVA) to induce allergic lung inflammation. OVA-specific serum immunoglobulin levels were lower in obese mice compared with non-obese control mice. The decline of OVA-specific IgE in the soybean oil group was found to be especially pronounced. However, obese mice with OVA-induced asthma showed a higher sensitivity of antigen-induced T-cell responses, and increased gamma interferon (IFN-gamma) production of splenocytes with phytohemagglutinin (PHA) stimulation. Furthermore, mast cell numbers in the tracheal mucosa were increased in obese mice upon sensitization by OVA. These results suggest that obesity-induced changes in T-cell function may be partly involved in the pathophysiology of asthma in human obesity, rather than Ig E-mediated allergic responses. Topics: Adipose Tissue; Animals; Asthma; Body Weight; Cell Division; Diet; Dietary Fats; Energy Metabolism; Immunoglobulins; Interferon-gamma; Interleukin-2; Leptin; Mice; Mice, Inbred C57BL; Mitogens; Obesity; Ovalbumin; Respiratory Hypersensitivity; Spleen | 2002 |
Resistance to the satiety action of leptin following chronic central leptin infusion is associated with the development of leptin resistance in neuropeptide Y neurones.
Leptin regulates food intake and body weight by acting primarily in the hypothalamus. In humans and rodents, obesity is associated with hyperleptinaemia, suggesting a possible state of leptin resistance. Thus, to begin to examine the mechanisms of leptin resistance, we developed a rat model in which chronic central leptin infusion results in the development of resistance to leptin's satiety action. Adult male rats were infused chronically into the lateral cerebroventricle with leptin (160 ng/h) or phosphate-buffered saline via Alzet pumps for 28 days, followed by artificial cerebrospinal fluid infusion for 3 weeks. After the initial decrease in food intake, rats developed resistance to the satiety action of leptin, and withdrawal of the chronic leptin infusion resulted in hyperphagia. During leptin infusion, body weight was gradually decreased to reach a nadir on day 12, and thereafter, body weight was sustained at a reduced level throughout the entire 28-day infusion, despite normalization in food intake. Body weight was mostly normalized by day 22 postleptin. Since neuropeptide Y (NPY) neurones are one of the targets of leptin signalling in the hypothalamus, we next examined whether the development of resistance to the satiety action of leptin was due to altered NPY gene expression. On day 3-4 of infusion, hypothalamic NPY mRNA levels, as determined by RNAse protection assay (RPA), were significantly decreased in leptin treated rats compared to controls. By contrast, on day 16 of infusion, NPY mRNA levels in the leptin treated group had returned to control levels. In situ hybridization study confirmed the results obtained with RPA and showed further that the effect of chronic leptin infusion on NPY mRNA levels was restricted to the rostral and middle parts of the arcuate nucleus. Overall, the finding that the action of continuous leptin exposure on NPY neurones was not sustained suggests that NPY neurones may be involved in the development of leptin resistance to the satiety action of leptin in the hypothalamus. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Drug Resistance; Eating; Epididymis; Gene Expression; Hypothalamus; Injections, Intraventricular; Insulin; Leptin; Male; Neurons; Neuropeptide Y; Organ Size; Rats; Rats, Sprague-Dawley; Satiation | 2002 |
Hypothalamic NPY, AGRP, and POMC mRNA responses to leptin and refeeding in mice.
Food deprivation (FD) increases hypothalamic neuropeptide Y (NPY) and agouti-related protein (AGRP) mRNA levels and decreases proopiomelanocortin (POMC) mRNA levels; refeeding restores these levels. We determined the time course of changes in hypothalamic NPY, AGRP, and POMC mRNA levels on refeeding after 24 h FD in C57BL mice by in situ hybridization. After 24 h deprivation, mice were refed with either chow or a palatable mash containing no calories or were injected with murine leptin (100 microg) without food. Mice were perfused 2 or 6 h after treatment. Food deprivation increased hypothalamic NPY mRNA (108 +/- 6%) and AGRP mRNA (78 +/- 7%) and decreased hypothalamic POMC mRNA (-15 +/- 1%). Refeeding for 6 h, but not 2 h, was sufficient to reduce (but not restore) NPY mRNA, did not affect AGRP mRNA, and restored POMC mRNA levels to ad libitum control levels. Intake of the noncaloric mash had no effect on mRNA levels, and leptin administration after deprivation (at a dose sufficient to reduce refeeding in FD mice) was not sufficient to affect mRNA levels. These results suggest that gradual postabsorptive events subsequent to refeeding are required for the restoration of peptide mRNA to baseline levels after food deprivation in mice. Topics: Agouti-Related Protein; Animals; Body Composition; Body Weight; Eating; Energy Intake; Food Deprivation; Hypothalamus; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Intestines; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Physical Stimulation; Pro-Opiomelanocortin; Protein Biosynthesis; Proteins; RNA, Messenger; Signal Transduction; Taste | 2002 |
Compensation for partial lipectomy in mice with genetic alterations of leptin and its receptor subtypes.
One hypothesis for the regulation of total body fat suggests that leptin is a lipostatic feedback signal that acts at brain sites involved in regulation of energy balance. The importance of leptin in recovery from partial surgical lipectomy was tested by performing bilateral epididymal lipectomy or sham surgery on wild-type and leptin-deficient ob/ob mice. Eight weeks later, nonexcised pads of lipectomized mice were increased but total carcass fat was lower than in sham-operated ob/ob mice. In experiment 2, ob/ob mice, wild-type mice, and two db/db mutants, C57BL/6J db(Lepr)/db(Lepr) (BL/6J) mice possessing short-form and circulating leptin receptors and C57BL/6J db(3J)/db(3J) (BL/3J) mice expressing only circulating receptors, were lipectomized or sham operated. Sixteen weeks later, body mass and carcass lipid were not different between sham and lipectomized ob/ob mice, wild-type mice, or BL/6J db/db mice, whereas there was incomplete (decreased carcass fat) but suggestive recovery (increased retroperitoneal fat mass and cell number) in lipectomized BL/3J db/db mice. These data indicate that leptin is not required for the regulation of total body fat. Topics: Adipocytes; Animals; Body Composition; Body Weight; Cell Size; Epididymis; Female; Leptin; Lipectomy; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptors, Cell Surface; Receptors, Leptin | 2002 |
Congenic BB.SHR (D4Mit6-Npy-Spr) rats: a new aid to dissect the genetics of obesity.
The phenotypic characterization of congenic BB.LL rats recombining a segment of the SHR chromosome 4 (D4Mit6-Npy-Spr; 12 cM) into the BB/OK background indicated that these rats were not lymphopenic and did not develop diabetes, but they were significantly heavier (at 16 weeks of age) and showed higher serum triglycerides and total cholesterol concentration.. BB.LL rats were longitudinally studied for facets of metabolic syndrome (body mass index, blood glucose, serum lipids, insulin, leptin, and systolic and diastolic blood pressure) from 2 to 12 months of age.. In this study, it was shown that BB.LL are obese, hyperleptinemic, hyperinsulinemic, and dyslipidemic compared with their parental BB/OK rats.. It can be concluded that there is a gene(s) in the introgressed segment causing incomplete metabolic syndrome, because they do not develop hypertension and diabetes. To identify the gene(s), the introgressed chromosomal segment must be systematically whittled down to generate recombinants and new subcongenic lines carrying a much smaller segment of the SHR/Mol rat to increase the chance of identification of the appropriate gene(s). Topics: Animals; Animals, Congenic; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Cholesterol; Crosses, Genetic; Disease Models, Animal; Female; Insulin; Leptin; Longitudinal Studies; Male; Obesity; Quantitative Trait, Heritable; Rats; Rats, Inbred BB; Rats, Inbred SHR; Triglycerides | 2002 |
Adiponectin is stimulated by adrenalectomy in ob/ob mice and is highly correlated with resistin mRNA.
Plasma levels of the adipocyte product adiponectin, a putative insulin-sensitizing agent, are reduced in obesity, whereas plasma levels of resistin, an agent that some believe to confer insulin resistance, are thought to increase with obesity. Because adrenalectomy can increase insulin sensitivity, we hypothesized that adrenalectomy would increase expression of adiponectin and decrease expression of resistin. Therefore, we measured adiponectin mRNA, adiponectin peptide, and resistin mRNA in adrenalectomized ob/ob mice. Adrenalectomy restored adiponectin expression in ob/ob mice to wild-type levels and stimulated adiponectin peptide to above wild-type levels. Surprisingly, expression of adiponectin and resistin was highly positively correlated even after statistical removal of effects of insulin, glucose, and adiposity. In addition, adiponectin and resistin expression were also highly correlated in diet-induced obese mice. The data support a role for adiponectin in mediating some effects of adrenalectomy on insulin sensitivity. Topics: Adiponectin; Adrenalectomy; Animals; Blood Glucose; Body Weight; Diet; Dietary Fats; Disease Models, Animal; Eating; Fasting; Gene Expression; Homozygote; Hormones, Ectopic; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Nerve Growth Factor; Obesity; Proteins; Regression Analysis; Resistin; RNA, Messenger | 2002 |
Thyroid status regulates CART but not AgRP mRNA levels in the rat hypothalamus.
We examined the effects of thyroid status on cocaine- and amphetamine-regulated transcript and agouti-related peptide expression in the rat hypothalamus. Hypo- and hyperthyroidism were induced in adult male rats, and the mRNA content of cocaine- and amphetamine-regulated transcript and agouti-related peptide was determined using in situ hybridization. Hyperthyroidism induces a reduction in cocaine- and amphetamine-regulated transcript mRNA levels in the paraventricular nucleus, without any change in the arcuate and dorsomedial nuclei and in the lateral hypothalamic area. On the other hand, hypothyroidism had not effect on cocaine- and amphetamine-regulated transcript expression in any of these nuclei. Agouti-related peptide expression in the arcuate nucleus was not affected by the thyroid status. These data indicate that the increments in food intake in hyperthyroidism could be mediated, at least in some extent, by a decreased expression, at the paraventricular nucleus of the hypothalamus, of the anorexigenic cocaine- and amphetamine-regulated transcript peptides. Topics: Agouti-Related Protein; Amitrole; Animals; Appetite Regulation; Body Weight; Down-Regulation; Enzyme Inhibitors; Hyperthyroidism; Hypothyroidism; Intercellular Signaling Peptides and Proteins; Leptin; Male; Nerve Tissue Proteins; Neurons; Paraventricular Hypothalamic Nucleus; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyrotropin; Thyroxine; Up-Regulation | 2002 |
Is leptin a key factor which develops obesity by ovariectomy?
Withdrawal of estrogen by ovariectomy increases adiposity, but decreases the circulating levels of the ob gene product, leptin, which inhibits food intake. The reduction of circulating leptin levels may thus play an important role in the induction of obesity by ovariectomy. To examine this hypothesis, body weight change by ovariectomy was investigated in leptin-deficient genetically obese (ob/ob) mice with leptin supplement. Prior to the operation, obese (ob/ob) female mice were treated with intraperitoneal administration of recombinant mouse leptin (1.0 microg/g body weight/day) for 8 days. Then, half of the leptin-treated mice and their lean littermates were bilaterally ovariectomized and their body weight changes were observed for 56 days. From 16 days after the operation, a significant increase in body weight by ovariectomy was observed only in lean mice without leptin treatment. From 44 days, a significant body weight gain by ovariectomy was observed in leptin-treated obese mice. Ovariectomy significantly increased retroperitoneal white adipose tissue weight in their lean littermates, but not in leptin-treated obese mice. It was suggested that the reduction of circulating leptin levels may play an important role in the increases of acute phase body weight gain by ovariectomy, but during static phase, the direct effects of estrogen withdrawal may appear independent of leptin-mediated effects. Topics: Adipose Tissue; Animals; Body Weight; Female; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Ovariectomy; Recombinant Proteins; Reference Values | 2002 |
Effect of high dietary fat on insulin secretion in genetically diabetic Goto-Kakizaki rats.
To clarify the effects of a high fat-diet on insulin secretion from genetically diabetic beta cells, Goto-Kakizaki rats and Wistar rats were subjected to oral glucose tolerance test (OGTT) after 12-week high-fat feeding.. We compared Wistar and Goto-Kakizaki (GK) rats fed a high-fat diet (45% fat content) for 12 weeks, measuring insulin secretion and insulin release.. Insulin secretion during oral glucose tolerance test (OGTT) was enhanced in high-fat diet-fed Wistar rats (WF) with normal glucose tolerance. Insulin secretion in high-fat diet-fed GK rats (GF) during OGTT also was enhanced together with deteriorated glucose tolerance. Basal insulin release from the isolated perfused pancreas at 3.3 m glucose in WF was comparable to that in normal chow-fed Wistar rats (WN), but basal insulin release in GF was remarkably higher than in normal chow-fed GK rats (GN). Stimulated insulin release induced by 16.7 m glucose was remarkably increased in WF compared with WN. Total insulin release at 16.7 m glucose in both GK rat groups was similar and minimal.. These results indicate that normal pancreatic beta-cells have the ability to secrete sufficient insulin to compensate for the insulin resistance induced by a high-fat diet. In contrast, glucose metabolism in diabetic rats after high-fat diet deteriorated partly because of insufficient insulin secretion caused by genetic defects and lipotoxicity due to chronically high FFA levels. Topics: Animals; Blood Glucose; Body Weight; Culture Techniques; Diabetes Mellitus, Type 2; Dietary Fats; Fatty Acids; Glucose; Glucose Tolerance Test; Insulin; Insulin Secretion; Leptin; Pancreas; Rats; Rats, Mutant Strains; Rats, Wistar; Triglycerides | 2002 |
[Examining consecutively serum leptin levels in normal pregnant and pregnancy-induced hypertension women].
To detect successsively serum leptin levels in normal, pregnancy-induced hypertension (PIH) pregnant women.. Levels of serum leptin were measured in the 16-20, 24-28, 32-36 weeks of gestation, at the delivery time in 50 healthy, 14 PIH pregnant women and their newborns and in 40 healthy non-pregnant women by Immuno-radioassay method. Serum leptin levels were correlated with body weight, body mass index (BMI), blood pressure and placental weight.. (1) The serum leptin levels were increased gradually during the normal (14.1 +/- 2.2)-(25.4 +/- 2.7) micro g/L and the PIH pregnancy [(13.4 +/- 3.0)-(21.4 +/- 3.7)] micro g/L, especially in the PIH women. It was found that leptin concentrations rose markedly from 28 to 36 weeks of gestation, but increased slightly before the 28 weeks of gestation and after the 36 weeks of gestation in normals, and in contrast to the normal pregnancy, consistently higher until to the delivery time in the PIH. (2) The positive correlations were significant between the levels of serum leptin with their body weight and BMI in the normal pregnant and non-pregnant women (r = 0.478-0.639, P < 0.05 or P < 0.01), but not significant in the PIH pregnant (r = 0.035-0.379, P > 0.05). (3) The positive correlations were significant between the serum leptin concentrations and the systolic blood pressure, diastolic blood pressure and mean artery pressure in the PIH women after 20 weeks of gestation (r = 0.639-0.852, P < 0.05), but not significant in the normal pregnant, the PIH before 20 weeks of gestation and the non-pregnant women (r = 0.113-0.498, P > 0.05). (4) Before the delivery time, the positive correlation between the serum leptin concentrations of the pregnant women and that of the newborns was not significant, and also not significant between the puerperas' serum leptin levels and the placental weight in the normal pregnant (r = 0.132, 0.097, P > 0.05). But it was interesting that significant positive correlation was found between the puerperas' serum leptin concentrations and the cord serum leptin levels (r = 0.792, P < 0.01) and significant negative correlation was detected between the puerperas' serum leptin levels and the placental weight in the PIH women (r = -0.819, P < 0.01). (5) The leptin levels of cord blood were positively correlated with the body weight and BMI of newborns in both of the normal and PIH pregnancy (r = 0.520-0.655, P < 0.05 or P < 0.01).. The characteristic change of serum leptin levels and correlations between the serum leptin concentrations and the related pregnant signs was different in normal and PIH pregnancy. Topics: Blood Pressure; Body Mass Index; Body Weight; Female; Humans; Hypertension; Leptin; Pregnancy; Pregnancy Complications, Cardiovascular; Time Factors | 2002 |
Long-term effect of fish oil diet on basal and stimulated plasma glucose and insulin levels in ob/ob mice.
In this study, the ob/ob mouse model was used to investigate epidemiological evidence linking fish intake to relative reduction in incidence of Type 2 diabetes mellitus and glucose. We have investigated, in comparison to low and high fat diets, the effect of a fish oil diet on basal and stimulated plasma glucose and insulin levels in male and female ob/ob mice. Mice were fed for 12 months with a saturated fat diet containing 25% lard, with a low fat diet containing 5% soybean oil, with a polyunsaturated fat diet containing 25% safflower seed oil (n-6) or with polyunsaturated fat diet containing 23% fish oil (n-3). Total body weight increased to approximately 100 g at the end of the experiment, with the highest increase in the order of lard > safflower oil > fish oil > soybean oil diet. Intercurrent deaths were found especially in the fish oil diet group. Compared to the other diet groups, plasma insulin levels of the fish oil diet group were significantly increased 3 months after the start of the diet and remained higher for another 3 months. Thereafter, the level declined to those of the other diet groups. Glucose-tolerance tests at 3, 6, 8 and 10 months showed a tendency of more efficient tissue glucose uptake in the fish oil group compared to the other groups, which was in accordance with a higher plasma insulin levels. At 12 months, microscopy revealed an increased severity of hepatic brown pigment accumulation and extramedullary haematopoiesis in the spleen of mice fed with fish oil. We conclude that fish oil diet in ob/ob mice reduced the body weight gain and increased the glucose-induced insulin secretion. Fish oil diet also increased intercurrent mortality. However, a consistent course of death could not be established using morphological parameters. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dietary Fats, Unsaturated; Fatty Acids, Omega-3; Female; Fish Oils; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Spleen | 2002 |
The effects of adrenalectomy and aldosterone replacement in transgenic mice expressing antisense RNA to the type 2 glucocorticoid receptor.
Bilateral adrenalectomy (ADX) either prevents or attenuates obesity in several animal models. Mice that express an antisense RNA to the glucocorticoid receptor (GCR) are obese. The present study was conducted to examine the effects of ADX and aldosterone (ALDO) replacement on the rate of weight gain and body composition of mice bearing an antisense GCR gene construct. Twenty-eight male transgenic mice bearing the antisense GCR construct and 16 male B6C/3F1 mice were either bilaterally ADX or given sham operations. At the time of surgery, some of the ADX mice and all of the sham-operated mice were implanted with 100-mg cholesterol (CHOL) pellets inserted subcutaneously in the subscapular region. The remaining ADX mice were implanted with 100-mg 1% w/w ALDO pellets using CHOL as vehicle. All mice were returned to their home cages for 2 weeks. They were then decapitated and the blood was collected for corticosterone, ALDO, insulin, and leptin radioimmunoassay. Carcasses were eviscerated and prepared for gravimetric analyses, including bomb calorimetry. ADX resulted in a significant drop in carcass fat in both transgenic and wildtype groups. ALDO prevented the decrease in carcass fat in both groups. Two weeks after ADX, transgenic mice were as fat as sham-operated wildtype controls, whereas both sham-operated and ALDO-treated transgenic groups were significantly fatter. Despite observing a reliable decrease in carcass fat following ADX, no corresponding decrease in circulating leptin was found. Topics: Adrenal Cortex Hormones; Adrenalectomy; Aldosterone; Animals; Blood Glucose; Body Composition; Body Weight; Drug Implants; Insulin; Leptin; Male; Mice; Mice, Transgenic; Receptors, Glucocorticoid; RNA, Antisense | 2002 |
Effects of leptin on arcuate pro-opiomelanocortin and cocaine-amphetamine-regulated transcript expression are independent of circulating levels of corticosterone.
In the hypothalamic arcuate nucleus, neurones that coexpress cocaine-amphetamine-regulated transcript (CART) and alpha-melanocyte-stimulating hormone [alpha-MSH; pro-opiomelanocortin (POMC) derived] peptides exert catabolic actions and are stimulated by leptin. However, leptin treatment also affects other circulating factors that influence hypothalamic gene expression. Notably, the hypercorticosteronaemia of ob/ob mice is lowered by leptin treatment. To examine the interaction between glucocorticoids and leptin on POMC/CART mRNA expression, an experiment combining leptin and adrenalectomy (ADX) in leptin deficient ob/ob mice was carried out. Obese ob/ob and lean littermate Ob/? mice were ADX or sham-operated. ADX mice received a pellet containing 25% corticosterone subcutaneously. Seven days postoperatively, mice were injected intraperitoneally for 5 days with either recombinant human leptin or vehicle. On the sixth day, the mice were decapitated and the brains removed and trunk blood was collected for corticosterone analysis. Plasma concentrations of corticosterone were elevated in all ob/ob groups compared to Ob/?. For both ob/ob and Ob/? groups, corticosterone concentrations exhibited a decline across groups: vehicle-sham>leptin-sham>ADX-vehicle>ADX-leptin. Leptin inhibited food intake and bodyweight in ob/ob-sham and ob/ob-ADX to a similar extent, whereas no effect of leptin was observed in Ob/? mice. Similarly, leptin caused an identical increase in arcuate POMC and CART mRNA expression in ob/ob-sham and ob/ob-ADX compared to vehicle. The present data support the view that leptin influences arcuate POMC and CART mRNA expression directly, and that the effect is not modulated by corticosterone across a wide range of circulating corticosterone concentrations. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Corticosterone; Eating; Humans; In Situ Hybridization; Leptin; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Pro-Opiomelanocortin | 2002 |
Contrasting effects of different levels of food intake and adiposity on LH secretion and hypothalamic gene expression in sheep.
Body reserves (long-term) and food intake (short-term) both contribute nutritional feedback to the hypothalamus. Reproductive neuroendocrine output (GnRH/LH) is stimulated by increased food intake and not by high adiposity in sheep, but it is unknown whether appetite-regulating hypothalamic neurons show this differential response. Castrated male sheep (Scottish Blackface) with oestradiol implants were studied in two 4 week experiments. In Experiment 1, sheep were fed to maintain the initial body condition (BC) score of 2.0+/-0.00 (lower BC (LBC), n=7) or 2.9+/-0.09 (higher BC (HBC), n=9), and liveweight of 43+/-1.1 and 59+/-1.6 kg respectively. LBC and HBC sheep had similar mean plasma LH concentration, pulse frequency and amplitude, but HBC animals had higher mean plasma concentrations of insulin (P<0.01), leptin (P<0.01) and glucose (P<0.01). Gene expression (measured by in situ hybridisation) in the hypothalamic arcuate nucleus (ARC) was higher in LBC than HBC sheep for neuropeptide Y (NPY; 486% of HBC, P<0.01), agouti-related peptide (AGRP; 467%, P<0.05) and leptin receptor (OB-Rb; 141%, P<0.05), but lower for cocaine- and amphetamine-regulated transcript (CART; 92%, P<0.05) and similar between groups for pro-opiomelanocortin (POMC). In Experiment 2, sheep with initial mean BC score 2.4+/-0.03 and liveweight 55+/-0.8 kg were fed a liveweight-maintenance ration (low intake, LI, n=7) while sheep with initial mean BC score 2.0+/-0.03 and liveweight 43+/-1.4 kg were fed freely so that BC score increased to 2.5+/-0.00 and liveweight increased to 54+/-1.4 kg (high intake, HI, n=9). Compared with LI, HI sheep had higher mean plasma LH (P<0.05), baseline LH (P<0.01) and pulse amplitude (P<0.01) and showed a trend towards higher pulse frequency. Although there were no differences in final mean plasma concentrations, there were significant increases over time in mean concentrations of insulin (P<0.001), leptin (P<0.05) and glucose (P<0.001) in HI sheep. Gene expression for AGRP in the ARC was higher in HI than LI animals (453% of LI; P<0.05), but expression levels were similar for NPY, OB-Rb, CART and POMC. Thus, the hypothalamus shows differential responses to steady-state adiposity as opposed to an increase in food intake, in terms of both reproductive neuroendocrine activity and hypothalamic appetite-regulating pathways. Differences in hypothalamic gene expression were largely consistent with contemporary levels of systemic leptin and insulin feedback; howev Topics: Adipose Tissue; Animals; Autoradiography; Blood Glucose; Body Weight; Eating; Fatty Acids, Nonesterified; Gene Expression; Hypothalamus; Insulin; Leptin; Luteinizing Hormone; Male; Orchiectomy; Sheep | 2002 |
Inducible ablation of adipocytes in adult transgenic mice expressing the E. coli nitroreductase gene.
We describe the use of an enzyme prodrug system based on E. coli nitroreductase (NTR) to achieve the specific ablation of adipose tissue. Transgenic mice expressing the NTR gene specifically in the adipose tissue were generated using the adipocyte specific promoter aP2. After treatment with the prodrug CB1954 these mice showed extensive cell depletion in all fat depots; this was directly correlated to both the dose of prodrug and the levels of NTR expression. Higher doses of CB1954 resulted in complete disappearance of visible adipose stores in some transgenic mice. These mice exhibited an impaired ability to thermoregulate body temperature. Lower doses of CB1954 resulted in a partial reduction of the adipose tissue leaving non-expressing cells that escape ablation. These animals show normal levels of blood glucose and triglycerides but have reduced leptin levels. After 30 days they were able to regenerate the fat depots and leptin levels returned to normal but, interestingly, no NTR-expressing cells were detectable. The present model provides a new approach to manipulate the number of adipocytes at different stages of mouse development and provides a new system for the study of fat metabolism especially in abnormal conditions such as obesity and its modulation through manipulation of the target cell population. Topics: Adipocytes; Adipose Tissue; Animals; Apoptosis; Aziridines; Blood Glucose; Blotting, Northern; Blotting, Western; Body Weight; Genes; Leptin; Male; Mice; Mice, Transgenic; Nitroreductases; Prodrugs; Promoter Regions, Genetic; Triglycerides | 2002 |
Induction of uncoupling protein 1 by central interleukin-6 gene delivery is dependent on sympathetic innervation of brown adipose tissue and underlies one mechanism of body weight reduction in rats.
Interleukin-6 (IL-6) is a multifunctional cytokine that may have a role in energy regulation. Using a recombinant adeno-associated viral vector expressing murine interleukin-6 (rAAV-IL-6), we examined the chronic effects of centrally expressed IL-6 on food intake, body weight and adiposity in male Sprague-Dawley rats, and investigated the underlying mechanisms. Direct delivery of rAAV-IL-6 into rat hypothalamus suppressed weight gain and visceral adiposity without affecting food intake over a 5-week period. rAAV-IL-6 enhanced uncoupling protein 1 (UCP1) protein levels in interscapular brown adipose tissue (BAT). To investigate if the induction of UCP1 and the reduction in body weight are dependent on sympathetic innervation of BAT, we administered rAAV-IL-6 or a control vector into the hypothalamus of rats in which the interscapular BAT was unilaterally denervated. Over 21 days, there was no difference in food consumption or body weight between rAAV-IL-6- and control vector-treated rats. rAAV-IL-6 delivery increased UCP1 mRNA and protein levels in innervated BAT pads but not denervated BAT pads. Hypothalamic IL-6 signal transduction, indicated by phosphorylated signal transducer and activator of transcription 3 (P-STAT3) levels, was elevated by 2.6-fold at day 21, but returned to control levels by day 35. However, the suppressor of cytokine signaling-3 mRNA level was significantly elevated both at day 21 and day 35. These data demonstrate that chronic elevation of IL-6 in the CNS reduces body weight gain and visceral adiposity without affecting food intake. The mechanism involves sympathetic induction of UCP1 in BAT and, presumably, enhanced thermogenesis in BAT. Furthermore, chronic central IL-6 stimulation desensitizes IL-6 signal transduction characterized by reversal of elevated P-STAT3 levels. Topics: Adipose Tissue, Brown; Animals; Appetite Regulation; Body Weight; Carrier Proteins; Cells, Cultured; Corticosterone; DNA-Binding Proteins; Energy Metabolism; Gene Expression Regulation; Genetic Vectors; Humans; Hypothalamus; Immunohistochemistry; Interleukin-6; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Sympathectomy; Sympathetic Nervous System; Thermogenesis; Trans-Activators; Transfection; Uncoupling Protein 1 | 2002 |
Corticosterone infused intracerebroventricularly inhibits energy storage and stimulates the hypothalamo-pituitary axis in adrenalectomized rats drinking sucrose.
When allowed to drink sucrose, bilaterally adrenalectomized (ADX) rats exhibit normal weight gain, food intake, sympathetic neural activity, and ACTH compared with sham-ADX rats. Furthermore, ADX rats drinking sucrose have normal corticotropin-releasing factor (CRF) mRNA throughout brain. In ADX rats without sucrose, all of these variables are abnormal. Systemic corticosterone (B) replacement also restores these variables in ADX rats to normal. To test whether B acts centrally, we infused B or saline intracerebroventricularly into ADX rats under basal conditions and after repeated restraint. Rats were exposed to no stress or 3 h/d restraint for 3 d. Body weights and food and fluid intakes were measured. Brains were analyzed using immunocytochemistry against glucocorticoid receptors (GR) and CRF. Intracerebroventricular B blocked the positive effects of sucrose on metabolism, increased basal ACTH concentrations, and augmented ACTH responses to restraint on d 3. B-infused rats exhibited nuclear GR staining in perirhinal cortex, hippocampus, and hypothalamic paraventricular nuclei, showing that infused B spreads effectively. CRF staining in the paraventricular nucleus of the hypothalamus was higher in B- than in saline-infused rats. We conclude that under basal conditions B acts systemically, but not in the brain, to restore metabolism and neuropeptides after adrenalectomy. By contrast, tonic GR occupancy in brain initiates metabolic and ACTH responses characteristic of stress. Topics: Adrenalectomy; Adrenocorticotropic Hormone; Animals; Blood Glucose; Body Weight; Brain; Brain Chemistry; Cerebral Ventricles; Corticosterone; Corticotropin-Releasing Hormone; Dietary Sucrose; Drinking; Energy Metabolism; Hypothalamus; Insulin; Leptin; Male; Pituitary Gland; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Restraint, Physical; Stress, Physiological | 2002 |
Relationships of serum leptin to clinical and anthropometric findings in obese patients.
The authors evaluated the relationship between leptin and the clinical, anthropometric and metabolic variables connected to the metabolic syndrome in obese individuals.. A large group of patients with different degrees of obesity was investigated: body mass index (BMI) values, serum leptin, fasting glucose and insulin, triglycerides and HDL-cholesterol concentrations, insulin resistance index and blood pressure were measured.. On multiple regression analysis, serum leptin levels appeared to be positively correlated to the BMI and to the serum HDL-cholesterol concentration. Principal component factor analysis revealed three factors, explaining 61.3% of the total variance of the sample. General features of these factors were: factor 1--BMI values and serum leptin and fasting glucose concentration; factor 2--systolic and diastolic blood pressure and serum triglycerides and HDL-cholesterol concentration; factor 3--fasting serum insulin concentration and insulin resistance index.. In obese subjects multiple factors underlie the metabolic syndrome and therefore more than one mechanism may account for the clustering characteristics. In obese patients leptin loads only one factor, and therefore leptin does not appear to be a key feature in the metabolic syndrome. On the contrary, multiple correlation and factor analysis data give rise to the hypothesis that in obese patients, leptin may play a protective role against cardiovascular risk. Topics: Adolescent; Adult; Anthropometry; Body Composition; Body Weight; Fasting; Female; Humans; Leptin; Male; Middle Aged; Obesity; Obesity, Morbid | 2002 |
Effects of adrenalectomy on AGRP, POMC, NPY and CART gene expression in the basal hypothalamus of fed and fasted rats.
Glucocorticoids regulate body energy balance through both peripheral and central mechanisms. In order to understand the central mechanisms that mediate these effects of glucocorticoids we studied the effects of adrenalectomy (ADX) and food deprivation on the expression of four neuropeptide genes (measured by S1 nuclease protection assay) in the medial basal hypothalamus (MBH), which are known to regulate energy balance: pro-opiomelanocortin (POMC), agouti-related peptide (AGRP), neuropeptide Y (NPY), and cocaine and amphetamine regulated transcript (CART). Adult male rats were ADX or sham operated (SHAM), and studied 1-2 weeks later. In the first study effects of ADX and corticosterone replacement on POMC and AGRP expression were determined. ADX decreased POMC and AGRP gene expression in the MBH by 27 and 38%, respectively, compared to SHAM rats. Corticosterone treatment increased the expression of POMC by 87% and AGRP by 45% in ADX rats. The second study was designed to determine if glucocorticoids are necessary for the fasting induced changes in POMC, AGRP, NPY and CART in the MBH. ADX caused a 20-30% decrease in the expression of all four neuropeptide genes in the MBH. As expected, fasting suppressed POMC and CART expression and increased AGRP and NPY expression. The fasting-induced increases in AGRP and NPY persisted after ADX but no further significant decreases in POMC or CART were noted after fasting in ADX rats. Plasma leptin and insulin declined significantly after ADX and increased with corticosterone replacement; both leptin and insulin declined further in fasted, ADX animals. In conclusion, ADX decreases both anorexigenic, POMC and CART, and orexigenic, AGRP and NPY, neuropeptide gene expression in the MBH. AGRP and NPY decrease after ADX despite the fall in plasma leptin and insulin concentrations which in other situations would increase these neuropeptides. Furthermore, glucocorticoids are not required for fasting-induced upregulation of AGRP and NPY expression. Topics: Adrenal Cortex; Agouti-Related Protein; Animals; Body Weight; Corticosterone; Energy Metabolism; Food Deprivation; Gene Expression Regulation; Glucocorticoids; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Male; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Pro-Opiomelanocortin; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2002 |
Targeted disruption of H3 receptors results in changes in brain histamine tone leading to an obese phenotype.
Histamine is an aminergic neurotransmitter that is localized in the CNS and in peripheral tissues. To date, four histamine receptors have been identified, and the H3 receptor, which was recently cloned, is predominantly expressed in the CNS. The peripheral functions of histamine have been investigated intensively using available molecular and pharmacological tools, and the molecular identification of the H3 receptor opens up new possibilities for investigating the role of histamine in central tissues. To understand the biological function of the histamine presynaptic autoreceptor H3, we inactivated the receptor through homologous recombination. H3(-/-) mice manifest mild obese phenotypes that are characterized by increases in body weight, food intake, and adiposity and by reductions in energy expenditure. Consistent with these observations, homozygous null mice have insulin and leptin resistance, increased levels of plasma leptin and insulin, and decreased levels of histamine in the hypothalamic/thalamic region of their brains coupled with increased histamine turnover. The expression of UCP1 in brown adipose tissue and of UCP3 in brown adipose tissue, white adipose tissue, and skeletal muscle is decreased in H3(-/-) mutants, and the anorexigenic activity of thioperamide is not observed. These results suggest that neuronal histamine is a mediator of body-weight homeostasis and that neuronal histamine functions through H3 receptors in mice. Topics: Animals; Biomarkers; Body Weight; Brain; Eating; Female; Gene Targeting; Histamine; Histamine Antagonists; Homeostasis; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Muscle, Skeletal; Neurons; Obesity; Phenotype; Piperidines; Receptors, Histamine H3 | 2002 |
Protein (lysine) restriction in primiparous lactating sows: effects on metabolic state, somatotropic axis, and reproductive performance after weaning.
Low protein intake during lactation has been demonstrated to increase the loss of body protein and to reduce the reproductive performance of female pigs. The objectives of the current experiment were 1) to determine whether protein (lysine) restriction alters levels of somatotropic hormones, insulin, follicle-stimulating hormone, and leptin around weaning, and 2) to evaluate the relationships between these eventual alterations and postweaning reproductive performance. One day after farrowing, crossbred primiparous sows were randomly allocated to one of two diets containing 20% crude protein and 1.08% lysine (C, n = 12) or 10% crude protein and 0.50% lysine (L, n = 14) during a 28-d lactation. Diets provided similar amounts of metabolizable energy (3.1 Mcal/kg). Feed allowance was restricted to 4.2 kg/d throughout lactation, and litter size was standardized to 10 per sow within 5 d after farrowing. Catheters were fitted in the jugular vein of 21 sows around d 22 of lactation. Serial blood samples were collected 1 d before (day W - 1) and 1 d after (day W + 1) weaning, and single blood samples were collected daily from weaning until d 6 postweaning (day W + 6). Sows were monitored for estrus and inseminated. They were slaughtered at d 30 of gestation. During lactation, litter weight gain was similar among treatment groups. Reduced protein intake increased (P < 0.001) sow weight loss (-30 vs -19 kg) and estimated protein mobilization throughout lactation (-4.1 vs -2.0 kg). On day W - 1, L sows had higher (P < 0.02) plasma glutamine and alanine concentrations, but lower (P < 0.05) plasma tryptophan and urea than C sows. Mean and basal plasma GH were higher (P < 0.001), whereas plasma IGF-I and mean insulin were lower in L than in C sows on day W - 1. Preprandial leptin did not differ between treatments on day W - 1, but was higher (P < 0.01) in L sows than in C sows on day W + 1. Mean FSH concentrations were similar in both treatments on day W - 1 (1.3 ng/mL), but L sows had greater (P < 0.001) mean FSH on day W + 1 than C sows (1.6 vs 1.2 ng/mL). The weaning-to-estrus interval (5 +/- 1 d) was similar in both groups. Ovulation rate was lower in L than in C sows (20.0 +/- 1 vs 23.4 +/- 1, P < 0.05). No obvious relationships between reproductive traits and metabolic hormone data were observed. In conclusion, these results provide evidence that protein (lysine) restriction throughout lactation alters circulating concentrations of somatotropic hormones and insuli Topics: Animals; Body Weight; Dietary Proteins; Energy Metabolism; Female; Follicle Stimulating Hormone; Growth Hormone; Insulin; Lactation; Leptin; Litter Size; Lysine; Random Allocation; Reproduction; Swine; Weaning | 2002 |
A longitudinal study of leptin and appetite, resting energy expenditure and body fat mass in weight-stable cancer patients.
Leptin and its relationship with energy metabolism in male weight-stable patients with colorectal liver metastases (n=14) was assessed at baseline and after 6 weeks. At baseline, median leptin concentration was 5.9 microg/l and the median percentage fat mass was 32.1%. Circulating leptin concentrations were correlated with measured percentage fat mass at baseline (r(s)=0.519, P=0.040) and with the changes after 6 weeks (r(s)=0.611, P=0.027) but not with insulin, cortisol, C-reactive protein, appetite or resting energy expenditure. Therefore, it would appear that leptin concentrations reflect changes in fat mass in male weight-stable patients with cancer and their role in the regulation of energy metabolism appears more complex than previously proposed. Topics: Adenocarcinoma; Adipose Tissue; Adult; Aged; Appetite; Body Composition; Body Weight; C-Reactive Protein; Colorectal Neoplasms; Energy Metabolism; Humans; Hydrocortisone; Insulin; Leptin; Liver Neoplasms; Longitudinal Studies; Male; Middle Aged; Serum Albumin | 2002 |
Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice.
Small body size has been associated with long life span in four stocks of mutant dwarf mice, and in two varieties of dietary restriction in rodents. In this study, small body size at ages 2-24 months was shown to be a significant predictor of life span in a genetically heterogeneous mouse population derived from four common inbred mouse strains. The association was strongest for weights measured early in adult life, and somewhat weaker, though still statistically significant, at later ages. The effect was seen both in males and females, and was replicated in an independent population of the same genetic background. Body size at ages 2-4 months was correlated with levels of serum leptin in both males and females, and with levels of IGF-I and thyroid hormone in females only. A genome scan showed the presence of polymorphic alleles on chromosomes 2, 6, 7 and 15 with significant effects on body weight at 2-4 months, at 10-12 months, or at both age ranges, showing that weight gain trajectory in this stock is under complex genetic control. Because it provides the earliest known predictor of life span, body weight may be usefully included in screens for induced mutations that alter aging. The evidence that weight in 2-month-old mice is a significant predictor of life span suggests that at least some of the lethal diseases of old age can be timed by factors that influence growth rate in juvenile rodents. Topics: Animals; Body Constitution; Body Weight; Female; Genetic Predisposition to Disease; Genetic Testing; Insulin-Like Growth Factor I; Leptin; Longevity; Male; Mice; Mice, Inbred Strains; Mutation; Polymorphism, Genetic; Sex Factors; Thyroid Hormones | 2002 |
Effect of leptin on LH and FSH release in ovariectomized rats.
We compared the estradiol/progesterone-induced luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release between normally fed and leptin-supplemented starved ovariectomized female rats and studied also the effect of hyper-leptinaemia on the steroid-induced hormonal release in normally fed ovariectomized rats. Three days' starvation completely abolished steroid-induced LH and FSH release. Significant recovery of the hormonal release was shown in the leptin-supplemented starved group. The magnitudes of LH and FSH release in the normally fed animals with a higher dose of leptin were statistically the same as those in the normally fed group without leptin. These observations indicate that physiological concentrations of circulating leptin exert a stimulatory effect on steroid-induced LH and FSH release. Topics: Analysis of Variance; Animals; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Follicle Stimulating Hormone; Hypothalamo-Hypophyseal System; Leptin; Luteinizing Hormone; Neuropeptide Y; Nitric Oxide; Ovariectomy; Rats; Reproductive Medicine; Starvation; Time Factors | 2002 |
Correlation between plasma leptin concentration and body fat content in dogs.
To evaluate the relationship between plasma leptin concentration and body fat content in dogs.. 20 spayed female Beagles that were 10 months old at the start of the experiment.. Dogs were kept under regulated feeding and exercise conditions for 21 weeks, resulting in a wide range of body weights, body condition scores (BCS), and subcutaneous thicknesses. Plasma leptin concentration was measured by use of a canine leptin-specific ELISA test to evaluate its correlation to body fat content estimated by the deuterium oxide dilution method. Plasma concentrations of glucose, cholesterol, triglycerides (TG), and nonesterified fatty acids (NEFA) were also measured.. Body fat content (9 to 60% of body weight) was positively and closely correlated (r = 0.920; n = 20; P < 0.001) to plasma leptin concentration (0.67 to 8.06 ng/ml), compared with other variables (ie, glucose, cholesterol, TG, and NEFA; r = 0.142, 0.412, 0.074, and 0.182, respectively).. The positive relationship between plasma leptin concentration and body fat content in dogs was similar to correlations reported for humans and rodents, suggesting that plasma leptin is a quantitative marker of adiposity in dogs. Topics: Adipose Tissue; Animal Feed; Animals; Biomarkers; Body Weight; Dog Diseases; Dogs; Female; Leptin; Obesity | 2002 |
Defense of body weight depends on dietary composition and palatability in rats with diet-induced obesity.
Sprague-Dawley rats selectively bred for diet-induced obesity (DIO) or diet resistance (DR) were characterized on diets of differing energy content and palatability. Over 10 wk, DR rats on a high-energy (HE) diet (31% fat) gained weight similarly to DR rats fed chow (4.5% fat), but they became obese on a palatable liquid diet (Ensure). DIO rats gained 22% more weight on an HE diet and 50% more on Ensure than chow-fed DIO rats. DIO body weight gains plateaued when switched from HE diet to chow. But, Ensure-fed DIO rats switched to chow spontaneously reduced their intake and weight to that of rats switched from HE diet to chow. They also reduced their hypothalamic proopiomelanocortin and dynorphin but not neuropeptide Y mRNA expression by 17-40%. When reexposed to Ensure after 7 wk, they again overate and matched their body weights to rats maintained on Ensure throughout. All Ensure-fed rats had a selective reduction in dynorphin mRNA in the ventromedial hypothalamic nucleus. Thus genetic background, diet composition, and palatability interact to produce disparate levels of defended body weight and central neuropeptide expression. Topics: Adipose Tissue; Animal Feed; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Diet; Dietary Sucrose; Dynorphins; Eating; Food, Formulated; Gene Expression; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2002 |
Determinants of leptin gene expression in fat depots of lean mice.
The relationship of leptin gene expression to adipocyte volume was investigated in lean 10-wk-old male C57BL/6J mice. mRNA levels for leptin, insulin receptor, glucocorticoid receptor, and tumor necrosis factor (TNF)-alpha in inguinal, epididymal, and retroperitoneal adipose tissues were quantified and related to adipocyte volume. Leptin mRNA levels were highly correlated with adipocyte volume within each fat depot. Multiple regression analysis of pooled data from the three depots showed that leptin mRNA levels were strongly correlated with adipocyte volumes (beta = 0.84, P < 0.001) and, to a smaller degree, with glucocorticoid receptor mRNA levels (beta = 0.36, P < 0.001). Depot of origin had no effect (P > 0.9). Rates of leptin secretion in vitro were strongly correlated with leptin mRNA levels (r = 0.89, P < 0.001). mRNA levels for TNF-alpha, insulin receptor, and glucocorticoid receptor showed no significant correlation with adipocyte volume. These results demonstrate that depot-specific differences in leptin gene expression are mainly related to the volumes of the constituent adipocytes. The strong correlation between leptin gene expression and adipocyte volume supports leptin's physiological role as a humoral signal of fat mass. Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; DNA Primers; Gene Expression; Homeostasis; Leptin; Male; Mice; Mice, Inbred C57BL; Receptor, Insulin; Receptors, Glucocorticoid; Receptors, Leptin; RNA, Messenger; Tumor Necrosis Factor-alpha | 2002 |
PRL-releasing peptide interacts with leptin to reduce food intake and body weight.
PRL-releasing peptide (PrRP) is a novel anorexigen that reduces food intake and body weight gain in rats. In common with other anorexigens, PrRP mRNA expression is reduced during states of negative energy balance, i.e. lactation and fasting in female rats. In this study, we examined the interaction between PrRP and the adiposity signal, leptin, which interacts with a number of peptidergic systems in the brain to regulate energy homeostasis. Intracerebroventricular coadministration of 4 nmol PrRP and 1 microg leptin in rats resulted in additive reductions in nocturnal food intake and body weight gain and an increase in core body temperature compared with each peptide alone. We show also, by quantitative in situ hybridization, that PrRP mRNA is reduced in fasted male rats and obese Zucker rats, indicating that PrRP mRNA expression, like that of other anorexigens, may be regulated by leptin. Finally we show, using immunohistochemistry, that greater than 90% of PrRP neurons in all regions where PrRP is expressed contain leptin receptors. Thus, we provide evidence for PrRP neurons forming part of the leptin-sensitive brain circuitry involved in the regulation of food intake and energy homeostasis. Topics: Animals; Body Temperature; Body Weight; Depression, Chemical; Dorsomedial Hypothalamic Nucleus; Drug Interactions; Eating; Energy Metabolism; Fluorescent Antibody Technique, Indirect; Hypothalamic Hormones; Immunohistochemistry; In Situ Hybridization; Injections, Intraventricular; Leptin; Male; Neuropeptides; Obesity; Prolactin; Prolactin-Releasing Hormone; Rats; Rats, Sprague-Dawley; Rats, Zucker; Solitary Nucleus; Tyrosine 3-Monooxygenase; Ventromedial Hypothalamic Nucleus | 2002 |
Ghrelin and leptin pulse discharge in fed and fasted rats.
Ghrelin stimulates and leptin inhibits appetite by modulating neuropeptide Y (NPY) signaling in the hypothalamus. Analysis of plasma ghrelin and leptin by sensitive radioimmunoassays showed that the two peripheral hormones are secreted in pulsatile fashion in rats consuming ad libitum rat chow. Fasting augmented all parameters of ghrelin pulsatile secretion and diminished leptin secretion by selectively attenuating the pulse amplitude; concomitantly it produced synchrony in ghrelin and leptin pulse discharge. These studies imply that a synchronous leptin restraint and ghrelin stimulus on NPYergic signaling may underlie robust appetitive drive. Topics: Animals; Body Weight; Fasting; Female; Ghrelin; Hypothalamus; Kinetics; Leptin; Neuropeptide Y; Peptide Hormones; Peptides; Radioimmunoassay; Rats; Rats, Sprague-Dawley | 2002 |
Effects of intracerebroventricularly and intraperitoneally administered growth hormone on body weight and food intake in fa/fa Zucker rats.
Growth hormone (GH) possesses multiple metabolic effects, in particular with regard to glucose and lipid homeostasis. Studies on the effects of GH on body weight and food and water intake are scarce and have yielded controversial results. We investigated the effects of different modes of GH administration on the parameters of body weight and food intake as well as on insulin and leptin concentrations in fa/fa Zucker rats. In control experiments, aqua pro injection was given. GH was administered over a time period of 11 days at a daily dose of 250 microg intraperitoneally (i.p.) and 25 microg intracerebroventricularly (i.c.v.). While both food intake and body weight were found to be unaltered in the four groups after this observation period, there was an enhanced food intake and consecutively an increase in body weight over the day period when compared to the night period in the groups of rats that received GH i.c.v. or i.p. This tendency was also shown for water intake. Insulin and leptin concentrations were similar in all groups. Thus, injection of GH appears to modify food intake-related behavior, since the periods of enhanced food and water intake were shifted from night- to daytime. Thus, while in general the metabolic parameters remained unchanged, the activity pattern was clearly modified. Topics: Animals; Body Weight; Carrier Proteins; Disease Models, Animal; Eating; Feeding Behavior; Growth Hormone; Homozygote; Injections, Intraperitoneal; Injections, Intraventricular; Insulin; Leptin; Male; Metabolic Syndrome; Mutation; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Time Factors | 2002 |
Effect of iron deficiency on placental cytokine expression and fetal growth in the pregnant rat.
Iron deficiency anemia is the most common nutritional disorder in the world. Anemia is especially serious during pregnancy, with deleterious consequences for both the mother and her developing fetus. We have developed a model to investigate the mechanisms whereby fetal growth and development are affected by maternal anemia. Weanling rats were fed a control or iron-deficient diet before and throughout pregnancy and were killed at Day 21. Dams on the deficient diet had lower hematocrits, serum iron concentrations, and liver iron levels. Similar results were recorded in the fetus, except that the degree of deficiency was markedly less, indicating compensation by the placenta. No effect was observed on maternal weight or the number and viability of fetuses. The fetuses from iron-deficient dams, however, were smaller than controls, with higher placental:fetal ratios and relatively smaller livers. Iron deficiency increased levels of tumor necrosis factor alpha (TNFalpha) only in the trophoblast giant cells of the placenta. In contrast, levels of type 1 TNFalpha receptor increased significantly in giant cells, labyrinth, cytotrophoblast, and fetal vessels. Leptin levels increased significantly in labyrinth and marginally (P = 0.054) in trophoblast giant cells. No change was observed in leptin receptor levels in any region of the placentas from iron-deficient dams. The data show that iron deficiency not only has direct effects on iron levels and metabolism but also on other regulators of growth and development, such as placental cytokines, and that these changes may, in part at least, explain the deleterious consequences of maternal iron deficiency during pregnancy. Topics: Animals; Antigens, CD; Blood Cell Count; Body Weight; Cytokines; Diet; Embryonic and Fetal Development; Female; Fertility; Hematocrit; Immunohistochemistry; Iron; Iron Deficiencies; Leptin; Litter Size; Liver; Placenta; Pregnancy; Rats; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Spectrophotometry, Atomic; Tumor Necrosis Factor-alpha | 2002 |
The obesity in bilateral ovariectomized rats is related to a decrease in the expression of leptin receptors in the brain.
We investigated the expression levels of leptin receptors in the brain of ovariectomized (OVX) rats. The mean expression level of ob mRNA in adipose tissues of OVX rats was significantly (P < 0.01) lower than that in the SHAM operation group rats, and the mean body weight of OVX rats was significantly (P < 0.01) greater than that in the SHAM group rats. However, there were no differences between serum leptin concentrations in these two groups. The mean level of leptin receptor (OB-R) mRNA expression in the brain tissue and the mean level of long form type OB-R (OB-RL) mRNA expression in the hypothalamus of the OVX rats were significantly (P < 0.05) lower than those in the SHAM group rats. These changes were cancelled by supplementation with 17 beta-estradiol in OVX rats. These results suggested that not only changes in the expression level of ob mRNA in adipose tissue and the serum leptin concentration but also changes in the OB-R mRNA in the brain are involved in the body weight increase in OVX rats and that a decrease in OB-R makes transmission of signals to suppress the amount of food intake difficult, thus leading to an increase in body weight. Topics: Animals; Body Weight; Brain; Carrier Proteins; Female; Gene Expression; Leptin; Obesity; Ovariectomy; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger | 2002 |
The concept of selective leptin resistance: evidence from agouti yellow obese mice.
Leptin, a hormone secreted by adipose tissue, acts to inhibit appetite and promote metabolism, thereby reducing body weight. Leptin also increases sympathetic activity and arterial pressure. Several murine models of obesity, including agouti obese mice, exhibit resistance to the anorexic and weight-reducing effects of leptin. Hypertension in agouti mice has been attributed to hyperleptinemia. These observations pose a seeming paradox. If these mice are leptin-resistant, then how can leptin contribute to hypertension? We tested the novel hypothesis that these mice have selective leptin resistance, with preservation of the sympathoexcitatory action despite resistance to the weight-reducing actions. Leptin-induced decreases in food intake and body weight were less in agouti obese mice than in lean littermates. In contrast, leptin-induced increases in sympathetic nerve activity did not differ in obese and lean mice. These findings support the concept of selective leptin resistance, with resistance to the metabolic actions of leptin but preservation of the sympathoexcitatory actions. This finding may have potential implications for human obesity, which is associated with elevated plasma leptin and is thought to be a leptin-resistant state. If leptin resistance is selective in obese humans, then leptin could contribute to sympathetic overactivity and its adverse consequences in human obesity. Topics: Animals; Body Weight; Drug Resistance; Eating; Leptin; Mice; Mice, Inbred Strains; Obesity; Reference Values; Sympathetic Nervous System | 2002 |
Variation in plasma leptin levels in response to fasting in Antarctic fur seals (Arctocephalus gazella).
Plasma leptin levels were determined in 8 lactating female and 20 pup Antarctic fur seals (Arctocephalus gazella) during fasting periods of normal duration. Plasma leptin levels ranged from 1.35 3.19 ng x ml(-1) in lactating females and 1.79-4.80 ng x ml(-1) in pups and were not positively correlated with body mass or condition. A negative trend, however, was observed between plasma leptin levels and body condition in lactating females upon their arrival at the colony following a foraging trip (beginning of fast). In accordance with findings in other species, plasma leptin levels dropped significantly (P < 0.02) in response to the 17-19% drop in body mass experienced by pups during fasting. In contrast, plasma leptin levels in lactating females increased during the first 24 h of fasting before decreasing throughout the remaining 48 h of the fast. This unexpected result could be due to the high level of energy expenditure by seals as they swim back to the colony (i.e. post-exercise response) or may be influenced by the intense suckling activity experienced by females during the onshore fasting periods. The results of this study support recent findings in other carnivore species which suggest the primary physiological role of leptin in these species may not necessarily be as a signal of the magnitude of body energy reserves. Topics: Animals; Animals, Suckling; Antarctic Regions; Body Weight; Eating; Energy Metabolism; Fasting; Female; Fur Seals; Lactation; Leptin; Male; Triglycerides | 2002 |
Leptin deficiency, not obesity, protects mice from Con A-induced hepatitis.
Leptin-deficient ob/ob mice are protected from Con A-induced hepatitis. However, it is unclear whether leptin deficiency or obesity itself is responsible for this protection. To address this question, wild-type (WT) obese mice with high serum leptin levels were generated by injection of gold thioglucose (WT GTG). Both Con A-injected WT and WT GTG mice developed hepatitis, whereas no hepatic damage was observed in ob/ob mice. Moreover, TNF-alpha and IFN-gamma levels as well as expression of the activation marker CD69 were elevated in liver mononuclear cells of WT and WT GTG mice, but not in ob/ob mice following administration of Con A. The liver of WT and WT GTG mice had the same percentage of NK T cells, a lymphocyte population involved in Con A-induced hepatitis. This population decreased equally in both WT and WT GTG mice after Con A injection. In contrast, the liver of ob/ob mice contained 50% less NK T cells compared to WT and WT GTG mice. Furthermore, no decrease in NK T cells was observed in Con A-injected ob/ob mice. We conclude that leptin-deficiency, not obesity, is responsible for protection from Con A-induced hepatitis. Topics: Animals; Aurothioglucose; Body Weight; Chemical and Drug Induced Liver Injury; Concanavalin A; Female; Interferon-gamma; Killer Cells, Natural; Leptin; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; T-Lymphocyte Subsets; Tumor Necrosis Factor-alpha | 2002 |
Orexins and adipoinsular axis function in the rat.
Orexin A and B are recently identified as peptides that are derived from the same precursor and their expression is highly specifically localized in neurons located in the lateral hypothalamic area, a region implicated in the feeding behaviour. These peptides appear to be a part of a complex circuit that integrates the aspects of energy metabolism, cardiovascular function, hormone homeostasis and sleep/wake behaviours. The functional linking of orexins with leptin and insulin suggests the possibility of its involvement in the regulation of the adipoinsular axis, and the present investigation was designed to examine the potential role of orexins in this axis regulation. In all the tested doses (8, 16 and 40 nmol/kg body weight (b.w.)), subcutaneous (s.c.) injections of orexin A caused the significant increase in insulin and leptin blood levels. These elevations were observed 60 and 120 min after peptide administration. On the other hand, after the orexin B administration, elevated insulin and leptin blood concentrations were found only at 60 min of the experiment, and in that time point, the increases were comparable to that evoked by orexin A. In comparison with the control animals, the administration of orexins for 7 days resulted in a significant gain in body weight. Prolonged administration of either orexin A or orexin B significantly elevated insulin and leptin blood concentrations. Under these conditions, the orexin A effect on the leptin secretion was more marked than on the insulin secretion, and this difference is reflected by the lowered insulin/leptin molar ratio. These results suggest that orexins play an important role in the adipoinsular axis function and may be a significant regulator of both insulin and leptin secretion. In this regard, we suggest the updated functional model of Kieffer and Habener [Am. J. Physiol.: Endocrinol. Metab. 27 (2000) E1] that proposed the adipoinsular axis. Our model is extended by the probable humoral links between orexins and leptin and orexins and insulin and points on the dependence of the effects evoked by orexins, leptin and insulin on the blood glucose levels. Topics: Adipocytes; Animals; Body Weight; Carrier Proteins; Female; Insulin; Insulin Secretion; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Leptin; Neuropeptides; Orexins; Rats; Rats, Wistar | 2002 |
Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats.
The interrelationship between insulin and leptin resistance in young Fischer 344 (F344) rats was studied. Young F344 and Sprague-Dawley (SD) rats were fed regular chow. F344 animals had two- to threefold higher insulin and triglyceride concentrations and increased stores of triglycerides within liver and muscle. F344 animals gained more body fat. Both acyl-CoA oxidase (ACO) and carnitine palmitoyltransferase I gene expression were 20-50% less in F344 animals than in age-matched SD animals. Peroxisome proliferator-activated receptor-alpha gene expression was reduced in 70-day-old F344 animals. Finally, resistin gene expression was similar in 70-day-old SD and F344 animals. Resistin gene expression increased fivefold in F344 animals and twofold in SD animals from 70 to 130 days, without a change in insulin sensitivity. We conclude that young F344 animals have both insulin and leptin resistance, which may lead to diminished fatty oxidation and accumulation of triglycerides in insulin-sensitive target tissues. We did not detect a role for resistin in the etiology of insulin resistance in F344 animals. Topics: Acyl-CoA Oxidase; Animals; Blood Glucose; Body Composition; Body Weight; Carnitine O-Palmitoyltransferase; Drug Resistance; Gene Expression; Glucose Tolerance Test; Hormones, Ectopic; Insulin; Insulin Resistance; Kinetics; Leptin; Lipid Metabolism; Lipids; Liver; Muscle, Skeletal; Nerve Growth Factor; Oxidoreductases; Proteins; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Resistin; Transcription Factors; Triglycerides | 2002 |
Effects of pair-feeding and growth hormone treatment on obese transgenic rats.
It has been shown that GH-deficient subjects tend to have fat accumulation. We have produced human GH (hGH) transgenic rats that exhibit low circulating hGH levels and hyperphagia. These rats are also characterized by severe obesity, hyperinsulinemia and hyperlipidemia.. The present study was conducted in order to elucidate how excess caloric intake and impaired GH secretion account for fat accumulation and metabolic abnormalities in the transgenic rats.. The transgenic rats were subjected to either pair-feeding with non-transgenic controls or hGH treatment from 4 to 12 weeks of age, and the effects on fat accumulation and some metabolic parameters were assessed.. At the age of 12 weeks, body weight and food intake were greater in transgenic than in control rats by 10% and 27% respectively. The ratio of epididymal white adipose tissue weight to body weight (WAT/BW) was more than three times greater in transgenic than in control rats. Although pair-feeding for 8 weeks decreased body weight, it did not affect the WAT/BW ratio. Treatment with hGH affected neither body weight nor food intake, while it reduced the WAT/BW ratio by 30%. Serum concentrations of triglyceride, free fatty acid, insulin and leptin were all significantly higher in the transgenic than in the control rats. Pair-feeding decreased serum triglyceride, insulin and leptin levels, but not serum free fatty acid levels. On the other hand, hGH treatment decreased only serum leptin concentrations.. These results suggest that severe fat accumulation in the transgenic rats mainly resulted from the decreased lipolytic action of GH, while metabolic abnormalities mainly resulted from excess caloric intake. Topics: Adipose Tissue; Aging; Animals; Animals, Genetically Modified; Body Weight; Eating; Epididymis; Fatty Acids, Nonesterified; Food; Gene Expression; Human Growth Hormone; Humans; Insulin; Leptin; Male; Obesity; Organ Size; Rats; Triglycerides | 2002 |
Decreased plasma leptin concentrations in tuberculosis patients are associated with wasting and inflammation.
Tuberculosis patients often suffer from severe weight loss, which is considered to be immunosuppressive and a major determinant of severity and outcome of disease. Because leptin is involved in weight regulation and cellular immunity, its possible role in tuberculosis-associated wasting was investigated. In an urban clinic in Indonesia, plasma leptin concentrations, indicators of adipocyte mass, appetite, C-reactive protein (CRP), tuberculin reactivity, and cytokine response were measured in tuberculosis patients and healthy controls. Plasma leptin concentrations were lower in patients than in controls (615 vs. 2,550 ng/liter; P < 0.001). Multivariate regression analysis showed that body fat mass and inflammation were two independent factors determining plasma leptin concentrations; there was a positive correlation between fat and leptin, whereas, unexpectedly, leptin was inversely associated with CRP and tumor necrosis factor-alpha production. Concentrations of both CRP and leptin were independently associated with loss of appetite. Our results do not support the concept that weight loss in tuberculosis is caused by enhanced production of leptin. Rather, loss of body fat leads to low plasma leptin concentrations, and prolonged inflammation may further suppress leptin production. Because leptin is important for cell-mediated immunity, low leptin production during active tuberculosis may contribute to increased disease severity, especially in cachectic patients. Topics: Adipose Tissue; Adult; Antitubercular Agents; Appetite; Body Weight; Cytokines; Female; Humans; Inflammation; Leptin; Male; Osmolar Concentration; Reference Values; Tuberculosis | 2002 |
Chronic central infusion of cocaine- and amphetamine-regulated transcript (CART 55-102): effects on body weight homeostasis in lean and high-fat-fed obese rats.
Cocaine- and amphetamine-regulated transcript (CART) is expressed within hypothalamic nuclei implicated in the regulation of feeding behaviour. It is up-regulated by leptin, and CART-derived peptides acutely inhibit food intake.. The present study was designed to assess the long-term effects of central CART administration on food intake, body weight, plasma levels of glucose, insulin, leptin, free fatty acids and triglycerides, and on fuel utilisation in normal and high-fat-fed obese rats.. Normal and high-fat-fed obese rats were cannulated intracerebroventricularly (i.c.v.) and infused for 6 days with CART (55-102) or its vehicle. At day 4, animals were placed in an indirect calorimeter for a 24 h period during which the respiratory quotient and the energy expenditure were determined hourly.. In both normal and obese animals, the chronic i.c.v. infusion of CART (55-102) had marked, sustained inhibitory effects on food intake and body weight gain that were accompanied by decreases in plasma insulin and leptin levels. Using indirect calorimetry, it was observed that CART infusion promoted an increase in lipid oxidation in normal and in obese animals, although this increase reached statistical significance only in the obese group. The hypothalamic CART mRNA expression was found to be higher in obese rats (displaying hyperleptinaemia) than in normal animals.. The data together show that chronic i.c.v. CART infusion is effective in inhibiting food intake, favouring lipid oxidation and limiting fat storage, both in normal and high-fat-diet-induced obese rats. The CART pathway thus seems to be an important determinant of body weight homeostasis in normal animals as well as in a model of nutritionally induced obesity. Topics: Animals; Blood Glucose; Blotting, Northern; Body Weight; Calorimetry, Indirect; Circadian Rhythm; Dietary Fats; Disease Models, Animal; DNA Primers; Energy Intake; Energy Metabolism; Fatty Acids, Nonesterified; Gene Expression Regulation; Infusion Pumps, Implantable; Insulin; Leptin; Male; Nerve Tissue Proteins; Obesity; Peptide Fragments; Polymerase Chain Reaction; Rats; Rats, Long-Evans; Respiration; RNA, Messenger; Triglycerides | 2002 |
Myostatin knockout in mice increases myogenesis and decreases adipogenesis.
Growth differentiation factor-8 (GDF-8), or Myostatin, plays an important inhibitory role during muscle development. Since muscle and adipose tissue develop from the same mesenchymal stem cells, we hypothesized that Myostatin gene knockout may cause a switch between myogenesis and adipogenesis. Male and female wild type (WT) and Myostatin knockout (KO) mice were sacrificed at 4, 8, and 12 weeks of age. The gluteus muscle (GM) was larger in KO mice compared to WT mice at 8 (P < 0.01) and 12 (P < 0.001) weeks. At 12 weeks, KO mice had decreased fat depots (P < 0.01). Compared to 12-week-old WT mice, serum leptin concentration in KO mice was lower (P < 0.001) and leptin mRNA expression was decreased (P < 0.01) in inguinal adipose tissue. CCAAT/enhancer binding protein-alpha (C/EBPalpha) and peroxisome proliferator-activated receptor-gamma (PPARgamma) levels in adipose tissue were significantly lower in KO mice compared to WT mice. Thus, increased muscle development in Myostatin knockout mice is associated with reduced adipogenesis and consequently, decreased leptin secretion. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; CCAAT-Enhancer-Binding Protein-alpha; Eating; Female; Kinetics; Leptin; Male; Mice; Mice, Knockout; Muscle Development; Myostatin; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Transcription Factors; Transforming Growth Factor beta | 2002 |
Characterizaton of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity.
Leptin deficiency causes obesity in rodents and humans, but circulating levels of leptin are paradoxically elevated in obesity. The mechanisms underlying this leptin resistance are unknown, but may involve reduced leptin transport across the blood-brain barrier via short isoforms of the leptin receptor (Ob-R). Here, we first quantified short Ob-R mRNA expression in isolated rat cerebral microvessels constituting the blood-brain barrier and found that Ob-Ra and Ob-Rc mRNA were abundantly expressed in similar amounts. Second, brain uptake of leptin was reduced in mice lacking Ob-R. Third, brain uptake of leptin in New Zealand Obese mice, a strain that responds to central, but not peripheral, leptin, was reduced, suggesting that their obesity is at least partly due to deficient leptin transport into the brain. Fourth, brain uptake of leptin was significantly reduced in diet-induced obese mice. Neither New Zealand Obese mice nor diet-induced obese mice exhibited significant decreases in Ob-R mRNA expression in isolated cerebral microvessels. These data support the ideas that short isoforms of Ob-R are involved in brain uptake of leptin and that impaired blood-brain barrier function contributes to the pathogenesis of obesity. However, the mechanisms by which obesity-related deficits in brain uptake of leptin occur remain to be defined. Topics: Animals; Blood-Brain Barrier; Body Weight; Brain Chemistry; Capillaries; Carrier Proteins; Cerebrovascular Circulation; Dietary Fats; Isomerism; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2002 |
Expression of uncoupling proteins-1, -2 and -3 mRNA is induced by an adenocarcinoma-derived lipid-mobilizing factor.
The abnormalities of lipid metabolism observed in cancer cachexia may be induced by a lipid-mobilizing factor produced by adenocarcinomas. The specific molecules and metabolic pathways that mediate the actions of lipid-mobilizing factor are not known. The mitochondrial uncoupling proteins-1, -2 and -3 are suggested to play essential roles in energy dissipation and disposal of excess lipid. Here, we studied the effects of lipid-mobilizing factor on the expression of uncoupling proteins-1, -2 and -3 in normal mice. Lipid-mobilizing factor isolated from the urine of cancer patients was injected intravenously into mice over a 52-h period, while vehicle was similarly given to controls. Lipid-mobilizing factor caused significant reductions in body weight (-10%, P=0.03) and fat mass (-20%, P<0.01) accompanied by a marked decrease in plasma leptin (-59%, P<0.01) and heavy lipid deposition in the liver. In brown adipose tissue, uncoupling protein-1 mRNA levels were elevated in lipid-mobilizing factor-treated mice (+96%, P<0.01), as were uncoupling proteins-2 and -3 (+57% and +37%, both P<0.05). Lipid-mobilizing factor increased uncoupling protein-2 mRNA in both skeletal muscle (+146%, P<0.05) and liver (+142%, P=0.03). The protein levels of uncoupling protein-1 in brown adipose tissue and uncoupling protein-2 in liver were also increased with lipid-mobilizing factor administration (+49% and +67%, both P=0.02). Upregulation by lipid-mobilizing factor of uncoupling proteins-1, -2 and -3 in brown adipose tissue, and of uncoupling protein-2 in skeletal muscle and liver, suggests that these uncoupling proteins may serve to utilize excess lipid mobilized during fat catabolism in cancer cachexia. Topics: Adenocarcinoma; Adipose Tissue, Brown; Animals; Blotting, Northern; Blotting, Western; Body Weight; Carrier Proteins; DNA Primers; Humans; Ion Channels; Leptin; Lipid Metabolism; Liver; Male; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Inbred Strains; Mitochondrial Proteins; Muscle, Skeletal; Peptides; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3; Up-Regulation | 2002 |
Attenuation of diabetic hyperphagia in neuropeptide Y--deficient mice.
The combined effects of increased hypothalamic signaling by neuropeptide Y (NPY) and decreased signaling by melanocortins are hypothesized to stimulate food intake when body fat stores are depleted. To investigate NPY's role in the hyperphagic response to uncontrolled diabetes, streptozotocin (STZ) (200 mg/kg intraperitoneally) or saline vehicle was given to NPY-deficient (Npy(--/--)) and wild-type (Npy(+/+)) mice. In Npy(+/+) mice, STZ-induced diabetes increased mean daily food intake to plateau values 50% above baseline intake (+2.0 +/- 0.6 g/day; P < or = 0.05), an effect that was not seen in STZ-treated Npy(--/--) mice (+0.8 +/- 0.1 g/day; NS), despite comparably elevated levels of plasma glucose and comparably decreased levels of body weight, fat content, and plasma leptin. Unlike the impaired feeding response to uncontrolled diabetes, Npy(--/--) mice exhibit intact hyperphagic responses to fasting (Erickson et al. [1], Nature 381:415-418, 1996). To investigate whether differences in hypothalamic melanocortin signaling can explain this discrepancy, we used in situ hybridization to compare the effects of STZ-diabetes and fasting on pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) mRNA levels in the hypothalamic arcuate nucleus (ARC) of Npy(--/--) and Npy(+/+) mice. AgRP mRNA levels were increased by both fasting and STZ-diabetes, but the increase in STZ-diabetes was small (50-80%) compared with the effect of fasting (approximately 20-fold increase of AgRP mRNA). STZ-diabetes also lowered POMC mRNA levels by 65% in the ARC of Npy(+/+) mice (P less-than-or-equal 0.05) but by only 11% in Npy(--/--) mice (NS); fasting significantly lowered POMC mRNA levels in both genotypes. We conclude that NPY is required for both the increase of food intake and the decrease of hypothalamic POMC gene expression induced by uncontrolled diabetes. In contrast, NPY is not required for either of these responses when the stimulus is food deprivation. Moreover, fasting is a more potent stimulus to hypothalamic AgRP gene expression than is STZ-diabetes. Therefore, central nervous system melanocortin signaling appears to be suppressed more effectively by fasting than by uncontrolled diabetes, which provides a plausible explanation for differences in the feeding response to these two stimuli in mice lacking NPY. Topics: Adipose Tissue; Agouti-Related Protein; alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Composition; Body Weight; Diabetes Mellitus, Experimental; Fasting; Hyperphagia; Hypothalamus; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Inbred C57BL; Neuropeptide Y; Pro-Opiomelanocortin; Proteins; RNA, Messenger; Signal Transduction | 2002 |
Cloned mice have an obese phenotype not transmitted to their offspring.
Mammalian cloning using somatic cells has been accomplished successfully in several species, and its potential basic, clinical and therapeutic applications are being pursued on many fronts. Determining the long-term effects of cloning on offspring is crucial for consideration of future application of the technique. Although full-term development of animals cloned from adult somatic cells has been reported, problems in the resulting progeny indicate that the cloning procedure may not produce animals that are phenotypically identical to their cell donor. We used a mouse model to take advantage of its short generation time and lifespan. Here we report that the increased body weight of cloned B6C3F1 female mice reflects an increase of body fat in addition to a larger body size, and that these mice share many characteristics consistent with obesity. We also show that the obese phenotype is not transmitted to offspring generated by mating male and female cloned mice. Topics: Adipose Tissue; alpha-MSH; Animals; Body Composition; Body Weight; Cloning, Organism; Corticosterone; Crosses, Genetic; Eating; Female; Food Deprivation; Insulin; Leptin; Male; Mice; Obesity; Phenotype; Pregnancy | 2002 |
Naloxone prevents cell-mediated immune alterations in adult mice following repeated mild stress in the neonatal period.
1. Mild stress plus mild pain (solvent injection) applied daily to neonatal mice induces hormonal, behavioural and metabolic changes perduring in the adult life. 2. We investigated whether daily mild stress to neonatal mice induces also long-term defined changes of immune response, and whether immune changes are prevented through repeated administration of the opioid antagonist naloxone. 3. Mild stress plus solvent injection administered from birth to the 21st postnatal day causes not only behavioural and metabolic changes, but also long-term (up to 110 days of life) splenocytes modifications, consisting in: increased release of the Th-1 type cytokines interleukin-2 (IL-2) (from an average of 346 to 788 pg ml(-1)), interferon-gamma (from 1770 to 3942) and tumour necrosis factor-alpha (from 760 to 1241); decreased release of the Th-2 type cytokines IL-4 (from 49.1 to 28.4) and IL-10 (from 1508 to 877). Moreover, enhanced natural killer-cell activity; enhanced proliferative splenocytes properties in resting conditions and following phytohemoagglutinin and concanavalin-A stimulation are observed. Immunological, behavioural and metabolic changes are prevented by the opioid antagonist (-)naloxone (1 mg kg(-1) per day s.c., administered instead of solvent) but not by the biologically inactive enantiomorph (+)naloxone. 4. In conclusion, endogenous opioid systems sensitive to naloxone are involved in long-lasting enhancement of the Th-1 type cytokines and cell-mediated immunological response caused by repeated mild stress administered postnatally. Topics: Animals; Animals, Newborn; Body Weight; Cytokines; Leptin; Male; Mice; Mice, Inbred Strains; Naloxone; Narcotic Antagonists; Pain Threshold; Spleen; Stress, Physiological; Th1 Cells | 2002 |
Middle-aged C57BL/6 mice have impaired responses to leptin that are not improved by calorie restriction.
Midlife weight gain occurs in many species, suggesting that leptin signaling is impaired at middle age. To test this hypothesis, we measured changes in food intake and body composition in young (Y) and middle-aged (MA) C57BL/6 male mice infused subcutaneously with phosphate-buffered saline or leptin. Leptin-induced decreases in food intake and body fat were delayed in MA mice and associated with catabolism after longer treatment periods. Endogenous plasma leptin levels did not correlate with body fat in MA mice. Calorie restriction (CR) reduced body fat, plasma leptin, and insulin in MA mice to levels in Y mice but did not upregulate leptin sensitivity. CR mice did not respond to leptin doses that inhibited food intake in MA mice and reduced food intake and body fat in Y mice significantly below levels in CR mice. Plasma corticosterone was significantly higher in leptin-treated CR vs. MA mice. We conclude that MA C57BL/6 mice exhibit impaired leptin signaling and that CR, possibly by elevating glucocorticoids, impairs appetite control without improving the metabolic actions of leptin. Topics: Adipose Tissue; Aging; Animals; Blood Glucose; Body Composition; Body Weight; Diet, Reducing; Eating; Energy Intake; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Proteins; Signal Transduction; Weight Gain | 2002 |
Hyperleptinemia in A(y)/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression.
The effects of leptin on cocaine- and amphetamine-regulated transcript (CART) and agouti-related protein (AGRP) expression in the hypothalamic arcuate nucleus of obese A(y)/a mice were investigated. CART mRNA expression was upregulated by 41% and AGRP mRNA downregulated by 78% in hyperleptinemic A(y)/a mice relative to levels in lean a/a mice. The mRNA expression of these neuropeptides in either young nonobese A(y)/a mice or rats treated with SHU-9119, a synthetic melanocortin-4 receptor (MC4R) antagonist, did not differ significantly from that in the corresponding controls. After a 72-h fast, which decreased the concentration of serum leptin, CART and AGRP mRNA expression decreased and increased, respectively, in A(y)/a mice. The expression levels of these neuropeptides in leptin-deficient A(y)/a ob/ob double mutants were comparable to those in a/a ob/ob mice. Leptin thus modulates both CART and AGRP mRNA expression in obese A(y)/a mice, whereas leptin signals are blocked at the MCR4R level. Taken together, the present findings indicate that differential expression of these neuropeptides in A(y)/a and ob/ob mice results in dissimilar progression toward obesity. Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Gene Expression Regulation; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Melanocyte-Stimulating Hormones; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurotransmitter Agents; Obesity; Proteins; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; Receptors, Peptide; RNA, Messenger; RNA, Ribosomal | 2002 |
Selective resistance to central neural administration of leptin in agouti obese mice.
We recently demonstrated that in a rodent model of obesity (agouti yellow mice), there is a selective leptin resistance with preservation of the sympathetic actions despite loss of appetite and weight-reducing actions of systemic leptin. Here, we examined whether selective leptin resistance exists in agouti mice during central neural administration of leptin. In agouti obese mice and lean controls, we tested the effects of single intracerebroventricular (ICV) injection of leptin or vehicle on food intake and body weight in the conscious state and on renal sympathetic nerve activity during anesthesia. Agouti obese mice had higher (P<0.0001) mean arterial pressure (100 +/- 2 mm Hg) than lean controls (90 +/- 2 mm Hg). In lean controls (n=9 to 10), ICV leptin caused a dose-dependent decrease in body weight (P<0.001) and food intake (P<0.001). For example, ICV leptin (3 microg) decreased food intake and body weight, respectively, by 3.3 +/- 0.3 g (P<0.001) and 2.6 +/- 0.3 g (P<0.001) in lean mice. However, in agouti obese mice (n=9 to 10), ICV leptin did not significantly decrease food intake or body weight. ICV leptin caused in RSNA a significant and dose-dependent increase in renal sympathetic nerve activity that was of the same magnitude in the lean and agouti obese mice. The rise in renal sympathetic nerve activity induced by ICV leptin (3 microg) was 274 +/- 67% (P<0.001) in lean controls and 275 +/- 46% (P<0.001) in the agouti obese mice. In summary, this study indicates that selective leptin resistance in agouti obese mice occurs with central neural administration of leptin, suggesting that selective leptin resistance in this model is not due to a defect in leptin transport across the blood brain barrier. It seems to result instead from alterations in the central neural pathways mediating effects of leptin. Topics: Animals; Body Weight; Disease Models, Animal; Drug Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Sympathetic Nervous System | 2002 |
Effects of a beta3-adrenergic agonist on glucose uptake and leptin expression and secretion in cultured adipocytes from lean and overweight (cafeteria) rats.
The increase in body and white adipose tissue weights induced by a high-fat diet were prevented by treatment with the beta3-adrenergic agonist Trecadrine. Plasma insulin levels were slightly elevated in overweight rats, while a decrease was observed in Trecadrine-treated groups. Insulin-dependent glucose uptake was impaired in adipocytes of the overweight rats in relation to lean animals. The beta3-adrenergic agonist induced an increase in insulin-stimulated glucose uptake by adipocytes as compared to the nontreated animals. In fact, Trecadrine treatment was able to restore to control values the impairment in insulin-mediated glucose uptake induced by the cafeteria diet, suggesting that Trecadrine prevents the development of insulin resistance in overweight animals. Basal leptin secretion was increased in adipocytes of the overweight rats in relation to lean animals. Trecadrine treatment induced a decrease in basal leptin secretion compared to the untreated animals. Insulin-stimulated leptin secretion reached similar levels in adipocytes of the overweight rats as in lean animals. There was a trend for insulin-induced leptin secretion to be lower at 24 h in Trecadrine-treated rats, but it did not reach statistical significance. In conclusion, adipocytes of diet-induced overweight animals have a higher basal leptin secretion, which is reduced by treatment with Trecadrine. However, neither the cafeteria diet nor the Trecadrine treatment significantly alters the ability of adipocytes to increase leptin secretion in response to insulin. Topics: Adipocytes; Adipose Tissue; Adrenergic beta-Agonists; Animals; Blood Glucose; Body Weight; Cells, Cultured; Eating; Insulin; Leptin; Male; Obesity; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3; Weight Gain | 2002 |
Plasma soluble tumor necrosis factor alpha receptors and leptin levels in normal-weight and obese women: effect of adiposity and diabetes.
To explore the determinants of the tumor necrosis factor alpha (TNFalpha) system and their relationship with plasma leptin levels.. We studied a cohort of 157 diabetic and non-diabetic females with a wide range of adiposity distributed into five groups: control--body mass index (BMI) between 19 and 27 kg/m(2) (n=24); obese--BMI between 27 and 40 kg/m(2) (n=63); obese type 2 diabetes mellitus--BMI between 27 and 40 kg/m(2) with diabetes mellitus (n=19); morbid obese--BMI >40 kg/m(2) (n=29); and morbid obese type 2 diabetes mellitus--BMI >40 kg/m(2) with diabetes (n=22). Fasting glucose levels, plasma total triglycerides and cholesterol, high-, low- and very low-density lipoprotein cholesterol were assayed by enzymatic and colorimetric methods. Plasma TNFalpha levels were measured by ELISA assay and insulin and leptin levels by radioimmunoenzymatic assays. Both soluble TNFalpha (sTNFalpha) receptors were measured by immunoenzymometric assays.. All groups of patients showed significant increases in both sTNFalpha receptors relative to control. sTNFalpha receptor 1 (sTNFR1) was higher in morbid obese diabetic individuals compared with their non-diabetic counterparts (P=0.003), while sTNFR2 was significantly different between obese and morbid obese subjects (P=0.036). Bivariate correlation analysis showed a significant relationship between both plasma sTNFalpha receptors and BMI, percentage of body fat, fasting glucose, insulin and leptin. In multivariate analysis, both sTNF receptor plasma levels were predicted by percentage of body fat and the presence of diabetes (R(2)=0.20 for sTNFR1 and sTNFR2). When plasma leptin levels were added into the model, this protein and the presence of diabetes explained 27% of the variance of the plasma sTNFR1 levels.. The presence of diabetes, adiposity or leptin levels are independent determinants of both sTNFalpha receptors. The independent association between plasma TNFalpha receptors and leptin levels in obese patients is consistent with the hypothesis that these proteins could be involved in the same pathway that regulates body adiposity. Topics: Adult; Aged; Aging; Body Height; Body Weight; Diabetes Mellitus, Type 2; Female; Humans; Hyperinsulinism; Leptin; Middle Aged; Obesity; Obesity, Morbid; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha | 2002 |
Leptin and estradiol as related to change in pubertal status and body weight.
Previous studies have examined the relationship between leptin, body mass, and pubertal status. The present study directly compares the relationship of leptin and estradiol in 5 groups of girls with different combinations of pubertal status and weight.. We studied girls with idiopathic precocious puberty, age-matched non-obese prepubertal girls, age-matched obese prepubertal girls, normal pubertal girls, and obese pubertal girls (n=12/group).. Leptin levels were significantly higher in obese pubertal girls (26.6+/-8.4 ng/mL) than in all others. Leptin levels were significantly higher in obese prepubertal girls (20.7+/-10.9 ng/mL) (mean+/-SD) compared to girls with precocious puberty (7.7+/-5.4 ng/mL, p<0.004), non-obese prepubertal girls (5.55+/-3.6 ng/mL, p<0.001), and normal pubertal girls (4.8+/-2.9 ng/mL, p<0.001). Leptin level did not correlate significantly with estradiol level. Leptin-SDS (standard deviation score), which corrects leptin level for gender, pubertal stage, and BMI, was significantly lower in the obese pubertal group than in the 3 non-obese groups.. These findings confirm previous studies that body mass, chronological age and pubertal stage are determinants of leptin level. However, these are not the only factors determining leptin level as evidenced by persistent differences in leptin level between obese and non-obese pubertal girls even when correcting for pubertal stage and BMI. While the present study provides no new answers to the question of pubertal regulation, it provides a direct comparison of combinations of weight, pubertal stage, and leptin level, as background for future studies. Topics: Body Mass Index; Body Weight; Case-Control Studies; Child; Estradiol; Female; Humans; Leptin; Obesity; Puberty; Puberty, Precocious | 2002 |
Leptin concentrations in periparturient ewes and their subsequent offspring.
Leptin is an adipocyte-derived hormone that suppresses feed intake and increases energy expenditure. Leptin is also involved in regulating body temperature. Thus, the presence of leptin in milk, which can be absorbed through the gut of neonates immediately after birth, may aid in the survival of neonates born in cold weather. Our objectives were to determine the temporal relationship between concentrations of leptin in postpartum ewe blood serum and ewe milk serum, and to determine whether ewe blood and milk serum leptin concentrations were correlated with concentrations of leptin in lamb blood serum in their off-spring. Approximately 1 wk before the expected date of lambing, blood samples, weights, and body condition scores (BCS; 0 to 5 scale) were collected from 27 mixed-parity ewes. Following parturition, ewe blood and milk samples were collected within 2 h of parturition (d 0), 12 h (d 0.5) and 24 h (d 1) after parturition, again on d 5, and weekly thereafter until d 47. Lambs were blood-sampled and weighed within 2 h of parturition (d 0), bled daily until d 5, and bled and weighed weekly thereafter to d 47. Prior to lambing, ewe blood serum leptin was positively correlated with congruent BCS (r2 = 0, 10, P = 0.06), but not weight (P = 0.14). Following parturition, ewe blood serum leptin was positively correlated with BCS, weight, and milk serum leptin (r2 = 0.14, P < 0.0001, r2 = 0.12, P < 0.0001, and r2 = 0.028, P = 0.04). Leptin in milk serum was correlated with ewe weight (r2=0.05, P = 0.007) but not ewe BCS (P = 0.7); however, concentrations of leptin in both ewe blood and milk serum varied with day of lactation (P = 0.0001), being maximal within 24 h of parturition and declining to nadir concentrations by d 5. Leptin in lamb serum was correlated with milk serum leptin, (r2 = -0.05; P = 0.001), but not ewe blood serum leptin (P = 0.5). Concentrations of leptin in lamb serum increased from birth to d 5 and declined thereafter to nadir concentrations by d 19. Elevated concentrations of leptin in milk during the early stages of lactation may provide a mechanism for thermoregulation, satiation, and homeostatic endocrine control in the neonate. Topics: Animals; Animals, Suckling; Body Composition; Body Temperature Regulation; Body Weight; Female; Leptin; Milk; Sheep; Time Factors | 2002 |
Relationships of metabolic hormones and serum glucose to growth and reproductive development in performance-tested Angus, Brangus, and Brahman bulls.
Understanding mechanisms that regulate growth and reproduction are important for improving selection strategies in cattle. In this study, Angus, Brangus, and Brahman bulls (n = 7 per breed) of similar age were selected from a group of 65 weanlings. Bulls were evaluated after weaning (i.e., approximately 6 mo of age) for 112 d for serum concentrations of metabolic hormones and glucose, growth, and reproductive traits. Performance data and blood sera were collected on d 0, 28, 56, 84, and 112. Sera were also collected in periods from d 50 to 59 (56D) and 103 to 112 (112D). Angus bulls were heavier (P < 0.05) throughout the study than Brahman bulls and were heavier than Brangus bulls on d 56, 84, and 112. Initial and final BW for Angus, Brangus, and Brahman bulls were 292.7, 260.6, and 230.4 and 468.3, 435.6, and 350.7 +/- 12 kg, respectively. Conversely, Brahman bulls had greater hip height (P < 0.05) than Brangus, and Brangus were taller (P < 0.05) than Angus. Angus bulls had the greatest (P < 0.05) scrotal circumference (SC) and Brahman bulls the least. Mean SC across days was 31.5, 29.7, and 25.0 +/- 0.6 cm for the three respective breeds. Serum testosterone was greater (P < 0.01) in Angus and Brangus bulls (10.0 and 8.9 +/- 1.4 ng/mL) than in Brahman bulls (4.0 +/- 1.4 ng/mL) throughout the study. After d 112, 100, 86, and 57% of the Angus, Brangus, and Brahman bulls passed a breeding soundness exam (P = 0.51). Serum concentrations of IGF-I and leptin were greater (P < or = 0.06) in Angus bulls on d 56, 84, and 112 than in Brangus and Brahman bulls. Serum concentrations of GH (P < 0.08) and glucose (P < 0.03) were greater in Brangus bulls than in Angus or Brahman bulls throughout the study. Prediction analyses suggested that serum concentrations of leptin could be used to predict (P < or = 0.08) BW and SC (R2 > 0.82) in the 56D and 112D periods among these breeds. Leptin was also useful in predicting (P < or = 0.09) serum concentrations of GH and testosterone in the 112D period (R2 > 0.32). Residual correlation analyses with the effect of breed removed suggested that leptin was correlated (r > or => 0.53, P < 0.05) with both SC and serum testosterone. Angus and Brahman cattle differ in phenotype, level of adiposity, and rate of sexual development. Data herein suggest that these characteristics could be due to varying mechanisms by which metabolic hormones such as leptin, GH, and(or) IGF-I are regulated. Topics: Animals; Blood Glucose; Body Weight; Breeding; Cattle; Growth Hormone; Leptin; Male; Reproduction; Scrotum; Sexual Maturation; Testosterone; Time Factors | 2002 |
Body-weight changes are clearly reflected in plasma concentrations of leptin in female mink (Mustela vison).
The mink is a seasonal breeder with a propensity for seasonal fatness, and it is very responsive to changes in energy supply. The objectives of the present study were first, to validate a multi-species leptin assay for mink (Mustela vison) plasma, and second, to evaluate how plasma leptin and insulin concentrations responded to energy restriction and body-weight loss and refeeding with restoration of body reserves. The study was performed with six very fat yearling females (initial mean body weight 1,451 (SD 119) g, i.e. approximately 300 g more than for a female in normal body condition). The animals were fed in restricted amounts (about 35 % metabolizable energy requirement for maintenance) in order to reach a very lean body condition. The target weight of 800 g was reached after about 1 month of restriction. The animals were then refed ad libitum until almost complete weight recovery. Blood samples were taken on days 1, 24, 34 (end of restriction), 44, 55 and 71 (end of experiment) and analysed for plasma concentrations of leptin and insulin. Three females were mated on day 44. Leptin and insulin concentrations mirrored each other and clearly reflected changes in body weight. Significant (P<0.001) Pearson correlation coefficients of 0.75 (leptin-insulin), 0.72 (leptin-body weight) and 0.59 (insulin-body weight) were found. Two of the three females that were mated gave birth to normal litters. It was concluded that the leptin assay yielded acceptable results for animals with body weight:fat content within the range investigated here, and that plasma leptin reflected body fat mass. Topics: Animals; Body Weight; Eating; Female; Food Deprivation; Insulin; Leptin; Mink | 2002 |
Developmental changes in adipose and muscle lipoprotein lipase activity in the atherosclerosis-prone JCR:LA-corpulent rat.
To characterize the developmental changes in adipose and muscle lipoprotein lipase (LPL) activity in the atherosclerosis-prone JCR:LA-corpulent rat, and to test the hypothesis that tissue-specific abnormalities in LPL activity precede the establishment of obesity.. Lean (+/?) and obese cp/cp male JCR:LA rats were studied at 4, 5 and 8 weeks of age, that is at the onset of obesity, and at a time when obesity is well established. Assessment was made of plasma variables related to glucose and lipid metabolism and of LPL activity in several adipose depots, skeletal muscles and the heart.. At week 4, body weights were identical in both genotypes and began to diverge at week 5. Eight-week-old cp/cp rats weighed 35% more than their lean counterparts. Perirenal and epididymal adipose depot weights were also identical in both genotypes at week 4 and began to increase in cp/cp rats at week 5, whereas the subcutaneous depot of 4-week-old cp/cp rats was slightly enlarged. At week 4, the cp/cp rats were hyperinsulinemic (5-fold), hyperleptinemic (30-fold) and hypertriglyceridemic (3-fold) compared to their lean counterparts, and their liver contained twice as much triglyceride. The 4-week-old cp/cp rats displayed 2-7-fold higher LPL specific activity in the various adipose depots compared to lean rats, and enzyme activity remained higher in obese than in lean rats at all subsequent ages. In contrast, LPL activity in the vastus lateralis, gastrocnemius and heart muscles of 4-week-old obese rats was approximately half that observed in lean animals.. Profound, persistent alterations in the tissue-specific modulation of LPL activity are established in the JCR:LA cp/cp rat prior to the development of frank obesity. The increase in adipose tissue LPL activity and its decrease in muscle tissues are likely to be related to the concomitant alterations in insulinemia and triglyceridemia, respectively. The pre-obesity, tissue-specific alterations in LPL activity may be considered as an integrated adaptation to increased lipid flux aimed at driving lipids toward storage sites and limiting their uptake by triglyceride-laden muscles. Topics: Adipose Tissue; Aging; Animals; Arteriosclerosis; Blood Glucose; Body Composition; Body Weight; Fatty Acids, Nonesterified; Genotype; Insulin; Leptin; Lipoprotein Lipase; Male; Muscle, Skeletal; Myocardium; Obesity; Organ Size; Rats; Rats, Mutant Strains; Triglycerides | 2002 |
Early events involved in the development of insulin resistance in Zucker fatty rat.
To clarify the mechanism by which insulin resistance develops in obesity, Zucker fatty rats (ZFR) and lean litter mates (ZLR) were temporally subjected to oral glucose tolerance tests (OGTT) at 6 and 15 weeks of age.. As candidates for causative factors of insulin resistance, plasma leptin, free fatty acids (FFA) and tumor necrosis factor (TNF)-alpha levels were evaluated.. There was no difference in the body weight between the two groups at 6 weeks of age, but ZFR were significantly heavier than ZLR at 15 weeks of age. At 6 weeks of age, blood glucose levels and area under the curve of glucose (AUCg) during OGTT were not significantly different between the two groups, while plasma insulin levels and area under the curve of insulin (AUCi) in the ZFR group were significantly higher than those in the ZLR group. At 15 weeks of age, the blood glucose levels and AUCg as well as plasma insulin levels and AUCi in the ZFR group during OGTT were significantly higher than those in the ZLR group. The ratio of fasting insulin to glucose in the ZFR group was significantly higher than that in the ZLR group at 6 and 15 weeks of age. Peripheral and portal plasma leptin and FFA levels were significantly higher in ZFR than ZLR both at 6 weeks and 15 weeks of age. Meanwhile, at 6 weeks, plasma TNF-alpha levels and expression of TNF-alpha protein in subcutaneous and visceral fat tissues were similar in both groups; however at 15 weeks, these were significantly higher in the ZFR group than the ZLR group.. These results suggest that FFA rather than TNF-alpha may play an important role in early events involved in the development of insulin resistance and TNF-alpha accelerates insulin resistance together with FFA in the later stage. Topics: Adipose Tissue; Animals; Blood Glucose; Blotting, Western; Body Weight; Eating; Fasting; Fatty Acids, Nonesterified; Glucose Tolerance Test; Glycogen; Insulin; Insulin Resistance; Leptin; Liver; Male; Obesity; Organ Size; Rats; Rats, Zucker; Tumor Necrosis Factor-alpha | 2002 |
Increased hypothalamic neuropeptide Y expression in deprived preweanling rats is reversed by intragastric infusion of milk.
Lean, preweanling Zucker rat pups increase neuropeptide Y (NPY) expression in the hypothalamic arcuate nucleus in response to a 24-h deprivation of food, water, and maternal interaction as early as postnatal day 2 (P2). In this study, we examined if replacing nutritive or tactile aspects of maternal behavior to deprived rat pups could block the increased expression of hypothalamic NPY measured by in situ hybridization. On P2, P12, or P15, littermates were assigned to one of four treatment groups: (1) left with the dam for 24 h, (2) deprived of the dam for 24 h and given tactile stimulation in the form of periodic anogenital stroking to elicit urination and defecation, (3) deprived of the dam and given periodic anogenital stroking plus continuous gastric infusion of milk for 24 h, or (4) deprived of the dam and given periodic anogenital stroking plus continuous infusion of water for 24 h. We found that gastric infusions of milk normalized NPY expression at all three ages, gastric infusions of water did not on P2 and P15, and anogenital stroking alone had no effect. We suggest that the lack of milk is the major cause of increased hypothalamic NPY expression during maternal deprivation in lean Zucker pups. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Carrier Proteins; Female; Food Deprivation; Genitalia; Genotype; Hypothalamus; In Situ Hybridization; Intubation, Gastrointestinal; Leptin; Male; Maternal Deprivation; Milk; Mutation; Neuropeptide Y; Physical Stimulation; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin | 2002 |
Plasma leptin concentration in fetal sheep during late gestation: ontogeny and effect of glucocorticoids.
The ontogeny and developmental control of plasma leptin concentration in the fetus are poorly understood. The present study investigated plasma leptin concentration in chronically catheterized sheep fetuses near term, and in neonatal and adult sheep. The effect of glucocorticoids on plasma leptin in utero was examined by fetal adrenalectomy and exogenous cortisol or dexamethasone infusion. In intact, untreated fetuses studied between 130 and 140 d (term, 145 +/- 2 d), plasma leptin concentration increased in association with the prepartum cortisol surge. Positive relationships were observed between plasma leptin in utero and both gestational age and plasma cortisol. Plasma leptin was also inversely correlated with fetal p(a)O(2). The ontogenic rise in plasma leptin was abolished by fetal adrenalectomy. In intact fetuses at 123-127 d, plasma leptin was increased by infusions of cortisol (3-5 mg kg(-1)d(-1), +127 +/- 21%) for 5 d and dexamethasone (45-60 microg kg(-1)d(-1), +268 +/- 61%) for 2 d. However, the cortisol-induced rise in plasma leptin was transient; by the fifth day of infusion, plasma leptin was restored to within the baseline range. These findings show that, in the sheep fetus, an intact adrenal gland is required for the normal ontogenic rise in plasma leptin near term. Furthermore, fetal treatment with exogenous and endogenous glucocorticoids increases circulating leptin concentration in utero. Topics: Adrenalectomy; Animals; Body Weight; Dexamethasone; Embryonic and Fetal Development; Female; Fetus; Gestational Age; Glucocorticoids; Hydrocortisone; Leptin; Organ Size; Oxygen Consumption; Pregnancy; Sheep | 2002 |
Evidence that leptin contributes to intestinal cholesterol absorption in obese (ob/ob) mice and wild-type mice.
In the present study, the effect of leptin on intestinal cholesterol absorption was investigated in C57 BL/6 OlaHsd Lep(ob)/Lep(ob) obese (ob/ob) mice and lean C57 BL/6 (wild-type) mice. Animals were treated either with or without recombinant leptin for 2 wk. Cholesterol absorption was measured by the constant isotope feeding method and indirectly by the ratio of campesterol to cholesterol in serum. In ob/ob mice, cholesterol absorption was significantly higher compared to wild-type mice [83.4 +/- 2.3% (SD) vs. 77.6 +/- 1.5%, P < 0.01]. Treatment with leptin significantly reduced cholesterol absorption in both ob/ob and wild-type mice by 8.5 (P < 0.001) and 5.2% (P < 0.05), respectively. Serum concentrations of campesterol and the ratio of campesterol to cholesterol in ob/ob mice were significantly higher compared to wild-type mice (2.2 +/- 0.3 mg/dL vs. 1.2 +/- 0.3 mg/dL, P< 0.001; and 36.8 +/- 2.8 microg/mg vs. 28.0 +/- 3.3 microg/mg, P < 0.001). After treatment of ob/ob mice with leptin, concentrations of campesterol and its ratio to cholesterol were significantly lower (2.2 +/- 0.3 mg/dL vs. 1.0 +/- 0.2 microg/mg, P < 0.001; and 36.8 +/- 2.8 microg/mg vs. 13.2 +/- 2.2 microg/mg, P < 0.001, respectively). In wild-type mice, the ratio of campesterol to cholesterol in serum was also significantly lower after treatment with leptin (28.0 +/- 3.3 microg/mg vs. 22.6 +/- 5.0 microg/mg, P < 0.05). A significant positive correlation (r = 0.701, P < 0.01) between cholesterol absorption and the ratio of campesterol to cholesterol in serum was found. It is concluded that leptin contributes to intestinal cholesterol absorption in ob/ob mice and lean wild-type mice. Topics: Animals; Body Weight; Cholesterol; Feeding Behavior; Intestinal Absorption; Leptin; Male; Mice; Obesity; Species Specificity | 2002 |
Evaluation of liver fatty acid oxidation in the leptin-deficient obese mouse.
We hypothesized that liver fatty acid oxidation (FAO) is compromised in the leptin-deficient obese (Lep(ob)/Lep(ob)) mouse model, and that this would be further challenged when these mice were fed a high-fat diet. Obese mice had a 3.8-fold increased body fat content and a 9-fold increased liver fat content as compared to control mice when both groups were fed a low-fat diet. The expression of liver FAO enzymes, carnitine palmitoyltransferase-1a, long-chain acyl-CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and short-chain acyl-CoA dehydrogenase, was not affected in obese mice as compared to controls on either a low-fat or a high-fat diet. The expression of very-long-chain acyl-CoA dehydrogenase was elevated in obese mice on the control diet, as compared to control mice. For all measures evaluated, increasing the level of fat in the diet had a smaller effect than leptin deficiency. In summary, despite obese mice having an excess of fat available for mitochondrial beta-oxidation in liver, overall energy balance appeared to dictate that the net liver FAO remained at control levels. Topics: Acyl-CoA Dehydrogenase; Acyl-CoA Dehydrogenase, Long-Chain; Adipose Tissue; Analysis of Variance; Animals; Blotting, Northern; Blotting, Western; Body Weight; Carnitine O-Palmitoyltransferase; Dietary Fats; Fatty Acids; Female; Leptin; Lipids; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Organ Size; Oxidation-Reduction; RNA, Messenger; Specific Pathogen-Free Organisms; Time Factors | 2002 |
Associations between body mass, leptin, IGF-I and circulating adrenal androgens in children with obesity and premature adrenarche.
To explain why adrenal androgens rise with increasing adiposity during childhood, the role of body mass index (BMI), leptin and IGF-I was studied. We also tested whether these parameters contribute to inducing premature adrenarche (PA).. In a cross-sectional study, 26 prepubertal obese children were compared with a group of 26 prepubertal children of normal weight, and 30 children under observation for PA were compared with 30 healthy children, matched for gender, bone age and BMI.. Relative contributions of BMI standard deviation scores (SDS) and height SDS, as well as unbound leptin and IGF-I, to the levels of androgens, dehydroepiandrosterone sulfate (DHEAS) and Delta4-androstenedione (AD) were investigated by means of stepwise regression models. Logarithms of all hormones were standardised for age using residuals of a simple regression analysis, labelled by the suffix '(res)'.. In the obese children, height SDS, IGF-I(res,) DHEAS(res) (all P<0.05), leptin(res) (P<0.01), and AD(res) (P=0.07) were higher than in the controls, and covariates were correlated with each other (leptin(res) versus BMI SDS r=0.71, IGF-I(res) versus height SDS r=0.61). In the stepwise regression analysis of control and obese children, BMI SDS explained 26% and leptin(res) explained 12% of the variability of DHEAS(res), but this percentage remained at 26% when both variables were simultaneously introduced into the model. In contrast, IGF-I(res) and BMI SDS alone each accounted for 15% of the variability of AD, and their joint influence accumulated to explain 28% of the variability of AD(res). In PA, neither BMI SDS nor leptin(res) were correlated with the increased androgens.. Before the onset of gonadal activity in obese and control children, DHEAS levels, to some extent, are explained by BMI and leptin, while IGF-I in addition to BMI in part accounts for AD levels. Enhanced adrenal androgen secretion in children with PA, however, may be explained by parameters other than leptin or BMI. Topics: Adolescent; Adrenal Cortex; Aging; Androgens; Androstenedione; Anthropometry; Body Weight; Child; Child, Preschool; Cross-Sectional Studies; Dehydroepiandrosterone Sulfate; Female; Humans; Insulin-Like Growth Factor I; Leptin; Male; Obesity; Reference Values; Regression Analysis | 2002 |
Leptin in anorexia nervosa and bulimia nervosa: importance of assay technique and method of interpretation.
Studies of the role of leptin in patients with anorexia nervosa and bulimia nervosa have conflicted in their data and interpretation. Such differences may be a result of the assay methods used or the way results are compared with those from normal controls. To investigate these possibilities, we analyzed serum leptin levels in anorexic, bulimic, obese, and control individuals, thereby spanning the full range of human body weights, using three frequently employed commercial kits. Kits from Linco (St Louis, MO) and DSL (Webster, TX) employ a radioimmunoassay method, and the R&D Systems kit (Minneapolis, MN) uses an enzyme-linked immunosorbent assay. We found that the three kits provide results that are highly linearly correlated with each other and remarkably linearly related to percent ideal body weight (%IBW) over more than three orders of magnitude (Linco, r = 0.90; R&D, r = 0.87; DSL, r = 0.86). For very low leptin levels, the more sensitive kits from R&D and Linco appeared to give more reliable results. Measurement method does not appear to explain the literature conflicts. We found that patients with anorexia nervosa have serum leptin values that lie above the line extrapolated from the %IBW/leptin curve generated from analysis of all non-anorexic patients. Therefore, in anorexia nervosa, inappropriately high leptin levels for %IBW may contribute to a blunted physiologic response to underweight and consequent resistance to dietary treatment. By contrast, most bulimic patients have leptin levels significantly below those predicted from the same %IBW/leptin curve. The relative leptin deficiency in bulimic subjects may contribute to food-craving behavior. We propose that using the %IBW/ leptin curve can facilitate identification of true pathophysiologic abnormalities in eating-disordered individuals and provide a basis for the design of therapeutic interventions or monitoring of response to treatment. Topics: Anorexia Nervosa; Body Weight; Bulimia; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Linear Models; Obesity; Radioimmunoassay; Reagent Kits, Diagnostic; Sensitivity and Specificity | 2002 |
Maternal serum leptin concentration during the second trimester of pregnancy: association with fetal chromosomal abnormalities.
Recent studies suggest that leptin, the product of the obese gene, is produced by the placenta during pregnancy. The present study addressed the question whether second trimester maternal serum leptin could be altered by fetal Down syndrome or Edwards syndrome. Maternal serum leptin concentrations were measured in 18 pregnancies complicated with Down syndrome, six pregnancies complicated with Edwards syndrome and 183 uncomplicated pregnancies during the second trimester of pregnancy. The present results demonstrate that leptin concentrations in uncomplicated pregnancies slightly decrease from the 16th week of pregnancy, reaching a minimum of 18.8 ng/ml around the 20th week, and then rapidly increase to 28.2 ng/ml by the 24th week. Leptin correlation with maternal body weight decreases from r=0.695 at 16-17 week of gestation to r=0.544 at >22 weeks of gestation. There was no significant difference between the mean MoMs of Down syndrome- (0.926) or Edwards syndrome- (0.960) affected pregnancies and normal pregnancies (1.002). A weak correlation (r=0.18, p<0.02) was observed between corrected leptin MoMs and human chorionic gonadotrophin (hCG) MoMs in normal pregnancies. It is assumed that around the 20th week of pregnancy placental leptin production is activated or at least is accelerated and it is added to the amount of leptin produced by maternal adipose tissue. Fetal Down syndrome or Edwards syndrome does not seem to alter maternal leptin concentration and therefore leptin cannot be used as a marker for these chromosomal abnormalities in the early second trimester of pregnancy. Topics: Adult; Body Weight; Chorionic Gonadotropin; Chromosome Aberrations; Down Syndrome; Female; Humans; Leptin; Pregnancy; Pregnancy Trimester, Second | 2002 |
Effects of continuous lumbar intrathecal infusion of leptin in rats on weight regulation.
Intracranial leptin alters food consumption and body weight. To systematically characterize the effects of extended continuous spinal intrathecal delivery on such regulation, female rats received continuous lumbar spinal infusion (14 days) through catheters connected to osmotic minipumps of a vehicle or one of several doses of recombinant murine leptin (0.03-10 microg/day). The following observations were made. (1) Leptin resulted in a dose-dependent suppression in body weight and food consumption at doses above 0.3 microg/day. (2) Food consumption was initially reduced. Weight fell for 7 days and then plateaued at a level proportional to dose. (3) The ratio of food consumed to body weight was constant for control animals across the study. Leptin-infused rats slowed the initial fall in weight by increasing food consumption, such that the food to body weight ratio returned to that of control values. Rats were thus regulating food consumption to sustain body weight as defined by leptin dose. (4) On day 14, cisternal cerebrospinal fluid was obtained and leptin measured. Concentrations covaried in a log linear fashion with infusion dose. Body weight and food consumption covaried similarly with cisternal leptin concentrations across dose groups. Our data suggest that steady state infusions of leptin induce a degree of appetite suppression that leads to a steady state level of body weight loss and not simply to a simple block of consumatory behavior. The unexpected potency of the observed effects of intrathecal leptin relative to doses that are required after i.c.v. delivery suggests that at least a portion of the effects of intrathecal leptin may reflect a medullary action. The observed correlation of cisternal leptin levels with the behavioral effects is also consistent with a reliable distribution of the infused leptin to target supraspinal sites. Topics: Animals; Appetite Regulation; Body Weight; Central Nervous System; Cerebrospinal Fluid; Cisterna Magna; Dose-Response Relationship, Drug; Drug Administration Schedule; Eating; Female; Infusion Pumps; Injections, Spinal; Leptin; Lumbar Vertebrae; Medulla Oblongata; Rats; Rats, Sprague-Dawley; Subarachnoid Space | 2002 |
Central leptin increases insulin sensitivity in streptozotocin-induced diabetic rats.
This study examined the effect of intracerebroventricular leptin on insulin sensitivity in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were cannulated in the lateral ventricle and, after recovery, administered either intravenous STZ (50 mg/kg) to induce diabetes or citrate buffer. Chronic leptin (10 microg/10 microl icv) or vehicle injections were administered daily for 14 days beginning 2 days after establishment of hyperglycemia in the diabetic animals. At the end of the 2 wk of injections, insulin sensitivity was measured by the steady-state plasma glucose (SSPG) method. Blood glucose concentrations were dramatically reduced and normalized by the 4th day in diabetic animals receiving intracerebroventricular leptin treatment. Diabetic animals exhibited insulin resistance, whereas intracerebroventricular leptin significantly enhanced insulin sensitivity, as indicated by decreased SSPG. Circulating leptin levels were not increased in animals injected with intracerebroventricular leptin. Thus the increased peripheral insulin sensitivity appears to be due solely to the presence of leptin in the brain, not to leptin acting peripherally. These data imply that inadequate central leptin signaling may lead to insulin resistance. Topics: Animals; Blood Glucose; Body Weight; Brain Chemistry; Diabetes Mellitus, Experimental; Eating; Fasting; Hyperglycemia; Injections, Intraventricular; Insulin; Insulin Resistance; Leptin; Male; Rats; Rats, Wistar; Signal Transduction | 2002 |
Overweight, waist circumference, age, gender, and insulin resistance as risk factors for hyperleptinemia.
To evaluate the influence of overweight, waist circumference, age, gender, and insulin resistance as risk factors for hyperleptinemia.. A cross-sectional study was carried out in a population of 197 subjects: 59 men (21 aged < 60 years and 38 aged > or =60 years) and 138 women (37 aged < 60 years and 101 aged > or =60 years). The groups were stratified by overweight and normal weight. After a 12-hour fasting period, we measured serum leptin and insulin levels with radioimmunoassay methods. We also measured serum glucose and lipid profile. The data were analyzed by means of comparative tests. A variance-stabilizing transformation (natural logarithmic) was used to meet multiple linear regression, analysis of covariance, and logistic regression models.. The leptin serum levels were higher and statistically significant in young and older women than they were in men. We observed an interaction between gender and body mass index to explain the difference in leptin levels (p < 0.0001). Our study demonstrated an inverse relationship between leptin with age and high-density lipoprotein cholesterol. In logistic regression analysis, the overweight x gender interaction and waist circumference have a statistically significant influence as independent variables on hyperleptinemia (overweight x gender odds ratio = 6.81; 95% confidence interval, 1.10 to 46.86; p < 0.05 and waist circumference odds ratio = 4.34; 95% confidence interval, 1.47 to 12.83; p = 0.001).. Women who were overweight or had a higher waist circumference (women > or = 88 cm and men > or = 102 cm) have a significantly higher risk of having hyperleptinemia. The increase in age as an isolated variable is not a risk factor for hyperleptinemia. Topics: Age Factors; Body Constitution; Body Mass Index; Body Weight; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Leptin; Linear Models; Male; Middle Aged; Odds Ratio; Risk Factors; Sex Factors | 2002 |
Ghrelin, macronutrient intake and dietary preferences in long-evans rats.
Ghrelin is a recently discovered peptide that is primarily produced by the stomach. As a ligand of the growth hormone (GH) secretagogue (GHS) receptor, it stimulates GH secretion but it also stimulates feeding and has adipogenic effects in rodents. Although its circulating levels are modulated by fasting and refeeding, its relationship with diet composition is not known. In the present paper, we measured plasma ghrelin as well as two important hormones (leptin and insulin) in Long-Evans rats placed in two different feeding situations, e.g., either with imposed diets or with food choice. In the first case, the rats were fed unbalanced diets (either high-carbohydrate (HC) or high-fat (HF) diets) for 14 weeks, whereas in the second situation, they had the choice between these 2 diets for 2 weeks and were selected for their fat or carbohydrate preference. The intake of the HF diet for 14 weeks was associated with lower levels of ghrelin (-30% vs control diet; P < 0.01). These levels increased when the percentage of carbohydrate in the diet increased (+26 to +42% vs control diet; P < 0.01 or less). Ghrelin was inversely correlated with plasma leptin (r = -0.55; P < 0.003) and blood glucose (r = -0.58; P < 0.001) as well as with body weight (r = -0.63; P < 0.0001) and body fat content estimated by the sampling of specific fat pads (r = -0.62; P < 0.0001). In the food choice experiment, fat-preferring rats had plasma ghrelin levels lower than the carbohydrate-preferring rats (-33%; P < 0.0002). Ghrelin secretion was therefore very sensitive to the diet composition. Its down-regulation by fat ingestion might serve as a counterregulatory mechanism to limit the development of dietary-induced adiposity. Ghrelin may signal when a high calorie diet is ingested. Topics: Animals; Blood Glucose; Body Weight; Choice Behavior; Dietary Carbohydrates; Dietary Fats; Down-Regulation; Eating; Energy Intake; Food Preferences; Gastric Mucosa; Ghrelin; Insulin; Leptin; Male; Peptide Hormones; Peptides; Rats; Rats, Long-Evans; Time | 2002 |
A peroxisome proliferator-activated receptor gamma agonist influenced daily profile of energy expenditure in genetically obese diabetic rats.
Otsuka Long Evans Tokushima Fatty (OLETF) rats were developed as a model of non-insulin-dependent diabetes mellitus (NIDDM) with mild obesity. We reported that the daily profiles of energy expenditure associated with two peaks (one between 05:00 and 08:00 and the other between 20:00 and 22:00) were observed at 8 weeks of age (without NIDDM), while these two peaks disappeared at 24 weeks of age with NIDDM. As a new anti-diabetic drug, a peroxisome proliferator-activated receptor y agonist pioglitazone hydrochloride has been developed, we examined whether pioglitazone normalized daily profiles of energy expenditure at 24 weeks of age. A control diet and pioglitazone (0.1%)-containing diet were fed from 6 weeks of age. The two peaks of daily profiles of energy expenditure, which disappeared in OLETF rats with the control diet at 24 weeks of age, were reproduced by administration of pioglitazone. The respiratory quotient was lower and fat derived energy used for combustion was increased by pioglitazone at both ages. The body weight, daily food intake, plasma levels of fat, insulin, leptin and the wet weight of visceral fat were not influenced, but the levels of blood hemoglobin Alc and plasma tumor necrosis factor a were decreased by pioglitazone. Administration of pioglitazone improved daily profiles of energy expenditure via affecting glucose and fat metabolisms. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diet; Energy Metabolism; Hypoglycemic Agents; Leptin; Lipids; Obesity; Organ Size; Pancreas; Pioglitazone; Rats; Rats, Inbred OLETF; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors; Tumor Necrosis Factor-alpha | 2002 |
Central leptin gene delivery evokes persistent leptin signal transduction in young and aged-obese rats but physiological responses become attenuated over time in aged-obese rats.
The purpose of this study was to determine if long-term leptin treatment desensitizes leptin signal transduction and the subsequent downstream anorexic and thermogenic responses in normal and leptin-resistant age-related obese rats. To this end, we administered, i.c.v., recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control virus into young and aged-obese rats and after 9 or 46 days, examined food intake, oxygen consumption, body weight, serum leptin, STAT3 phosphorylation, hypothalamic NPY and POMC mRNAs, and UCP1 expression and protein level in brown adipose tissue (BAT). In young rats, rAAV-leptin depleted body fat and both anorexic and thermogenic mechanisms contributed to this effect. Moreover, leptin signal transduction was not desensitized, and there were persistent physiological responses. Similarly, in the aged-obese rats, there was unabated leptin signal transduction, however, both the anorexic and thermogenic responses completely attenuated sometime after day 9. This attenuation, downstream of the leptin receptor, may be contributing to the leptin-resistance and age-related weight gain in these aged-obese rats. Finally, in young rats, although the initial responses to rAAV-leptin were dominated by anorexic responses, by 46 days, the predominant response was thermogenic rather than anorexic, suggesting that energy expenditure may be an important component of long-term weight maintenance. Topics: Adipose Tissue, Brown; Aging; Animals; Body Weight; DNA, Complementary; Drug Delivery Systems; Eating; Genetic Therapy; Genetic Vectors; Injections, Intraventricular; Leptin; Male; Obesity; Oxygen Consumption; Rats; Rats, Inbred BN; Rats, Inbred F344; Signal Transduction | 2002 |
Daily CCK injection enhances reduction of body weight by chronic intracerebroventricular leptin infusion.
In the present study, we tested the hypothesis that a single daily injection of the gut peptide CCK, together with continuous leptin infusion, would produce significantly greater loss of body weight than leptin alone. We found that a single daily intraperitoneal injection of CCK-8 (0.5 microg/kg) significantly enhanced the weight-reducing effects of 0.5 microg/day leptin infused continuously into the lateral ventricle of male Sprague-Dawley rats by osmotic minipump. However, CCK and leptin together did not enhance reduction of daily chow intake. Furthermore, there was no synergistic reduction of 30-min sucrose intake, although a significant main effect of both leptin and CCK was observed on sucrose intake. These results 1) confirm our previous reports of synergy between leptin and CCK on body weight, 2) demonstrate that enhancement of leptin-induced weight loss does not require bolus administration of leptin, and 3) suggest that enhanced body weight loss following leptin and CCK does not require synergistic reduction of food intake by leptin and CCK. Topics: Animals; Body Weight; Cholecystokinin; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Eating; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Rats; Rats, Sprague-Dawley; Time Factors | 2002 |
Resting and circadian release of nitric oxide is controlled by leptin in male rats.
Because leptin stimulates nitric oxide (NO) release from the hypothalamus and anterior pituitary gland, we hypothesized that it also might release NO from adipocytes, the principal source of leptin. Consequently, plasma concentrations of leptin and NO, estimated from its metabolites NO(3) and NO(2) (NO(3)-NO(2)), were measured in adult male rats. There was a linear increase of both leptin and NO(3)-NO(2) with body weight that was associated with a parallel rise in fat mass. These findings indicate that release of leptin and NO is directly related to adipocyte mass. Furthermore, there was a parallelism in circadian rhythm of both substances, with peaks at 0130 h and nadirs at 0730 h. Measurement of both leptin and NO(3)-NO(2) in plasma from individual rats revealed that NO(3)-NO(2) increased linearly with leptin. Incubation of epididymal fat pads with leptin or its i.v. injection in conscious rats increased NO(3)-NO(2) release. The release of NO(3)-NO(2) in vivo and in vitro exceeded that of leptin by many fold, indicating that leptin activates NO synthase. Leptin increased tumor necrosis factor (TNF)-alpha release at a 100-fold lower dose than required for NO release in vitro and in vivo, suggesting that it also may participate in leptin-induced NO release. However, because many molecules of leptin were required to release a molecule of TNF-alpha in vivo and in vitro, we believe that leptin-induced TNF-alpha release is an associated phenomenon not involved in NO production. The results support the hypothesis that adipocytes play a major role in NO release by activating NO synthase in the adipocytes and the adjacent capillary endothelium. Topics: Adipocytes; Animals; Body Weight; Circadian Rhythm; Dose-Response Relationship, Drug; Leptin; Male; Models, Biological; Nitric Oxide; Rats; Time Factors; Tumor Necrosis Factor-alpha | 2002 |
Pituitary-thyroid axis, thyroid volume and leptin in healthy adults.
Patients with thyroid diseases usually have disturbances relating to body weight and thermogenesis. On the other hand, leptin is involved in the regulation of body weight, food intake and thermogenesis. Some studies have investigated the relationship between leptin and dysthyroid states, but the complex interactions between leptin and pituitary-thyroid axis have led to controversial results.. The aims of this cross-sectional study were to investigate the relationship among basal TSH, ultrasonographic thyroid volume and leptin in a group of 268 healthy adults randomly selected from our city, L'Hospitalet de Llobregat, Barcelona, an area free of iodine deficiency. In this euthyroid group, we determined basal TSH, thyroid autoantibodies, leptin concentrations, and thyroid volume by ultrasonography, body anthropometry, and body composition.. All subjects were free of goitre and were negative for anti-thyroid antibodies. Basal TSH concentrations were 1.49 +/- 0.8 mU/l in males and 1.67 +/- 0.83 mU/l in females (p = 0.6). Anti-thyroid antibodies were negative in all cases; leptin concentrations were 6.1 +/- 4 ng/ml in males and 16.8 +/- 11.7 ng/ml in females (p = 0.0001). Thyroid volume was 9.8 +/- 4.6 ml in males and 6.5 +/- 2 ml in females (p = 0.001). There were significant correlations among leptin concentrations and anthropometric and body composition variables in both sexes, without correlation with TSH concentrations. There was no significant correlation between anthropometric and body composition variables and thyroid volume in males but there was a correlation in females. In females, there was a positive correlation between leptin and thyroid volume (r = 0.181, p = 0.038). In males, there was a negative correlation between TSH concentrations and thyroid volume (r = - 0.271, p = 0.002).. We did not find any correlation between leptin levels and pituitary-thyroid axis in this control population. The correlation between leptin and thyroid volume in females is probably a consequence that leptin and thyroid volume are regulated in parallel by variables relating to anthropometry and body composition. Topics: Adult; Autoantibodies; Body Composition; Body Constitution; Body Mass Index; Body Water; Body Weight; Cross-Sectional Studies; Female; Humans; Iodine; Leptin; Male; Middle Aged; Pituitary Gland; Reference Values; Sex Characteristics; Spain; Thyroid Gland; Thyrotropin; Ultrasonography | 2002 |
Effects of acute and chronic administration of the melanocortin agonist MTII in mice with diet-induced obesity.
High-fat diet-induced obesity (DIO) in rodents is associated with hyperleptinemia and resistance to leptin, but the response to agents acting downstream of leptin receptors remains unknown. We assessed the response of mice with DIO to treatment with MTII, an alpha-melanocyte-stimulating hormone analog. MTII delivered four times daily by intraperitoneal injection to C57BL/6J mice produced a dose-responsive effect on food intake, body weight, leptin, corticosterone, insulin, and free fatty acids. In DIO mice, administration of MTII 100 microg q.i.d. i.p. markedly suppressed feeding during the first 4 days of treatment, with food intake returning to control levels at day 5. Progressive weight loss also occurred over the first 4 days, after which weight plateaued at a level below control. After 8 days of treatment, MTII-treated DIO mice had major suppression of both leptin and insulin levels. Central administration of MTII for 4 days (10 nmol/day) in DIO mice significantly suppressed food intake, induced weight loss, and increased energy expenditure. These results indicate that 1) MTII administration to DIO mice causes suppression of food intake and body weight loss, and decreased food intake is primarily responsible for weight loss; 2) peripheral MTII improves insulin resistance in DIO mice; 3) "tachyphylaxis" to the effect of chronic MTII treatment on food intake occurs; and 4) at least some of the effects of MTII are exerted centrally. In conclusion, treatment with a melanocortin agonist is a promising therapeutic approach to DIO and associated insulin resistance. Topics: alpha-MSH; Animals; Blood Glucose; Body Weight; Corticosterone; Diet; Eating; Energy Metabolism; Injections, Intraperitoneal; Injections, Intraventricular; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Oligopeptides; Receptors, Corticotropin; Receptors, Melanocortin | 2002 |
The neuropeptide Y Y1 receptor regulates leptin-mediated control of energy homeostasis and reproductive functions.
The orexigenic neurotransmitter neuropeptide Y (NPY) plays a central role in the hypothalamic control of food intake and energy balance. NPY also exerts an inhibition of the gonadotrope axis that could be important in the response to poor metabolic conditions. In contrast, leptin provides an anorexigenic signal to centrally control the body needs in energy. Moreover, leptin contributes to preserve adequate reproductive functions by stimulating the activity of the gonadotrope axis. It is of interest that hypothalamic NPY represents a primary target of leptin actions. To evaluate the importance of the NPY Y1 and Y5 receptors in the downstream pathways modulated by leptin and controlling energy metabolism as well as the activity of the gonadotrope axis, we studied the effects of leptin administration on food intake and reproductive functions in mice deficient for the expression of either the Y1 or the Y5 receptor. Furthermore, the role of the Y1 receptor in leptin resistance was determined in leptin-deficient ob/ob mice bearing a null mutation in the NPY Y1 locus. Results point to a crucial role for the NPY Y1 receptor in mediating the NPY pathways situated downstream of leptin actions and controlling food intake, the onset of puberty, and the maintenance of reproductive functions. Topics: Alleles; Animals; Anorexia; Body Weight; Energy Metabolism; Fasting; Female; Homeostasis; Hyperphagia; Kinetics; Leptin; Luteinizing Hormone; Male; Mice; Mice, Knockout; Models, Biological; Receptors, Leptin; Receptors, Neuropeptide Y; Sexual Maturation | 2002 |
The leptin defense against wasting is abolished in the IL-2-deficient mouse model of inflammatory bowel disease.
Anorexia is a major complication of inflammatory bowel disease (IBD). We postulated that chronic intestinal inflammation with increased proinflammatory cytokines elevates serum leptin concentration, thereby contributing to anorexia. This hypothesis was studied in interleukin-2-deficient (IL-2(-/-)) mice, a model of IBD with elevated proinflammatory cytokine production. IL-2(-/-), wild-type pair-fed and wild-type control male mice (8 wk old) were fed regular laboratory mouse food for 2 wk. The IL-2(-/-) and pair-fed groups consumed less food and lost weight. Serum leptin concentrations in the IL-2(-/-) mice in the fed state were lower than controls, but not different from pair-fed mice, and paradoxically increased in the starved state to levels significantly higher than both starved control and pair-fed groups. This result did not change when serum leptin was adjusted for amount of body fat. These data show abnormal leptin responses in IL-2(-/-) mice with increased leptin concentrations disproportionate to fat mass and prevention of the normal decline in leptin with food restriction. Topics: Animals; Anorexia; Body Weight; Cytokines; Disease Models, Animal; Eating; Energy Intake; Food Deprivation; Inflammatory Bowel Diseases; Interleukin-2; Leptin; Male; Mice; Mice, Inbred C57BL; Wasting Syndrome | 2002 |
Dietary modulation of circulating leptin levels: site-specific changes in fat deposition and ob mRNA expression.
In order to study the effects of diet on fat distribution, circulating leptin levels and ob mRNA expression, diets of different macronutrient composition were fed to lean mice and gold thioglucose-obese mice. A high-fat diet and 2 high-carbohydrate diets, one containing mostly high-glycaemic-index starch and the other containing low-glycaemic-index starch were fed ad libitum for 10 weeks and were compared to standard laboratory chow. Weight gain was attenuated by feeding low-glycaemic-index starch in all mice and by feeding a high-fat diet in lean mice. Reduced adiposity was seen in lean mice fed low-glycaemic-index starch, whereas increased adiposity was seen in both lean and obese mice fed on the high-fat diet. Circulating leptin levels, when corrected for adiposity, were decreased in all mice fed either the high-fat diet or the low-GI diet. In epididymal fat pads, decreased ob mRNA expression was seen after both high-fat and high-glycaemic-index starch feeding. These results show that diet macronutrient composition contributes to the variability of circulating leptin levels by the combined effects of diet on fat distribution and on site-specific changes in ob mRNA expression. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Dietary Carbohydrates; Dietary Fats; Glycemic Index; Insulin; Leptin; Male; Mice; Mice, Inbred CBA; Mice, Obese; Obesity; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2002 |
Seasonal weight regulation of the raccoon dog (Nyctereutes procyonoides): interactions between melatonin, leptin, ghrelin, and growth hormone.
The raccoon dog (Nyctereutes procyonoides, Canidae, Carnivora) is a middle-sized omnivore with excessive autumnal fattening and winter sleep. We studied seasonal weight regulation of the species by following the plasma leptin, ghrelin, and growth hormone (GH) levels of farm-bred raccoon dogs (n = 32) for 6 months. In August, half of the raccoon dogs received continuous-release melatonin implants, and in November, half of the animals of both the sham-operated and melatonin-treated groups were fasted for 2 months. In the autumn, the plasma leptin and GH levels were low, but the ghrelin levels were relatively high and correlated positively with energy intake. This represents the period of energy storage. Leptin and GH levels peaked simultaneously in late October, and melatonin advanced the peaks by 1 week. Thereafter, the levels rapidly declined, representing the transition period from autumnal anabolism to wintertime catabolism. In the winter, the leptin and GH levels rose to high levels, but the ghrelin-leptin ratio was very low. This is the period of winter sleep, with fat accumulated in the autumn as the principal metabolic fuel. In the winter, leptin, ghrelin, and GH may work in synergy to increase lipolysis. GH may also induce winter sleep to the raccoon dog. Fasting had no effect on the hormone levels, unlike in humans and rodents. Instead of the amount of fat in the body, the main regulators of the levels of these hormones in the raccoon dog are presumably seasonal rhythms entrained by melatonin. Topics: Adipose Tissue; Animals; Basal Metabolism; Body Weight; Carnivora; Drug Implants; Eating; Energy Metabolism; Fasting; Female; Ghrelin; Growth Hormone; Hibernation; Leptin; Male; Melatonin; Peptide Hormones; Peptides; Photoperiod; Seasons | 2002 |
Failure of polycythemia-induced increase in arterial oxygen content to suppress the anorexic effect of simulated high altitude in the adult rat.
The anorexic effect of exposure to high altitude may be related to the reduction in the arterial oxygen content (Ca(O2)) induced by hypoxemia and possibly the associated decreased convective oxygen transport (COT). This study was then performed to evaluate the effects of either transfusion-induced polycythemia or previous acclimation to hypobaria with endogenously induced polycythemia on the anorexic effect of simulated high altitude (SHA) in adult female rats. Food consumption, expressed in g/d/100 g body weight, was reduced by 40% in rats exposed to 506 mbar for 4 d, as compared to control rats maintained in room air. Transfusion polycythemia, which significantly increased hematocrit, hemoglobin concentration, Ca(O2), and COT, did not change the anorexic response to the exposure to hypobaric air. Depression of food intake during exposure to SHA also occurred in rats fasted during 31 h before exposure and allowed to eat ad libitum for 2 h during exposure. Body mass loss was similar in 48-h fasted rats that were either hypoxic or normoxic. Body mass loss was similar in normoxic and hypoxic rats, the former eating the amount of food freely eaten by the latter. Hypoxia-acclimated rats with endogenously induced polycythemia taken to SHA again had diminished food intake and lost body mass at rates that were very close to those found in nonacclimated ones. Exposure to SHA also led to a decrease in food consumption, body weight, and plasma leptin in adult female mice. Analysis of data suggest that body mass loss that accompanies SHA-induced hypoxia is due to hypophagia and that experimental manipulation of the blood oxygen transport capacity cannot ameliorate it. Leptin does not appear to be an inducer of the anorexic response to hypoxia, at least in mice and rats. Topics: Acclimatization; Altitude Sickness; Animals; Anorexia; Appetite; Blood Gas Analysis; Body Weight; Fasting; Female; Hypoxia; Leptin; Mice; Oxygen; Polycythemia; Rats; Rats, Wistar; Reference Values | 2002 |
Dietary fat source regulates ob gene expression in white adipose tissue of rats under hyperphagic feeding.
This work was designed to investigate the effect of different lipid sources on ob gene expression and serum leptin levels in rats with two different feeding protocols: (1) free access to food; or (2) energy-controlled feeding. Male Wistar rats were fed diets containing 40 % energy as fat (olive oil, sunflower oil or beef tallow), for 4 weeks. In Expt 1 rats had free access to food, and in Expt 2 rats were fed a controlled amount of food (16 g/d, equivalent to 300 kJ/d). Insulin and leptin were determined by ELISA and ob mRNA by Northern blot. When rats had free access to food, ob mRNA levels were higher in animals fed either olive oil or sunflower oil than in those fed beef tallow. In marked contrast with feeding ad libitum, no differences were found among dietary fat groups in rats fed energy-controlled diets. When both feeding protocols were compared, free access to food induced an increased expression of ob mRNA in perirenal and/or epididymal adipose tissues from rats fed either olive oil or sunflower oil, but not from rats fed beef tallow. Dietary lipid type did not induce modifications in serum leptin concentrations. A tendency to higher serum leptin levels was observed more in rats with free access to food than in rats fed energy-controlled feeding. No differences were found in insulin levels. Dietary fat type importantly affects ob mRNA expression in rat white adipose tissue under hyperphagic conditions. Further study is needed in order to elucidate the mechanism underlying this effect. Topics: Adipose Tissue; Animals; Blotting, Northern; Body Weight; Dietary Fats; Dietary Fats, Unsaturated; Eating; Gene Expression Regulation; Hyperphagia; Insulin; Leptin; Male; Rats; Rats, Wistar; RNA, Messenger; Weight Gain | 2002 |
Malnutrition during lactation as a metabolic imprinting factor inducing the feeding pattern of offspring rats when adults. The role of insulin and leptin.
The aim of the present study was to determine the impact of malnutrition during early postnatal life and the feeding pattern of rat offspring when adults (2 months and 1 year old). In comparison with rats normally fed during lactation, we observed that adult offspring displayed a faster process of feeding reduction when a protein-free diet was offered. In addition, we studied the concentration of insulin and leptin in the lactating pups (10 days) and when these offspring became adult after the onset of a new feeding pattern induced by the protein-free diet. When the diet was changed at 60 days, the offspring malnourished during lactation displayed, after 3 days, a food intake reduction around 41.4 vs 14.2% of the control group. At 10 days of life, plasma leptin and insulin were higher in the malnourished pups when compared with normally fed rats (leptin: 4.6 +/- 0.8 vs 2.25 ng/ml; insulin: 0.73 +/- 0.12 vs 0.22 +/- 0.03 ng/ml) while at 60 days they showed reduction of both hormones when compared with the control group (leptin: 1.03 +/- 0.25 vs 1.43 +/- 0.5 ng/ml; insulin: 0.54 +/- 0.3 vs 0.61 +/- 0.4 ng/ml). Despite the different food intake reductions, the malnourished and control rats displayed a similar reduction of insulin and leptin after 3 days of protein-free diet (from 60 to 63 days). The data suggest that the high concentration of insulin and leptin found at 10 days in the malnourished pups may elicit a sustained long-term and unique feeding pattern. Topics: Animals; Body Weight; Diet, Protein-Restricted; Eating; Feeding Behavior; Female; Insulin; Lactation; Leptin; Nutrition Disorders; Pregnancy; Rats | 2002 |
Relationship between body weight and hematological and serum biochemical parameters in female cynomolgus monkeys (Macaca fascicularis).
Obesity is a risk factor triggering a variety of metabolic diseases. Cynomolgus monkeys (Macaca fascicularis) exhibit spontaneous onset of obesity in adulthood, similar to such onset exhibited by humans. To clarify the characteristics accompanying obesity in female cynomolgus monkeys, we used simple and multiple regression analyses to determine the relationship between body weight and hematological and serum biochemical parameters as well as obesity-related hormones, namely, leptin and insulin. Simple regression analysis showed that body weight was significantly (P < 0.05) correlated with leptin level, insulin level, hemoglobin concentration, hematocrit values, mean corpuscular volume, glucose concentration, and triglyceride concentration. In addition, a multiple regression model containing leptin level, insulin level, mean corpuscular volume, and red blood cell count explained 66.9% of the variance in body weight. Therefore, female cynomolgus monkeys show similar obesity characteristics to humans, i.e., obesity is associated with enhanced synthesis and excretion of leptin in adipocytes, high risk of diabetes mellitus, and high levels of hematocytes. Our results indicate that female cynomolgus monkeys are good models for studying obesity in humans. Topics: Animals; Blood Glucose; Body Weight; Disease Models, Animal; Erythrocyte Indices; Female; Hematocrit; Hemoglobins; Humans; Insulin; Leptin; Macaca fascicularis; Monkey Diseases; Obesity; Triglycerides | 2002 |
Experimental and clinical studies on plasma leptin in obese dogs.
Leptin is a protein synthesized and secreted primarily by adipocytes, and the circulating leptin concentration is elevated in obese humans and rodents. Recently, we have established a sandwich enzyme-linked immunosorbent assay for canine leptin. In the present study, plasma leptin concentrations were measured in experimentally developed obese beagles and in clinically obese dogs. When 5 male beagles were given a high-energy diet for 3 months, all of them became obese and the plasma leptin concentration significantly increased from 2.4+/-1.2 to 4.9+/-0.9 ng/ml, positively correlating with body fat content estimated by the deuterium oxide dilution method (r=0.87). The leptin concentrations of plasma samples collected from 59 dogs in veterinary practices were compared with their body condition scores (BCS). The plasma leptin concentrations of obese dogs were 9.7+/-0.7 and 12.3+/-1.5 ng/ml at BCS=4 and BCS=5, respectively, which were significantly higher than those of optimal (BCS=3) dogs (2.7+/-0.3 ng/ml). There was no significant effect of sex and breed. A weak positive correlation (r=0.37) was found between the plasma leptin concentration and age, probably due to the lesser content of visceral fat in puppies younger than 1 year old. These results indicate that plasma leptin is a good index of adiposity in dogs regardless of breed, age and sex, and may be useful for quantitative assessment of obesity in small animal practice. Topics: Animals; Body Weight; Dog Diseases; Dogs; Enzyme-Linked Immunosorbent Assay; Female; Leptin; Male; Obesity; Regression Analysis | 2002 |
The effect of lean growth rate on puberty attainment in gilts.
Two hundred sixteen prepubertal Genex Manor hybrid F1 gilts were used to determine the impact of lean growth rate on sexual development of gilts. This study was composed of two experiments (Exp. 1 and Exp. 2). In Exp. 1, at approximately 96 d of age and 54 kg weight, gilts were allocated with respect to growth rate and litter origin to one of two dietary treatments: 1) a diet formulated to maximize lean growth potential (LP; n = 84) or 2) a diet formulated to produce a lower lean growth rate (LL; n = 84). In Exp. 2, at approximately 88 d of age and 50 kg weight, gilts were allocated with respect to growth rate and litter origin to one of two dietary treatments: 1) a diet formulated to maximize lean growth potential (LP; n = 24) or 2) a diet formulated to restrict lean growth further than was achieved in LL in Exp. 1 (RL; n = 24). All gilts were fed treatment diets for ad libitum consumption and housed in groups of six. Weight, backfat depth and loin depth, and feed intake were measured weekly. Starting at 135 d of age, gilts received 20 min of direct daily exposure to a boar as a pen group for pubertal stimulation. Puberty attainment was determined as the day gilts first exhibited the standing reflex in response to contact with a boar. At pubertal estrus, body weight, backfat depth, and loin depths were recorded. Diet affected (P < or = 0.05) estimated fat-free lean gain (LP, 424 vs LL, 347 g/d, Exp. 1; LP, 397 vs RL, 376 g/d, Exp. 2) during the growth period (start to stimulation). However, age at puberty was not affected by diet (LP, 157.3 vs LL, 157.6, Exp. 1; LP, 166.7 vs RL, 167.3, Exp. 2) or overall lean growth at stimulation (P > or = 0.05 in both experiments), confirming that innate variability in sexual development of commercial genotypes, rather than growth performance, determines onset of sexual maturity. A negative correlation between age at puberty and growth rate from 50 kg until puberty (P < or = 0.05) (LP, r = -0.40, LL, r = -0.36, Exp. 1; LP, r = -0.64, RL, r = -0.48, Exp. 2) was a consequence of reduced lean tissue growth during the stimulation period in later-maturing gilts. Topics: Adipose Tissue; Age Factors; Animals; Body Composition; Body Weight; Energy Intake; Female; Genotype; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Sexual Maturation; Swine | 2002 |
Serotonergic activation rescues reproductive function in fasted mice: does serotonin mediate the metabolic effects of leptin on reproduction?
Negative energy balance inhibits reproduction by restraining GnRH secretion. Leptin is a permissive metabolic signal for reproduction, but GnRH neurons do not appear to express leptin receptors, suggesting that interneurons transmit leptin signals to these cells. Serotonin (5HT) has satiety effects similar to those of leptin and alters LH release, and serotonergic neurons, which have been shown to express leptin receptors, terminate on GnRH neurons. We hypothesized that serotonergic neurons convey leptin signals to the reproductive neuroendocrine axis. To test this, mice were fasted for 48 h beginning on Diestrous Day 1. While fasting, mice received saline or leptin every 12 h or the 5HT-selective reuptake-inhibitor fluoxetine once at the start of the fast. Estrous cycles of fasted mice were longer (mean +/- SEM, 10.2 +/- 0.5 days; P < 0.0001) than those of fed mice (4.5 +/- 0.2 days). As previously reported, leptin prevented fasting-induced cycle lengthening (4.6 +/- 0.7 days). Fluoxetine also rescued estrous cycles in fasted mice (4.7 +/- 0.6 days), suggesting that 5HT and leptin have similar positive effects on reproduction. Coadministration of the 5HT 1/2/7 receptor-antagonist metergoline blocked rescue of cycle length by fluoxetine and by leptin. Treating leptin-deficient ob/ob and leptin receptor-deficient db/db mice with fluoxetine did not normalize body weight or rescue fertility, perhaps due to altered serotonergic tone in these animals. Together, these data demonstrate a permissive role for serotonergic systems in the metabolic control of reproduction and are consistent with the hypothesis that serotonergic neurons convey leptin signals to GnRH neurons. Topics: Animals; Body Weight; Diabetes Mellitus; Eating; Estrous Cycle; Fasting; Female; Fertility; Fluoxetine; Gonadotropin-Releasing Hormone; Leptin; Metergoline; Mice; Mice, Inbred C57BL; Mice, Obese; Neurons; Obesity; Reproduction; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Antagonists; Signal Transduction; Time Factors | 2002 |
The leptin-like effects of 3-d peripheral administration of a melanocortin agonist are more marked in genetically obese Zucker (fa/fa) than in lean rats.
The effects of a 3-d peripheral administration of an alpha-MSH agonist, MTII, on body weight and the expression of uncoupling proteins (UCPs) and carnitine palmitoyltransferase-1 were determined in lean and genetically obese fa/fa rats by comparing MTII-treated animals with two different control groups, one being ad libitum fed, the other pair-fed to the amount of food consumed by MTII-treated rats. MTII treatment of lean and obese rats lowered food intake and body weight, the effects being more marked in obese than in lean rats. In both groups, MTII administration suppressed the increased plasma FFA levels brought about by food restriction. In lean rats, MTII prevented the decrease in brown adipose tissue UCP1, UCP2, and UCP3 expression and muscle UCP3 occurring during food restriction. In obese animals, MTII markedly increased brown adipose tissue (7-fold) and muscle (2.5-fold) UCP3 expression. The decrease in liver carnitine palmitoyltransferase-1 elicited by food restriction in lean and obese rats was prevented by MTII administration. In summary, the effects of MTII resemble those of leptin and are more marked in obese than in lean animals, in keeping with their reported reduced endogenous melanocortin tone. Melanocortin agonists may be useful in the treatment of obesity associated with impaired leptin signaling. Topics: Adipose Tissue; alpha-MSH; Animals; Blood Glucose; Blotting, Northern; Body Weight; Carnitine O-Palmitoyltransferase; Eating; Fatty Acids, Nonesterified; Injections, Intraperitoneal; Insulin; Leptin; Lipid Metabolism; Liver; Male; Melanocyte-Stimulating Hormones; Muscle, Skeletal; Obesity; Peptides, Cyclic; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2002 |
Inactivation of the GR in the nervous system affects energy accumulation.
The homeostatic regulation of body weight protects the organism from the negative consequences of starvation and obesity. Glucocorticoids (GCs) modulate this regulation, although the underlying mechanisms remain unclear. To address the role of central GRs in the regulation of energy balance, we studied mice in which GRs have selectively been inactivated in the nervous system. Mutant mice display marked growth retardation. During suckling age this is associated with normal fat deposition causing a 60% temporary increase of percent body fat, compared with control littermates. After weaning, fat and protein depositions are reduced so that adults are both smaller and leaner than their controls. Decreased food intake and, after weaning, reduced metabolic efficiency account for these developmental disturbances. Plasma levels of leptin and insulin, two important energy balance regulators, are elevated in young mutants but normal in adults. Leptin/body fat ratio is higher at all ages, suggesting disturbed control of circulating leptin as a consequence of chronically elevated GC levels in mutant animals. Adult mutants display increased hypothalamic CRH and NPY levels, but peptide levels of melanin concentrating hormone and Orexin A and B are unchanged. The increased levels of plasma GCs and hypothalamic CRH may act as catabolic signals most likely leading to persistently reduced energy accumulation. Topics: Aging; Animals; Body Composition; Body Weight; Corticotropin-Releasing Hormone; Eating; Energy Metabolism; Glucocorticoids; Growth; Human Growth Hormone; Immunohistochemistry; Insulin; Insulin-Like Growth Factor I; Leptin; Mice; Mice, Knockout; Nervous System Physiological Phenomena; Neuroglia; Neurons; Paraventricular Hypothalamic Nucleus; Rats; Receptors, Glucocorticoid; Thyroxine | 2002 |
Insulin and leptin combine additively to reduce food intake and body weight in rats.
Leptin and insulin are distinct adiposity signals that regulate food intake and body weight. Because recent evidence suggests that the central catabolic action of each is mediated by the hypothalamic melanocortin system, we tested the hypothesis that leptin and insulin interact within the brain, either additively or synergistically, to suppress food intake and reduce body weight. Using a within-subjects design, we co-administered leptin and insulin into the 3rd cerebral ventricle (i.c.v.) over a wide range of doses, and compared the combined effects to what occurred following the administration of each peptide alone. The data suggest that leptin and insulin interact sub-additively to regulate food intake and body weight over the first few hours. That is, the ability of combinations of leptin and insulin to reduce food intake and body weight was less than what would be predicted by the sum of their independent actions. Over 24 hours, however, the combined doses fit a strictly additive model. These data therefore imply a redundancy in the functional intracellular pathways or neuronal circuits that leptin and insulin utilize in the acute regulation of food intake and body weight, and they further imply that over time, the redundancy dissipates. Topics: Animals; Body Weight; Depression, Chemical; Dose-Response Relationship, Drug; Drug Synergism; Eating; Energy Metabolism; Hypoglycemic Agents; Hypothalamus; Injections, Intraventricular; Insulin; Leptin; Male; Melanocyte-Stimulating Hormones; Rats; Rats, Sprague-Dawley | 2002 |
Serum insulin and leptin levels in valproate-associated obesity.
Weight gain is an important adverse effect of valproate (VPA) therapy, and it is associated with hyperinsulinemia and hyperandrogenism in women with epilepsy. Leptin is considered a signaling factor regulating body weight and energy metabolism. In human subjects, obesity is in general associated with elevated serum leptin levels, suggesting decreased sensitivity to leptin. The present study aimed at evaluating the role of insulin and leptin in VPA-related obesity.. Body mass index (BMI) was calculated, and serum insulin and leptin levels were measured in 81 patients with epilepsy taking VPA and in 51 healthy control subjects.. Forty (49%) of the patients taking VPA and 25 (49%) of the control subjects were obese. The mean insulin levels were higher in VPA-treated patients than in the control subjects despite similar BMI values, when all subjects were included in the comparison. Both obese male and female patients taking VPA had higher serum insulin levels than the respective control subjects with similar BMI values. Serum insulin levels also were higher in lean male and lean female patients compared with the lean control subjects of same sex. Serum leptin levels did not differ between the VPA-treated patients and the control subjects.. Both obese and lean patients taking VPA for epilepsy have hyperinsulinemia, suggesting development of insulin resistance. This may be one of the factors leading to weight gain during VPA treatment. However, the results of the present study do not suggest an independent role for leptin in the pathogenesis of VPA-related obesity. Topics: Adult; Body Mass Index; Body Weight; Epilepsy; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Sex Factors; Valproic Acid | 2002 |
The effect of adrenalectomy on leptin levels and some metabolic parameters in rats with diet-induced obesity.
Recently, there has been many investigations on the relationship between leptin and obesity, which is the main health problem in developed countries. In some reports, it has been claimed that the adrenalectomy has lead to weight loss and thus prevented obesity induced in rodents in various ways. It has also been accepted that diet-induced obesity in animals is very similar to obesity in humans beings. In this study, obesity has been developed with high-calorie diet given for 8 weeks in Sprague-Dawley rats. Then, it has been investigated how leptin and some metabolic parameters change in blood samples obtained from rats 15 d after adrenalectomy. Leptin levels was determined with Radio Immun Assay (RIA, Linco Research Co) method. Our study showed that, there were statistically significant increases in leptin (p<0.001), glucose (p<0.05), triglyceride (p<0.01) levels in diet-induced obese rats (n=19) when compared with the findings of control rats, lean ones (n=16), (Tables 3, 4). Adrenalectomy led to decreased serum leptin (p<0.001) and triglyceride (p<0.01) levels both in the obese and lean rats (Table 5). As a conclusion, it could be claimed that the decrease in leptin levels may be attributed to reduced adipose tissue due to adrenalectomy. On the other hand, the decreases in glucose and triglyceride levels might be the consequence of reduced lipogenesis and impaired gluconeogenesis with the effect of adrenalectomy. It was concluded that adrenalectomy might prevent obesity by affecting leptin and intermediate metabolism. Topics: Adrenalectomy; Animals; Blood Glucose; Body Weight; Cholesterol; Diet; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Triglycerides | 2002 |
Distinct role of adiposity and insulin resistance in glucose intolerance: studies in ventromedial hypothalamic-lesioned obese rats.
It remains unclear whether adiposity plays an important role in glucose intolerance independently of insulin resistance. We investigated whether adiposity and insulin resistance had distinct roles in glucose intolerance in rats. We examined glucose tolerance and insulin resistance using ventromedial hypothalamic (VMH)-lesioned rats in the dynamic and the static phases of obesity (2 and 14 weeks after lesioning, respectively). Rats were fed either normal chow or a fructose-enriched diet (60% of total calories). The intravenous glucose tolerance test (IVGTT) was performed by bolus injection of glucose solution (1 g/kg) and blood sampling after 0, 5 10, 30, and 60 minutes. Insulin resistance was evaluated from the steady-state plasma glucose (SSPG) value during continuous infusion of glucose, insulin, and somatostatin. SSPG was not increased in VMH-lesioned rats in the dynamic phase of obesity, but increased markedly in the static phase. The area under the glucose curve (glucose AUC) during IVGTT was increased in VMH-lesioned rats in the static phase, but not in the dynamic phase, when compared with their sham-operated counterparts. A fructose-enriched diet for 2 or 14 weeks increased SSPG values to a similar extent in both sham-operated and VMH-lesioned rats without inducing excess adiposity, but glucose intolerance was only developed in the obese rats. The plasma leptin level, an excellent indicator of adiposity, was significantly related to the glucose AUC independently of the insulin level. Insulin resistance or increased adiposity alone is not sufficient to impair glucose tolerance, but increased adiposity plays an important role in the development of glucose intolerance in an insulin-resistant state. Topics: Animals; Area Under Curve; Blood Glucose; Body Weight; Dietary Supplements; Disease Models, Animal; Eating; Fatty Acids, Nonesterified; Female; Fructose; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Obesity; Rats; Triglycerides; Ventromedial Hypothalamic Nucleus | 2002 |
Neutering induces changes in food intake, body weight, plasma insulin and leptin concentrations in normal and lipoprotein lipase-deficient male cats.
Topics: Animals; Body Weight; Cats; Eating; Insulin; Leptin; Lipoprotein Lipase; Male; Orchiectomy; Osmolar Concentration; Reference Values | 2002 |
Plasma concentrations of leptin mirror changes in body weight but do not influence the pattern of the preovulatory luteinizing hormone surge in mink (Mustela vison).
Topics: Animal Feed; Animals; Body Weight; Energy Intake; Female; Follicular Phase; Food Deprivation; Leptin; Luteinizing Hormone; Mink; Osmolar Concentration | 2002 |
Placental GH, IGF-I, IGF-binding protein-1, and leptin during a glucose challenge test in pregnant women: relation with maternal body weight, glucose tolerance, and birth weight.
The prediction of birth weight may be improved by the measurement of hormones or growth factors in the mother. We measured body weight (BW) and plasma levels of placental GH (PGH), IGF-I, IGF-binding protein-1 (IGFBP-1), and leptin at the time of the glucose challenge test (GCT) in 289 women, who were pregnant with a single fetus, between 24 and 29 wk gestational age (GA). Delivery occurred 12 +/- 2 (mean +/- SD) wk later. First, we examined which variables regulate these hormonal factors. Multiple regression showed that PGH concentrations were determined by GA at sampling and were negatively related to BW. IGF-I levels were mainly determined by PGH, and also by insulin, BW, and (negatively) age. IGFBP-1 concentrations were negatively determined by BW, insulin, and IGF-I. BW was also a powerful determinant of leptin levels, with insulin as a less robust determinant. Second, we examined the relation to glucose levels. PGH, IGF-I, and IGFBP-1 concentrations were not correlated with post-GCT glucose levels and were comparable in women with a normal or disturbed GCT (glucose >/=7.8 mmol/liter; n = 72). Finally, we examined the relation with birth weight and placental weight. Birth weight, corrected for GA and stratified into percentile groups, and the ponderal index at birth were strongly related to maternal BW, but not to maternal PGH, IGF-I, or IGFBP-1 levels. Neither was maternal leptin related to birth weight, but leptin concentrations were slightly higher in women who delivered obese babies. Placental weight was not related to any of the hormonal factors. This prospective study indicates that the variation in circulating PGH, IGF-I, IGFBP-1, and leptin between 24 and 29 wk of pregnancy is strongly dependent on maternal BW, but is unrelated to glucose tolerance. In addition, the measurement of PGH, IGF-I, IGFBP-1, or leptin at the time of the GCT is not useful clinically to predict birth weight. Topics: Adolescent; Adult; Birth Weight; Blood Glucose; Body Weight; Female; Glucose; Glucose Tolerance Test; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Leptin; Organ Size; Placenta; Pregnancy; Prostaglandins H | 2002 |
Direct measurement of renal sympathetic nervous activity in high-fat diet-related hypertensive rats.
The elevation of renal sympathetic nervous activity (SNA) is a possible cause of blood pressure (BP) elevation. Although a high-fat diet (FAT) often induces BP elevation in animals, the effect of FAT on renal SNA in animals is not consistent between studies. Thus, we compared the basal levels of efferent renal SNA and BP in FAT- or high-carbohydrate diet (CHO)-fed rats. Twenty-four male Sprague-Dawley rats were fed FAT (P/F/C=20/45/35% cal) or CHO (20/5/75) from 5 weeks of age. After 20-21 weeks of feeding, a 24-h urine sample was collected to measure sodium excretion. The next day, blood (0.2 ml) was withdrawn from a femoral artery, and basal efferent renal nerve discharges and mean arterial pressure (MAP) were recorded under anesthesia. Immediately after the experiment, abdominal (epididymal, perirenal and mesenteric) adipose tissues were dissected. Total abdominal fat weight was significantly greater in the FAT group than in the CHO group. The plasma level of leptin was significantly higher in the FAT group, but blood glucose and plasma insulin levels did not differ between the two groups. MAP and renal SNA were significantly higher in the FAT group. In addition, the ratio of urinary sodium excretion to dietary sodium intake was significantly lower in the FAT group than in the CHO group. The data suggest that the increased renal SNA may contribute to BP elevation in FAT-fed rats. The present study firstly demonstrated that renal SNA was elevated with FAT-related BP elevation. Topics: Animals; Blood Pressure; Body Weight; Dietary Carbohydrates; Dietary Fats; Heart Rate; Hypertension; Kidney; Leptin; Male; Rats; Rats, Sprague-Dawley; Sodium; Sympathetic Nervous System | 2002 |
Effects of fluoxetine administration on neuropeptide y and orexins in obese zucker rat hypothalamus.
The aim of this work was to study the potential involvement of neuropeptide Y (NPY) and orexins in the anorexigenic mechanism of fluoxetine in obese Zucker rats, assessing the effects of chronic fluoxetine treatment on NPY and orexin immunostaining in several hypothalamic regions.. Male obese Zucker (fa/fa) rats were administered fluoxetine (10 mg/kg intraperitoneally) daily for 2 weeks. The control group was administered 0.9% NaCl solution. Carcass composition was assessed using the official methods of the Association of Official Analytical Chemists. To test the potential thermogenic effect of fluoxetine administration, total body oxygen consumption was measured daily for 60 minutes before fluoxetine or saline injection and for 30 minutes after drug or saline injection. Hypothalamic arcuate and paraventricular nuclei, and the lateral hypothalamic area were immunostained for NPY, orexin A, and orexin B. Commercial kits were used for serum determinations.. Chronic fluoxetine administration in obese Zucker rats generated a reduction in body weight gain, food intake, adipocyte size, fat mass, and body protein. A decrease in NPY immunostaining in the paraventricular nucleus, without changes in the arcuate, was observed. However, no changes were observed in the number of neural cells immunostained for orexin A or orexin B in the lateral hypothalamic area.. Due to the hyperphagic effect of NPY in the paraventricular nucleus, these results suggest that NPY, but not orexins, could be involved in the anorexigenic effect of fluoxetine in obese Zucker rats. Topics: Adipocytes; Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Weight; Carrier Proteins; Cell Size; Drinking; Eating; Fluoxetine; Hypothalamus; Immunoenzyme Techniques; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Organ Size; Oxygen Consumption; Rats; Rats, Zucker; Selective Serotonin Reuptake Inhibitors; Thyroid Hormones; Triglycerides | 2002 |
Breast milk leptin: its relationship to maternal and infant adiposity.
Leptin, the product of the obese gene (ob), is synthesized by adipose tissue and contributes to the regulation of energy homeostasis and food intake. Recently, immunoreactive leptin was reported to be present in human milk. The objective was to determine if there was a relation between breast milk leptin concentrations and adiposity in exclusively breast-fed infants.. Fifty healthy, exclusively breast-fed infants beyond neonatal period, and their mothers were included into the study. Infants whose weight-for-length was above the 90th percentile were defined as obese (n=17), and non-obese if the weight for length between 20-90th percentile (n=33). Anthropometric measurements of infants and mothers were also made and breast milk samples were analyzed for leptin.. There was no significant difference between breast milk leptin concentrations of obese and non-obese infants' mothers. Breast milk leptin concentrations were significantly correlated with mothers' body mass index when all subjects analyzed. There was no significant correlation between breast milk leptin concentrations and body mass index of infants.. Leptin concentrations of human milk are not different in the mothers of obese and non-obese infants. These findings suggests that milk-borne leptin has no significant effect on adiposity during infancy. Topics: Adipose Tissue; Adult; Body Mass Index; Body Weight; Breast Feeding; Female; Homeostasis; Humans; Infant; Infant Food; Infant Nutritional Physiological Phenomena; Infant, Newborn; Leptin; Male; Milk, Human; Mothers; Obesity | 2002 |
Energy metabolism and expression of uncoupling proteins 1, 2, and 3 after 21 days of recovery from intracerebroventricular mouse leptin in rats.
Animals tend to maintain a lower body weight for an extended period after leptin administration has ended. This may be due to an enhancement of metabolic rate that persists after treatment withdrawal. Our objectives were to determine the period of leptin influence, when injected intracerebroventricularly (icv), on food intake, body weight, and energy expenditure. Additionally, the relationship between expressions of UCP1, UCP2, and UCP3 in different adipose tissues and heat production (HP) was assessed. Twenty-four adult male Sprague-Dawley rats were injected intracerebroventricularly with either 10 g mouse leptin or 10 l vehicle once per day for 4 days. At 24 h after the last injection, one group was killed while the other was placed in calorimetry chambers and monitored for 21 days of recovery. Leptin-injected rats exhibited an overshoot of food intake and respiratory quotient (RQ) during recovery, but body weight remained significantly lower up to 6 days. HP decreased in both groups over time but remained higher in the leptin group through recovery. However, retained energy (RE) was significantly greater than control for about 8 days. Overall, UCP expression was reduced at the end of recovery in parallel with the decline in HP. Brown adipose tissue (BAT) was the most responsive to leptin administration by dramatically changing UCP1 and UCP3 mRNA levels. Our data show that leptin has extended effects on energy expenditure but relieves control on food intake and RQ after treatment withdrawal. This translated into a reduced positive energy balance that slowed body weight recovery. Topics: Animals; Body Weight; Calorimetry, Indirect; Carrier Proteins; DNA Primers; Eating; Energy Metabolism; Injections, Intraventricular; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mitochondrial Proteins; Oxygen Consumption; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thermogenesis; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3 | 2002 |
Respiratory uncoupling lowers blood pressure through a leptin-dependent mechanism in genetically obese mice.
Insulin resistance is commonly associated with hypertension, a condition that causes vascular disease in people with obesity and type 2 diabetes. The mechanisms linking hypertension and insulin resistance are poorly understood. To determine whether respiratory uncoupling can prevent insulin resistance-related hypertension, we crossed transgenic mice expressing uncoupling protein 1 (UCP1) in skeletal muscle with lethal yellow (A(y)/a) mice, genetically obese animals known to have elevated blood pressure. Despite increased food intake, UCP-A(y)/a mice weighed less than their A(y)/a littermates. The metabolic rate was higher in UCP-A(y)/a mice than in A(y)/a mice and did not impair their ability to alter oxygen consumption in response to temperature changes, an adaptation involving sympathetic nervous system activity. Compared with their nontransgenic littermates, UCP-A(y)/a mice had lower fasting insulin, glucose, triglyceride, and cholesterol levels and were more insulin sensitive. Blood pressure, serum leptin, and urinary catecholamine levels were also lower in uncoupled mice. Independent of sympathetic nervous system activity, low-dose peripheral leptin infusion increased blood pressure in UCP-A(y)/a mice but not in their A(y)/a littermates. These data indicate that skeletal muscle respiratory uncoupling reverses insulin resistance and lowers blood pressure in genetic obesity without affecting thermoregulation. The data also suggest that uncoupling could decrease the risk of atherosclerosis in type 2 diabetes. Topics: Animals; Blood Pressure; Body Composition; Body Weight; Breeding; Carrier Proteins; Diet; Energy Metabolism; Female; Glucose; Infusions, Parenteral; Ion Channels; Leptin; Membrane Proteins; Mice; Mice, Transgenic; Mitochondrial Proteins; Muscle, Skeletal; Obesity; Oxygen Consumption; Uncoupling Protein 1 | 2002 |
Opioid receptor blockade in rat nucleus tractus solitarius alters amygdala dynorphin gene expression.
It has been suggested that an opioidergic feeding pathway exists between the nucleus of the solitary tract (NTS) and the central nucleus of the amygdala. We studied the following three groups of rats: 1) artificial cerebrospinal fluid (CSF) infused in the NTS, 2) naltrexone (100 microg/day) infused for 13 days in the NTS, and 3) artificial CSF infused in the NTS of rats pair fed to the naltrexone-infused group. Naltrexone administration resulted in a decrease in body weight and food intake. Also, naltrexone infusion increased dynorphin, but not enkephalin, gene expression in the amygdala, independent of the naltrexone-induced reduction in food intake. Gene expression of neuropeptide Y in the arcuate nucleus and neuropeptide Y peptide levels in the paraventricular nucleus did not change because of naltrexone infusion. However, naltrexone induced an increase in serum leptin compared with pair-fed controls. Thus chronic administration of naltrexone in the NTS increased dynorphin gene expression in the amygdala, further supporting an opioidergic feeding pathway between these two brain sites. Topics: Amygdala; Animals; Body Weight; Dynorphins; Eating; Gene Expression; Leptin; Male; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Solitary Nucleus | 2002 |
Melatonin regulates energy balance and attenuates fever in Siberian hamsters.
Fever is considered an important host defense response but requires significant metabolic energy. During winter many animals must balance immune function with competing physiological demands (i.e. thermoregulation) to survive. Winterlike patterns of melatonin secretion induce a number of energy-saving adaptations. For instance, Siberian hamsters attenuate the duration of fever during simulated short winter day lengths, presumably to conserve energy. To determine the proximate role of melatonin in mediating this photoperiodic response, hamsters housed in long days were injected with saline or melatonin 4 h before lights off for either 1 or 6 wk and assessed for fever following injections of bacterial lipopolysaccharide. Fever duration was attenuated (32%) only in hamsters that decreased body mass, increased cortisol, and exhibited gonadal regression in response to 6 wk of melatonin. Because melatonin-treated hamsters lost significant body mass, fever was assessed in a second long-day group following ad libitum food intake, food restriction, or 24-h food deprivation. Food restriction sufficient to reduce body mass by approximately 25%, but not to reduce leptin, did not influence fever, and 24-h food deprivation virtually abolished fever. Our data suggest that long-term exposure to long-duration melatonin signals is required to induce the physiological changes necessary for short-day immune responses, perhaps involving interactions with hormones such as cortisol and leptin. Topics: Animals; Antioxidants; Body Temperature; Body Weight; Cricetinae; Darkness; Eating; Energy Metabolism; Fever; Hydrocortisone; Leptin; Lipids; Lipopolysaccharides; Male; Melatonin; Organ Size; Phodopus; Photoperiod; Radioimmunoassay; Testis; Testosterone | 2002 |
Metabolic syndrome and aging in Wistar Ottawa Karlsburg W rats.
Comparative studies have shown that Wistar Ottawa Karlsburg W (RT1u) rats (WOKW) develop a nearly complete metabolic syndrome with obesity, moderate hypertension, dyslipidemia, hyperinsulinemia, and impaired glucose tolerance up to an age of 28 weeks. Because metabolic data thereafter are missing, WOKW and disease-resistant DA rats were studied for 12 months beginning at an age of 5 months.. Eighteen male inbred WOKW and DA rats were studied monthly from the 5th to the 17th month of life for traits of the metabolic syndrome such as body weight, body mass index (BMI), serum triglycerides, total cholesterol, leptin, insulin as well as glucose tolerance, 24 h excretion of urine total protein and creatinine including telemetric measurement of blood pressure in six males per each group.. Except for serum total cholesterol, the measured values for most traits studied were significantly higher in WOKW than in DA rats at an age of 5 months. At an age of 17 months all traits were significantly elevated in WOKW compared with DA rats. WOKW rats were hypertensive, dyslipidemic, obese, glucose intolerant, hyperinsulinemic and proteinuric.. Considering the phenotype of the WOKW rat described until now and the fact that the metabolic syndrome in this rat is polygenetically determined, the WOKW rat is the most suitable animal model to study the pathophysiology of the facets of the syndrome. Topics: Aging; Animals; Blood Pressure; Body Mass Index; Body Weight; Cholesterol; Creatinine; Glucose Tolerance Test; Insulin; Leptin; Male; Metabolic Syndrome; Proteinuria; Rats; Triglycerides | 2002 |
Chronic leptin treatment normalizes basal glucose transport in a fiber type-specific manner in high-fat-fed rats.
The aim of this investigation was to determine if a high-fat diet impaired and subsequent leptin administration improved non-insulin-stimulated (basal) glucose transport in rodents. Twenty-four male Sprague Dawley rats were divided into 1 of 2 groups: (1) normal diet (control [CON], n = 8) or (2) high-fat diet (n = 16) and received standard rat chow or a high-fat diet, respectively, for 12 weeks. The high-fat diet animals were then further subdivided into high fat (HF) (n = 8) or high-fat-leptin (HF-LEP) (n = 8) groups. The HF-LEP animals were injected with leptin (10 mg leptin/kg/d), while the CON and HF animals received vehicle over a 12-day treatment period. Following the 12-day treatment period, all animals were subjected to hind limb perfusion to assess rates of basal skeletal muscle 3-O-methyl-D-glucose (3-MG) transport. Compared with the CON group, rates of 3-MG transport were reduced in the soleus (sol) and plantaris (plant) of the HF, but not the HF-LEP animals. Differences in skeletal muscle 3-MG transport could not be accounted for by an altered GLUT1 protein concentration. In contrast, a high-fat diet reduced and chronic leptin treatment normalized the skeletal muscle GLUT4 protein concentration. The results indicate that a high-fat diet reduces and subsequent leptin treatment improves basal skeletal muscle glucose transport in a fiber-type-specific manner, but these changes do not appear to be due to alterations in the GLUT1 protein concentration. Topics: 3-O-Methylglucose; Animals; Biological Transport; Body Weight; Dietary Fats; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 4; Hindlimb; Leptin; Male; Monosaccharide Transport Proteins; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Perfusion; Rats; Rats, Sprague-Dawley; Time; Triglycerides | 2002 |
Prevention of obesity-linked renal disease: age-dependent effects of dietary food restriction.
Hyperphagic obese Zucker rats develop glomerular injury and die of renal disease, an outcome prevented by food restriction at an early age. We examined the effects of food restriction imposed at different ages on systemic, renal hemodynamic, and hormonal changes to gain insight into the mechanisms of obesity-linked glomerular injury.. At 6 weeks of age obese Zucker rats were either fed ad libitum or were restricted in food intake at various ages (6, 12, 26, or 50 weeks) to that consumed by lean Zucker rats (14 g/day). Every four weeks 24-hour urine collections, blood pressure, and venous blood samples were obtained until the end of study (60 weeks).. Food restriction at 6 or 12 weeks of age prevented glomerular injury and hypertrophy and delayed the development of hypertension, hypercholesterolemia, and hyperinsulinemia. Food restriction at 26 weeks of age reduced proteinuria, while restriction at 50 weeks prevented further increases in proteinuria without altering pre-existing hypercholesterolemia, hypertension, or hyperinsulinemia. Hypertriglyceridemia and glomerular hyperfiltration in the obese animals were reversed at any age by food restriction. Plasma leptin levels were elevated in all obese groups.. (1) Early food restriction provided the greatest metabolic and renal benefits; (2) glomerular injury correlated with hyperphagia-induced hyperfiltration and hypertriglyceridemia and both were prevented by food restriction; (3) hypercholesterolemia was due to an increase in LDL and/or VLDL cholesterol; and (4) leptin does not directly contribute to glomerular injury in the obese Zucker rat. Topics: Age Factors; Animals; Blood Pressure; Body Weight; Eating; Female; Glomerular Filtration Rate; Insulin; Kidney Diseases; Kidney Glomerulus; Leptin; Lipoproteins, LDL; Lipoproteins, VLDL; Obesity; Organ Size; Proteinuria; Rats; Rats, Zucker; Renal Circulation | 2002 |
Central LIF gene therapy suppresses food intake, body weight, serum leptin and insulin for extended periods.
Leukemia inhibitory factor (LIF) overexpression, induced by the intracerebroventricular (i.c.v.) injection of an recombinant adeno-associated viral vector encoding LIF (rAAV-LIF), resulted in a dose-dependent reduction in body weight (BW) gain, food intake (FI) and adiposity, evidenced by suppression of serum leptin and free fatty acids for an extended period in outbred adult female rats. A dose-dependent reduction in serum insulin levels and unchanged serum glucose, energy expenditure through thermogenesis as indicated by uncoupling protein-1 (UCP-1) mRNA expression in brown adipose tissue (BAT), and metabolism as indicated by serum T3 and T4, accompanied the blockade of weight gain. Thus, central rAAV-LIF therapy is a viable strategy to voluntarily reduce appetite and circumvent leptin resistance, a primary factor underlying age-dependent weight gain and obesity in rodents and humans. Topics: Adipose Tissue, Brown; Animals; Appetite; Blood Glucose; Body Weight; Brain; Carrier Proteins; Dose-Response Relationship, Drug; Female; Genetic Therapy; Growth Inhibitors; Insulin; Interleukin-6; Ion Channels; Leptin; Leukemia Inhibitory Factor; Lymphokines; Membrane Proteins; Mitochondrial Proteins; Obesity; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Uncoupling Protein 1 | 2002 |
Maternal dietary intake of essential fatty acids affects adipose tissue growth and leptin mRNA expression in suckling rat pups.
We have previously shown that maternal intake of essential fatty acids during late gestation and lactation affects the level of serum leptin in pups. The aim of the present study was to investigate the effect of dietary essential fatty acids on leptin content in the milk of rat dams and leptin expression in white adipose tissue of pups during the suckling period. During late gestation and throughout lactation, rats were fed a control or an essential fatty acid-deficient (EFAD) diet. Milk of the EFAD dams contained more saturated and less polyunsaturated fatty acids compared with the control dams. Milk leptin levels were higher in the EFAD dams than in the control dams at 3 wk of lactation. The weight of inguinal white adipose tissue depots and the serum leptin levels of the EFAD pups were significantly lower than in the control pups during the whole suckling period. In addition, semiquantitative reverse transcriptase-PCR analysis of leptin mRNA levels in inguinal white adipose tissue showed a reduction in the EFAD pups compared with the control pups at 3 wk of age. We conclude that maternal dietary essential fatty acid intake affects serum leptin levels in pups by regulating both the amount of adipose tissue and the leptin mRNA expression. Topics: Adipose Tissue; Animals; Animals, Suckling; Body Constitution; Body Weight; Dietary Fats; Fatty Acids, Essential; Female; Gene Expression; Leptin; Milk; Phospholipids; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2002 |
Longer life spans and delayed maturation in wild-derived mice.
Nearly all the experimental mice used in aging research are derived from lineages that have been selected for many generations for adaptation to laboratory breeding conditions and are subsequently inbred. To see if inbreeding and laboratory adaptation might have altered the frequencies of genes that influence life span, we have developed three lines of mice (Idaho [Id], Pohnpei [Po], and Majuro [Ma]) from wild-trapped progenitors, and have compared them with a genetically heterogeneous mouse stock (DC) representative of the laboratory-adapted gene pool. Mean life span of the Id stock exceeded that of the DC stock by 24% (P < 0.00002), and maximal life span, estimated as mean longevity of the longest-lived 10% of the mice, was also increased by 16% (P < 0.003). Mice of the Ma stock also had a significantly longer maximal longevity than DC mice (9%, P = 0.04). The longest-lived Id mouse died at the age of 1450 days, which appears to exceed the previous longevity record for fully fed, non-mutant mice. The life table of the Po mice resembled that of the DC controls. Ma and Id mice differ from DC mice in several respects: both are shorter and lighter, and females of both stocks, particularly Id, are much slower to reach sexual maturity. As young adults, Id mice have lower levels of insulin-like growth factor 1 (IGF-I), leptin, and glycosylated hemoglobin compared with DC controls, implicating several biochemical pathways as potential longevity mediators. The results support the idea that inadvertent selection for rapid maturation and large body size during the adaptation of the common stocks of laboratory mice may have forced the loss of natural alleles that retard the aging process. Genes present in the Id and Ma stocks may be valuable tools for the analysis of the physiology and biochemistry of aging in mice. Topics: Animals; Animals, Wild; Body Height; Body Weight; Female; Glycated Hemoglobin; Insulin-Like Growth Factor I; Leptin; Longevity; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Reproduction; Sexual Maturation; Thyroxine | 2002 |
Fighting fat. New drugs against obesity in the pipeline.
Topics: Animals; Anti-Obesity Agents; Body Weight; Drug Design; Drug Industry; Fats; Homeostasis; Humans; Leptin; Obesity | 2002 |
A phosphatidylinositol 3-kinase phosphodiesterase 3B-cyclic AMP pathway in hypothalamic action of leptin on feeding.
Using male Sprague-Dawley rats implanted with third intracerebroventricular (ICV) cannulae, we found that cilostamide, a phosphodiesterase 3 (PDE3) inhibitor, (i) reversed the established effects of leptin on food intake and body weight, (ii) blocked, at the hypothalamic level, the leptin-induced tyrosine phosphorylation of signal transducer and activator of transcription 3 (Stat3) and (iii) blocked the DNA binding of p-Stat3. Additionally, ICV administration of leptin increased hypothalamic phosphatidylinositol 3-kinase (PI3K) and PDE3B activities and decreased cyclic AMP (cAMP) concentration. These results indicate that a PI3K-PDE3B-cAMP pathway interacting with the Janus kinase 2 (Jak2)-Stat3 pathway constitutes a critical component of leptin signaling in the hypothalamus. Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Body Weight; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 3; DNA; DNA-Binding Proteins; Electrodes, Implanted; Enzyme Activation; Enzyme Inhibitors; Feeding Behavior; Hypothalamus; Injections, Intraventricular; Janus Kinase 2; Leptin; Male; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Binding; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Quinolones; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor; Trans-Activators | 2002 |
The antipsychotic drug sulpiride does not affect bodyweight in male rats. Is insulin resistance involved?
Previous studies have shown that prolonged administration of antipsychotic drugs induces obesity in female but not in male rats. To explore the mechanisms involved in this sex-dependent effect, we administered the dopamine antagonist sulpiride (20 mg/kg i.p.) or vehicle (0.1 N HCl) to adult male rats during 21 days and daily assessed bodyweight and food intake. Then, we evaluated the glucose tolerance and the serum levels of insulin, leptin, total testosterone, dehydroepiandrosterone-sulfate (DHEA-S), thyroid hormones and blood lipids. In another experiment, food intake and water intake were assessed after acute injections of sulpiride or vehicle into the perifornical lateral hypothalamus. Lastly, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) in the lateral hypothalamus were assessed by in vivo microdialysis after acute systemic injections of sulpiride and vehicle. Chronic sulpiride administration did not affect bodyweight gain and food intake. However, prolactin levels and the area under the glucose and insulin curves were significantly elevated. Acute sulpiride significantly increased food intake, water intake, DOPAC and HVA levels. The acute effects of sulpiride show that this drug is active at the perifornical lateral hypothalamus, which is a brain area where blockade of dopamine receptors stimulates feeding. However, after prolonged administration, sulpiride did not affect body weight. This lack of effect may be related to the impairment of insulin sensitivity, which may prevent body weight gain, and counteract other effects of sulpiride that promote adiposity such as hyperprolactinemia. These findings noticeably contrast with those observed in sulpiride-treated female rats that appear to display enhanced insulin sensitivity. The changes in insulin sensitivity do not appear related to a decrease in androgenic activity, because testosterone and DHEA-S levels were not affected by sulpiride. However, these results should be considered as preliminary because other relevant endocrine variables such as free testosterone, steroid binding globulin and pituitary gonadotrophin levels were not evaluated. Since the same sex-dependent effect on body weight and food intake in rats has been observed during administration of risperidone, which has a different pharmacological profile than sulpiride, future studies must evaluate other neurotransmitters involved in food intake regulation such as serotonin, noradrenaline and hist Topics: Animals; Antipsychotic Agents; Body Weight; Dehydroepiandrosterone Sulfate; Dopamine; Dose-Response Relationship, Drug; Drinking; Eating; Hypothalamic Area, Lateral; Insulin Resistance; Leptin; Lipids; Male; Prolactin; Rats; Rats, Wistar; Sulpiride; Testosterone; Thyrotropin; Thyroxine | 2002 |
Leptin, the adipocyte hormone.
Topics: Animals; Body Weight; Humans; Leptin; Mice; Obesity | 2001 |
Leptin and its relation to obesity and insulin in the SHR/N-corpulent rat, a model of type II diabetes mellitus.
The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic animal model that exhibits obesity, metabolic features of hyperinsulinemia, hyperglycemia, and hyperlipidemia, which are characteristic of type II diabetes and mild hypertension. To determine the role of leptin, the protein product of the ob gene, in the development of obesity and diabetes in this model, we measured steady-state circulating levels of leptin in obese and lean SHR/N-cp rats and examined the relation between plasma leptin levels and metabolic variables at the stage of established obesity in these animals. Mean fasting plasma leptin concentration was 8-fold higher in obese than in lean rats (p < 0.01). This was associated with a 6-fold elevation in plasma insulin in the obese group. Fasting levels of plasma glucose, cholesterol, and triglyceride were all significantly higher in obese rats than in lean controls. Spearman correlation analysis showed a significant positive correlation between plasma leptin concentration and body weight among the animals (r = 0.73, p < 0.01). Similarly, plasma insulin concentration was significantly correlated with BW in all animals (r = 0.54, p < 0.05). There was also a significant positive correlation between plasma leptin and plasma insulin in the entire group (r = 0.70, p < 0.01). However, this relationship was significant only for lean rats but not for obese rats (r = 10.59, p < 0.05 for lean rats, and r = 0.23, p = NS, for obese rats). Plasma leptin also correlated positively with fasting plasma glucose (r = 0.75, p < 0.05), total cholesterol (r = 0.63, p < 0.05), and triglyceride (r = 0.67, p < 0.05). The marked elevation of plasma leptin in obese SHR/N-cp rats suggests that obesity in this animal model is related to up-regulation of the ob gene. Circulating leptin appears to be one of the best biological markers of obesity and that hyperleptinemia is closely associated with several metabolic risk factors related to insulin resistance in the diabesity syndrome. Topics: Analysis of Variance; Animals; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Hyperinsulinism; Hyperlipidemias; Insulin; Leptin; Male; Obesity; Rats; Rats, Inbred SHR; Reference Values | 2001 |
Modulation of circulating leptin levels by its soluble receptor.
Leptin is an adipocyte-derived hormone with potent weight reducing effects. Genetically obese rodents with mutations of leptin or the leptin receptor are defective in leptin signaling and develop morbid obesity and diabetes. Interestingly, the levels of both leptin mRNA and protein are increased by up to 20-fold in these animals, suggesting the existence of a feedback mechanism controlling the amount of leptin in circulation. In this report, we attempted to determine whether the up-regulation of circulating leptin in Zucker Diabetic Fatty rats, which are nonresponsive to leptin due to a receptor point mutation, is entirely due to increased expression of leptin. We demonstrate that the high level of circulating leptin in these rats is attributable to at least two factors: increased leptin expression by the adipose tissue and delayed clearance of leptin from circulation due to binding to its soluble receptor. The latter conclusion was supported by three lines of evidence: 1) The soluble leptin receptor is up-regulated by about 20-fold in Zucker Diabetic Fatty rats; 2) Adenovirus-mediated overexpression of the soluble leptin receptor results in a similar -fold increase of circulating leptin; 3) In ob/ob mice, which have no endogenous leptin, exogenously administered leptin reaches a higher level when the soluble leptin receptor is overexpressed. The weight-reducing effect of leptin is enhanced in C57Bl/6 ob/ob mice with overexpression of the soluble leptin receptor. Soluble leptin receptor may be a significant factor determining the amount of total leptin in circulation. Topics: Animals; Body Weight; Carrier Proteins; Eating; Female; Leptin; Mice; Mice, Inbred C57BL; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger | 2001 |
Transgenic mice overexpressing leptin accumulate adipose mass at an older, but not younger, age.
Sensitivity to leptin is associated with a normal regulation of the adipose mass, whereas decreased leptin sensitivity results in elevated adipose tissue stores. To address whether the effects of chronic hyperleptinemia are sustained with age, we generated transgenic mice that overexpress leptin under the control of the fat specific aP2 promoter/enhancer. At 6-9 weeks of age, transgenic mice overexpressed 5-fold more human leptin than endogenous mouse levels and had consistently low body weights, with reduced brown and white fat depots characterized by adipocytes either devoid of or containing minute lipid droplets. However, at 33-37 weeks, despite continuous secretion of human leptin, the transgenic mice showed a rebound effect characterized by an increase in body weight, accumulation of adipose mass, and lipid-filled adipocytes. Thus, this mouse model exhibits a two-stage phenotype, with respect to fat accumulation. In addition, plasma glucose, triglycerides, and cholesterol levels were markedly depressed in young, but not older, transgenic mice. A detrimental consequence of early hyperleptinemia was a failure of the transgenic mice to acclimatize to the cold, as a result of depleted fat stores within their brown adipocytes. Cold exposure was tolerated after a 2-week high-fat diet or at an older age when fat depots had naturally accumulated. Treatment of the older transgenic mice with large doses of leptin stimulated weight loss, demonstrating that the leptin pathway still responds to pharmacological levels of leptin. Overall, these studies show that moderate hyperleptinemia in normal mice results in a sensitivity of the adipose mass to leptin at a younger (but not older) age. The mechanisms that lead to the accumulation of fat at an older age remain largely unknown, and this hyperleptinemic mouse model will allow the uncovering of at least some of these mechanisms. Topics: Adipocytes; Adipose Tissue; Adipose Tissue, Brown; Aging; Animals; Blood Glucose; Body Weight; Cholesterol; Female; Humans; Leptin; Male; Mice; Mice, Transgenic; Reverse Transcriptase Polymerase Chain Reaction; Sex Characteristics; Triglycerides | 2001 |
The role of leptin resistance in the lipid abnormalities of aging.
Leptin resistance has been implicated in the pathogenesis of obesity-related complications involving abnormalities of lipid metabolism that resemble those of old age. To determine whether development of leptin resistance in advancing age might account for such abnormalities, we compared the effects of hyperleptinemia (>40 ng/ml) induced in 2-month-old and 18-month-old lean wild-type (+/+) Zucker diabetic fatty rats by adenovirus gene transfer. The decline in food intake, body weight, and body fat in old rats was only 25%, 50%, and 16%, respectively, of the young rats. Whereas in young rats plasma free fatty acids fell 44% and triacylglycerol (TG) 94%, neither changed in the rats. In hyperleptinemic young rats, adipocyte expression of preadipocyte factor 1 increased dramatically and leptin mRNA virtually disappeared; there was increased expression of acyl CoA oxidase, carnitine palmitoyl transferase 1, and their transcription factor peroxisome proliferator-activated receptor alpha, accounting for the reduction in body fat. These hyperleptinemia-induced changes were profoundly reduced in the old rats. On a high-fat diet, old rats consumed 28% more calories than the young and gained 1.5x as much fat, despite greater endogenous hyperleptinemia. Expression of a candidate leptin resistance factor, suppressor of cytokine signaling 3 (SOCS-3), was compared in the hypothalamus and white adipocytes of young and old rats before and after induction of hyperleptinemia; hypothalamic SOCS-3 mRNA was approximately 3x higher in old rats before, whereas it was 3x higher in WAT after, hyperleptinemia. We conclude that the anorexic and antilipopenic actions of leptin decline with age, possibly through increased SOCS-3 expression, and that this could account for the associated abnormalities in lipid metabolism of the elderly. Topics: Acyl-CoA Oxidase; Adipose Tissue; Aging; Animals; Body Weight; Carnitine O-Palmitoyltransferase; Dietary Fats; Drug Resistance; Enzyme Induction; Fatty Acids; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Membrane Proteins; Oxidoreductases; Proteins; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear; Repressor Proteins; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors; Triglycerides; Up-Regulation | 2001 |
Leptin selectively reduces white adipose tissue in mice via a UCP1-dependent mechanism in brown adipose tissue.
We tested the hypothesis that leptin, in addition to reducing body fat by restraining food intake, reduces body fat through a peripheral mechanism requiring uncoupling protein 1 (UCP1). Leptin was administered to wild-type (WT) mice and mice with a targeted disruption of the UCP1 gene (UCP1 deficient), while vehicle-injected control animals of each genotype were pair-fed to each leptin-treated group. Leptin reduced the size of white adipose tissue (WAT) depots in WT mice but not in UCP1-deficient animals. This was accompanied by a threefold increase in the amount of UCP1 protein and mRNA in the brown adipose tissue (BAT) of WT mice. Leptin also increased UCP2 mRNA in WAT of both WT and UCP1-deficient mice but increased UCP2 and UCP3 mRNA only in BAT from UCP1-deficient mice. These results indicate that leptin reduces WAT through a peripheral mechanism requiring the presence of UCP1, with little or no involvement of UCP2 or UCP3. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Carrier Proteins; Eating; Epididymis; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mice; Mitochondrial Proteins; Organ Size; Proteins; RNA, Messenger; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3 | 2001 |
Body weight and fat deposition in prolactin receptor-deficient mice.
To explore the roles of the lactogens in adipose tissue development and function, we measured body weight, abdominal fat content, and plasma leptin concentrations in a unique model of lactogen resistance: the PRL receptor (PRLR)-deficient mouse. The absence of PRLRs in knockout mice was accompanied by a small (5-12%), but progressive, reduction in body weight after 16 weeks of age. Females were affected to a greater degree than males. The reduction in weight in female PRLR-deficient mice (age 8-9 months) was associated with a 49% reduction in total abdominal fat mass and a 29% reduction in fat mass expressed as a percentage of body weight. Lesser reductions were noted in male mice. Plasma leptin concentrations were reduced in females but not in males. That the reductions in abdominal fat may reflect in part the absence of lactogen action in the adipocyte is suggested by the demonstration of PRLR messenger RNA in normal mouse white adipose tissue. Nevertheless, steady state levels of PRLR messenger RNA in mature adipocytes are very low, suggesting that the effects of lactogens might be mediated by other hormones or cellular growth factors. Our observations suggest roles for the lactogens in adipose tissue growth and metabolism in pregnancy and postnatal life. Topics: Abdomen; Adipocytes; Adipose Tissue; Animals; Body Weight; Cellular Senescence; Cross-Sectional Studies; Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Prolactin; Reference Values; RNA, Messenger; Sex Characteristics | 2001 |
Effects of 2 G on adiposity, leptin, lipoprotein lipase, and uncoupling protein-1 in lean and obese Zucker rats.
Male Zucker rats were exposed to 2 G for 8 wk to test the hypothesis that the leptin regulatory pathway contributes to recovery from effects of 2 G on feeding, growth, and nutrient partitioning. After initial hypophagia, body mass-independent food intake of the lean rats exposed to 2 G surpassed that of the lean rats maintained at 1 G, but food intake of the obese rats exposed to 2 G remained low. After 8 wk at 2 G, body mass and carcass fat were less in both genotypes. Leptin and percent fat were lower in lean rats exposed to 2 G vs. 1 G but did not differ in obese rats exposed to 2 G vs. 1 G. Although exposure to 2 G did not alter uncoupling protein-1 levels, it did elicit white fat pad-specific changes in lipoprotein lipase activity in obese but not lean rats. We conclude that 2 G affects both genotypes but that the lean Zucker rats recover their food intake and growth rate and retain "normal" lipoprotein lipase activity to a greater degree than do the obese rats, emphasizing the importance of a functional leptin regulatory pathway in this acclimation. Topics: Adipose Tissue, Brown; Animals; Body Weight; Carrier Proteins; Centrifugation; Eating; Gravitation; Ion Channels; Leptin; Lipoprotein Lipase; Male; Membrane Proteins; Mitochondrial Proteins; Obesity; Rats; Rats, Zucker; Thinness; Uncoupling Protein 1 | 2001 |
Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance.
Several lines of investigation suggest that the hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates body weight in mammals. Obese mice lacking functional leptin overexpress the MCH message in the fed or fasted state. Acute intracerebroventricular injection of MCH increases energy intake in rats. Mice lacking the MCH gene are lean. To test the hypothesis that chronic overexpression of MCH in mice causes obesity, we produced transgenic mice that overexpress MCH (MCH-OE) in the lateral hypothalamus at approximately twofold higher levels than normal mice. On the FVB genetic background, homozygous transgenic animals fed a high-fat diet ate 10% more and were 12% heavier at 13 weeks of age than wild-type animals, and they had higher systemic leptin levels. Blood glucose levels were higher both preprandially and after an intraperitoneal glucose injection. MCH-OE animals were insulin-resistant, as demonstrated by markedly higher plasma insulin levels and a blunted response to insulin; MCH-OE animals had only a 5% decrease in blood glucose after insulin administration, compared with a 31% decrease in wild-type animals. MCH-OE animals also exhibited a twofold increase in islet size. To evaluate the contribution of genetic background to the predisposition to obesity seen in MCH-OE mice, the transgene was bred onto the C57BL/6J background. Heterozygote C57BL/6J mice expressing the transgene showed increased body weight on a standard diet, confirming that MCH overexpression can lead to obesity. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Eating; Glucose Tolerance Test; Homeostasis; Hypothalamic Hormones; Hypothalamus; Insulin Resistance; Leptin; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Pituitary Hormones; Time Factors | 2001 |
Actions of leptin on growth hormone secretagogue-responsive neurones in the rat hypothalamic arcuate nucleus recorded in vitro.
In the arcuate nucleus, the growth hormone (GH) secretagogue (GHS)-responsive cells include a subpopulation of the neuropeptide Y (NPY) neurones. It is not known whether these include the orexigenic NPY population that are inhibited by the satiety hormone, leptin. Thus we investigated whether (i) the arcuate nucleus cells electrically excited by GHS are inhibited by leptin and (ii) chronic central leptin infusion alters GHS-induced Fos expression. Of 36 cells recorded from a trimmed hypothalamic slice containing arcuate nucleus, 13 cells were excited by the nonpeptide GHS, CP-459,599. The predominant response of these cells to leptin was inhibitory: six inhibited, three excited and four unresponsive. Similar responses were observed in a population of arcuate cells recorded from a preparation in which synaptic transmission was blocked, suggesting that leptin acts directly on a subpopulation of GHS-responsive neurones. Intracerebroventricular infusion of leptin for 1 week did not alter the number of cells expressing Fos following GHS administration. Thus, while leptin does not appear to influence the central actions of GHS to induce immediate early gene expression, it does act directly on a subpopulation of cells excited by GHS, eliciting mostly inhibitory but also some excitatory responses. It will be interesting to discover the consequences of leptin's inhibitory effects on the hypothalamic circuits excited by GHS, particularly since leptin paradoxically has a stimulatory effect on GH secretion, presumed to reflect a suppression of central NPY pathways. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Electrophysiology; Growth Hormone; In Vitro Techniques; Injections, Intraventricular; Leptin; Male; Neurons; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar | 2001 |
Oral nicotine administration decreases tumor necrosis factor-alpha expression in fat tissues in obese rats.
To investigate the effect of oral nicotine administration on insulin resistance and insulin secretion in an animal model of obesity, Zucker fatty rats were administered nicotine tartrate dihydrate orally through tap water (4.6 mg/kg/d, N group). Plasma nicotine concentrations in N group were 33.67 +/- 10.49 ng/mL. The control (C) group consisted of pair-fed control rats. After 8 weeks of nicotine administration, both groups of rats were administered glucose (2 g/kg) orally in an anesthetized state, and blood was collected for glucose and plasma insulin measurements. The pancreases were isolated and perfused in vitro under pentobarbital anesthesia 1 week after glucose administration. The fat tissues were excised. The levels of tumor necrosis factor (TNF)-alpha protein were assessed using enzyme-linked immunosorbent assay (ELISA) or Western blot analysis. Serum leptin levels were measured using radioimmunoassay (RIA). Blood glucose levels in N group were significantly lower than in C group before and 120 minutes after glucose administration. The insulin secretion from the isolated perfused pancreases of N group appeared to be decreased compared with C group, but there was no significant difference. Histologic examination showed that the mean size of the pancreatic islets in N group was significantly smaller than in C group. The composition ratios of alpha and beta cell mass of the pancreatic islets and fibroelastic tissues were not altered by nicotine administration. Portal TNF-alpha levels were comparable to peripheral levels in both groups. There were no significant differences in peripheral serum levels of TNF-alpha, free fatty acids (FFA), or leptin levels between N and C group. The TNF-alpha levels in visceral fat tissues in N group were significantly lower than those in C group. These results suggest that oral nicotine administration reduces insulin resistance in obese diabetic rats by decreasing production of TNF-alpha in the visceral fat tissues. Decreased islet size may be a secondary phenomenon induced by ameliorated insulin resistance, because the cellularity and fibroelastic tissues were not affected by the nicotine. Topics: Adipocytes; Administration, Oral; Animals; Blood Glucose; Body Weight; Eating; Fatty Acids, Nonesterified; Ganglionic Stimulants; Insulin; Islets of Langerhans; Leptin; Male; Nicotine; Obesity; Pancreas; Rats; Rats, Zucker; Tumor Necrosis Factor-alpha | 2001 |
Agouti-related protein is a mediator of diabetic hyperphagia.
To explore the role of agouti-related protein (AGRP) in diabetic hyperphagia changes in hypothalamic AGRP mRNA levels were examined in diabetic rats. Rats rendered diabetic by streptozotocin displayed marked hyperglycemia (blood glucose 456.0+/-8.4 mg/dl versus 71.8+/-1.9 mg/dl) and hyperphagia (36.9+/-1.0 g/day versus 22.0+/-0.4 g/day), that was associated with a 286.6+/-4.4% increase in hypothalamic AGRP mRNA and a 178.9+/-13.5% increase in hypothalamic NPY mRNA. Insulin treatment of diabetic rats partially corrected blood glucose (147.4+/-13.1 mg/dl) and ameliorated hyperphagia (26.6+/-2.0 g/day). Insulin replacement was also associated with a return of hypothalamic AGRP mRNA (111.7+/-8.3% of controls) and NPY mRNA (125.0+/-8.9% of controls) from the elevated levels that were observed in untreated diabetic rats. In contrast to insulin treated rats, sodium orthovanadate treated diabetic rats remained significantly hyperglycemic (361.5+/-12.5 mg/dl). However, despite their persistent hyperglycemia, orthovanadate treated diabetic rats were still observed to have a significant reduction of hypothalamic AGRP mRNA (138.7+/-11.4%) and NPY mRNA (129.9+/-9.8%). Simultaneous measurement of serum leptin revealed suppressed levels in both untreated diabetic (0.5+/-0.1 ng/ml) and sodium orthovanadate treated rats (0.5+/-0.1 ng/ml) compared to non-diabetic controls (2.1+/-0.1 ng/ml). These data indicate that AGRP is a mediator of diabetic hyperhpagia and suggest that insulin can directly influence hypothalamic AGRP and NPY mRNA expression. Topics: Agouti-Related Protein; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Drinking; Eating; Enzyme Inhibitors; Hyperphagia; Hypothalamus; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Protein Tyrosine Phosphatases; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vanadates | 2001 |
Bezafibrate induces acyl-CoA oxidase mRNA levels and fatty acid peroxisomal beta-oxidation in rat white adipose tissue.
Rats treated with bezafibrate, a PPAR activator, gain less body weight and increase daily food intake. Previously, we have related these changes to a shift of thermogenesis from brown adipose tissue to white adipose tissue attributable to bezafibrate, which induces uncoupling proteins (UCP), UCP-1 and UCP-3, in rat white adipocytes. Nevertheless, UCP induction was weak, implying additional mechanisms in the change of energy homeostasis produced by bezafibrate. Here we show that bezafibrate, in addition to inducing UCPs, modifies energy homeostasis by directly inducing aco gene expression and peroxisomal fatty acid beta-oxidation in white adipose tissue. Further, bezafibrate significantly reduced plasma triglyceride and leptin concentrations, without modifying the levels of PPARgamma or ob gene in white adipose tissue. These results indicate that bezafibrate reduces the amount of fatty acids available for triglyceride synthesis in white adipose tissue. Topics: Acyl-CoA Oxidase; Adipose Tissue; Animals; Bezafibrate; Body Weight; Cells, Cultured; Cholesterol; Fatty Acids; Hypolipidemic Agents; Leptin; Liver; Male; Oxidoreductases; Oxygen; Peroxisomes; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Temperature; Time Factors; Transcription Factors; Triglycerides | 2001 |
Antecedent protein restriction and high-fat feeding interactively sensitise the leptin response to elevated insulin.
Using a rat model of moderate (8 vs. 20% protein) isocaloric protein restriction initiated in early life (low protein, LP), we examined the possible basis for the association between impaired early growth and elevated leptin levels in later life in man by examining the acute leptin response to insulin and its relationship with glucose utilisation. We placed subsets of LP rats on a high-saturated-fat (HF) diet containing 20% protein for 4 weeks (LP-4HF) or 8 weeks (LP-8HF), making comparison with age-matched control (C) groups (C, C-4HF, C-8HF). At ambient insulin concentrations, LP was not associated with altered leptinaemia compared with C, despite a more active lipolytic programme as inferred from increased adipocyte sensitivity to norepinephrine. HF feeding led to insulin resistance with respect to whole-body glucose disposal (R(d)) (measured using [3-(3)H] glucose at steady state) in both LP and C in vivo and impaired suppression of agonist-stimulated lipolysis by insulin in LP but not C in vitro. Whereas insulin infusion for 2 h (while maintaining euglycaemia) only modestly increased plasma leptin levels in vivo in C, C-4HF, C-8HF and LP groups, the leptin response to insulin was greatly enhanced in the HF-fed LP groups. A close positive correlation (r = 0.96) existed between plasma leptin levels and R(d) in the C groups (viz. C, C-4HF, C-8HF) whereas a close inverse correlation (r = 0.95) existed between plasma leptin levels and insulin-stimulated R(d) in the LP groups (viz. LP, LP-4HF, LP-8HF). Glucose utilisation (estimated from 2-deoxy-D-[1-(3)H] glucose 6-phosphate accumulation) in vivo in two intra-abdominal and two superficial adipose-tissue depots was consistently higher in the LP group. After HF feeding, glucose utilisation by the superficial adipose-tissue depots was threefold higher in the LP than in the C group. We conclude that protein restriction from conception to adulthood followed by high-fat feeding sensitizes the acute leptin response to insulin, an adaptation associated with enhanced glucose utilisation by adipose tissue. This effect is observed despite impaired insulin sensitivity, both at the level of whole-body glucose disposal and adipocyte anti-lipolysis, and increased lipolytic activity (although the latter is not in itself sufficient to influence the leptin response). We propose that associations between a low birthweight and elevated leptin concentrations in later life may reflect long-term modulation of adipocyte glucose Topics: Adipocytes; Animals; Blood Glucose; Body Weight; Diet, Atherogenic; Diet, Protein-Restricted; Eating; Female; Insulin; Leptin; Lipolysis; Norepinephrine; Radioimmunoassay; Rats; Rats, Wistar | 2001 |
Effect of cold exposure on energy balance and liver respiratory capacity in post-weaning rats fed a high-fat diet.
Variations in energy balance, body composition, and nutrient partitioning induced by high-fat feeding, cold exposure or by concomitant high-fat feeding and cold exposure were studied in young Wistar rats. Changes in hepatic metabolism as well as in serum free triiodothyronine and leptin levels were also evaluated. Rats were exposed to either 24 or 4 degrees C and fed either a low- or high-fat diet (10 % or 50 % energy respectively) for 2 weeks. Relative to low-fat feeding at 24 degrees C, both energy intake and expenditure were increased by high-fat feeding or by cold exposure, and these changes were accompanied by increased serum triiodothyronine levels. In response to concomitant high-fat feeding and cold exposure, serum triiodothyronine tended to be further elevated, but no further increases in energy intake or energy expenditure were observed. Independently of diet, the increased energy expenditure in cold-exposed rats was not completely balanced by adaptive hyperphagia, with consequential reductions in protein and fat gain, accompanied by marked decreases in serum leptin. Furthermore, unlike high-fat feeding at 24 degrees C, cold exposure enhanced hepatic mitochondrial oxidative capacity both in the low-fat- and high-fat-fed groups. It is concluded that in this strain of young Wistar rats, despite similarly marked stimulation of energy expenditure by high-fat feeding at 24 degrees C, by cold exposure and by concomitant high-fat feeding and cold exposure, an increased hepatic oxidative capacity occurred only in the presence of the cold stimulus. Topics: Animals; Body Composition; Body Weight; Cold Temperature; Dietary Fats; Energy Metabolism; Leptin; Liver; Male; Mitochondria, Liver; Organ Size; Oxidation-Reduction; Peroxisomes; Rats; Rats, Wistar; Triiodothyronine | 2001 |
Hormonal regulation of appetite and body mass in patients with advanced prostate cancer treated with combined androgen blockade.
Cachexia is rarely observed in patients with advanced prostate cancer treated with combined androgen blockade. Androgens play an important role in the regulation of body mass composition and influence the secretion of leptin, the appetite regulating hormone. The aim of the study was to assess the influence of a combined treatment with nonsteroidal antiandrogen and LH-RH analogue on the hormonal regulation of appetite and changes in body mass in patients with advanced prostate cancer (Whitmore-Jewett stage D1 or D2). Eighteen patients with prostate cancer and 17 healthy subjects matched for age and body mass index were included. In all patients serum concentrations of leptin, neuropeptide Y (NPY), insulin, testosterone and estradiol were measured before and after four and twelve weeks of androgen blockade. Pretreatment serum leptin levels were similar in patients with prostate cancer and in the controls. In a multiple regression analysis only body mass index and testosterone significantly contributed to the variation of plasma leptin. During the treatment body mass and plasma leptin significantly increased while NPY decreased. The change of plasma NPY was significant only after 4 weeks of therapy. This study shows that the afferent regulation of leptin secretion is unchanged in advanced prostate cancer. Androgen ablation significantly increases body mass and influences secretion of appetite regulating hormones. Testosterone appears to play a significant role in the regulation of leptin secretion. Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Appetite; Body Constitution; Body Mass Index; Body Weight; Estradiol; Flutamide; Goserelin; Humans; Insulin; Leptin; Male; Middle Aged; Neuropeptide Y; Prostatic Neoplasms; Regression Analysis; Testosterone | 2001 |
Central leptin infusion attenuates the cardiovascular and metabolic effects of fasting in rats.
The role of reduced leptin signaling in the regulation of cardiovascular responses to negative energy balance is not known. We tested the hypothesis that central infusion of leptin would attenuate the cardiovascular and metabolic responses to fasting. Male Sprague-Dawley rats, instrumented with telemetry devices and intracerebroventricular cannulas, were housed in metabolic chambers for continuous (24 hours) measurement of dark-phase (active) and light-phase (inactive) mean arterial pressure, heart rate, oxygen consumption, and respiratory quotient. Rats received central infusions of either saline (0.5 microL/h) or leptin (42 ng/h) for 6 days through osmotic pumps and were either fed ad libitum or were fasted for 48 hours followed by refeeding for 4 days. In ad lib animals, continuous intracerebroventricular leptin infusion significantly reduced caloric intake, body weight, and respiratory quotient compared with saline controls while having no effect on mean arterial pressure or heart rate. Fasting reduced mean arterial pressure, heart rate, oxygen consumption, and respiratory quotient in rats receiving saline infusions. Fasting-induced reductions in mean arterial pressure were specific to the active phase and were not attenuated by central leptin infusion. In contrast, intracerebroventricular leptin, at a dose that had no cardiovascular effects in ad lib control animals, completely prevented fasting-induced decreases in light-phase heart rate and oxygen consumption and blunted fasting-induced reductions in dark-phase heart rate and oxygen consumption. The results are consistent with the hypothesis that reductions in central leptin signaling contribute to the integrated cardiovascular and metabolic responses to acute caloric deprivation. Topics: Animals; Blood Pressure; Body Weight; Cardiovascular System; Energy Intake; Fasting; Heart Rate; Infusion Pumps, Implantable; Injections, Intraventricular; Leptin; Male; Oxygen Consumption; Rats; Rats, Sprague-Dawley | 2001 |
Elevated leptin levels are associated with excess gains in fat mass in girls, but not boys, with type 1 diabetes: longitudinal study during adolescence.
Adolescents, in particular girls, with type 1 diabetes may gain excessive weight during puberty. We present the results of a longitudinal study aimed to determine the roles of leptin and insulin in changes in body composition in subjects with type 1 diabetes and controls. Forty-six children (23 boys) with type 1 diabetes and 40 controls (20 boys) were followed from 8-17 yr of age. Height, weight, and sc skinfolds were assessed every 6 months, and a blood sample taken for leptin determination. Throughout the age range, body mass index (mean +/- SEM) was greater by 1.45 +/- 0.69 kg/m(2) in girls and 1.46 +/- 0.55 kg/m(2) in boys with type 1 diabetes compared with control values. In girls with type 1 diabetes, this reflected greater percent body fat (3.2 +/- 1.0%; P = 0.002), whereas in boys it related to differences in fat-free mass. Both boys and girls with type 1 diabetes had higher leptin levels adjusted for percent body fat than controls; in the girls this was related to insulin dose (regression coefficient B = 0.006 +/- 0.003; P = 0.04) and greater gains in fat mass. Hyperinsulinemia and raised leptin levels are associated with gains in fat mass throughout puberty in girls, but not boys, with type 1 diabetes. Topics: Adipose Tissue; Adolescent; Aging; Body Composition; Body Height; Body Weight; Child; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Longitudinal Studies; Male; Puberty; Sex Characteristics; Skinfold Thickness | 2001 |
Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean.
Members of the muscarinic acetylcholine receptor family (M1-M5) have central roles in the regulation of many fundamental physiological functions. Identifying the specific receptor subtype(s) that mediate the diverse muscarinic actions of acetylcholine is of considerable therapeutic interest, but has proved difficult primarily because of a lack of subtype-selective ligands. Here we show that mice deficient in the M3 muscarinic receptor (M3R-/- mice) display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic messenger RNA levels of melanin-concentrating hormone (MCH), which are normally upregulated in fasted animals leading to an increase in food intake, are significantly reduced in M3R-/- mice. Intra-cerebroventricular injection studies show that an agouti-related peptide analogue lacked orexigenic (appetite-stimulating) activity in M3R-/- mice. However, M3R-/- mice remained responsive to the orexigenic effects of MCH. Our data indicate that there may be a cholinergic pathway that involves M3-receptor-mediated facilitation of food intake at a site downstream of the hypothalamic leptin/melanocortin system and upstream of the MCH system. Topics: Animals; Appetite Regulation; Body Weight; Eating; Feeding and Eating Disorders; Feeding Behavior; Female; Gene Targeting; Glucose Tolerance Test; Hormones; Insulin; Leptin; Locomotion; Male; Mice; Mice, Inbred C57BL; Neuropeptides; Oxygen Consumption; Receptor, Muscarinic M3; Receptors, Muscarinic; Thinness; Triglycerides | 2001 |
Leptin acts in the central nervous system to produce dose-dependent changes in arterial pressure.
Systemic leptin increases energy expenditure through sympathetic mechanisms, decreases appetite, and increases arterial pressure. We tested the hypothesis that the pressor action of leptin is mediated by the central nervous system. The interaction of dietary salt with leptin was also studied. Leptin was infused for 2 to 4 weeks into the third cerebral ventricle of Sprague-Dawley rats. Arterial pressure was measured by radiotelemetry. To control for the effects of leptin on body weight, vehicle-treated rats were pair-fed to the leptin group. Intracerebroventricular infusion of leptin at 200 ng/h in salt-depleted rats caused a reduction in food intake, weight loss, tachycardia, and decreased arterial pressure. Leptin at 1000 ng/h caused further reduction in food intake, weight loss, and tachycardia and prevented the hypotensive effect of weight loss observed in pair-fed, vehicle-treated animals. Intracerebroventricular leptin at 1000 ng/h in high-salt-fed rats also caused a sustained pressor response (+3+/-1 mm Hg), but high-salt intake did not potentiate the pressor effect of leptin. Intracerebroventricular leptin potentiated the pressor effect of air-jet stress. Intravenous administration of the same dose of leptin (1000 ng/h) did not change weight or arterial pressure, suggesting a direct central nervous system action. In contrast, a high dose of intravenous leptin (18 000 ng/h) caused weight loss and prevented the depressor effect of weight loss. In conclusion, this study demonstrates that high-dose leptin increases arterial pressure and heart rate through central neural mechanisms but leptin does not enhance salt sensitivity of arterial pressure. Leptin appears to oppose the depressor effect of weight loss. Topics: Animals; Blood Pressure; Body Weight; Central Nervous System; Diet, Sodium-Restricted; Dose-Response Relationship, Drug; Eating; Heart Rate; Injections, Intraventricular; Leptin; Male; Rats; Rats, Sprague-Dawley; Sodium Chloride; Stress, Physiological; Tachycardia; Telemetry | 2001 |
The beta 3-adrenergic receptor gene and obesity in a population sample of African Americans.
To examine the role of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene and the beta 3-adrenergic receptor gene locus in obesity-related traits in African Americans.. A total of 687 individuals representing 193 African American families who were residents of metropolitan Chicago.. Genotyping of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene and three microsatellite markers flanking the beta 3-adrenergic receptor gene (ADRB3) locus and measuring various obesity-related traits, including body mass index (BMI), fat-free mass, fat mass, percentage fat mass, waist circumference and serum lipid levels.. The prevalence of obesity (defined as body mass index > or = 30 kg/m(2)) in the population was 27.3% and 51.2% in men and women, respectively. The frequency of the Arg64 allele was 10.0%. Multivariate regression analyses confirmed the existence of a significant contribution of familial variance to each of the five obesity-related traits noted above. Likelihood ratio statistics computed in a multivariate regression analysis failed to demonstrate a significant association between the Arg64 allele and any of the five obesity-related traits. Single and multipoint analyses using extended Haseman--Elston regression analyses failed to demonstrate suggestive evidence of linkage of three microsatellite markers that flank the beta 3-adrenergic receptor gene to BMI, percentage body fat, waist circumference or serum leptin levels.. Given the contribution of familial variance to obesity-related traits in this population, neither the null finding for the Arg64 allele nor the lack of evidence of linkage of the ADRB3 locus to obesity-related traits could be attributed to lack of transmissibility of the traits suggesting that neither the Arg64 variant of the beta 3-adrenergic receptor gene nor another genetic variant in or near the ADRB3 locus contribute significantly to familial aggregation of obesity-related traits in African Americans. International Journal of Obesity (2001) 25, 54-60 Topics: Adipose Tissue; Adolescent; Adult; Aged; Black People; Body Mass Index; Body Weight; Female; Gene Frequency; Genotype; Humans; Illinois; Leptin; Lipids; Male; Middle Aged; Obesity; Polymorphism, Genetic; Prevalence; Receptors, Adrenergic, beta-3; Regression Analysis | 2001 |
Dietary and lifestyle factors in relation to plasma leptin concentrations among normal weight and overweight men.
Leptin, the product of the obesity (ob) gene, is a multi-functional polypeptide that is important in energy metabolism, which is strongly correlated with body fat mass and body mass index (BMI). In a recent prospective study, we found that leptin was positively associated with 4 y weight gain among overweight and obese men. This suggests that leptin resistance, marked by hyperleptinemia among obese subjects, may be an important marker for weight gain. The purpose of this study is to evaluate whether modifiable dietary and lifestyle factors are associated with plasma leptin concentrations among US men.. We included 268 men aged 47--83 y (who were free of cardiovascular disease, diabetes mellitus and cancer, except nonmelanoma skin cancer) from the ongoing Health Professionals Follow-up Study. These subjects completed a detailed dietary and lifestyle questionnaire (including cigarette smoking, alcohol drinking and physical activity) and provided a fasting venous blood sample in 1994. All blood samples were stored in a deep freeze (-70 degrees C) for 4--5 y before being analyzed. Plasma leptin concentrations were measured by radioimmunoassay.. Men in the highest quintile of plasma leptin (mean=14.4 ng/ml) weighed more, were less physically active, and had higher total and saturated fat and cholesterol intake than men in the lowest quintile (mean=3.0 ng/ml). Physical activity and current smoking were inversely associated with plasma leptin concentrations (P<0.001). A 20 MET difference in physical activity per week (equivalent to approximately 3 h of jogging) was associated with 0.38--0.58 ng/ml lower plasma leptin concentrations for normal weight and overweight men after adjusting for total energy and fat intake, BMI and other confounding variables. Total fat and monounsaturated fat intakes were positively associated with plasma leptin concentrations even after adjusting for BMI and other confounding variables; however, this association was limited to men of normal weight (BMI<25 kg/m(2)).. These data suggest that physical activity may be a significant determinant of plasma leptin concentrations in men. Increasing physical activity is associated with lower plasma leptin concentrations even after adjusting for BMI. Physical activity may lower leptin concentrations not only due to decreased body fat mass, but potentially through an increase in leptin sensitivity. International Journal of Obesity (2001) 25, 106-114 Topics: Aged; Aged, 80 and over; Aging; Body Mass Index; Body Weight; Cross-Sectional Studies; Diet; Dietary Fats; Exercise; Humans; Leptin; Life Style; Male; Middle Aged; Multivariate Analysis; Obesity; Prospective Studies; Radioimmunoassay; Smoking; Surveys and Questionnaires | 2001 |
Dissociation of leptin and body weight in hyperthyroid patients after radioiodine treatment.
Leptin regulates energy production rates and body weight, which are frequently altered in hyperthyroidism. Data on a possible interaction between leptin and thyroid hormones are controversial. We assessed leptin serum concentrations, BMI, proportional fat tissue mass and thyroid hormones in hyperthyroid patients in a long-term follow-up after radioiodine therapy.. The study included 28 hyperthyroid patients (mean age 66 y) before and up to one y after radioiodine therapy. Leptin and thyroid hormones, general parameters, BMI, proportional fat tissue (PFT) measurements by DEXA and thyroid morphology were recorded. Twenty-four age-matched euthyroid individuals (mean age 63 y) served as controls.. At baseline, leptin concentrations were significantly decreased in all hyperthyroid patients as compared to controls. One year after radioiodine therapy, 71% of the patients were euthyroid (group A) and 29% remained hyperthyroid (group B). BMI and PFT increased in both groups. While leptin concentrations remained low in group B, they normalised in group A after 6 to 12 months. Changes in leptin and thyroid hormone concentrations were positively correlated in group A patients (r=0.49, P=0.03) but not in patients remaining hyperthyroid.. Our data indicate a dissociation in the regulation of plasma leptin and BMI as well as proportional fat tissue in hyperthyroid patients which may be attributable to differences in lean and adipose mass weight gain after radioiodine therapy or direct influences of thyroid hormones on leptin regulation. International Journal of Obesity (2001) 25, 115-120 Topics: Absorptiometry, Photon; Adipose Tissue; Aged; Aged, 80 and over; Body Mass Index; Body Weight; Bone Density; Female; Humans; Hyperthyroidism; Iodine Radioisotopes; Leptin; Male; Middle Aged; Thyroid Hormones; Thyrotropin | 2001 |
Heritability of leptin levels and the shared genetic effects on body mass index and leptin in adult Finnish twins.
Leptin is involved in the regulation of body weight, but the relative role of genetic and environmental influences on inter-individual variation in leptin levels is unknown.. To investigate the genetic and environmental contributions to the association of body mass index (BMI) with serum leptin levels, 58 monozygotic (MZ, 27M, 31F), and 74 like-sexed dizygotic (DZ, 32M, 42F) Finnish twin pairs aged 50--76 y were studied.. Serum leptin levels, weight, height, hip and waist measurements.. Women had higher mean leptin levels (16.8+/-9.5 ng/ml), and more overall variability in leptin levels than men (6.4+/-3.5 ng/ml; P<0.0001). Leptin levels correlated highly with BMI in men and women. Among women, the MZ and DZ pairwise correlations for leptin were 0.41 (P=0.009) and 0.07 (P=0.32), respectively. Among men the MZ and DZ pairwise correlations for leptin were 0.47 (P=0.006) and 0.23 (P=0.10). Univariate twin analysis indicated that, among women, 34% and, among men, 45% of the variance in leptin can be attributed to additive genetic effects, and the remainder to unique environmental effects. Significant non-additive genetic or shared familial effects could not be demonstrated. A bivariate twin analysis of leptin and BMI indicated that the correlation between additive genetic effects on leptin and BMI was 0.79 (95% CI 0.68--0.86) in women, and 0.68 (0.51--0.80) in men. The correlation between environmental effects on leptin and BMI was 0.77 (95% CI 0.66--0.85) in women, and 0.48 (0.26--0.66) in men.. Leptin levels are moderately heritable in older adults, and a substantial proportion of genetic effects are in common on leptin levels and obesity in both women and men. International Journal of Obesity (2001) 25, 132-137 Topics: Aged; Body Height; Body Mass Index; Body Weight; Cohort Studies; Environment; Female; Finland; Humans; Leptin; Male; Middle Aged; Models, Genetic; Obesity; Sex Characteristics; Twins, Dizygotic; Twins, Monozygotic | 2001 |
Agouti regulates adipocyte transcription factors.
Agouti is a secreted paracrine factor that regulates pigmentation in hair follicle melanocytes. Several dominant mutations cause ectopic expression of agouti, resulting in a phenotype characterized by yellow fur, adult-onset obesity and diabetes, increased linear growth and skeletal mass, and increased susceptibility to tumors. Humans also produce agouti protein, but the highest levels of agouti in humans are found in adipose tissue. To mimic the human agouti expression pattern in mice, transgenic mice (aP2-agouti) that express agouti in adipose tissue were generated. The transgenic mice develop a mild form of obesity, and they are sensitized to the action of insulin. We correlated the levels of specific regulators of insulin signaling and adipocyte differentiation with these phenotypic changes in adipose tissue. Signal transducers and activators of transcription (STAT)1, STAT3, and peroxisome proliferator-activated receptor (PPAR)-gamma protein levels were elevated in the transgenic mice. Treatment of mature 3T3-L1 adipocytes recapitulated these effects. These data demonstrate that agouti has potent effects on adipose tissue. We hypothesize that agouti increases adiposity and promotes insulin sensitivity by acting directly on adipocytes via PPAR-gamma. Topics: 3T3 Cells; Adipocytes; Agouti Signaling Protein; alpha-MSH; Animals; Body Weight; DNA-Binding Proteins; Gene Expression; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Transgenic; Phenotype; Proteins; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Signal Transduction; STAT1 Transcription Factor; STAT3 Transcription Factor; Trans-Activators; Transcription Factors; Transcription, Genetic | 2001 |
Mc3 and Mc4 receptors: complementary role in weight control.
Topics: Adipose Tissue; alpha-MSH; Animals; Body Weight; Eating; Humans; Leptin; Mice; Mice, Knockout; Mutation; Obesity; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Corticotropin | 2001 |
Maternal essential fatty acid deficiency depresses serum leptin levels in suckling rat pups.
Dietary lipid quantity and quality have recently been shown to affect serum leptin levels in adult rats. Moreover, suckling pups from dams fed a high fat diet had increased serum leptin levels. The aim of the present study was to analyze the influence of essential fatty acid (EFA) deficiency on serum leptin levels in dams and their pups during the suckling period. For the last 10 days of gestation and throughout lactation, pregnant rats were fed a control or an EFA-deficient (EFAD) diet. The levels of leptin and EFA in the serum of the dams and pups were analyzed 1, 2, and 3 weeks after delivery. In parallel, serum levels of glucose and corticosterone were analyzed in the pups. Low serum leptin levels were found in the control lactating dams during the entire lactation period compared with the age-matched nonlactating animals. The leptin concentrations in the lactating dams fed the EFAD diet were lower compared with those fed the control diet. The serum leptin levels of suckling pups from dams on the EFAD diet were markedly decreased compared with controls (P < 0.05). The reduced serum leptin levels could not be explained by nutritional restriction as evaluated by serum levels of glucose and corticosterone. These results indicate the importance of the EFA composition of the maternal diet for serum leptin levels in both dams and pups. EFA deficiency in lactating dams may cause long-term effects on the pups through dysregulation of leptin and leptin-dependent functions. -- Korotkova, M., B. Gabrielsson, L. A. Hanson, and B. Strandvik. Maternal essential fatty acid deficiency depresses serum leptin levels in suckling rat pups. J. Lipid Res. 2001. 42: 359--365. Topics: Aging; alpha-Linolenic Acid; Animals; Animals, Suckling; Blood Glucose; Body Weight; Corticosterone; Dietary Fats; Fatty Acids, Essential; Female; Lactation; Leptin; Linoleic Acid; Phospholipids; Rats; Rats, Sprague-Dawley | 2001 |
Effects of chronic central nervous system administration of agouti-related protein in pair-fed animals.
The melanocortin receptor (MC3-R and MC4-R) antagonist, agouti-related protein (AGRP), is a potent stimulant of food intake. We examined the effect of chronic intracerebroventricular (ICV) AGRP treatment on energy metabolism and pituitary function in ad libitum fed rats and rats administered AGRP and then pair-fed to a saline control group. Chronic ICV AGRP (83-132) administration (1 nmol/day for 7 days) significantly increased food intake and body weight in ad libitum fed animals compared with saline-treated controls (body weight on day 7: 272 +/- 6 [saline] vs. 319 +/- 8 g [AGRP ad libitum fed]; P < 0.001). A significant increase in the epididymal fat pad weight, interscapular brown adipose tissue (BAT) weight, and plasma leptin was also observed in the ad libitum fed group. In the AGRP pair-fed group, a significant increase in the epididymal fat pad weight, BAT weight, and plasma leptin was again observed, suggesting that AGRP caused metabolic changes independent of increased food intake. BAT uncoupling protein 1 (UCP-1) content was significantly decreased compared with saline controls in both the AGRP ad libitum fed (21 +/- 8% of saline control; P < 0.01) and AGRP pair-fed groups (24 +/- 7% of saline control; P < 0.01). Plasma thyroid-stimulating hormone (TSH) was significantly suppressed compared with saline controls in both the AGRP ad libitum fed and AGRP pair-fed groups (3.5 +/- 0.3 [saline] vs. 2.7 +/- 0.4 [AGRP ad libitum fed] vs. 2.1 +/- 0.2 ng/ml [AGRP pair-fed]; P < 0.01). This study demonstrates that independent of its orexigenic effects, chronic AGRP treatment decreased BAT UCP-1, suppressed plasma TSH, and increased fat mass and plasma leptin, suggesting that it may play a role in energy expenditure. Topics: Adipose Tissue; Adipose Tissue, Brown; Agouti-Related Protein; Animals; Body Weight; Carrier Proteins; Central Nervous System; Eating; Hormones; Injections, Intraventricular; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Organ Size; Pituitary Hormones; Proteins; Rats; Rats, Wistar; Time Factors; Uncoupling Protein 1 | 2001 |
Central infusion of histamine reduces fat accumulation and upregulates UCP family in leptin-resistant obese mice.
Leptin resistance has recently been confirmed not only in animal obese models but in human obesity. Evidence is rapidly emerging that suggests that activation of histamine signaling in the hypothalamus may have substantial anti-obesity and antidiabetic actions, particularly in leptin-resistant states. To address this issue, effects of central, chronic treatment with histamine on food intake, adiposity, and energy expenditure were examined using leptin-resistant obese and diabetic mice. Infusion of histamine (0.05 pmol x g body wt(-1) x day(-1)) into the lateral cerebroventricle (i.c.v.) for 7 successive days reduced food intake and body weight significantly in both diet-induced obesity (DIO) and db/db mice. Histamine treatment reduced body fat weight, ob gene expression, and serum leptin concentration more in the model mice than in pair-fed controls. The suppressive effect on fat deposition was significant in visceral fat but not in subcutaneous fat. Serum concentrations of glucose and/or insulin were reduced, and tests for glucose and insulin tolerance showed improvement of insulin sensitivity in those mice treated with histamine compared with pair-fed controls. On the other hand, gene expression of uncoupling protein (UCP)-1 in brown adipose tissue and UCP-3 expression in white adipose tissue were upregulated more in mice with i.c.v. histamine infusion than in the pair-fed controls. These upregulating effects of histamine were attenuated by targeted disruption of the H1-receptor in DIO and db/db mice. Sustained i.c.v. treatment with histamine thus makes it possible to partially restore the distorted energy intake and expenditure in leptin-resistant mice. Together, i.c.v. treatment with histamine contributes to improvement of energy balance even in leptin-resistant DIO and db/db mice. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Blood Glucose; Body Weight; Carrier Proteins; Diet; Drug Resistance; Eating; Fatty Acids, Nonesterified; Gene Expression; Glucose Tolerance Test; Histamine; Injections, Intraventricular; Insulin; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Obesity; Receptors, Histamine H1; Receptors, Leptin; Uncoupling Protein 1; Up-Regulation | 2001 |
Leptin during assisted reproductive cycles: the effect of ovarian stimulation and of very early pregnancy.
Leptin may have a role in human reproduction. The impact of IVF and of very early pregnancy on serum leptin concentrations was studied in 66 infertile patients, of whom 19 became pregnant. Ovarian suppression was accompanied by a fall in leptin concentrations (21 +/- 4%, mean +/- SE; P < 0.01) from the mid-luteal phase, and ovarian stimulation by a rise (76 +/- 8%; P < 0.0001) from suppression. The mid-luteal concentration of leptin after stimulation was 28 +/- 7% higher than that during the preceding normal cycle (P < 0.001). Concentrations of leptin and oestradiol were related before treatment, at ovarian suppression and at 8 days after oocyte retrieval. In addition, the rises in leptin and oestradiol concentrations during stimulation were correlated, but only in those patients who became pregnant (r = 0.69; P = 0.001). Women with a successful pregnancy had higher concentrations of leptin (18.7 +/- 4.8 microg/l) at 12 days after embryo transfer than those who had miscarriages (10.0 +/- 1.9 microg/l; P < 0.001), or those failing to become pregnant (11.6 +/- 1.2 microg/l; P < 0.0001). We concluded that leptin concentrations are influenced by ovarian function and that the relationship between leptin and oestrogen (but not a single leptin concentration), may be an important factor for the outcome of IVF. Topics: Adult; Body Weight; Embryo Transfer; Estradiol; Female; Fertilization in Vitro; Humans; Leptin; Ovary; Ovulation Induction; Predictive Value of Tests; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, First | 2001 |
Troglitazone corrects metabolic changes but not vascular dysfunction in dietary-obese rats.
Insulin resistance has been attributed to the defect in vascular function associated with obesity, type 2 diabetes and dyslipidaemia. We have investigated vascular effects of chronic (3-week) administration of troglitazone on female Wistar rats with moderate dietary obesity. Compared with lean controls, untreated obese rats had significantly higher body weights, fat pad masses, plasma triglycerides, free fatty acids and leptin levels (for all P < 0.01). These metabolic changes were corrected by troglitazone treatment. In mesenteric arteries, responses to noradrenaline or KCl were similar in all groups. However, in noradrenaline-preconstricted arteries, vasorelaxations to acetylcholine and insulin were significantly (50-60% less than in lean, P < 0.001) attenuated in both untreated and troglitazone-treated obese rats. Relaxations to sodium nitroprusside showed similar but lesser impairment in both untreated and troglitazone-treated obese animals. Our data show that although troglitazone markedly improved obesity-induced metabolic changes, it failed to correct vascular dysfunction associated with obesity in female Wistar rats. Topics: Acetylcholine; Animals; Blood Glucose; Body Weight; Chromans; Diet; Dose-Response Relationship, Drug; Endothelium, Vascular; Energy Metabolism; Fatty Acids, Nonesterified; Female; Hypoglycemic Agents; In Vitro Techniques; Insulin; Leptin; Mesenteric Arteries; Nitroprusside; Norepinephrine; Obesity; Potassium Chloride; Rats; Rats, Wistar; Thiazoles; Thiazolidinediones; Triglycerides; Troglitazone; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents | 2001 |
Effects of adrenalectomy and hormone replacement on B6C3F1 mice fed a high-fat diet.
Bilateral adrenalectomy (ADX) causes decreased circulating leptin in both obese and lean mice. It remains unclear whether the decreased plasma leptin after ADX is due to decreased adipose tissue or is due to decreased circulating glucocorticoids. The present experiment was performed to test the hypothesis that the absence of glucocorticoids from circulation is sufficient to decrease circulating leptin. Sixty-four adult male B6C3F1 mice were individually housed and fed either Purina rat chow or an experimental diet. After 6 weeks, mice fed the experimental diet gained more weight than mice fed the control diet. Each dietary group was then subdivided into four groups: ADX with cholesterol replacement (ADX-CHOL), ADX with corticosterone (CORT) replacement (ADX+CORT), ADX with aldosterone (ALDO) replacement (ADX+ALDO), and sham operation (SHAM). Two days after surgery, mice were killed and exsanguinated and the carcasses were prepared for gravimetric analyses. Blood was collected and centrifuged and the plasma was assayed for leptin, CORT, and ALDO. Blood glucose was determined using whole blood taken before centrifugation. There was no difference in body weight due to ADX after 2 days. Mice fed the experimental diet had higher circulating leptin than those fed the control diet. The ADX+CORT groups (both experimental and control diets) had higher plasma leptin concentrations than the other groups. No differences were observed between ADX-CHOL and SHAM groups. These results suggest that circulating leptin is not directly controlled by glucocorticoids. The effect of ADX on circulating leptin reported by others may be the consequence of decreased adiposity. Topics: Adrenal Cortex Hormones; Adrenalectomy; Aldosterone; Animals; Blood Glucose; Body Composition; Body Weight; Cholesterol; Diet; Dietary Fats; Hydrocortisone; Leptin; Male; Mice; Mice, Inbred Strains; Obesity | 2001 |
Inhibitory effects of central neuropeptide Y on the somatotropic and gonadotropic axes in male rats are independent of adrenal hormones.
Neuropeptide Y (NPY) in the hypothalamus exerts multiple physiological functions including stimulation of adipogenic pathways such as feeding and insulin secretion as well as inhibition of the somatotropic and gonadotropic axes. Since hypothalamic NPY-ergic activity is increased by negative energy balance, NPY enables coordinated regulation of growth and reproduction in parallel with energy availability. Chronic pathological increases in central NPY-ergic activity contribute to obesity. Many of the adipogenic effects of NPY are specifically dependent on adrenal glucocorticoids. However, in the current study we show that central NPY does not require adrenal hormones to inhibit the somatotropic and gonadotropic axes in rats. Male adrenalectomized and sham-operated normal rats were intracerebroventricularly (ICV) infused with NPY (15 microg/day) or saline for 5-7 days, and plasma leptin, insulin-like growth factor (IGF-1) and testosterone were assayed, and epididymal white adipose tissue (WATe) was weighed. In normal intact rats, WATe weight and leptinemia were significantly increased by NPY, and these effects were prevented by adrenalectomy. In normal rats, NPY markedly reduced plasma IGF-1 levels (470 +/- 40 versus 1260 +/- 90 ng/ml) and testosterone (0.53 +/- 0.28 versus 5.4 +/- 0.80 nmol/l in saline-infused controls, p < 0.0001). Adrenalectomy decreased plasma IGF-1 concentrations to 290 +/- 30 (p < 0.0001 versus normal rats), which were significantly reduced further by NPY. However, adrenalectomy had no significant effect on basal nor on NPY-induced plasma testosterone concentrations. In conclusion unlike the stimulatory effects of NPY on fat mass and leptinemia, NPY-induced inhibition of the somatotropic and gonadotropic axes in male rats do not require adrenal hormones. Topics: Adipose Tissue; Adrenal Glands; Animals; Body Weight; Growth Hormone; Insulin-Like Growth Factor I; Leptin; Male; Neuropeptide Y; Rats; Rats, Wistar; Testosterone | 2001 |
Congenic BB.SHR rat provides evidence for effects of a chromosome 4 segment (D4Mit6-Npy approximately 1 cm) on total serum and lipoprotein lipid concentration and composition after feeding a high-fat, high-cholesterol diet.
Congenic BB.SHR (previously referred to as BB.LL) rats were generated by transferring the segment of chromosome 4 flanked by the D4Mit6 and Spr loci from the spontaneously hypertensive rat (SHR/Mol) onto the genetic background of the diabetes-prone BB/OK rat. In this study, the influence of the above-mentioned region of chromosome 4 on triglyceride, cholesterol, and phospholipid phenotypes after a high-fat, high-cholesterol diet was examined by comparison of BB.SHR congenic rats with BB/OK rats. BB/OK and BB.SHR had comparable concentrations of basal and postdietary serum insulin, as well as of basal total serum triglycerides and had an identical body weight and food intake at the beginning of the test period. However, after 4 weeks on the test diet, BB.SHR rats were significantly heavier than BB/OK rats and had significantly higher food intake and lower total serum triglyceride concentrations. The basal serum leptin level was significantly lower, but postdietary serum leptin concentration did not show a significant difference between the 2 strains. Furthermore, significantly higher basal total serum cholesterol and phospholipid levels were observed in BB.SHR rats, but this difference disappeared after feeding the high-fat, high-cholesterol diet. Postdietary high-density lipoprotein (HDL)(2) cholesterol and phospholipid levels were significantly elevated in BB.SHR rats when compared with BB/OK rats. The 2 strains also differed slightly, but significantly, with respect to the other HDL phospholipid concentrations. In addition to previously described differences between BB/OK and BB.SHR rats, the results of this study clearly show the impact of genes, lying within the transferred segment, on serum lipid phenotypes after high-fat, high-cholesterol diet. Topics: Alleles; Animals; Animals, Congenic; Blood Glucose; Body Weight; Cholesterol, Dietary; Chromosomes; Diet; Dietary Fats; Eating; Insulin; Leptin; Lipids; Lipoproteins; Phenotype; Rats; Rats, Inbred BB; Rats, Inbred SHR | 2001 |
Cerulenin mimics effects of leptin on metabolic rate, food intake, and body weight independent of the melanocortin system, but unlike leptin, cerulenin fails to block neuroendocrine effects of fasting.
Cerulenin and a related compound, C75, have recently been reported to reduce food intake and body weight independent of leptin through a mechanism hypothesized, like leptin, to involve hypothalamic nutrition-sensitive neurons. To assess whether these inhibitors act through mechanisms similar to mechanisms engaged by leptin, ob/ob and Ay (agouti) mice, as well as fed and fasted wild-type mice, were treated with cerulenin. Like leptin, cerulenin reduced body weight and food intake and increased metabolic rate in ob/ob mice, and cerulenin produced the same effects in wild-type mice, whereas lithium chloride, at doses that produce conditioned taste aversion, reduced metabolic rate. However, in contrast to leptin, cerulenin did not prevent effects of fasting on plasma corticosterone or hypothalamic levels of neuropeptide Y, agouti-related peptide, pro-opiomelanocortin, or cocaine- and amphetamine-related peptide mRNA. Also, in contrast to leptin, cerulenin was highly effective to reduce body weight in Ay mice, in which obesity is caused by blockade of the melanocortin receptor. These data demonstrate that cerulenin produces metabolic effects similar to effects of leptin, but through mechanisms that are independent of, or down-stream from, both leptin and melanocortin receptors. Topics: Animals; Body Weight; Cerulenin; Drug Resistance; Eating; Endocrine Glands; Fasting; Hypothalamus; Leptin; Male; Melanocyte-Stimulating Hormones; Metabolism; Mice; Mice, Inbred CBA; Mice, Inbred Strains; Neurosecretory Systems; Obesity | 2001 |
Genome-wide search for loci controlling serum IGF binding protein levels of mice.
A segregating F(2) pedigree based on two mouse lines (DU6i and DBA/2) with extremely different growth characteristics was generated to search for loci affecting serum levels of insulin-like growth factor (IGF) binding proteins (IGFBPs) and to estimate their effects on growth and body composition. DU6i is characterized by high body mass and obesity associated with hyperinsulinemia, hyperleptinemia, and elevated serum IGF-I concentrations. Furthermore, significantly elevated serum levels of IGFBP-2, IGFBP-3, and IGFBP-4 were found in DU6i vs. DBA/2 mice. Linkage analysis identified loci with major effects on the serum level of IGFBP-3 on Chromosome 5 at 58 cM (Igfbp3q1; F = 9.9) and on Chromosome 10 at 46 cM (Igfbp3q2; F = 33.8). A locus significantly influencing serum IGFBP-2 levels in males was found on Chromosome 7. Additional linkage was detected in males and females for IGFBP-2 on Chromosomes 8, 11, 14, 17, and X, and for IGFBP-4 on Chromosome 4. Additional loci affecting IGFBPs acted in a sex-specific manner. The identified loci coincide in part with chromosomal regions controlling growth and obesity. Thus, multiple genes or pleiotropic gene effects may be assumed for these chromosomal regions. The identification of quantitative trait loci for IGFBPs as subcomponents of growth regulation and differentiation will further improve the understanding of complex trait regulation. Topics: Animals; Body Weight; Chromosome Mapping; Chromosomes; Female; Insulin; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred DBA; Obesity; Quantitative Trait, Heritable | 2001 |
Sibutramine reduces feeding, body fat and improves insulin resistance in dietary-obese male Wistar rats independently of hypothalamic neuropeptide Y.
We studied the effects of the novel noradrenaline and serotonin (5-HT) reuptake inhibitor sibutramine on feeding and body weight in a rat model of dietary obesity, and whether it interacts with hypothalamic neuropeptide Y (NPY) neurones. Chow-fed and dietary-obese (DIO) male Wistar rats were given sibutramine (3 mg kg(-1) day(-1) p.o.) or deionized water for 21 days. Sibutramine decreased food intake throughout the treatment period in both dietary-obese rats (P<0.0001) and lean rats (P<0.0001). Weight gain was reduced so that final body weight was 10% lower in dietary-obese (P<0.005) and 8% lower in lean (P<0.05) rats versus their untreated controls. Plasma leptin concentration was lower in sibutramine-treated dietary-obese rats (P<0.05), and in treated lean rats (P<0.05). Using the homeostasis model assessment (HOMA) as a measure of insulin resistance, untreated DIO rats were significantly more insulin resistant than controls (P<0.005), and this was corrected by sibutramine treatment (P<0.05). Neither hypothalamic NPY mRNA nor NPY peptide levels in a number of hypothalamic nuclei were significantly altered by sibutramine compared to untreated controls. The hypophagic and anti-obesity effects of sibutramine in dietary-obese Wistar rats appear not to be mediated by inhibition of ARC NPY neurones. Topics: Adipose Tissue; Animals; Appetite Depressants; Body Weight; Cyclobutanes; Diet; Feeding Behavior; Hypothalamus; Insulin Resistance; Leptin; Male; Neurons; Neuropeptide Y; Obesity; Rats; Rats, Wistar; RNA, Messenger | 2001 |
The influence of tibolone upon serum leptin levels in post-menopausal women.
To estimate serum leptin levels in post-menopausal women, to relate these to the duration of the post-menopausal period, and to body mass index (BMI), and to assess the influence of tibolone on them.. Fifteen women (age 49-64 years) were included. Three groups were studied; I, those with normal BMI taking tibolone; II, those with a raised BMI taking tibolone, and III, a group with raised BMI not taking tibolone. Blood samples were drawn before and 1, 2, 6, 9 and 12 months after the initiation of tibolone or, in group III, after the start of the study.. Serum leptin concentrations were high in all women with abnormal BMI. Long-term tibolone administration did not have any significant effect on serum leptin concentrations. There was no correlation between serum leptin levels and the age and the duration of post-menopausal period. There was a high positive correlation between serum leptin levels and BMI values.. BMI values affect serum leptin concentrations but long-term tibolone administration does not seem to have any effect on serum leptin levels. Topics: Age Factors; Aged; Anabolic Agents; Body Weight; Female; Humans; Leptin; Middle Aged; Norpregnenes; Postmenopause | 2001 |
Dietary oleoyl-estrone delays the growth rate of young rats.
Oleoyl-estrone administration induces the rapid loss of fat preserving body protein.. We intended to check whether the fat-shedding effect of oleoyl-estrone arrests growth in young rats, limiting the buildup of protein and fat.. Oleoyl-estrone diluted in a powdered hyperlipidic diet (33 mumol/kg) was given for 30 days to 30-day old Zucker lean (Fa/?) rats. Their body weight and food consumption were followed daily; on day 30 of treatment (60-day old rats), whole body composition (lipid, protein) was determined, and plasma energy parameters and leptin were measured.. Oleoyl-estrone-treated rats grew more slowly than controls fed the hyperlipidic diet alone, and on day 60 their lipid content was about half that of controls. Protein content per kg was identical in both groups, but treated rats tended to accumulate less nitrogen and energy because of their smaller size. No changes in plasma glucose, urea, triacylglycerols or total cholesterol were observed, but oleoyl-estrone-treated rats showed lower circulating leptin than controls.. Despite limiting the accumulation of lipids, oleoyl-estrone slowed, but did not arrest growth of young rats, nor elicit a loss of fat or protein. Topics: Animals; Anti-Obesity Agents; Body Composition; Body Weight; Energy Intake; Energy Metabolism; Estrone; Female; Growth; Leptin; Nitrogen; Oleic Acids; Rats; Rats, Zucker | 2001 |
Relatively low serum leptin levels in adults born with intra-uterine growth retardation.
In-utero under-nutrition dramatically alters the development of adipose tissue, during the fetal and the neonatal period.. To investigate whether adults born with intra-uterine growth retardation (IUGR) show evidence of impaired adipose tissue development and leptin regulation.. Serum leptin concentrations were measured in 26 healthy adults born with IUGR and 25 controls aged 24 y who have been studied previously, 3 y ago.. The IUGR group demonstrated a significant increase of body mass index (BMI) in comparison to controls between 21 and 24 y of age (4.8+/-7.7%, P=0.004 vs 0.8+/-6.7%, P=0.70). Percentage of total body fat mass was significantly higher in IUGR-born subjects than in controls (27.2+/-7.6 vs 22.0+/-7.3%, P=0.02). Fasting insulin was significantly higher in the IUGR group (7.5+/-3.8 vs 5.3+/-2.3 miccroU/ml, P=0.03). Surprisingly, crude serum leptin concentrations did not significantly differ between the two groups. Moreover, adjusted means of serum leptin levels were significantly lower in IUGR-born subjects than in controls when corrected for body fat mass, gender and fasting insulin (11.3 vs 13.8 ng/ml, P=0.02).. Adults born with IUGR developed an excess of adipose tissue associated with relatively low serum leptin levels suggestive of an altered adipocyte function. Considering the close relationship between adipose tissue and insulin-sensitivity, these observations point to the potential implication of abnormal adipose tissue development in the long-term metabolic consequences associated with in-utero undernutrition. Topics: Adipocytes; Adipose Tissue; Adult; Aging; Body Constitution; Body Mass Index; Body Weight; Case-Control Studies; Female; Fetal Growth Retardation; Humans; Insulin; Insulin Resistance; Leptin; Male; Nutritional Status | 2001 |
Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys.
Adiponectin is an adipose-specific plasma protein whose plasma concentrations are decreased in obese subjects and type 2 diabetic patients. This protein possesses putative antiatherogenic and anti-inflammatory properties. In the current study, we have analyzed the relationship between adiponectin and insulin resistance in rhesus monkeys (Macaca mulatta), which spontaneously develop obesity and which subsequently frequently progress to overt type 2 diabetes. The plasma levels of adiponectin were decreased in obese and diabetic monkeys as in humans. Prospective longitudinal studies revealed that the plasma levels of adiponectin declined at an early phase of obesity and remained decreased after the development of type 2 diabetes. Hyperinsulinemic-euglycemic clamp studies revealed that the obese monkeys with lower plasma adiponectin showed significantly lower insulin-stimulated peripheral glucose uptake (M rate). The plasma levels of adiponectin were significantly correlated to M rate (r = 0.66, P < 0.001). Longitudinally, the plasma adiponectin decreased in parallel to the progression of insulin resistance. No clear association was found between the plasma levels of adiponectin and its mRNA levels in adipose tissue. These results suggest that reduction in circulating adiponectin may be related to the development of insulin resistance. Topics: Adiponectin; Adipose Tissue; Amino Acid Sequence; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Progression; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Macaca mulatta; Male; Molecular Sequence Data; Obesity; Organ Size; Primate Diseases; Proteins; Sequence Alignment; Sequence Homology, Amino Acid | 2001 |
Isomer-specific antidiabetic properties of conjugated linoleic acid. Improved glucose tolerance, skeletal muscle insulin action, and UCP-2 gene expression.
Conjugated linoleic acid (CLA) isomers have a number of beneficial health effects, as shown in biomedical studies with animal models. Previously, we reported that a mixture of CLA isomers improved glucose tolerance in ZDF rats and activated peroxisome proliferator-activated receptor (PPAR)-gamma response elements in vitro. Here, our aim was to elucidate the effect(s) of specific CLA isomers on whole-body glucose tolerance, insulin action in skeletal muscle, and expression of genes important in glucose and lipid metabolism. ZDF rats were fed either a control diet (CON), one of two CLA supplemented diets (1.5% CLA) containing differing isoforms of CLA (47% c9,t11; 47.9% c10,t12, 50:50; or 91% c9,t11, c9,t11 isomers), or were pair-fed CON diet to match the intake of 50:50. The 50:50 diet reduced adiposity and improved glucose tolerance compared with all other ZDF treatments. Insulin-stimulated glucose transport and glycogen synthase activity in skeletal muscle were improved with 50:50 compared with all other treatments. Neither phosphatidlyinositol 3-kinase activity nor Akt activity in muscle was affected by treatment. Uncoupling protein 2 in muscle and adipose tissue was upregulated by c9,t11 and 50:50 compared with ZDF controls. PPAR-gamma mRNA was downregulated in liver of c9,t11 and pair-fed ZDF rats. Thus, the improved glucose tolerance in 50:50 rats is attributable to, at least in part, improved insulin action in muscle, and CLA effects cannot be explained simply by reduced food intake. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Dietary Supplements; Energy Intake; Fatty Acids, Nonesterified; Feeding Behavior; Gene Expression Regulation; Glucose Tolerance Test; Insulin; Ion Channels; Isomerism; Leptin; Linoleic Acids; Male; Membrane Transport Proteins; Mitochondrial Proteins; Muscle, Skeletal; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Transcription Factors; Transcription, Genetic; Triglycerides; Uncoupling Agents; Uncoupling Protein 2 | 2001 |
Leptin as a possible modulator of craving for alcohol.
Topics: Adult; Alcoholism; Animals; Behavior, Addictive; Body Mass Index; Body Weight; Ethanol; Humans; Hydrocortisone; Leptin; Radioimmunoassay; Rats; Substance Withdrawal Syndrome | 2001 |
Apolipoprotein D interacts with the long-form leptin receptor: a hypothalamic function in the control of energy homeostasis.
Topics: Animals; Apolipoproteins; Apolipoproteins D; Body Weight; Carrier Proteins; Dietary Fats; Hypothalamus; Immunoblotting; Immunohistochemistry; Leptin; Male; Mice; Mice, Obese; Mice, Transgenic; Obesity; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Recombinant Fusion Proteins; RNA, Messenger; Two-Hybrid System Techniques | 2001 |
The not-so-odd couple--the clinician and the experimentalist.
Topics: Animals; Body Weight; Bone Density; Bone Development; Female; Humans; Leptin | 2001 |
Serum leptin levels are associated with bone mass in nonobese women.
Both serum leptin and bone mineral density are positively correlated with body fat, generating the hypothesis that leptin may be a systemic and/or local regulator of bone mass. We investigated 214 healthy, nonobese Australian women aged 20-91 yr. Bone mineral content, projected bone area, and body fat mass were measured by dual energy x-ray absorptiometry and fasting serum leptin levels by RIA. Associations between bone mineral content (adjusted for age, body weight, body fat mass, and bone area) and the natural logarithm of serum leptin concentrations were analyzed by multiple regression techniques. There was a significant positive association at the lateral spine, two proximal femur sites (Ward's triangle and trochanter), and whole body (partial r(2) = 0.019 to 0.036; all P < 0.05). Similar trends were observed at the femoral neck and posterior-anterior-spine. With bone mineral density the dependent variable (adjusted for age, body weight, and body fat mass), the association with the natural logarithm of leptin remained significant at the lateral spine (partial r(2) = 0.030; P = 0.011), was of borderline significance at the proximal femur sites (partial r(2) = 0.012 to 0.017; P = 0.058 to 0.120), and was not significant at the other sites. Our results demonstrate an association between serum leptin levels and bone mass consistent with the hypothesis that circulating leptin may play a role in regulating bone mass. Topics: Adult; Aged; Aged, 80 and over; Body Weight; Bone Density; Cross-Sectional Studies; Female; Humans; Leptin; Middle Aged; Regression Analysis | 2001 |
Nicotine infusion alters leptin and uncoupling protein 1 mRNA expression in adipose tissues of rats.
We attempted to clarify whether leptin and uncoupling protein 1 (UCP1) are involved in the action of nicotine on the energy balance. Male Wistar rats were infused subcutaneously with nicotine (12 mg x kg(-1) x day(-1)) for 4 or 14 days. At the end of the 4-day period, the plasma concentrations of leptin of the nicotine-treated and pair-fed rats were lower than those of the freely fed rats, although the levels of leptin mRNA expression in various white adipose tissues did not differ among the three groups. At the end of the 14-day nicotine infusion period, plasma concentrations of leptin were higher, and leptin mRNA expression in the omentum and epididymal and retroperitoneal adipose tissues was stronger in the nicotine-treated rats than in the pair-fed and freely fed rats. UCP1 mRNA expression in the brown adipose tissue of nicotine-treated was stronger than that of the pair-fed rats. These results suggest that continuous nicotine infusion differentially affects the synthesis and secretion of leptin according to the duration of infusion and stimulates UCP1 mRNA expression, probably in a manner independent of leptin. Topics: Adipose Tissue; Animals; Body Weight; Carrier Proteins; Eating; Energy Metabolism; Gene Expression; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Nicotine; Nicotinic Agonists; Rats; Rats, Wistar; RNA, Messenger; Uncoupling Protein 1 | 2001 |
Effect of neonatal hypoxia on leptin, insulin, growth hormone and body composition in the rat.
The purpose of the present study was to evaluate the effect of exposure to hypoxia from birth to 7 days of age on leptin, insulin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), glucose, corticosterone, body weight, and body composition in rats studied at 7 days of age and then after return to normoxia. Hypoxia for the first 7 days of life resulted in a significant decrease in plasma leptin, body weight, and an increase in corticosterone and insulin with no change in plasma glucose, GH or IGF-1. There was no significant effect of hypoxia on % lean body mass, but a small but significant increase in % body fat. Bone mineral density (BMD) was lower in 7-day-old hypoxic rats as compared to normoxic controls. All hormonal variables and BMD had normalized by 7 days after return to normoxia. However, body weight remained lower even 5 weeks after return to normoxia. We conclude that leptin is decreased during neonatal hypoxia despite no change in adiposity. Furthermore, insulin is increased probably to overcome the effects of increased counterregulatory hormones (such as corticosterone). Topics: Animals; Animals, Newborn; Body Composition; Body Weight; Bone Density; Female; Human Growth Hormone; Hypoxia; Insulin; Leptin; Pregnancy; Rats; Rats, Sprague-Dawley | 2001 |
Lose weight STAT: CNTF tops leptin.
Topics: Animals; Anti-Obesity Agents; Body Weight; Brain-Derived Neurotrophic Factor; Ciliary Neurotrophic Factor; DNA-Binding Proteins; Humans; Leptin; Mice; Mice, Obese; STAT3 Transcription Factor; Trans-Activators | 2001 |
Neuropeptide Y has a central inhibitory action on the hypothalamic-pituitary-thyroid axis.
Recent evidence suggests that neuropeptide Y (NPY), originating in neurons in the hypothalamic arcuate nucleus, is an important mediator of the effects of leptin on the central nervous system. As these NPY neurons innervate hypophysiotropic neurons in the hypothalamic paraventricular nucleus (PVN) that produce the tripeptide, TRH, we raised the possibility that NPY may be responsible for resetting of the hypothalamic-pituitary-thyroid (HPT) axis during fasting. To test this hypothesis, the effects of intracerebroventricularly administered NPY on circulating thyroid hormone levels and proTRH messenger RNA in the PVN were studied by RIA and in situ hybridization histochemistry, respectively. NPY administration suppressed circulating levels of thyroid hormone (T(3) and T(4)) and resulted in an inappropriately normal or low TSH. These alterations were associated with a significant suppression of proTRH messenger RNA in the PVN, indicating that NPY infusion had resulted in a state of central hypothyroidism. Similar observations were made in NPY-infused animals pair fed to the vehicle-treated controls. These data are reminiscent of the effect of fasting on the thyroid axis and indicate that NPY may play a major role in the inhibition of HPT axis during fasting. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Arcuate Nucleus of Hypothalamus; Autoradiography; Body Weight; Brain; Eating; Epididymis; Hypothalamus; In Situ Hybridization; Leptin; Male; Neuropeptide Y; Organ Size; Pituitary Gland; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine | 2001 |
Sex, fat and the tilt of the earth: effects of sex and season on the feeding response to centrally administered leptin in sheep.
Whilst there have been many studies in various species examining the effects of leptin on food intake, there is a paucity of data comparing responsiveness in the two sexes. We have, therefore, addressed this issue in sheep. Because this species shows seasonal variation in voluntary food intake (VFI), we also considered the possibility that there might be seasonal variation in the responsivity to leptin. Centrally administered leptin was relatively ineffective as a satiety factor in either sex during AUTUMN: In Spring, leptin had a profound inhibitory effect on VFI in the females, but only a slight effect in males. These data indicate that responsiveness to leptin depends on sex and also on season in animals that are substantially affected by photoperiod. Topics: Animals; Body Weight; Eating; Female; Leptin; Male; Orchiectomy; Ovariectomy; Photoperiod; Satiation; Seasons; Sex Characteristics; Sheep | 2001 |
Systemically and topically supplemented leptin fails to reconstitute a normal angiogenic response during skin repair in diabetic ob/ob mice.
In diabetic patients impaired wound healing conditions are a therapeutic problem of clinical importance. Recently, we showed that supplemented leptin induced an acceleration of impaired wound closure in diabetic ob/ob mice by reversion of the delayed re-epithelialization process. Additionally, angiogenesis is central to a normal repair. As leptin has been reported to represent an angiogenic factor, we hypothesized that leptin-mediated angiogenic processes at the wound site might participate in leptin-mediated improvement of disturbed repair in ob/ob mice.. Using a model of excisional wounding, C57BL/6J-ob/ob mice were treated systemically and topically with recombinant murine leptin during the phase of repair. Changes in blood glucose concentrations and body weight were monitored. We measured expression of the vascular endothelial growth factor (VEGF) and the endothelial cell marker protein CD31 as a read-out for angiogenic processes at the wound site.. Expression of VEGF protein upon injury was reduced (30 to 40%) in ob/ob mice compared with wild-type C57BL/6 animals. Systemic and topical administration of leptin reconstituted normal wound VEGF expressions but failed to reverse the strongly reduced angiogenic response in ob/ob mice. Immunohistochemistry confirmed that the epithelium and blood vessels located in the granulation tissue expressed the functional leptin receptor obRb isoform during skin repair.. These data suggest that leptin reconstituted epithelial expression of VEGF during skin repair in ob/ob mice but failed to improve wound angiogenesis in the granulation tissue. Thus, the accelerated wound closure observed in leptin-supplemented ob/ob mice is not coupled to an improved wound angiogenesis. Topics: Administration, Topical; Animals; Blood Glucose; Body Weight; Diabetes Complications; Diabetes Mellitus; Endothelial Growth Factors; Endothelium, Vascular; Female; Gene Expression; Keratinocytes; Leptin; Lymphokines; Mice; Mice, Inbred C57BL; Mice, Obese; Neovascularization, Physiologic; Obesity; Recombinant Proteins; RNA, Messenger; Skin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Wound Healing | 2001 |
Leptin and phospholipid-esterified docosahexaenoic acid concentrations in plasma of women: observations during pregnancy and lactation.
The n-3 fatty acid status changes during pregnancy and lactation. Plasma leptin concentrations and gene expression have been related to n-3 fatty acids.. To investigate the relation between plasma leptin concentration and the docosahexaenoic acid (22:6n-3) content of plasma phospholipids during early pregnancy and the postpartum period.. Leptin (radioimmunoassay) and the phospholipid fatty acid profile (capillary gas-liquid chromatography) were measured in plasma of women during two independent longitudinal observational studies. Dietary intake of n-3 fatty acids was also determined.. Within the first 10 weeks after the last menstrual period, an almost parallel increase in leptin concentration and the 22:6n-3 content (mg/l and % wt/wt) of plasma phospholipids was seen (study 1, n = 21). During the postpartum period (study 2, n = 57), leptin levels decreased quickly, preceding the changes in 22:6n-3 concentrations. During both studies, leptin concentrations did not consistently relate to dietary intake of n-3 fatty acids or to 22:6n-3 concentrations in plasma phospholipids. Before and during early pregnancy (study 1), significant positive associations between leptin levels and the total amount of phospholipid-associated fatty acids were found. No such association was seen during late pregnancy or the postpartum period (study 2). The postpartum decrease in leptin levels did not differ between lactating and non-lactating women.. Not the 22:6n-3 content, but the total amount of phospholipid-associated fatty acids was related to plasma leptin concentration, before and during early pregnancy but not during late pregnancy and the postpartum period. Topics: Body Mass Index; Body Weight; Diet; Docosahexaenoic Acids; Fatty Acids, Omega-3; Female; Humans; Lactation; Leptin; Longitudinal Studies; Phospholipids; Postpartum Period; Pregnancy; Pregnancy Trimester, First; Time Factors | 2001 |
Contribution of weight cycling to serum leptin in human obesity.
To investigate to what extent serum leptin concentrations in obese humans are influenced by a history of weight cycling.. Cross-sectional study on serum leptin concentrations and body composition in a cohort of obese subjects in whom a retrospective recall of weight and diet history was made.. One hundred and twenty-eight obese patients (89 females and 39 males), aged 18-61 y, body mass index (BMI) 31.2-63.4 kg/m(2).. Serum leptin; various fatness and fat distribution parameters (by anthropometry and bioelectrical impedance analysis); history of overweight at puberty; number, magnitude and timing of previous diet episodes and of consequent weight regain by interview.. By univariate analysis, serum leptin concentrations were significantly correlated with weight, waist-hip ratio, percentage body fat, maximal percentage weight loss in a single diet episode, cumulative percentage weight loss in all diet episodes, cumulative weight regained in all diet episodes, but not with the number of diet episodes. All correlations related to anthropometric and body composition parameters were stronger for men, compared to women, although the male subgroup was smaller. On the contrary, there was a strong positive correlation between weight cycling parameters and serum leptin in women but not in men. Leptin concentrations were significantly higher in patients who were overweight at puberty than in those who were not overweight at puberty. After correction for percentage body fat, presence of overweight at puberty did not correlate any longer with leptin concentrations in either gender. In women, cumulative percentage weight loss in all diet episodes contributed an additional 5% to the variance of serum leptin in the overall model.. The positive correlation between weight cycling and leptin concentration in obesity is mainly accounted for the higher percentage body fat in obese weight cyclers, although in women weight cycling per se independently contributes to the variance of serum leptin. Topics: Adolescent; Adult; Anthropometry; Body Composition; Body Constitution; Body Mass Index; Body Weight; Cohort Studies; Cross-Sectional Studies; Electric Impedance; Female; Humans; Leptin; Male; Middle Aged; Obesity; Retrospective Studies; Weight Loss | 2001 |
Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production.
Single-gene mutations that extend lifespan provide valuable tools for the exploration of the molecular basis for age-related changes in cell and tissue function and for the pathophysiology of age-dependent diseases. We show here that mice homozygous for loss-of-function mutations at the Pit1 (Snell dwarf) locus show a >40% increase in mean and maximal longevity on the relatively long-lived (C3H/HeJ x DW/J)F(1) background. Mutant dw(J)/dw animals show delays in age-dependent collagen cross-linking and in six age-sensitive indices of immune system status. These findings thus demonstrate that a single gene can control maximum lifespan and the timing of both cellular and extracellular senescence in a mammal. Pituitary transplantation into dwarf mice does not reverse the lifespan effect, suggesting that the effect is not due to lowered prolactin levels. In contrast, homozygosity for the Ghrhr(lit) mutation, which like the Pit1(dw) mutation lowers plasma growth hormone levels, does lead to a significant increase in longevity. Male Snell dwarf mice, unlike calorically restricted mice, become obese and exhibit proportionately high leptin levels in old age, showing that their exceptional longevity is not simply due to alterations in adiposity per se. Further studies of the Pit1(dw) mutant, and the closely related, long-lived Prop-1(df) (Ames dwarf) mutant, should provide new insights into the hormonal regulation of senescence, longevity, and late life disease. Topics: Aging; Animals; Body Weight; Collagen; DNA-Binding Proteins; Female; Growth Hormone; Insulin-Like Growth Factor I; Leptin; Longevity; Male; Mice; Mice, Inbred C3H; Mice, Mutant Strains; Pituitary Gland; T-Lymphocyte Subsets; T-Lymphocytes; Transcription Factor Pit-1; Transcription Factors | 2001 |
Sex differences in HAART-associated dyslipidaemia.
Because female sex protects against dyslipidaemia and atherosclerosis in normal subjects, we aimed to reveal potential sex differences in metabolic side-effects of a newly initiated highly active antiretroviral therapy (HAART) regimen, and to relate these changes to endothelial cell activation as measured by levels of circulating E-selectin (cE-selectin).. Prospective longitudinal cohort study.. Tertiary care centre at a University Hospital.. HIV-seropositive male (n = 27) and female patients (n = 13) with a plasma viral load of > or = 10 000 copies/ml and 35 healthy controls were enrolled in the study. All participants were weight stable, free of acute opportunistic infections, and had not taken any protease inhibitors before. Serum levels of lipids, insulin, leptin, and cE-selectin were measured before initiation of HAART, and at 3 and 6 months thereafter.. HAART increased serum levels of triglycerides, leptin, and low-density lipoprotein (LDL) cholesterol; these effects were more distinct in women. Fasting insulin levels and the LDL : high density lipoprotein (HDL) ratio increased only in female HIV-infected patients (P < 0.02 versus men). In contrast, endothelial activation, as measured by cE-selectin, decreased more in men (P < 0.02) than in women. As a consequence, women had higher triglycerides and leptin levels after therapy than did men, and the LDL : HDL ratio and cE-selectin levels, which were initially higher in men, were no longer different between the sexes.. Metabolic adverse effects during HAART are more pronounced in women than in men. Hence, female HIV-infected patients seem to loose part of their natural protection from atherosclerosis during antiretroviral therapy. Topics: Adult; Antiretroviral Therapy, Highly Active; Body Composition; Body Weight; CD4 Lymphocyte Count; E-Selectin; Endothelium, Vascular; Female; HIV Infections; Humans; Hyperlipidemias; Insulin; Leptin; Lipids; Male; Middle Aged; Prospective Studies; Sex Factors; Viral Load | 2001 |
Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes.
Lipoatrophic diabetes is caused by a deficiency of adipose tissue and is characterized by severe insulin resistance, hypoleptinemia, and hyperphagia. The A-ZIP/F-1 mouse (A-ZIPTg/+) is a model of severe lipoatrophic diabetes and is insulin resistant, hypoleptinemic, hyperphagic, and shows severe hepatic steatosis. We have also produced transgenic "skinny" mice that have hepatic overexpression of leptin (LepTg/+) and no adipocyte triglyceride stores, and are hypophagic and show increased insulin sensitivity. To explore the pathophysiological and therapeutic roles of leptin in lipoatrophic diabetes, we crossed LepTg/+ and A-ZIPTg/+ mice, producing doubly transgenic mice (LepTg/+:A-ZIPTg/+) virtually lacking adipose tissue but having greatly elevated leptin levels. The LepTg/+:A-ZIPTg/+ mice were hypophagic and showed improved hepatic steatosis. Glucose and insulin tolerance tests revealed increased insulin sensitivity, comparable to LepTg/+ mice. These effects were stable over at least 6 months of age. Pair-feeding the A-ZIPTg/+ mice to the amount of food consumed by LepTg/+:A-ZIPTg/+ mice did not improve their insulin resistance, diabetes, or hepatic steatosis, demonstrating that the beneficial effects of leptin were not due to the decreased food intake. Continuous leptin administration that elevates plasma leptin concentrations to those of LepTg/+:A-ZIPTg/+ mice also effectively improved hepatic steatosis and the disorder of glucose and lipid metabolism in A-ZIP/F-1 mice. These data demonstrate that leptin can improve the insulin resistance and diabetes of a mouse model of severe lipoatrophic diabetes, suggesting that leptin may be therapeutically useful in the long-term treatment of lipoatrophic diabetes. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Lipoatrophic; Eating; Gene Expression; Infusion Pumps; Injections; Insulin Resistance; Leptin; Lipids; Mice; Mice, Inbred Strains; Mice, Transgenic; Organ Size; Transgenes | 2001 |
Effects of leptin on secretion of LH and FSH from primary cultured female rat pituitary cells.
Leptin, which is the product of the obese gene, is believed to play important roles in pubertal development and reproductive function in females. In a study using adult male rats, it was found that leptin stimulated secretion of gonadotropin from the pituitary in a dose-related manner. However, there has been no such study in female rats.. To investigate the effects of leptin on the production of LH and FSH from the pituitary in female rats, using primary cultured pituitary cells.. In this study, we determined body weight, serum leptin concentration and serum estradiol (E(2)) concentration in female Wistar rats at 3, 5, 6, 7, 9 and 11 weeks of age, and cultured pituitary cells from 6-week-old female Wistar rats with leptin (0--10(-7) mol/l) and GnRH (0 or 10(-8) mol/l). Then basal and GnRH-stimulated extra- and intracellular LH and FSH were assayed by RIA.. Serum leptin concentration increased with increases in body weight and E(2) concentration. The pubertal serum leptin concentration was about 10(-10) mol/l. At a lower or moderate concentration, leptin produced dose-related increases in both basal and GnRH-stimulated extra- and intracellular LH and FSH in pituitary cells. At a concentration of 10 mol/l, leptin significantly (P<0.05) stimulated both basal and GnRH-stimulated extra- and intracellular LH and FSH. However, at greater concentrations, these effects diminished.. These results indicated that leptin induced pituitary cells to produce and secrete both LH and FSH, with or without GnRH. The concentration of leptin that induced the greatest production of gonadotropins by pituitary cells was 10(-10) mol/l, which was the same as the physiological pubertal concentration. Leptin may be involved in the onset of puberty. It is also conceivable that leptin may be a cause of ovulatory failure, not only in weight loss but also in weight gain. Topics: Animals; Body Weight; Cells, Cultured; Estradiol; Extracellular Space; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Leptin; Luteinizing Hormone; Pituitary Gland; Rats | 2001 |
Effects of conjugated linoleic acid on serum leptin concentration, body-fat accumulation, and beta-oxidation of fatty acid in OLETF rats.
We investigated the efficacy of a 4-wk supplementation of conjugated linoleic acid (CLA) as free fatty acid (FFA) or triacylglycerol (TG) on serum leptin concentration, body-fat accumulation, and mitochondrial beta-oxidation in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. A significant reduction of serum leptin concentration (42%) and a decrease in the wet weights of perirenal, epididymal, and omental/visceral-adipose tissue in TG-CLA and FFA-CLA groups were found in comparison with the OLETF control group. Both forms of CLA supplementation produced a 5.2% decrease in body weight compared with the control even though food intake was similar in the OLETF groups. Moreover, both forms of CLA enhanced carnitine-palmitoyltransferase activity in brown adipose tissue, perirenal adipose tissue, red gastrocnemius muscle, and liver in comparison with the OLETF control group. Serum concentrations of non-esterified fatty acid and TG also were reduced in rats fed diets supplemented with TG-CLA and FFA-CLA. Topics: Adipose Tissue; Animals; Body Weight; Carnitine O-Palmitoyltransferase; Eating; Fatty Acids; Fatty Acids, Nonesterified; Leptin; Linoleic Acid; Liver; Male; Oxidation-Reduction; Rats; Rats, Inbred OLETF; Treatment Outcome; Triglycerides; Weight Gain | 2001 |
Up-regulation of a thermogenesis-related gene (UCP1) and down-regulation of PPARgamma and aP2 genes in adipose tissue: possible features of the antiobesity effects of a beta3-adrenergic agonist.
A number of experiments have demonstrated the antiobesity effects of beta(3)-adrenergic receptor stimulation by promoting thermogenesis and/or lipolysis. While many studies have been performed in order to develop beta(3)-adrenergic agonists as a novel strategy in the management of obesity, more information is needed about the mechanisms involved in thermogenesis and the actions of these drugs on adipocyte differentiation. To address this, the possible thermogenic and antiadipogenic properties of Tertatolol, a beta(3)-adrenergic agonist, in a diet-induced obesity model has been tested. Animals fed on a high-fat diet gained more weight and fat mass as compared with control and high-fat fed animals treated with Tertatolol. A RT-PCR was carried out in white adipose tissue specific genes involved in thermogenesis such as uncoupling proteins (UCPs) and adipogenesis such as peroxisome proliferator-activated receptor (PPARgamma2), retinoid receptors (RXRalpha/RARalpha), and fatty acid binding protein (aP2). Levels of UCP1 mRNA were augmented in the Tertatolol-treated group as compared to non-treated high-fat fed animals, while the beta(3)-adrenergic agonist treatment significantly decreased the expression levels of aP2 and transcription factors such as PPARgamma2 and the ratio RXRalpha/RARalpha as compared to obese rats. Altogether these data suggest that the antiobesity effects of beta(3)-adrenergic agonists are not limited to the promotion of thermogenesis and/or lipolysis and support the implication that these beta(3)-adrenergic agonists also affect fat deposition by impairing adipogenesis in white adipose tissue (WAT). Topics: Adaptor Protein Complex 2; Adaptor Protein Complex alpha Subunits; Adaptor Proteins, Vesicular Transport; Adipose Tissue; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Anti-Obesity Agents; Body Temperature; Body Weight; Carrier Proteins; Down-Regulation; Female; Ion Channels; Leptin; Membrane Proteins; Mitochondrial Proteins; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoid X Receptors; RNA, Messenger; Transcription Factors; Uncoupling Protein 1; Up-Regulation | 2001 |
Changes of leptin and metabolic hormones in preterm infants: a longitudinal study in early postnatal life.
Very little is known concerning the physiological role of leptin and growth in the early postnatal period and the association of leptin with other metabolic hormones in preterm infants. This study aims to investigate these relationships, and to explore the longitudinal and dynamic profile of leptin and metabolic hormones including insulin, ACTH, cortisol and FT4 in this category of patient. We also postulate that a rapid increase in body weight and body mass index in the first few weeks of life may be associated with a corresponding increase in serum leptin if the 'adipoinsular axis' is active at this stage.. A longitudinal study in a cohort of preterm infants < 34 weeks gestation for the first five weeks of postnatal life.. Sixty-one preterm newborns < 34 weeks gestation were prospectively enrolled. Blood samples were collected in the morning when the newborns were 24 h of age (day 1), and on days 5, 14 and 35 of life. Serum leptin, insulin, cortisol, FT4, glucose and plasma ACTH concentrations were analysed using standard biochemical methods. Spearman's correlation coefficient was used to assess the inter-relationship of different metabolic hormones on the first day of life, and the relationship between metabolic hormones on day 1 and anthropometric or clinical parameters. The mixed-effects models were further used for analysing the multiple longitudinal measurements, and also for comparing the hormone concentrations between day 1 (baseline) and their corresponding levels on days 5, 14 and 35.. Serum leptin on day 1 (baseline) was significantly associated with serum insulin (r = 0.30, P < 0.05) and insulin:glucose ratio (r = 0.29, P < 0.05) in infants < 34 weeks gestation. Female preterm infants had significantly higher serum leptin (P < 0.05) and insulin (P < 0.05) levels than male infants. In addition, the duration between the last dose of antenatal dexamethasone and delivery significantly influenced the serum concentrations of leptin (r = - 0.27, P < 0.05), cortisol (r = 0.52, P < 0.001), plasma ACTH (r = 0.28, P < 0.05) and insulin:glucose ratio (r = - 0.27, P < 0.05) on the first day of life. Despite significant increase in body weight (P < 0.00001) and body mass index (P < 0.00001) by day 35 when compared to birth weight, no corresponding significant changes were observed for serum leptin, insulin and FT4. However, there was an increasing though statistically nonsignificant trend in serum leptin after day 14 of life.. This study characterized the longitudinal profile of leptin and metabolic hormones in preterm infants < 34 weeks gestation in the first 5 weeks of life. Serum leptin was significantly associated with serum insulin and insulin:glucose ratio supporting the hypothesis that an 'adipoinsular axis' exists and is likely to be functional before 34 weeks of gestation. Although a significant increase in body weight was demonstrated by day 35, no significant corresponding changes occurred with regard to serum leptin. We postulate that the limited quantity of adipose tissue at this stage of development might have contributed to this observation. Moreover, our results also showed that the duration between the last dose of antenatal corticosteroid and delivery could influence the postnatal concentrations of adipoinsular and pituitary-adrenal hormones. Thus, it is possible that antenatal dexamethasone might affect fetal growth and development via these neuroendocrine pathways in early intrauterine life. Topics: Adrenocorticotropic Hormone; Blood Glucose; Body Mass Index; Body Weight; Female; Gestational Age; Humans; Hydrocortisone; Infant Nutritional Physiological Phenomena; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Insulin; Leptin; Longitudinal Studies; Male; Multivariate Analysis; Prospective Studies; Statistics, Nonparametric; Thyroxine | 2001 |
Hypothalamic control of photoperiod-induced cycles in food intake, body weight, and metabolic hormones in rams.
This study used a hypothalamo-pituitary disconnected (HPD) sheep model to investigate the central regulation of long-term cycles in voluntary food intake (VFI) and body weight (BW). VFI, BW, and circulating concentrations of metabolic hormones [alpha-melanocyte-stimulating hormone (alpha-MSH), insulin-like growth factor-1 (IGF-1), insulin, and leptin] were measured in HPD and control Soay rams exposed to alternating 16 weekly periods of long and short days for 80 wk. In the controls, the physiology was cyclical with a 32-wk periodicity corresponding to the lighting regimen. VFI and BW increased under long days to a maximum early into short days, and there were associated increases in blood concentrations of alpha-MSH, insulin, and leptin. In the HPD rams, there were no significant photoperiod-induced changes in any of the parameters. VFI increased after surgery for 8 wk and then gradually declined, although BW increased progressively and the HPD rams became obese. Concentrations of alpha-MSH, insulin, and leptin in peripheral blood were permanently increased (>200%), and levels of IGF-1 decreased (<55%). The HPD lesion effectively destroyed the entire median eminence [no nerve terminals immunostained for tyrosine hydroxylase (TH) and gonadotropin-releasing hormone] and the adjacent arcuate nucleus (no perikarya immunostained for proopiomelanocortin or TH, and no cells expressed neuropeptide Y mRNA). The results support the conclusion that arcuate hypothalamic systems generate long-term rhythms in VFI, BW, and energy balance. Topics: Adaptation, Physiological; Adipose Tissue; alpha-MSH; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Denervation; Eating; Energy Metabolism; Glucose; Gonadotropin-Releasing Hormone; Hypoglycemic Agents; Hypothalamo-Hypophyseal System; Immunohistochemistry; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Neuropeptide Y; Obesity; Photoperiod; Pro-Opiomelanocortin; RNA, Messenger; Seasons; Sheep; Tyrosine 3-Monooxygenase | 2001 |
Evidence for a circulating islet cell growth factor in insulin-resistant states.
Insulin resistance is a feature of many common disorders including obesity and type 2 diabetes mellitus. In these disorders, the beta-cells compensate for the insulin resistance for long periods of time with an increase in secretory capacity, an increase in beta-cell mass, or both. To determine whether the beta-cell response might relate to a circulating growth factor, we have transplanted normal islets under the kidney capsule of normoglycemic insulin-resistant mice with two different models of insulin resistance: lean mice that have a double heterozygous deletion of the insulin receptor and insulin receptor substrate-1 (DH) or the obese, hyperglycemic ob/ob mice. In the grafts transplanted into both hosts, there was a marked increase in beta-cell mitotic activity and islet mass that was comparable with that observed in the endogenous pancreas. By contrast, islets of the DH mouse transplanted into normal mice showed reduced mitotic index. These data suggest the insulin resistance is associated with a circulating islet cell growth factor that is independent of glucose and obesity. Topics: Animals; Blood Glucose; Body Weight; Growth Substances; Hyperglycemia; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Islets of Langerhans; Islets of Langerhans Transplantation; Leptin; Male; Mice; Mice, Knockout; Mice, Obese; Obesity; Phosphoproteins; Receptor, Insulin; Subrenal Capsule Assay | 2001 |
Insulin-sensitizing action of rosiglitazone is enhanced by preventing hyperphagia.
We investigated whether pair-feeding to prevent hyperphagia would potentiate the insulin-sensitizing effect of rosiglitazone in chow-fed and insulin-resistant dietary obese rats, and studied the role of leptin and hypothalamic neuropeptide Y as mediators of weight gain during treatment.. Dietary obese and chow-fed rats (575 +/- 10 vs. 536 +/- 7 g; p < 0.01) were given rosiglitazone (30 mg/kg p.o.) or vehicle daily for 14 days.. Energy intake and weight gain were greater in rosiglitazone-treated ad-lib-fed rats (body weight: chow + 24 +/- 2 g, rosiglitazone-treated + 55 +/- 2 g, p < 0.001; dietary obese + 34 +/- 2 g, rosiglitazone-treated + 74 +/- 7 g, p < 0.001). Half of each rosiglitazone-treated group were pair-fed to vehicle-treated controls. Rosiglitazone normalized circulating free fatty acids (FFAs) and insulin sensitivity in dietary obese rats (homeostasis model assessment (HOMA): chow-fed controls, 3.9 +/- 0.3; dietary obese controls, 6.7 +/- 0.7; rosiglitazone-treated, ad lib-fed dietary obese, 4.2 +/- 0.5; both p < 0.01). Insulin sensitivity improved further with pair-feeding (HOMA: 2.9 +/- 0.4; p < 0.05 vs. rosiglitazone-treated, ad lib-fed dietary obese), despite unchanged FFAs. Qualitatively similar findings were made in chow-fed rats. Pair-feeding prevented rosiglitazone-related weight gain in chow-fed, but not dietary obese rats (body weight: + 49 +/- 5 g, p < 0.001 vs. untreated dietary obese controls). Adipose tissue OB mRNA was elevated in dietary obese rats, reduced 49% (p < 0.01) by rosiglitazone treatment, and further (by 16%) with pair-feeding (p < 0.0001). Plasma leptin, however, only fell in the pair-fed group. Hypothalamic neuropeptide Y mRNA was unchanged throughout, suggesting that weight gain associated with high-dose rosiglitazone treatment is independent of hypothalamic neuropeptide Y.. Food restriction potentiates the insulin-sensitizing effect of rosiglitazone in rats, and this effect is independent of a fall in FFAs. Topics: Animals; Body Weight; Carrier Proteins; Eating; Food Deprivation; Hyperphagia; Hypoglycemic Agents; Hypothalamus; Insulin Resistance; Ion Channels; Leptin; Male; Mitochondrial Proteins; Neuropeptide Y; Obesity; Rats; Rats, Wistar; RNA, Messenger; Rosiglitazone; Thiazoles; Thiazolidinediones; Uncoupling Protein 3 | 2001 |
Leptin effects on immune function and energy balance are photoperiod dependent in Siberian hamsters (Phodopus sungorus).
Many adaptations have evolved in small mammals to maximize survival during winter. One such coping tactic in many species is an alteration of immune function in advance of the stressful conditions of winter. Leptin is a hormone produced by adipose tissue, and in addition to its central role in energy metabolism, leptin mediates the interactions among energy allocation, immune function, and reproduction. To examine this interaction further, exogenous leptin was administered for 2 weeks via osmotic minipumps to Siberian hamsters (Phodopus sungorus) housed in long or short days for a total of 12 weeks. Short-day hamsters displayed the expected reductions in humoral immune function, body mass, fat mass, and food intake. In Exp 1, exogenous leptin counteracted the reduction in food intake and the suppression of immune function in short days. In Exp 2, when the leptin-induced increase in food intake in short-day hamsters was prevented, leptin did not enhance immune function. In most of the measured fat pads and body mass, leptin had no effect in long days. In sum, leptin administered to short-day animals caused them to respond, in many cases, like long-day animals. Taken together, these data suggest that leptin acts indirectly to mediate energy allocation to humoral immune function. Additionally, leptin appears to act differentially, according to photoperiod, to regulate both immune and energetic parameters. Topics: Animals; Body Weight; Cricetinae; Eating; Energy Metabolism; Hydrocortisone; Immune System; Leptin; Male; Organ Size; Phodopus; Photoperiod | 2001 |
Maternal undernutrition induces neuroendocrine immune dysfunction in male pups at weaning.
The present study was designed to assess the effect of maternal undernutrition, during gestation and lactation, on the neuroendocrine [hypothalamo-pituitary-adrenal (HPA)]-immune axis response to endotoxin (LPS) administration. For this purpose, 21-day-old male rats from both well-nourished (WN) and undernourished (UN) mothers were examined 2 h after injection (i.p.) of vehicle alone (VEH) or containing LPS (130 microg/kg BW). Circulating levels of glucose (GLU), ACTH, corticosterone (B), tumor necrosis factor-alpha (TNFalpha) and leptin were explored. The results indicate that: (a) mother body weight was significantly (p < 0.05) reduced, as a consequence of UN, at the second and third weeks of pregnancy; (b) no differences in basal glycemia were found in the two groups of pups, and LPS treatment did not induce hypoglycemia, in either group; (c) basal plasma ACTH, B and TNFalpha levels were similar in the two groups, and LPS-induced ACTH, B and TNFalpha secretions, although severalfold higher than respective VEH values (p < 0.05) in pups from WN mothers, were fully (ACTH and B) and partially (TNFalpha) abolished in products from UN mothers; (d) both mean body weights and basal plasma leptin levels were significantly (p < 0.05) lower in pups from UN than from WN mothers, and LPS administration did not modify plasma leptin values in products from both groups. In addition, results of dispersed total adrenal cells incubated in vitro indicate that: (a) both basal and ACTH (22 pM)-induced B secretion were significantly (p < 0.05) lower in cells from UN than WN pups, and (b) leptin (100 nM) was able to inhibit partially ACTH-stimulated B output by adrenal gland (AG) cells from WN pups; however, it failed to inhibit ACTH-stimulated glucocorticoid release by AG cells from UN pups. The present results indicate that undernutrition in mothers, during the very critical periods of gestation and lactation, induces in their male pups at weaning: (a) reduced circulating leptin levels and body weight values; (b) metabolic adaptation to normal carbohydrate metabolism; (c) hyporesponsiveness of the HPA and immune (TNFalpha) axes during endotoxemia, and (d) leptin resistance at the adrenocortical level. This study strongly supports that undernutrition of mothers results in neuroendocrine immune dysfunction of their pups; however, adrenal resistance to the inhibitory effect of leptin on glucocorticoid output is developed, probably as an adaptive mechanism to counteract unfavor Topics: Adaptation, Physiological; Adrenal Glands; Adrenocorticotropic Hormone; Animals; Animals, Suckling; Blood Glucose; Body Weight; Corticosterone; Female; Gestational Age; Hypothalamo-Hypophyseal System; Immunologic Deficiency Syndromes; Lactation; Leptin; Lipopolysaccharides; Male; Maternal-Fetal Exchange; Neuroimmunomodulation; Nutrition Disorders; Pituitary-Adrenal System; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred F344; Tumor Necrosis Factor-alpha; Weaning | 2001 |
A reassessment of leptin's role in triggering the onset of puberty in the rat and mouse.
Leptin is an adipocyte-derived hormone that has been implicated to serve as a metabolic signal to the reproductive axis. The role of leptin in pubertal maturation, however, has been a much-debated topic. We have previously reported that leptin serves as a permissive signal to the onset of puberty in the female rat. In an attempt to further understand the mechanics of leptin during pubertal maturation in rodent species, we had three experimental objectives: first, to describe the temporal relationship of leptin with development in the male and female rat; second, to seek evidence for an increase in responsiveness of the neuroendocrine axis to leptin by assessing for possible changes in leptin receptor expression during pubertal developmental in the female rat; and, third, to reevaluate the possible role of leptin as a permissive signal to the onset of puberty in the mouse. We found that serum leptin levels remain relatively constant during the prepubertal and postpubertal stages of both sexes. In addition, we could not detect any significant developmental changes in leptin receptor gene expression in the hypothalamus of the female rat. Lastly, we corroborated our findings in the female rat that leptin reversed the delay in pubertal maturation secondary to food restriction but did not advance the onset of puberty in female mice. Together, these results suggest that leptin is not a metabolic trigger for the onset of puberty in the rodent; instead, leptin is one of several permissive factors, whose presence may be necessary but alone is not sufficient to initiate sexual maturation in these species. Topics: Animals; Body Weight; Carrier Proteins; Eating; Female; Follicle Stimulating Hormone; Hypothalamus; Leptin; Luteinizing Hormone; Male; Mice; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Sexual Maturation | 2001 |
Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30.
We studied 31 nondiabetic, habitually (> or =5 years) morbidly obese subjects (mean +/- SD body mass index [BMI] 43 +/- 8.7, median 43). Our specific aim was to determine whether metformin (2.55 g/d for 28 weeks) would ameliorate morbid obesity and reduce centripetal obesity; lipid and lipoprotein cholesterol, insulin, and leptin levels; and plasminogen activator inhibitor activity (PAI-Fx), risk factors for coronary heart disease (CHD). The patients were instructed to continue their prestudy dietary and exercise regimens without change. After 2 baseline visits 1 week apart, the 27 women and 4 men began receiving metformin, 2.55 g/d, which was continued for 28 weeks with follow-up visits at study weeks 5, 13, 21, and 29. Daily food intake was recorded by patients for 7 days before visits then reviewed with a dietitian. Kilocalories per day and per week were calculated. At each visit, fasting blood was obtained for measurement of lipid profile, insulin, leptin, and PAI-Fx. The mean +/- SD kilocalories consumed per day, 1,951 +/- 661 at entry, fell by week 29 to 1,719 +/- 493 (P =.014) but did not differ at weeks 5, 13, and 21 from that at week 29 (P >.2). Weight fell from 258 +/- 62 pounds at entry to 245 +/- 54 pounds at week 29 (P =.0001). Girth was reduced from 51.8 +/- 6.2 to 49.2 +/- 4.5 inches (P =.0001). Waist circumference fell from 44.0 +/- 6.4 inches to 41.3 +/- 5.9 (P =.0001). The waist/hip ratio fell from 0.85 +/- 0.09 to 0.84 +/- 0.09 (P =.04). Fasting serum insulin, 28 +/- 15 microU/mL at entry, fell to 21 +/- 11 microU/mL at week 29 (P =.0001), and leptin fell from 79 +/- 33 ng/mL to 55 +/- 27 ng/mL (P =.0001). On metformin, there were linear trends in decrements in weight, girth, waist circumference, waist/hip ratio, insulin, and leptin throughout the study period (P <.007). Low-density lipoprotein (LDL) cholesterol, 126 +/- 34 mg/dL at study entry, fell to 112 +/- 43 mg/dL at week 29 (P =.001), with a linear trend toward decreasing levels throughout (P =.036). By stepwise linear regression, the higher the entry weight, the larger the reduction in weight on metformin therapy (partial R(2) = 31%, P =.001). The greater the reduction in kilocalories consumed per day, the greater the decrease in weight on metformin therapy (partial R(2) = 15%, P =.011). The higher the waist/hip ratio at entry, the greater its reduction on metformin therapy (partial R(2) = 11%, P =.004). The higher the entry serum leptin, the greater its reduction on metformin t Topics: Adult; Aged; Body Mass Index; Body Weight; Cholesterol, LDL; Coronary Disease; Fasting; Female; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Metformin; Middle Aged; Obesity; Risk Factors; Tissue Plasminogen Activator | 2001 |
Serum leptin levels in pregnant women with type 1 diabetes mellitus.
Leptin is an important weight regulator and during pregnancy leptin is not only synthesized in adipose tissue but also in the placenta.. To examine changes in serum leptin levels in women with type 1 diabetes mellitus during pregnancy and post delivery in relation to concomitant changes in maternal body weight, birth weight, glycemic control, and blood pressure.. Non-fasting serum leptin from 45 women with type 1 diabetes mellitus were studied consecutively throughout pregnancy and 3 months post partum.. Serum leptin was positively associated with HbA1c in week 18, 22 and 30 (r=0.38, 0.41, and 0.54, respectively, p<0.05, adjusted for body weight). Moreover, serum leptin correlated positively with maternal body weight and BMI (0.45 Topics: Adult; Birth Weight; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Insulin; Leptin; Pregnancy; Pregnancy in Diabetics | 2001 |
Impact of maternal undernutrition on hypothalamo-pituitary-adrenal axis and adipocyte functions in male rat offspring.
Malnutrition induces profound deleterious effects on several metabolic and neuroendocrine functions. In the present study, we examined the impact of maternal food restriction, during gestation and lactation, on the metabolic-neuroendocrine function of their male offspring at 21 and 60 d of age. Well-nourished (WN) and undernourished (UN) pregnant rats were used, during gestation and lactation, until pups were weaned. Twenty-one-day-old WN and UN male pups were studied in basal and postinsulin conditions. Additional groups of weaned (WN and UN) male rats were fed either ad libitum (WN-WN and UN-WN) or in a restricted fashion (WN-UN and UN-UN) until experimentation at age 60 d. Body weights of mothers and their male offspring were monitored. Basal and postinsulin plasma concentrations of several metabolic fuels were evaluated. Our results indicate that 21-d-old UN male rats exhibited (vs their WN counterparts), decreased body weights, similar basal and postinsulin glycemia, similar basal plasma adrenocorticotropic hormone (ACTH) and corticosterone levels but diminished ACTH response to insulin treatment, and basal hypoleptinemia and significant insulin-induced leptin release. Finally, at 60 d of age, long-term UN (WN-UN and UN-UN) rats showed lower plasma (basal and postinsulin) glucose, and basal triglyceride levels than their counterparts (WN-WN and UN-WN). Sixty-day-old rats submitted to either food restriction protocol also showed a reduced hypothalamo-pituitary-adrenal axis response to insulin-induced hypoglycemia and basal hypoleptinemia, in spite of restoration of normal body weights. These results further indicate a clear metabolic-neuroendocrine dysfunction in male pups of UN mothers, with the abnormality partially present at weaning and deteriorated by adulthood, even after the recovery of normal body weight. Our study strongly supports the importance of the irreversibility of a deleterious allostatic state resulting from fetal and early postnatal undernutrition. Topics: Adipocytes; Adrenocorticotropic Hormone; Animals; Blood Glucose; Blood Proteins; Body Weight; Eating; Female; Glucocorticoids; Hypoglycemia; Hypothalamo-Hypophyseal System; Lactation; Leptin; Male; Nutrition Disorders; Pituitary-Adrenal System; Pregnancy; Rats; Rats, Inbred F344; Triglycerides | 2001 |
Obesity is induced in mice heterozygous for cyclooxygenase-2.
In mice heterozygous for the cyclooxygenase-2 gene (COX-2+/-) the body weight was enhanced by 33% as compared to homozygous COX-2-/- mice. The weights of the gonadal fat pads in COX-2+/- mice were enhanced by 3.5 to 4.7 fold as compared to COX-2-/- mice and by 1.5 to 3.5 fold as compared to wild-type controls+/+ Serum leptin levels and leptin release by cultured adipose tissue of COX-2+/- mice were both elevated as compared to either control or COX-2-/- animals. The basal release of PGE2 or 6 keto PGF1alpha per fat pad over a 24 h incubation of adipose tissue was reduced by 80% and 95% respectively in tissue from COX-2-/- mice. NS-398, a specific COX-2 inhibitor, inhibited leptin release by 27% in adipose tissue from control mice, 31% in tissue from COX-1-/- mice and by 23% in tissue from COX-2+/- mice while having no effect on leptin release by adipose tissue from COX-2-/- mice. These data indicate that heterozygous COX-2 mice develop obesity which is not secondary to a defect in leptin release by adipose tissue. Topics: 6-Ketoprostaglandin F1 alpha; Adipose Tissue; Animals; Body Weight; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Epididymis; Female; Heterozygote; Humans; Isoenzymes; Leptin; Male; Membrane Proteins; Mice; Mice, Knockout; Nitrobenzenes; Obesity; Organ Size; Prostaglandin-Endoperoxide Synthases; Statistics as Topic; Sulfonamides | 2001 |
Leptin-deficient mice backcrossed to the BALB/cJ genetic background have reduced adiposity, enhanced fertility, normal body temperature, and severe diabetes.
A deficiency of leptin synthesis in mice results in a complex phenotype characterized by morbid obesity, diabetes, sterility, and defective thermogenesis. To determine whether the genetic background could alter the pleiotropic effects of leptin deficiency, we backcrossed the ob mutation for 10 generations from the C57BL/6J to the BALB/cJ genetic background. Compared with C57BL/6J ob/ob mice, BALB/cJ ob/ob mice showed at 27 wk of age a 35-40% reduction in body weight attributed to a 60% decrease in white adipose tissue mass. Food intake was not significantly different between the two obese strains, suggesting distinct utilization of energy intake. In the fed state, BALB/cJ ob/ob mice had elevated insulin and triglycerides levels, demonstrating a worsening effect on diabetes. At the reproductive level and in contrast to sterile C57BL/6J ob/ob mice, male and female BALB/cJ ob/ob mice were capable of reproducing after a mating period of 16 and 32 wk, respectively. At thermoneutrality, the body temperature of BALB/cJ ob/ob mice was 2.9 C higher than that of C57BL/6J ob/ob mice, whereas exposure of both groups to 4 C demonstrated a prolonged cold tolerance of BALB/cJ ob/ob mice. These studies show that the abnormalities caused by leptin deficiency can be genetically dissected and separated from each other, suggesting discrete pathways controlled by leptin modifier genes. Topics: Adipose Tissue; Animals; Blood; Body Temperature; Body Temperature Regulation; Body Weight; Diabetes Mellitus; Eating; Fertility; Hybridization, Genetic; Leptin; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Reference Values | 2001 |
Subcutaneous adipose tissue layers as a stable correlate of leptin in response to short term energy restriction in obese girls.
We studied the relationship of subcutaneous adipose tissue layers (SAT-layers) measured at 15 specified body sites with leptin before and after a weight loss program for three weeks.. In 70 obese girls, SAT-layers were measured by means of the optical device, lipometer. Fat mass (FM) was estimated by means of bioelectrical impedance.. At the beginning of the study, all estimates of adiposity, insulin, and SAT-layers from the upper body (from 1-neck to 6-lateral chest) were correlated to leptin at a P-value of<0.0001. Percentage FM together with SAT-layer 4-upper back and insulin explained 75% of the variation in leptin (P<0.0001). After three weeks, estimates of adiposity and leptin were reduced (all P<0.0001). Most SAT-layers were reduced, but SAT-layers 8-lower abdomen and 9-lower back were significantly increased. Changes in leptin were best explained by initial leptin, but percentage change (Delta) in insulin, Delta SAT-layer 1-neck, and Delta SAT-layer 3-biceps contributed to the Delta leptin (adj. r(2)=0.47, P<0.0001). In the weight-reduced state, circulating leptin was best explained by three SAT-layers and insulin (adj. r(2)=0.67, P<0.0001).. The results suggest that Delta changes in leptin are attributable to changes in the endocrine state and subcutaneous fat, and SAT-layers may serve as a stable correlate of leptin in the weight-reduced state. Topics: Adipose Tissue; Body Mass Index; Body Weight; Child; Diet, Reducing; Electric Impedance; Female; Humans; Insulin; Leptin; Obesity | 2001 |
Metabolic cues for puberty onset in free grazing Holstein heifers naturally infected with nematodes.
Leptin is a new plausible candidate for the molecular link between nutritional status and the reproductive axis. In previous studies we described that continuous natural nematode infections in heifers retarded growth and delayed the onset of puberty, and that the insulin-like growth factor I (IGF-I) was involved. In the present study we monitored the leptin levels during development in heifers naturally parasitized versus those chronically treated with ivermectin and we investigated whether growth hormone (GH) accounted for the differences in IGF-I previously noted. Insulin levels were also measured. Prolactin hormone was recorded as an indicator of immune system activation. We found a direct correlation between leptin and body weight during development and a prepubertal surge of the hormone 2 weeks before the first progesterone peak that indicates the onset of puberty. This suggests that leptin may act as a signal for this event. Insulin did not vary during growth and prepuberty. On the other hand, GH as not responsible for diminished IGF-I levels in parasitized animals as levels were similar in both groups. The GH levels were high at birth and then diminished rapidly and remained constant during development and puberty. The last hormone studied, prolactin, followed seasonal changes of sunlight duration and presented sporadic bursts in infected animals. These were related to high nematode infection and are probably involved in the immune response of the host. Topics: Animals; Antinematodal Agents; Body Weight; Cattle; Cattle Diseases; Feces; Female; Growth Hormone; Insulin; Insulin-Like Growth Factor I; Ivermectin; Leptin; Nematoda; Nematode Infections; Parasite Egg Count; Progesterone; Prolactin; Sexual Maturation | 2001 |
Synergy of sibutramine and low-dose leptin in treatment of diet-induced obesity in rats.
Tachyphylaxis to the effects of anorexigenic agents, such as sibutramine (S), may be due, in part, to counterregulatory decreases in energy expenditure (EE) and increases in hunger that result from reduced circulating leptin (L) due to loss of body fat and lowered L production/adipocyte. The present study was conducted to test the hypothesis that L administered at low doses sufficient to restore ambient L to preweight loss concentrations would enhance the intercurrent efficacy of S by reducing the strength of physiologic counterregulation to weight loss. Forty male Sprague-Dawley rats were fed a high-fat (HF) diet (45% energy) to induce obesity. After 8 weeks, the obese rats (600 +/- 58 g) were weight-matched into 4 groups (N = 8/group) and implanted subcutaneously (SC) with 2 mL, 7-day Alzet mini-pumps that provided: vehicle (V, saline), L (0.5 mg/kg/d), S (3 mg/kg/d), or L+S. Food intake (FI) on the HF diet was measured daily. On day 7, 24-hour EE was measured by indirect calorimetry, and the animals then killed for body composition analysis. Compared with vehicle, treatment with S alone, but not L alone, produced significant weight loss (-23 +/- 26 v -6 +/- 16 g, P <.01). L alone, or with S, increased fat oxidation (decreased respiratory quotient [RQ]) compared with V (P <.05). The lack of decline in EE with S may be due to its documented effect to stimulate thermogenesis. Administration of L with S synergistically decreased FI and increased weight loss and fractional fat loss. A reduction in plasma L concentration may contribute to the "plateau phenomenon" observed in studies of weight loss therapies. Replacement doses of L during S administration increased weight loss and fractional fat loss by (1) decreasing food intake and (2) by increasing fat oxidation. Such drug combinations may be useful in the treatment of human obesity. Topics: Animals; Body Composition; Body Weight; Cyclobutanes; Diet; Drug Synergism; Energy Intake; Energy Metabolism; Feeding Behavior; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley | 2001 |
Weight-related differences in glucose metabolism and free fatty acid production in two South African population groups.
The effects of free fatty acids (FFA), leptin, tumour necrosis factor (TNF) alpha and body fat distribution on in vivo oxidation of a glucose load were studied in two South African ethnic groups.. Anthropometric and various metabolic indices were measured at fasting and during a 7 h oral glucose tolerance test (OGTT). Body composition was measured using bioelectrical impedance analysis and subcutaneous and visceral fat mass was assessed using a five- and two-level CT-scan respectively. Glucose oxidation was evaluated by measuring the ratio of (13)CO(2) to (12)CO(2) in breath following ingestion of 1-(13)C-labelled glucose.. Ten lean black women (LBW), ten obese black women (OBW), nine lean white women (LWW) and nine obese white women (OWW) were investigated after an overnight fast.. Visceral fat levels were significantly higher (P<0.01) in obese white than black women, despite similar body mass indexes (BMIs). There were no ethnic differences in glucose oxidation however; in the lean subjects of both ethnic groups the area under the curve (AUC) was higher than in obese subjects (P<0.05 for both) and was found to correlate negatively with weight (r=-0.69, P<0.01) after correcting for age. Basal TNF alpha concentrations were similar in all groups. Percentage suppression of FFAs at 30 min of the OGTT was 24+/-12% in OWW and -38+/-23% (P<0.05) in OBW, ie the 30 min FFA level was higher than the fasting level in the latter group. AUC for FFAs during the late postprandial period (120--420 min) was significantly higher in OWW than OBW (P<0.01) and LWW (P<0.01) and correlated positively with visceral fat mass independent of age (r=0.78, P<0.05) in the OWW only. Leptin levels were higher (P<0.01) both at fasting and during the course of the OGTT in obese women from both ethnic groups compared to the lean women.. Glucose oxidation is reduced in obese subjects of both ethnic groups; inter- and intra-ethnic differences were observed in visceral fat mass and FFA production and it is possible that such differences may play a role in the differing prevalences of obesity-related disorders that have been reported in these two populations. Topics: Adipose Tissue; Adult; Area Under Curve; Black or African American; Black People; Body Composition; Body Weight; Breath Tests; Carbon Isotopes; Fasting; Fatty Acids, Nonesterified; Female; Glucose; Glucose Tolerance Test; Humans; Leptin; Obesity; South Africa; Tumor Necrosis Factor-alpha; White People | 2001 |
Dose-dependent effects of central leptin gene therapy on genes that regulate body weight and appetite in the hypothalamus.
We have examined the dose-dependent effects and central action of intraventricular administration of a recombinant adeno-associated virus encoding rat leptin (rAAV-leptin) in suppressing body weight (BW) gain in adult female rats. A low dose of rAAV-leptin (5x10(10) particles) suppressed weight gain (15%) without changing daily food intake (FI), but a twofold higher dose decreased BW by 30% along with a reduction in daily FI. Reduced BW was due to a loss in body adiposity because serum leptin was reduced. Serum insulin levels were decreased (96%) by only the high dose along with a slight reduction in glucose. Uncoupling protein-1 (UCP-1) mRNA expression in brown adipose tissue (BAT), reflecting energy expenditure through thermogenesis, was upregulated to the same magnitude by the two rAAV-leptin doses. We analyzed by in situ hybridization the expression in the hypothalamus of genes encoding the appetite-regulating neuropeptides. Only the high dose decreased expression of neuropeptide Y (NPY), the orexigenic peptide, and increased proopiomelanocortin (POMC), precursor of the an orexigenic peptide, alpha-MSH. Our studies show for the first time that increased availability of leptin within the hypothalamus through central leptin gene therapy dose-dependently decreases weight gain, adiposity, and serum insulin by increasing energy expenditure and decreasing FI. The decrease in FI occurs only when NPY is reduced and alpha-MSH is increased in the hypothalamus by the high dose of rAAV-leptin. Delivery of the leptin gene centrally through rAAV vectors is a viable therapeutic modality for long-term control of weight and metabolic hormones. Topics: Agouti-Related Protein; Animals; Appetite; Body Weight; Carrier Proteins; Dependovirus; Female; Genetic Therapy; Genetic Vectors; Hypothalamus; In Situ Hybridization; Insulin; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Membrane Proteins; Mitochondrial Proteins; Neuropeptide Y; Plasmids; Pro-Opiomelanocortin; Proteins; Rats; Rats, Sprague-Dawley; Uncoupling Protein 1 | 2001 |
Ontogenesis of leptin expression in different adipose tissue depots in the rat.
Serum leptin levels and leptin mRNA expression by adipose tissue increase with age and are mainly associated with an increase in adiposity. Regional changes in both leptin production and fat distribution contribute to circulating leptin levels and may play a role in the regulation of body weight. a capacity that changes during development. Here, we have studied leptin mRNA expression in four different white adipose tissue depots (epididymal, retroperitoneal, mesenteric, inguinal; namely, EWAT, RWAT, MWAT, IWAT) and in interscapular brown adipose tissue (IBAT). We have also studied their relationship with lipid content and adiposity changes, together with serum leptin levels in male rats at different ages (18, 55, 93, 159, 212, 294 and 355 days). Serum leptin levels increased during development, reaching stable levels at the age of 7 months, and, as expected, were highly correlated with both the adiposity index (r=0.908, P<0.01) and body weight (r=0.906, P<0.01). Leptin mRNA expression also increased with age, following characteristic ontogenic patterns in every adipose tissue depot. The patterns were similar in EWAT and RWAT: leptin expression increased very rapidly during the first 55 days for EWAT and 3 months for RWAT, with a peak in the latter at 7 months, and high expression levels were retained for the rest of the study period. In IWAT and IBAT, leptin expression increased steadily during the 12-month period studied and was significantly lower than levels in EWAT and RWAT. Leptin expression in MWAT increased progressively with age to reach levels close to those of EWAT and RWAT in 10-month-old animals. The pattern of leptin expression in both EWAT and RWAT paralleled their lipid content, and leptin mRNA expression per unit of tissue lipid content was maintained high and constant from a very young age (about 2 and 3 months, respectively). However, the expression of mRNA for leptin (expressed per unit of tissue lipid concentration) in MWAT, IWAT and IBAT increased steadily during the whole period studied, without attaining the maximal levels observed in EWAT and RWAT. MWAT, IWAT and IBAT maintained their capacity to increase leptin mRNA expression in response to an additional accumulation of lipids. Our data demonstrate that there are regional-specific differences and different rates of increase of leptin gene expression within distinct depots of WAT and BAT. These changes cannot be uniquely explained by changes in adiposity or lipid content, implying Topics: Adipose Tissue; Age Factors; Animals; Animals, Suckling; Body Weight; Gene Expression Regulation, Developmental; Leptin; Lipids; Male; Rats; Rats, Wistar; RNA, Messenger | 2001 |
[D-LEU-4]-OB3, a synthetic leptin agonist, improves hyperglycemic control in C57BL/6J ob/ob mice.
We have recently shown that the activity of a synthetic peptide corresponding to amino acid residues 116-130 of secreted mouse leptin is contained in a restricted sequence at the amino terminus of the peptide, between residues 116-122 (Ser-Cys-Ser-Leu-Pro-Gln-Thr, OB3). Substitution of the Leu residue at position 4 of OB3 with its D-isomer ([D-Leu-4]-OB3) enhanced the ability of OB3 (1 mg/day, ip, 7 days) to reduce body weight gain, food and water intake, and serum glucose in female C57BL/6J ob/ob mice. In the present study, we have utilized a pair-feeding approach to demonstrate that the antihyperglycemic action of [D-Leu-4]-OB3 is not solely due to its effects on caloric intake. One group of female C57BL/6J ob/ob mice (n=6) was fed ad libitum, and two additional groups (n=6 per group) were allowed 3.0 g food/mouse daily, an amount previously determined to satisfy [D-Leu-4]-OB3-treated mice. At the end of the 7-day test period, vehicle-injected mice fed ad libitum were approximately 10% heavier than their initial body weights, while pair-fed mice injected with vehicle and [D-Leu-4]-OB3-treated mice lost 5% of their initial body weights. After 1 day of treatment, blood glucose was reduced by 20% in pair-fed vehicle-injected mice, and by 40% in mice given [D-Leu-4]-OB3. Food restriction reduced blood glucose throughout the 7-day study, but not to levels seen in wild-type nonobese C57BL/6J mice of the same sex and age. After 2 days of treatment with [D-Leu-4]-OB3, however, blood glucose was reduced to levels comparable to those seen in wild-type nonobese mice. [D-Leu-4]-OB3 also lowered serum insulin levels by 53% when compared to mice fed ad libitum. Neither pair-feeding nor [D-Leu-4]-OB3 treatment had any apparent effect on thermogenesis. These results suggest that [D-Leu-4]-OB3 exerts its effects on serum glucose not only by suppressing caloric intake, but also through a separate effect on glucose metabolism which may involve increased tissue sensitivity to insulin. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drinking; Eating; Female; Hyperglycemia; Hypoglycemic Agents; Injections, Intraperitoneal; Insulin; Insulin Resistance; Leptin; Matched-Pair Analysis; Mice; Mice, Inbred C57BL; Mice, Obese; Peptide Fragments; Thermogenesis; Time Factors | 2001 |
Effect of short-term fasting on free and bound leptin concentrations in lean and obese women.
Plasma leptin exists in protein-bound and free forms, which may affect its hormonal bioactivity. Therefore, the relationship between bound and free leptin may be particularly important during physiological conditions that cause rapid alterations in total plasma leptin concentration, such as fasting. The purpose of this study was to evaluate the effect of short-term fasting on bound and free plasma leptin concentrations and leptin binding capacity (a measure of plasma leptin-binding protein content) in lean and obese women. Six lean (body mass index, 21 +/- 1 kg/m2) and 6 abdominally obese (BMI, 36 +/- 1 kg/m2) women were studied after 14 h and 22 h of fasting. Although total plasma leptin concentration was more than 6-fold greater in obese (45.4 +/- 7.6 microg/liter) compared with lean (7.4 +/- 1.0 microg/liter) women at 14 h of fasting (P < 0.05), the percentage of leptin in the bound form was greater in lean than obese subjects (29 +/- 2% vs. 12 +/- 3%; P < 0.05). Arterial total, free, and bound plasma leptin concentrations all declined between 14 h and 22 h of fasting in both lean and obese groups, but the relative decline of these fractions was greater in lean (36 +/- 4%, 60 +/- 9%, and 51 +/- 13%, respectively) than in obese (19 +/- 5%, 21 +/- 8%, and 12 +/- 7%, respectively) subjects (all P < 0.05). In contrast, leptin binding capacity was unchanged. The percentage of total plasma leptin present in bound form was constant between 14 h and 22 h of fasting in lean subjects and increased slightly but significantly in obese subjects. These data demonstrate that both free and bound fractions of leptin in plasma decrease quickly in response to energy restriction, but the decline is blunted in abdominally obese compared with lean women. In addition, the equilibrium between bound and free leptin fractions is maintained during brief fasting and is not regulated by leptin binding capacity. Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Body Weight; Fasting; Female; Humans; Leptin; Obesity; Radial Artery; Radioimmunoassay; Reference Values; Regression Analysis; Thinness; Veins | 2001 |
Seasonal changes in serum leptin, food intake, and body weight in photoentrained woodchucks.
Male woodchucks (Marmota monax) were maintained in northern vs. southern hemisphere photoperiods, provided feed and water ad libitum, and evaluated every 2 wk for 23 mo for body weight, absolute and relative food intake, body temperature, serum testosterone, and serum concentrations of leptin measured using an anti-mouse leptin enzyme-linked immunoassay. During late spring and summer, body weight increased 56 +/- 4% above winter nadirs, and during the autumn and early winter weights decreased 27 to 43% below midsummer maxima. Serum leptin initially increased during increases in body weight, in the late spring, reached peak values (490 +/- 32 pg/ml) in summer during the initial decline in body weight, and later decreased along with body weight to reach basal values (20 +/- 5 pg/ml) in late winter. Spontaneous declines in food intakes in summer began 2-6 wk before resulting declines in body weight and occurred during increases in leptin >100 pg/ml. The rate of decline in food intakes was greatest when serum leptin was at or near peak values. Food intake increased in late winter when leptin was low and 7-10 wk before resulting increases in body weight. Testis recrudescence occurred when leptin was declining to near basal levels. The results suggest that leptin is involved in the hormonal regulation of the circannual cycle in the drive for voluntary food intake in this species. Topics: Animals; Body Temperature; Body Weight; Eating; Energy Metabolism; Leptin; Male; Marmota; Photoperiod; Seasons; Testosterone | 2001 |
Opposite regulation of hypothalamic orexin and neuropeptide Y receptors and peptide expressions in obese Zucker rats.
Many hyothalamic neuropeptides are involved in the regulation of food intake and body weight. The orexins (OX) which are synthesized in the lateral hypothalamus are among the most recently characterized whereas neuropeptide Y (NPY) belongs to a group of "older" peptides extensively studied for their effects on feeding behavior. Both stimulate food ingestion in rodents. In this experiment, we measured the expressions of these peptides as well as of their receptors (OX1-R and OX2-R, Y1 and Y5) in the hypothalamus of obese hyperphagic and lean Zucker rats by real-time RT-PCR using the TaqMan apparatus. NPY mRNA expression in the obese rats was significantly increased by a factor of 10 (P < 0.002) whereas expressions of the Y1 and Y5 receptors were decreased by 25% (P < 0.01) and 50% (P < 0.002), respectively. Their prepro-orexin mRNA expression was more than twofold decreased (P < 0.01) and expressions of their OX receptors 1 and 2 mRNA were five- and fourfold increased (P < 0.05), respectively. An inverse phenomenon was therefore noted between the two peptides: for NPY, increased levels and downregulation of receptors; and for OX, diminished levels with upregulation of receptors. The reasons for these changes might be linked to the absence of leptin signaling as similar profiles are found in the ob/ob mice. For orexins at least, other factors such as hyperglycemia might be involved. Based on anatomical considerations, a direct effect of NPY or of other brain peptides such as CRH cannot be excluded. We conclude that the diminution in the OX tone might participate in a counterregulatory system necessary to limit the noxious effects of NPY on food intake and body weight. Topics: Animals; Body Weight; Carrier Proteins; Eating; Hypothalamus; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Neuropeptides; Obesity; Orexin Receptors; Orexins; Peptides; Protein Precursors; Rats; Rats, Zucker; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Receptors, Neuropeptide Y; RNA, Messenger | 2001 |
The age-related differences in obese and fatty acid synthase gene expression in white adipose tissue of rat.
To determine if the age-dependent increase of adiposity is directly related to altered obese (ob) and fatty acid synthase (FAS) gene expression, we assessed an adiposity index, leptin and FAS mRNA levels, FAS activity in perirenal adipose tissue and serum leptin concentration in rats aged 1, 2, 3, 6 and 20 months. The results indicate that there are two distinct phases of changes in perirenal white adipose tissue leptin mRNA level and serum leptin concentration. The first phase, between 1 and 3 months of the animals' lives, was characterized by a strong positive correlation between adiposity index and leptin mRNA level as well as serum leptin concentration. In the second phase (over 3 months) no significant changes of leptin mRNA and serum concentration occurred. A close correlation between the age-induced increase of leptin mRNA abundance and serum leptin concentration and the age-induced suppression of FAS gene expression in the same tissue was observed. This suggests that the changes of FAS gene expression occur in response to serum leptin concentration and that in mature rats the high level of ob gene expression and consequently the high leptin concentration protect the white adipose tissue cells against fat overload by two independent mechanisms: (a) preventing an increase of food intake through the leptin action on the hypothalamus; (b) inhibiting FAS gene expression and consequently decreasing the rate of lipogenesis. Topics: Adipose Tissue; Age Factors; Animals; Body Weight; Fatty Acid Synthases; Gene Expression Regulation, Enzymologic; Leptin; Male; Obesity; Rats; Rats, Wistar; RNA, Messenger | 2001 |
[Leptin: factor in the central nervous system regulation of bone mass. Development of a new understanding of bone remodeling, skeletal reconstruction, skeletal preservation and skeletal repair].
Bone remodeling is the physiologic process used by vertebrates to maintain a constant bone mass between the end of puberty and gonadal failure. Besides the well-characterized and critical local regulation of bone remodeling, recent genetic studies have shown that there is a central control of bone formation, one aspect of bone remodeling. This central regulation involves leptin, an adipocyte-secreted hormone that controls body weight, reproduction, and bone remodeling following binding to its receptor located on the hypothalamic nuclei. This genetic result in rodents is in line with clinical observations in humans and offers a whole new direction for research in bone physiology. Topics: Adolescent; Adult; Age Factors; Animals; Body Weight; Bone and Bones; Bone Density; Bone Development; Bone Remodeling; Carrier Proteins; Female; Fractures, Bone; Humans; Hypothalamus; Leptin; Mice; Middle Aged; Osteoporosis; Rats; Receptors, Cell Surface; Receptors, Leptin; Research; Risk Factors | 2001 |
Dexamethasone during late gestation exacerbates peripheral insulin resistance and selectively targets glucose-sensitive functions in beta cell and liver.
We examined whether low-dose dexamethasone administration during late pregnancy modifies hepatic and/or peripheral insulin action or glucose-stimulated insulin secretion. Dexamethasone (100 microg/kg maternal body weight/d) was administered via an osmotic minipump from d 14--19 of gestation. Maternal glucose-insulin homeostasis was assessed on d 19 of pregnancy in the postabsorptive state. Insulin secretion and glucose tolerance was assessed after iv glucose, and insulin action examined during insulin infusion at euglycemia. Dexamethasone treatment during late pregnancy elicited fasting hyperinsulinaemia (by 88%; P < 0.001) and hyperglycaemia (by 20%; P < 0.05), and enhanced endogenous glucose production (by 29%; P < 0.001). Insulin secretion and rates of glucose disappearance after iv glucose were greatly impaired (by 44% and 39% respectively; P < 0.05). Suppression of endogenous glucose production by insulin was enhanced by dexamethasone treatment, but insulin's ability to promote glucose clearance was diminished. We demonstrate that excess maternal glucocorticoids during late pregnancy impairs glucose-stimulated insulin secretion and insulin-simulated glucose clearance but enhances insulin's ability to suppress endogenous glucose production. The data also indicate that elevated maternal glucocorticoids impair adaptations of the endocrine pancreas to pregnancy in vivo in that insulin hypersecretion in response to deteriorating peripheral insulin action is no longer apparent, leading to impaired glucose tolerance. Topics: Animals; Body Weight; Dexamethasone; Eating; Female; Glucocorticoids; Glucose; Hyperglycemia; Hyperinsulinism; Injections, Intravenous; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Liver; Postprandial Period; Pregnancy; Pregnancy Complications; Pregnancy, Animal; Rats; Rats, Wistar | 2001 |
Fasting, leptin treatment, and glucose administration differentially regulate Y(1) receptor gene expression in the hypothalamus of transgenic mice.
NPY is a potent orexigenic signal and represents a key component of targets through which leptin exerts a regulatory restraint on body adiposity. Part of the orexigenic effects of NPY are mediated by hypothalamic NPY-Y(1) receptors. Here we studied the effect of fasting, leptin, and glucose administration on Y(1) receptor gene expression using a transgenic mouse model carrying a mouse Y(1) receptor/LacZ fusion gene. Transgene expression was determined by quantitative analysis of beta-galactosidase histochemical staining in the paraventricular, arcuate, ventromedial, and dorsomedial hypothalamic nuclei and in the medial amygdala, as a control region. Food deprivation for 72 h decreased transgene expression in the paraventricular nucleus but not in the arcuate nucleus. Leptin treatment, that was per se ineffective, counteracted the decrease of transgene expression induced in the paraventricular nucleus by 72 h fasting. Supplementing the drinking water with 10% glucose increased beta-galactosidase expression both in the paraventricular nucleus and arcuate nucleus of control mice. Finally, none of the treatments altered transgene expression in the dorsomedial hyphothalamic, ventromedial, and amygdaloid nuclei. Results suggest that changes in energetic balance affect Y(1) receptor expression in the paraventricular and arcuate nuclei and that leptin regulates the NPY-Y(1) system in the paraventricular nucleus. Different regulatory signals might modulate the NPY-Y(1) transmission in the dorsomedial hyphothalamic and ventromedial hyphothalamic nuclei. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Drinking; Fasting; Gene Expression; Glucose; Hypothalamus; Lac Operon; Leptin; Mice; Mice, Transgenic; Receptors, Leptin; Receptors, Neuropeptide Y; Solutions; Transgenes | 2001 |
Do baseline serum leptin levels predict weight regain after dieting in obese women?
Weight loss achieved during weight reduction programme is difficult to maintain. We investigated the possible role of circulating leptin in failure or success in maintaining weight loss.. Serum leptin levels were measured in 30 healthy premenopausal obese women before and after 12 weeks of dietary intervention and after 5 months of follow-up.. After intervention body mass index (BMI) decreased from 30.6 to 25.4 kg/m2 (p < 0.01) and leptin levels decreased from 16.7 to 7.7 ng/ml (p < 0.01). After 5 months follow-up 12 women regained reduced weight and 18 women maintained weight loss. In the regainers leptin levels increased again, but remained low in the maintainers. Baseline leptin concentrations were lower in the regainers than in the maintainers (12.1 vs. 21.2 ng/ml, p = 0.04). During intervention leptin levels decreased three times more in the maintainers than in the regainers, although weight loss was similar in both groups.. This study shows that obese women who regain weight after dieting have significantly lower baseline leptin levels than women who maintain weight loss. Our results suggest that differences in leptin resistance might exist in similarly obese women which could influence the success of dieting. Topics: Adult; Biomarkers; Body Mass Index; Body Weight; Diet, Reducing; Female; Follow-Up Studies; Humans; Leptin; Middle Aged; Obesity; Predictive Value of Tests; Premenopause; Weight Gain; Weight Loss | 2001 |
Amifostine protects against early but not late toxic effects of doxorubicin in infant rats.
The improved prognosis and increased expected lifetime among long-term survivors of childhood malignancies have made these patients especially sensitiveto the late toxicity of cancer therapy and prone to secondary malignancies. Recently, new strategies aiming to protect against cancer treatment toxicity have been developed, including the drug amifostine (Ethyol), which is suggested to protect normal tissues from the toxic effects of radiation and cytotoxic agents. In the present study, the possible protective effect of amifostine against toxicity induced by a single injection of doxorubicin (3 mg/kg) in immature rats was evaluated. Specifically, we evaluated the protection against long-term toxicity and the effects of amifostine on growing immature tissues. Amifostine (50-200 mg/kg) given 15 min before doxorubicin had a significant protective effect against doxorubicin-induced early alopecia in young rats. Significant protection against cataract formation was obtained by the use of low-dose amifostine (50 mg/kg). However, amifostine did not protect young rats against the late toxic effect of doxoubicin on linear growth, body weight, plasma leptin levels, and heart or testicular tissue. Worrisome, and in contrast to earlier studies in adult rats, an increased doxorubicin toxicity actually was observed and mortality was increased when the higher doses of amifostine (100-200 mg/kg) were used. The present results suggest that more data from growing immature animal models are needed to analyze the safety of amifostine treatment and its mechanisms of action before wider clinical use of this drug in pediatric cancer patients is recommended. Topics: Age Factors; Alopecia; Amifostine; Animals; Animals, Suckling; Antibiotics, Antineoplastic; Body Weight; Cardiomyopathies; Cataract; Dose-Response Relationship, Drug; Doxorubicin; Female; Heart; Leptin; Male; Myocardium; Rats; Rats, Sprague-Dawley; Testicular Diseases; Testis; Testosterone | 2001 |
Effects of ultrapure dialysis fluid on nutritional status and inflammatory parameters.
Malnutrition and chronic systemic inflammatory response syndrome not only coexist in uraemia, but may also have a bi-directional cause-and-effect relationship. To evaluate the role of dialysate-related cytokine induction in inflammatory response and nutritional status, we conducted a prospective comparison of two dialysis fluids differing in their microbiological quality.. Forty-eight early haemodialysis patients were assigned to either treatment with conventional (potentially microbiologically contaminated) or on-line produced ultrapure dialysis fluid. Study parameters were bacterial growth, markers of systemic inflammation (C-reactive protein (CRP) and interleukin 6), and parameters of nutritional status (estimated dry weight, upper mid-arm muscle circumference, serum albumin concentration, insulin-like growth factor 1, leptin, and protein catabolic rate). Patients were followed for 12 months.. There were no statistically significant differences in demographic and treatment characteristics, degree of bacterial contamination of the dialysate, markers of systemic inflammation, or parameters of nutritional status among the two treatment groups at recruitment. Changing from conventional to ultrapure dialysis fluid reduced significantly the levels of IL-6 (19+/-3 pg/ml to 13+/-3 pg/ml) and CRP (1.0+/- 0.4 mg/dl to 0.5+/-0.2 mg/dl), and resulted in significant increases in estimated dry body weight, mid-arm muscle circumference, serum albumin concentration, levels of the humoral factors, and in protein catabolic rate after 12 months. Continuous use of conventional dialysis fluid (median 40-60 c.f.u./ml) was not associated with significant alterations in markers of inflammation (IL-6 21+/-4 pg/ml vs 24+/-6 pg/ml, CRP 0.9+/-0.3 mg/dl vs 1.1+/-0.4 mg/dl) or of nutritional status at any time of the study. All differences in systemic inflammation and nutritional parameters observed during the study period (from recruitment to month 12) were significant between the two patient groups.. Cytokine induction by microbiologically contaminated dialysis fluid has a negative impact on nutritional parameters of early haemodialysis patients. The microbiological quality of the dialysis fluid represents an independent determinant of the nutritional status in addition to known factors, such as dose of dialysis and biocompatibility of the dialyser membrane. Ultrapure dialysis fluid adds to the cost of the dialytic treatment, but may improve the nutritional status in long-term haemodialysis patients. Topics: Aged; Body Weight; C-Reactive Protein; Dialysis Solutions; Drug Contamination; Female; Humans; Inflammation; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Male; Middle Aged; Muscle, Skeletal; Nutritional Status; Prospective Studies; Serum Albumin | 2001 |
Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(-/-) mouse liver.
Insulin receptor substrate (IRS)-2(-/-) mice develop diabetes because of insulin resistance in the liver and failure to undergo beta-cell hyperplasia. Here we show by DNA chip microarray analysis that expression of the sterol regulatory element-binding protein (SREBP)-1 gene, a downstream target of insulin, was paradoxically increased in 16-week-old IRS-2(-/-) mouse liver, where insulin-mediated intracellular signaling events were substantially attenuated. The expression of SREBP-1 downstream genes, such as the spot 14, ATP citrate-lyase, and fatty acid synthase genes, was also increased. Increased liver triglyceride content in IRS-2(-/-) mice assures the physiological importance of SREBP-1 gene induction. IRS-2(-/-) mice showed leptin resistance; low dose leptin administration, enough to reduce food intake and body weight in wild-type mice, failed to do so in IRS-2(-/-) mice. Interestingly, high dose leptin administration reduced SREBP-1 expression in IRS-2(-/-) mouse liver. Thus, IRS-2 gene disruption results in leptin resistance, causing an SREBP-1 gene induction, obesity, fatty liver, and diabetes. Topics: Age Factors; Animals; ATP Citrate (pro-S)-Lyase; Blotting, Northern; Body Weight; CCAAT-Enhancer-Binding Proteins; Crosses, Genetic; DNA-Binding Proteins; DNA, Complementary; Fatty Acid Synthases; Glucose; Heterozygote; Insulin Receptor Substrate Proteins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Leptin; Liver; Male; Mice; Mice, Transgenic; Oligonucleotide Array Sequence Analysis; Phosphoproteins; Sterol Regulatory Element Binding Protein 1; Time Factors; Transcription Factors; Triglycerides | 2001 |
Serum leptin levels in wild and captive populations of baboons (papio): implications for the ancestral role of leptin.
Leptin has emerged as the major lipostat, regulating adiposity by affecting feeding behavior and thermogenesis. Leptin levels in normal-weight Western humans and in captive rodents are 5-15 ng/ml. But evidence suggests that these levels are abnormally high and that leptin may have evolved as a more general metabolic signal, with its most robust effects at lower levels. If this is true, then wild, healthy animal populations should have lower levels of leptin than captive populations and Western Man. We examined leptin levels in wild, East African populations of baboons (Papio anubis, P. hamadryas, and anubis/hamadryas hybrids). Serum leptin levels averaged less than 1 ng/ml, and no differences occurred in leptin levels among the species. In wild baboons, serum leptin levels were highest in the youngest baboons, with a trend toward an inverse relation between dental age and serum leptin levels. In comparison, captive baboons had levels about three times higher than wild baboons, with a clear inverse relation between age and leptin levels. These results support the view that leptin evolved to be effective at low levels. Topics: Aging; Animals; Body Weight; Female; Leptin; Male; Papio; Quality Control; Species Specificity | 2001 |
The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability.
Genetic variation at the leptin receptor gene locus may play an important role in the pathophysiology of human obesity, a leptin-resistant state. Previous studies exploring potential associations between leptin receptor gene polymorphisms and obesity have reported conflicting results. The aim of this study was to evaluate a genetically homogeneous population for associations between body composition variables and three common leptin receptor gene polymorphisms (K109R, Q223R, and K656N) that have potential functional significance as well as to assess the contributions of these polymorphisms to the variability of obesity. One hundred and eighteen consecutively enrolled subjects (62 women: mean age, 17.5 +/- 1.6 yr; body mass index range, 16.2-30.1; 56 men: mean age, 17.8 +/- 1.8 yr; body mass index range, 15.4-35.9) were genotyped for the three polymorphisms, and their body mass index, sum of 4 skinfolds, fat-free mass, percent fat mass, serum leptin levels, caloric intake, fat intake, and exercise patterns were determined. Allele frequencies were estimated by the gene-counting method, and genotype distributions between 89 normal weight (body mass index, < or =25 kg/m(2)) and 29 overweight-obese (body mass index, >25 kg/m(2)) subjects were compared using chi(2) test (using codominant, dominant, and recessive models). Analysis of covariance was also performed to evaluate associations between the polymorphisms and body composition variables after controlling for potential confounders. For the Q223R polymorphism, there was a higher prevalence of the R223 allele in the homozygous form among overweight-obese subjects vs. normal weight subjects (20.7% vs. 4.5%; P = 0.01). Furthermore, simple and multiple regression analyses revealed that the R223 allele in the homozygous form is a significant predictor of both body mass index (P = 0.015) and percent fat mass (P = 0.02) even after adjusting for age and gender and explains 4.5% of the variance in percent fat mass and 5% of the variance in body mass index. There was no significant difference in allele frequencies or genotype distributions for the K109R or K656N polymorphisms. These findings support the hypothesis that the Q223R polymorphism (but not the K109R or K656N polymorphism) of the leptin receptor gene is associated with obesity and predicts a small percentage of body weight and body composition variability in a genetically homogeneous population. Topics: Adolescent; Adult; Aging; Body Composition; Body Weight; Carrier Proteins; DNA; Exons; Female; Gene Frequency; Genotype; Humans; Leptin; Male; Obesity; Polymorphism, Genetic; Receptors, Cell Surface; Receptors, Leptin; Sex Characteristics | 2001 |
Lipid deposition in rats centrally infused with leptin in the presence or absence of corticosterone.
The aim of the present study was to assess whether the glucocorticoid corticosterone (Cort) modulates the effects of leptin on food intake and lipid deposition. Rats were subjected to a 6-day intracerebroventricular infusion of leptin and were either sham-adrenalectomized (Sham-ADX) or ADX and supplemented with 0 (C0), 40 (C40), or 80 mg (C80) of Cort. Investigation of potential peripheral sites of interaction of leptin and Cort included liver and plasma triglyceride (TG) content and lipoprotein lipase (LPL) activity in adipose and muscle tissues. The study confirmed the respective anorectic and orexigenic effects of leptin and Cort and revealed that the leptin-induced reduction in food intake was dampened by the high dose of Cort replacement. Such an interaction did not, however, extend to body and adipose tissue weights, which were lowered by leptin infusion independently of the Cort status. Leptin and ADX significantly reduced liver TG content and triglyceridemia, whereas Cort replacement significantly increased these variables. Central infusion of leptin also lowered plasma insulin levels, accompanied by a reduction in LPL activity of storage tissues (inguinal and epididymal white adipose tissue, 2- and 3-fold, respectively). In contrast, leptin infusion increased LPL activity in oxidative tissues (soleus and vastus lateralis muscles, 3- and 4-fold, respectively). Cort replacement prevented the ADX-induced fall in epididymal LPL activity but failed to do so in leptin-infused rats. The study demonstrates that, whereas the anorectic effect of leptin is dampened by high but physiological plasma levels of corticosterone, leptin can produce its effects on body weight, lipid transport and accumulation, and adipose and muscle LPL activity in the absence or presence of an intact hypothalamic-pituitary-adrenal axis. Topics: Adipose Tissue; Adrenalectomy; Analysis of Variance; Animals; Blood Glucose; Body Weight; Cerebral Ventricles; Corticosterone; Dose-Response Relationship, Drug; Energy Intake; Factor Analysis, Statistical; Infusions, Parenteral; Insulin; Leptin; Lipid Metabolism; Lipoprotein Lipase; Male; Muscle, Skeletal; Organ Size; Rats; Rats, Sprague-Dawley; Triglycerides | 2001 |
Dexamethasone treatment induces long-lasting hyperleptinemia and anorexia in old rats.
Aging brings poor adaptation to stress, the causes of which remain unclear. We previously reported impairment of nitrogen metabolism in glucocorticoid-treated old rats due to profound anorexia. Here we investigated whether leptin, a satiety hormone, was implicated in impaired adaptation to stress. Plasma glucose and insulin levels, which are known to modulate leptin secretion, were also studied. Adult (3 months, n = 18) and aged (24 months, n = 18) rats were treated with dexamethasone (DEX) (1.5 mg/kg/d, intraperitoneal [IP] injection) for 3, 5, and 7 days. Results were compared with ad libitum (n = 12) and pair-fed groups, receiving intraperitoneal saline injection, for each age (n = 6 per group). Transitory anorexia was observed in adult rats (day 3 to day 5), whereas anorexia persisted in aged rats until day 7. This anorexia was associated (r = -.65, P <.05) with an elevated constant hyperleptinemia. In contrast, hyperleptinemia was moderate and reverted rapidly to basal values by day 5 in adult rats. The time course of plasma insulin and glucose levels was similar in old and adult rats, except for marked hyperglycemia noted in aged animals. In old stressed rats, DEX treatment induces an anorexia, which is concomitant to an increase in serum leptin levels. Thus, leptin may be implicated in the poor adaptation to stress of aged compared with adult rats. Topics: Aging; Animals; Anorexia; Blood Glucose; Body Weight; Dexamethasone; Disease Models, Animal; Eating; Insulin; Leptin; Male; Metabolic Diseases; Rats; Rats, Sprague-Dawley; Stress, Physiological | 2001 |
Effects of vagal and splanchnic section on food intake, weight, serum leptin and hypothalamic neuropeptide Y in rat.
Truncal vagotomy can cause reduced food intake and weight loss in humans and laboratory animals. In order to investigate some of the factors that might contribute to this effect, we studied changes in ingestive behaviour, whole body and organ weights, serum leptin and hypothalamic neuropeptide Y in rats with bilateral vagal section, bilateral splanchnic nerve section and combined vagotomy plus splanchnectomy. Pyloromyotomy was combined with vagotomy to lessen effects of vagotomy on gastric emptying. Animals with vagotomy or vagotomy plus splanchnectomy lost weight and decreased their daily food intake relative to animals with splanchnectomy alone, rats with bilateral sham exposure of one or both nerve, or rats with pyloromyotomy alone. Serum leptin and white fat mass, 4 weeks after vagotomy, were about 20% of the values in the sham-operated animals at this time. No effect for splanchnic nerve section alone was observed. Pyloromyotomy caused no reduction in weight or fat mass, but reduced serum leptin. Following vagotomy with or without splanchnic nerve section, neuropeptide Y was elevated in the arcuate nucleus relative to values for the other four groups. Changes in neuropeptide Y were inversely correlated with levels of serum leptin. It is concluded that the effect of vagotomy could be due to the loss of a feeding signal carried by vagal afferent neurons, or to changed humoral signals, for example, increased production of a satiety hormone. However, it cannot be attributed to signals that reduce feeding (for example, gastric distension) reaching the central nervous system via the splanchnic nerves. The changes were sufficient to cause weight loss even though serum leptin was decreased, a change that would be expected to increase food intake. Topics: Adipose Tissue; Animals; Body Weight; Calcitonin Gene-Related Peptide; Eating; Female; Hypothalamus; Immunohistochemistry; Leptin; Myenteric Plexus; Nerve Fibers; Neuropeptide Y; Organ Size; Rats; Rats, Sprague-Dawley; Satiety Response; Splanchnic Nerves; Vagotomy; Vagus Nerve | 2001 |
Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity.
Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated in the light/dark exploration test. They also had mature onset obesity characterized by a dramatic 80-150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor for alpha-MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state. Topics: Animals; Anxiety; Body Weight; Brain; Brain-Derived Neurotrophic Factor; Fasting; Fluoxetine; Gene Deletion; Gene Expression; Hyperglycemia; Hyperinsulinism; Hyperkinesis; Hypothalamus; Integrases; Leptin; Mice; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger; Selective Serotonin Reuptake Inhibitors; Serotonin; Transfection; Viral Proteins | 2001 |
Maternal glucocorticoid treatment modulates placental leptin and leptin receptor expression and materno-fetal leptin physiology during late pregnancy, and elicits hypertension associated with hyperleptinaemia in the early-growth-retarded adult offspring.
Leptin concentrations are increased during late pregnancy, and leptin receptors are expressed in placental and fetal tissues, suggesting a role for leptin in placental and/or fetal growth, or both. In humans, leptin concentrations in adulthood are inversely related to body weight at birth, independent of adult adiposity, and correlate with fasting insulin. Glucocorticoids and insulin regulate leptin secretion. Excessive exposure to glucocorticoids during late fetal development in the rat causes intrauterine growth retardation (IUGR), together with hypertension and hyperinsulinaemia in adulthood. Leptin may have a role in the development of some forms of hypertension.. To determine whether IUGR induced by maternal glucocorticoid treatment during the last third of pregnancy in the rat is associated with modulation of either maternal or fetal leptin concentrations, the placental expression of leptin or the short form of the leptin receptor (ObR-S), or combinations thereof, and to evaluate whether hypertension or hyperinsulinaemia in the early-growth-retarded adult progeny of dexamethasone-treated dams is associated with altered leptin concentrations.. Dexamethasone was administered to pregnant rats from day 15 to day 21 of gestation via a chronically implanted subcutaneous osmotic minipump. Protein expression of leptin and ObR-S in the placenta at day 21 of pregnancy was measured by western blotting. Plasma leptin and insulin concentrations were determined by radioimmunoassay and ELISA respectively. Systolic hypertension was measured by tail cuff plethysmography.. Dexamethasone administration during the last third of pregnancy decreased placental mass and fetal body weight at day 21 of gestation, caused maternal hyperleptinaemia but fetal hypoleptinaemia, and suppressed placental leptin protein expression whilst up-regulating placental protein expression of ObR-S. The male and female offspring of dexamethasone-treated dams were hypertensive from 12 weeks of age. One-year-old offspring of dexamethasone-treated dams exhibited significant hyperleptinaemia compared with age-matched controls, an effect associated with hyperinsulinaemia in the male, but not female, offspring.. The rat model of maternal dexamethasone treatment is established as a paradigm of 'programmed' hypertension in man. Our data show modification of placental leptin and leptin receptor protein expression by dexamethasone treatment during the last third of pregnancy. We also show that leptin concentrations are suppressed during fetal life but increased in adulthood in this rat model of programmed hypertension. Our data do not necessarily establish a causal relationship between fetal hypoleptinaemia and impaired fetal growth during early life, or between hyperleptinaemia and hypertension in adulthood. Nevertheless, they suggest that hyperleptinaemia may be a component of the cluster of metabolic abnormalities seen in the insulin resistance syndrome in man. They also suggest that excessive fetal exposure to glucocorticoids could be a common early-life stimulus to the association between hyperinsulinaemia, hypertension and hyperleptinaemia often seen in individuals of low birthweight. Topics: Animals; Body Weight; Carrier Proteins; Dexamethasone; Dose-Response Relationship, Drug; Eating; Embryonic and Fetal Development; Female; Fetal Growth Retardation; Fetus; Glucocorticoids; Hypertension; Insulin; Leptin; Male; Organ Size; Placenta; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Time Factors | 2001 |
Effect of exercise training on serum leptin levels in type 2 diabetic patients.
To evaluate the effect of exercise training on serum leptin levels 50 sedentary subjects with type 2 diabetes were enrolled in either 6 weeks of aerobic exercise training with diet therapy (n = 23) or diet therapy alone (n = 27). The training program consisted of walking and cycle ergometer exercise for 1 hour at least 5 times per week, with the intensity of exercise maintained at 50% of maximum oxygen uptake. Serum leptin levels decreased significantly in the exercise training (TR) group (7.2 +/- 3.6 to 4.6 +/- 2.5 ng/mL, P <.05), but not in the sedentary (SED) group (6.9 +/- 3.4 to 5.6 +/- 2.9 ng/mL). Leptin levels standardized for percentage body fat (dividing serum leptin level by percentage body fat) after treatment were lower in the TR subjects compared with the SED subjects. Body weight and percentage body fat decreased in all patients; however, no significant changes were observed in either group. Fasting concentrations of plasma insulin and cortisol and the urinary excretion of 17-hydroxycorticosteroid (17-OHCS) did not differ between the groups either before or after treatment. Fasting plasma glucose and hemoglobin A(1c) (HbA(1c)) improved significantly in both groups, although no significant differences were observed between the groups either before or after treatment. Ventilatory threshold increased significantly in the exercise training subjects. This study demonstrates that exercise training in type 2 diabetic subjects reduces serum leptin levels independent of changes in body fat mass, insulin, or glucocorticoids. Topics: 17-Hydroxycorticosteroids; Adipose Tissue; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Energy Metabolism; Exercise; Exercise Therapy; Fasting; Female; Humans; Hydrocortisone; Insulin; Leptin; Male; Time Factors | 2001 |
Hyperoxia increases leptin production: a mechanism mediated through endogenous elevation of corticosterone.
Leptin, a cytokine involved in the regulation of food intake, has been reported to be decreased in lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis and increased in critically ill patients with sepsis. We investigated the role of leptin during hyperoxia in mice, which results in alveolar edema, severe weight loss, and death within 3-4 days. In oxygen-breathing mice, serum leptin was increased six- to sevenfold and its mRNA was upregulated in white adipose tissue. Leptin elevation could not be attributed to changes in circulating tumor necrosis factor-alpha but was completely dependent on endogenous corticosterone elevation because adrenalectomized mice did not exhibit any increase in leptin levels. Using leptin-deficient mice and wild-type mice treated with anti-leptin antibody, we demonstrate that weight loss was leptin independent. Lung damage was moderately attenuated in leptin-deficient mice but was not modified by anti-leptin antibody or leptin administration, suggesting that leptin does not play an essential role in the direct and short-term effects of oxygen-induced injury. Topics: Adipose Tissue; Animals; Body Weight; Corticosterone; DNA Fragmentation; Female; Hyperoxia; Immunoglobulin G; Interleukin-6; Leptin; Lung; Mice; Mice, Inbred C57BL; Mice, Obese; Organ Size; Oxygen; RNA, Messenger; Tumor Necrosis Factor-alpha | 2001 |
High fat diet enhances colonic cell proliferation and carcinogenesis in rats by elevating serum leptin.
We postulated that high fat diet enhances colon cell proliferation and carcinogenesis by elevating serum leptin. To examine this possibility, the present study was conducted to investigate the effect of leptin on the growth of human colon cancer cells (HT29) and the relationship between serum leptin and colon cell proliferation and aberrant crypt foci (ACF) in the 1,2-dimethylhydrazine-treated rats fed graded levels of dietary fat for 28 days. In cell culture experiments, leptin stimulated the growth and proliferation (BrdU incorporation) of colon cancer cells and the expression of c-fos protein. In the in vivo experiments, an elevation of dietary fat caused higher serum leptin and adipose-tissue weight. Colonic cell proliferation (BrdU incorporation), c-fos protein expression and ACF were elevated with increasing dietary fat. There was a significant correlation between serum concentration of leptin and colon cell proliferation and ACF. The results suggest that the enhancement of colon cell proliferation and carcinogenesis by high fat diet is mediated through elevating serum leptin. Topics: 1,2-Dimethylhydrazine; Adipose Tissue; Animals; Body Weight; Bromodeoxyuridine; Carcinogens; Cell Division; Colonic Neoplasms; Dietary Fats; DNA, Neoplasm; Leptin; Male; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Tumor Cells, Cultured | 2001 |
Histamine H1 receptors mediate the anorectic action of the pancreatic hormone amylin.
We investigated the role of histamine H1 receptors in mediating the anorectic effect of intraperitoneally injected amylin (5 and 20 microg/kg), the amylin agonist salmon calcitonin (sCT; 10 microg/kg), leptin (1.3 mg/kg), and cholecystokinin (CCK; 20 microg/kg). The experiments were performed with mice lacking functional H1 receptors (H1Rko) and wild-type (WT) controls. The mice were also injected with the H3 antagonist thioperamide (20 mg/kg), which reduces feeding by enhancing the release of endogenous histamine through presynaptic H3 receptors. The feeding-suppressive effect of thioperamide was abolished in H1Rko mice. The anorectic effects of amylin and sCT were significantly reduced in 12-h food-deprived H1Rko mice compared with WT mice [1-h food intake: WT-NaCl 0.51 +/- 0.05 g vs. WT-amylin (5 microg/kg) 0.30 +/- 0.06 g (P < 0.01); H1Rko-NaCl 0.45 +/- 0.05 g vs. H1Rko-amylin 0.40 +/- 0.04 g; WT-NaCl 0.40 +/- 0.09 g vs. WT-sCT (10 microg/kg) 0.14 +/- 0.10 g (P < 0.05); H1Rko-NaCl 0.44 +/- 0.08 g vs. H1Rko-sCT 0.50 +/- 0.06 g]. The anorectic effect of leptin was absent in ad libitum-fed H1Rko mice, whereas CCK equally reduced feeding in WT and H1Rko animals. This suggests that the histaminergic system is involved in mediating the anorectic effects of peripheral amylin and sCT via histamine H1 receptors. The same applies to leptin but not to CCK. H1Rko mice showed significantly increased body weight gain compared with WT mice, supporting the role of endogenous histamine in the regulation of feeding and body weight. Topics: Amyloid; Animals; Anorexia; Body Weight; Calcitonin; Cholecystokinin; Eating; Histamine Antagonists; Islet Amyloid Polypeptide; Leptin; Male; Mice; Mice, Knockout; Pancreas; Piperidines; Receptors, Histamine H1 | 2001 |
Sexual dimorphism in relationship of serum leptin and relative weight for the standard in normal-weight, but not in overweight, children as well as adolescents.
To demonstrate sexual dimorphism in serum leptin levels not only during puberty, but also in childhood in Japan.. Cross-sectional study.. Hamamatsu-Hokuen study in Japan.. Body weight and height were measured in normal-weight Japanese children and adolescents (143 boys, 178 girls), and 161 boys and 129 girls whose percentage of overweight for the standard (%Wt) was more than+25%. Serum leptin levels were compared with %Wt. Subjects were divided into group 1 (6-10 y of age) and group 2 (11-15 y of age) according to their age.. In overweight subjects, leptin was more highly correlated with %Wt in boys of group 2 (r=0.67, P<0.0001) than group 1 (r=0.32, P=0.004). In girls as well, a correlation coefficient was greater in group 2 (r=0.67, P<0.0001) than group 1 (r=0.44, P=0.0011). In normal-weight boys, there was no significant correlation between serum leptin and %Wt both in groups 1 and 2. On the contrary, statistical significance was demonstrated in the correlation between serum leptin and %Wt in group 1 (r=0.31, P=0.0019) and group 2 (r=0.35, P=0.0014) as well as in the total normal-weight girls (r=0.28, P=0.0011).. It is suggested that sexual dimorphism is present in serum leptin levels, especially when compared to weight, as early as during childhood. Topics: Adolescent; Body Composition; Body Weight; Child; Cross-Sectional Studies; Female; Humans; Leptin; Male; Obesity; Puberty; Sex Characteristics | 2001 |
Leptin-deficient mice commence hypersecreting insulin in response to acetylcholine between 1 and 2 weeks of age.
Leptin-deficient Lep(ob)/Lep(ob)mice develop hyperinsulinemia early in life, before they begin to overeat or develop insulin resistance. Pancreatic islets from these young mice do not yet hypersecrete insulin in response to glucose, but they hyperrespond to acetylcholine. Islets from 4-day, and 1-, 2-, and 4-week-old mice were used in the present study to determine when leptin-deficient mice first hypersecrete insulin in response to acetylcholine. This relative hypersecretion of insulin from islets of leptin-deficient mice occurred between 1 and 2 weeks of age. The divergence in insulin secretion occurred at this time because islets from lean, leptin-sufficient mice became relatively less responsive to acetylcholine between 1 and 2 weeks of age, whereas islets from leptin-deficient mice maintained a high responsiveness to acetylcholine during development. Leptin addition to islets isolated from 4-day, and 2-, and 4-week-old leptin-deficient mice rapidly (i.e., within 30 min) suppressed acetylcholine-induced insulin secretion at each stage of development. In contrast, islets from 4-day, and 2- and 4-week-old leptin-sufficient mice became progressively less responsive to leptin with development. Leptin targets pancreatic islets early in development to specifically constrain the overall capacity for acetylcholine-induced insulin secretion, and to acutely modulate this secretion. Topics: Acetylcholine; Animals; Animals, Newborn; Body Weight; Female; Glucose; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains | 2001 |
The anorectic effect of oestradiol does not involve changes in plasma and cerebrospinal fluid leptin concentrations in the rat.
Oestradiol is a potent anorectic agent that reduces both food intake and body weight. Since leptin is known to reduce food intake, we first analysed if the anorectic effect of oestradiol is driven by an increased leptin concentration in either cerebrospinal fluid or plasma. Oestradiol also reduces body weight and fat mass. Accordingly, a decrease in plasma leptin concentration can also be expected after an oestradiol-driven reduction in fat mass. To test this hypothesis was the second aim of this study. Female Wistar rats received oestradiol chronically during 14 days. During the first week of treatment there was a reduction in food intake, body weight and fat mass that returned to initial values during the second week, but no changes in ob mRNA levels were found in white adipose tissue depots. There was no effect of treatment or time on plasma and cerebrospinal fluid leptin concentrations. Therefore, the anorectic effect of oestradiol is not driven by an increase in leptin concentration either in plasma or in cerebrospinal fluid, and the reduction in fat mass that oestradiol produces is not followed by a reduction leptin concentration. Topics: Adipose Tissue; Analysis of Variance; Animals; Appetite Depressants; Body Composition; Body Weight; Estradiol; Female; Leptin; Rats; Rats, Wistar; RNA, Messenger | 2001 |
Obesity research. Fat hormone makes a comeback.
Topics: Adipose Tissue; Body Mass Index; Body Weight; Cohort Studies; Humans; Leptin; Mutation; Obesity; Obesity, Morbid | 2001 |
A new perspective on adiposity in a naturally obese mammal.
Many mammals seasonally reduce body fat due to inherent periods of fasting, which is associated with decreased leptin concentrations. However, no data exist on the correlation between fat mass (FM) and circulating leptin in marine mammals, which have evolved large fat stores as part of their adaptation to periods of prolonged fasting. Therefore, FM was estimated (by tritiated water dilution), and serum leptin and cortisol were measured in 40 northern elephant seal (Mirounga angustirostris) pups early (<1 wk postweaning) and late (6-8 wk postweaning) during their natural, postweaning fast. Body mass (BM) and FM were reduced late; however, percent FM (early: 43.9 +/- 0.5, late: 45.5 +/- 0.5%) and leptin [early: 2.9 +/- 0.1 ng/ml human equivalents (HE), late: 3.0 +/- 0.1 ng/ml HE] did not change. Cortisol increased between early (9.2 +/- 0.5 microg/dl) and late (16.3 +/- 0.9 microg/dl) periods and was significantly and negatively correlated with BM (r = 0.426; P < 0.0001) and FM (r = 0.328; P = 0.003). FM and percent FM were not correlated (P > 0.10) with leptin at either period. The present study suggests that these naturally obese mammals appear to possess a novel cascade for regulating body fat that includes cortisol. The lack of a correlation between leptin and FM may reflect the different functions of fat between terrestrial and marine mammals. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Female; Humans; Hydrocortisone; Leptin; Male; Obesity; Seals, Earless | 2001 |
Chronic maternal nicotine exposure alters neuronal systems in the arcuate nucleus that regulate feeding behavior in the newborn rhesus macaque.
It is well known that maternal smoking during pregnancy can lead to low birth weight and low body fat in human newborns. The purpose of this study was to determine whether chronic maternal nicotine treatment alters levels of known regulators of energy balance in the newborn offspring. Pregnant rhesus monkeys were treated with nicotine tartrate (1.5 mg/kg x d) starting on d 26 of pregnancy and maintained through d 160 of gestation. Nicotine exposure had no significant effect on absolute birth weights of the neonatal monkeys, although there was a 10% reduction in birth weights with nicotine exposure when they were normalized to maternal weight. Postnatal d 1 plasma leptin levels were significantly reduced by about 50% in the nicotine treatment group compared with saline controls, suggesting that the infant monkeys exposed to nicotine may also have lower body fat levels. In situ hybridization studies demonstrated that chronic nicotine exposure resulted in a significant decrease in arcuate NPY mRNA expression in the neonatal monkeys. In addition, there was a 2-fold increase in POMC mRNA in the arcuate nucleus in the nicotine-exposed group. These data suggest that nicotine exposure during pregnancy may increase energy expenditure in the developing fetus through actions on hypothalamic systems, resulting in lower birth weights and body fat levels. Topics: Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Body Weight; Embryonic and Fetal Development; Feeding Behavior; Female; Gestational Age; Hydrocortisone; Image Processing, Computer-Assisted; In Situ Hybridization; Leptin; Macaca mulatta; Neurons; Neuropeptide Y; Nicotine; Pregnancy; Pro-Opiomelanocortin; RNA, Messenger | 2001 |
Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy.
Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many forms of obesity in rodents, including those that are leptin or leptin receptor deficient. Obesity is associated with hyperleptinemia and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 microg icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-PCR, Western blots, and mobility shift assays was used to evaluate the leptin signaling pathway in whole hypothalami from sham-operated, ADX and corticosterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increased the expression of leptin receptor mRNA, increased STAT-3 mRNA and protein levels, induced constitutive STAT-3 phosphorylation and DNA binding activity, and also reduced suppressor of cytokine signaling-3 (SOCS-3) mRNA and protein levels. ADX and leptin treatment increased STAT-3 phosphorylation, but with no concomitant increase in DNA binding activity. Leptin and ADX decreased NPY mRNA expression, but their combination did not further decrease NPY mRNA. Corticosterone supplementation of ADX rats partially reversed many of these effects. In conclusion, ADX through activation of STAT-3 and inhibition of SOCS-3 activates the JAK-STAT signaling pathway. These effects most probably explain the ability to prevent the development of obesity by removal of adrenal steroids. Topics: Acute-Phase Proteins; Adipose Tissue; Adrenalectomy; Animals; Body Weight; Cerebral Ventricles; Corticosterone; DNA Primers; DNA-Binding Proteins; Energy Intake; Epididymis; Gene Expression Regulation; Hypothalamus; Infusions, Parenteral; Injections, Intraventricular; Insulin; Leptin; Male; Organ Size; Polymerase Chain Reaction; Proteins; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Repressor Proteins; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Trans-Activators; Transcription Factors; Transcription, Genetic | 2001 |
The ontogeny of leptin mRNA expression in growing broilers and its relationship to metabolic body weight.
The polypeptide hormone leptin is produced by both adipose tissue and the liver and has been shown to induce satiety in chickens. In this study we have investigated the developmental regulation of leptin mRNA expression in growing broiler chickens. Leptin expression generally increases in all tissues from 1-12 weeks of age. In the subcutaneous fat depot there is an apparent pattern of increased leptin mRNA expression occurring at 2, 6, and 10 weeks post-hatch. This pattern was not evident in the other tissues surveyed and may relate to the cycle of loading and unloading of adipocytes with lipid. No consistent gender differences in leptin expression patterns were detected in the tissues surveyed, as is often observed in mammals. Positive correlations between metabolic body weight and adipose leptin expression levels were observed. Leptin expression by the liver was highly correlated with metabolic body weight from 1-6 weeks of age, and uncorrelated from 6-12 weeks of age. This pattern of increasing liver leptin expression with increasing body weight during the early rapid growth phase of the bird may be due to limited fat storage during this period, which is followed by rapid body fat accumulation from 6-12 weeks. The characterization and tissue specific distribution of leptin mRNA expression in the growing broiler indicate similar patterns of leptin production to that of growing mammals. Leptin may be involved in lipid flux through the adipocyte as well as the shift in lipid metabolism to increased storage during pre-puberty. Topics: Adipose Tissue; Animals; Body Weight; Chickens; Female; Gene Expression Regulation, Developmental; Leptin; Liver; Longitudinal Studies; Male; Regression Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2001 |
Long-term effects of exogenous leptin on body weight and fat in post-obese female rats.
This study was designed to test the hypothesis that short-term leptin infusion during the post-obese refeeding phase of weight-reduced rats would reduce the rate of weight regain and, as a result, reduce the final body weight and fat content in weight-reduced rats. Ninety-six female Wistar rats were divided into four groups: (1) LFCON (low-fat control) group: Rats in this group were fed the control low-fat (LF) diet ad lib for the entire study period. (2) HFCON (high-fat control) group: Rats in this group were fed the high-fat (HF, 40% fat) diet ad lib for the study period. (3) HFRLP (high-fat fed, weight-reduced, leptin treatment) group: Obese rats in this group were weight-reduced and received leptin infusion for 2 weeks (miniosmotic pumps, 0.5 microg/kg/day) during the post-obese refeeding period. (4) HFRSM (high-fat fed, weight-reduced, sham control) group: Rats in this sham-control group were treated the same as the rats in the HFRLP group with the exception that no leptin was actually infused during the first 2 weeks of refeeding period. The results demonstrated that 2 weeks of leptin treatment during the early refeeding phase did not prevent weight regain in weight-reduced rats, but it significantly reduced body fat content in these rats as compared to ad lib fed obese control rats. One cycle of weight reduction and regain did not alter the body weight and body fat content in HFRSM rats when compared to obese control rats. Therefore, leptin treatment was effective in reducing body fat content in post-obese rats for up to 7 weeks, but the long-term effect of short-term leptin treatment needs to be further examined. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Diet, Fat-Restricted; Dietary Fats; Eating; Female; Leptin; Rats; Rats, Wistar | 2001 |
Metabolic effects of 20 kDa and 22 kDa human growth hormones on adult male spontaneous dwarf rats.
Two molecular forms of human GH (hGH) have been shown to be biologically active. The 20 kDa form has been reported to have weaker diabetogenic and lipolytic actions than the 22 kDa form.. To analyze the carbohydrate metabolism of 20 kDa and 22 kDa hGH, using the adult male spontaneous dwarf rat (SDR), which is GH deficient.. SDRs were given 20 kDa or 22 kDa hGH in doses of 125 microg/rat or 500 microg/rat, or saline, for 10 days, and their weight, serum IGF-I, glucose, insulin, leptin and body composition were measured.. Weight and serum IGF-I increased both in the 20 kDa and 22 kDa groups, but IGF-I concentrations were significantly lower in the 20 kDa group than in the 22 kDa group. Serum glucose was not increased by either 20 kDa or 22 kDa hGH, whereas insulin was significantly increased after the higher dose of the 22 kDa hGH. Although blood concentrations of leptin were decreased by both 20 kDa and 22 kDa hGH, values were lower in the high-dose 20 kDa group than in the group given the same dose of 22 kDa hGH. Both forms of GH increased the percentage body water and body protein content, and decreased the percentage of body fat by the same degree. The observation that the higher dose of the 22 kDa hGH increased insulin concentrations without changing blood glucose demonstrates that this concentration of the hormone induces insulin resistance, whereas the same dose of 20 kDa hGH does not.. The results can be interpreted to indicate that the higher dose of the 22 kDa hGH has diabetogenic activity, as reported previously, whereas the 20 kDa hGH has lower diabetogenic activity. The 20 kDa form of hGH may therefore be more useful in treating adult GH deficiency, especially those with severe obesity. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Dwarfism; Human Growth Hormone; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Molecular Weight; Rats; Rats, Sprague-Dawley | 2001 |
Melanocortin receptor agonist transiently increases oxygen consumption in rats.
Acute injections of melanocortin (MC) agonist and antagonist are highly effective in reducing or increasing food take, respectively. Much less is known about how injection of MC receptor active substances affects metabolism, in particular during long term administration. Here we investigated the effect of 8 days continuous i.c.v. infusion of either MC receptor agonist MTII or the selective MC4 receptor antagonist HS024 on oxygen consumption, food intake and body weight in rats. We observed significant increase in oxygen consumption 2 days after the start of the MTII infusion. However, this increase had disappeared by day 4 of the study. No difference was observed in the oxygen consumption after injection of HS024. MTII substantially decreased the food intake during the first days, but then the feeding recovered and the body weight stabilised at a new level. The immediate effect of the MC receptor agonist on both food intake and metabolism was thus transient, even though the weight loss was maintained. The HS024 treated rats were hyperphagic throughout the test period, continuously gaining weight, resulting in increased fat pads and high leptin levels. This is the first study that describes long term effects of MC receptor agonist and antagonist on metabolism and energy balance. Topics: alpha-MSH; Animals; Appetite; Body Weight; Drug Administration Schedule; Eating; Energy Metabolism; Leptin; Male; Organ Size; Oxygen Consumption; Peptides, Cyclic; Rats; Rats, Wistar; Receptors, Corticotropin; Receptors, Melanocortin | 2001 |
Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus.
Agouti-related protein (AGRP) is synthesized in the same neurones in the arcuate nucleus as neuropeptide Y (NPY), another potent orexigenic peptide. AGRP antagonizes the action of alpha-melanocyte stimulating hormone, a derivative of pro-opiomelanocortin (POMC) at the hypothalamic MC4 receptor to increase food intake. Although leptin has been shown to regulate Agrp/Npy and Pomc-expressing neurones, there are differences with respect to Agrp regulation in leptin receptor-deficient mice and rats. Unlike the obese leptin receptor-deficient db/db mouse, which exhibits upregulation of Agrp mRNA expression in the medial basal hypothalamus (MBH) compared to lean controls, the obese leptin receptor-deficient (faf; Koletsky) rat does not exhibit upregulation of Agrp expression. To determine whether this represents a general difference between leptin receptor-deficient mice and rats, neuropeptide gene expression was analysed in the MBH of lean and obese rats segregating for a different leptin receptor mutation, Leprfa (Zucker). Fasting in lean rats (+/fa) for 72 h significantly increased Agrp and Npy mRNA expression, and decreased Pomc mRNA expression as detected by a sensitive solution hybridization/S1 nuclease protection assay. Npy mRNA levels were significantly increased in fed obese fa/fa compared to lean rats, and further increased in the obese animals after fasting. In contrast, Agrp mRNA levels did not differ between fed lean and fed obese rats, and fasting did not significantly change Agrp levels in obese rats. To determine whether the change in Agrp expression that occurs with food deprivation in lean rats could be prevented by leptin replacement, Sprague-Dawley rats were fasted and infused via subcutaneous osmotic micropumps for 48 h with either saline or recombinant mouse leptin. Fasting significantly increased Agrp and Npy, and decreased Pomc mRNA levels. Leptin infusion almost completely reversed these changes such that there was no significant difference between the levels in the fasted rats and those that were fed ad libitum. Thus, in fasted lean rats, Agrp and Npy are upregulated in parallel when leptin levels fall and are downregulated by leptin infusion. By contrast, the absence of a functional leptin receptor results in the upregulation of Npy but not Agrp mRNA. Topics: Agouti-Related Protein; Animals; Body Weight; Carrier Proteins; Fasting; Food Deprivation; Gene Expression; Hypothalamus, Middle; Intercellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proteins; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger | 2001 |
Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y.
Altered fat distribution is a consequence of menopause, but the mechanisms responsible are unknown. Estrogen insufficiency in humans can be modeled using ovariectomized rats. We have shown that increased adiposity in these rats is due to reduced physical activity and transient hyperphagia, and can be reversed with 17beta-estradiol treatment. The aims of this study were to examine whether this altered energy balance is associated with circulating leptin insufficiency, central leptin insensitivity, decreased hypothalamic leptin receptor (Ob-Rb) expression, and/or increased hypothalamic neuropeptide Y (NPY).. Plasma leptin levels, adipose tissue ob gene expression, energy balance responses to i.c.v. leptin, hypothalamic Ob-Rb expression and NPY concentration in five separate hypothalamic regions were measured in adult female rats after either ovariectomy or sham operations.. Obesity was not associated with hypoleptinemia or decreased ob gene expression in ovariectomized rats; however, it was associated with insensitivity to central leptin administration. Food intake was less suppressed and spontaneous physical activity was less stimulated by leptin. This was not due to decreased hypothalamic Ob-Rb expression. NPY concentration in the paraventricular nucleus of the hypothalamus was elevated in the ovariectomized rats, consistent with leptin insensitivity; however this effect was transient and disappeared as body fat and leptin levels increased further and hyperphagia normalized.. Impaired central leptin sensitivity and overproduction of NPY may contribute to excess fat accumulation caused by estrogen deficiency. Topics: Absorptiometry, Photon; Adipose Tissue; Animals; Body Composition; Body Weight; Carrier Proteins; Disease Models, Animal; Energy Intake; Estrogens; Female; Hypothalamus; Leptin; Neuropeptide Y; Obesity; Ovariectomy; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger | 2001 |
Body weight gain, insulin, and leptin in olanzapine-treated patients.
Topics: Antipsychotic Agents; Benzodiazepines; Body Weight; Female; Humans; Insulin; Leptin; Male; Metabolic Syndrome; Obesity; Olanzapine; Pirenzepine; Psychotic Disorders | 2001 |
Effects of pinealectomy on the circadian release pattern of leptin in male rat.
Exogenous and endogenous melatonin decrease leptin release. It is not known whether melatonin also has an effect on circadian release pattern of leptin. So, this study was planned to investigate the possible changes in the circadian release of leptin following pinealectomy.. A group of rats were surgically pinealectomized while some others were exposed to sham operation. The animals were decapitated at 13.30 p.m. and 01.30 a.m. Serum leptin levels were measured by radioimmunoassay.. Serum leptin levels at 13.30 p.m. were lower than the values at 01.30 a.m. in both pinealectomized (P<0.002) and sham rats P<0.001). Serum leptin levels measured at 13.30 p.m. and 01.30 a.m. were significantly elevated (P<0.05 and P<0.01, respectively) in the pinealectomized rats in comparison to sham animals.. The circadian release of leptin does not seem to be regulated by melatonin release from the pineal gland whereas melatonin, physiologically released, may have a decreasing effect on leptin release. Topics: Animals; Body Weight; Circadian Rhythm; Leptin; Male; Melatonin; Pineal Gland; Rats; Rats, Wistar | 2001 |
Serum leptin changes during weight loss in obese diabetic subjects with and without microalbuminuria.
To evaluate the changes of serum leptin levels after weight reduction in diabetic subjects with and without microalbuminuria, we studied 10 obese healthy subjects, 12 obese diabetics with persistent microalbuminuria and 10 obese diabetic subjects without microalbuminuria. Obese diabetic patients with microalbuminuria showed serum leptin levels significantly higher than normoalbuminuric diabetics, while no difference was found between obese diabetics without microalbuminuria and healthy controls. All obese subjects followed a 12-month intensive weight reduction program during which the mean change in body mass index was similar between obese diabetic and obese healthy subjects (obese diabetics without microalbuminuria: 35.2+/-4.3 vs 29.9+/-4.1, p<0.05; obese diabetics with microalbuminuria: 35.7+/-3.9 vs 30.3+/-4.0, p<0.05; obese healthy subjects: 35.5+/-4.0 vs 30.1+/-3.9, p<0.05). The mean changes in serum leptin levels tended to be similar in two groups of subjects studied (obese diabetics without microalbuminuria: 37.6+/-4.1 vs 19.7+/-4.9, p<0.001; obese healthy subjects: 37.1+/-4.3 vs 20.1+/-5.1, p<0.001); obese microalbuminuric subjects showed higher leptin levels (42.4+/-4.0 vs 30.3+/-4.2, p<0.001) than normoalbuminuric diabetic and obese healthy subjects. In conclusion, during weight loss, independently from the quality of metabolic control, serum leptin concentrations declined in both groups of obese diabetics. The changes of leptin in diabetics seem to be similar to those observed in healthy obese subjects. Topics: Adolescent; Albuminuria; Body Mass Index; Body Weight; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Humans; Leptin; Obesity; Weight Loss | 2001 |
Effects of estrogen on serum leptin levels and leptin mRNA expression in adipose tissue in rats.
In this study, we examined changes in serum leptin levels during the estrus cycle and the role of estrogen in these changes.. We measured serum leptin levels during normal estrus cycles in intact rats and estradiol-17beta (E2)-induced artificial estrus cycles in ovariectomized rats.. Serum leptin levels increased 1.6-fold from 4.2 +/- 0.2 ng/ml during diestrus stage 2 to 6.7 +/- 0.9 ng/ml during proestrus stage during the 4-day estrus cycle. During the E2-induced estrus cycle, serum leptin levels increased 2.3-fold from 2.3 +/- 0.1 ng/ml at estrus to 5.4 +/- 1.2 ng/ml at proestrus. E2 also increased serum leptin concentrations and leptin mRNA expression in adipose tissue of immature rats.. These findings suggest that increased serum leptin induced by estrogen during proestrus may trigger the preovulatory release of luteinizing hormone. Furthermore, our findings indicate that estrogen has a positive effect on leptin production in adipose tissue. Topics: Adipose Tissue; Animals; Body Weight; Diestrus; Estradiol; Estrogen Antagonists; Estrogens; Female; Leptin; Osmolar Concentration; Ovariectomy; Proestrus; Rats; Rats, Sprague-Dawley; Reference Values; RNA, Messenger; Tamoxifen | 2001 |
Aromatase-deficient (ArKO) mice accumulate excess adipose tissue.
Aromatase is the enzyme which catalyses the conversion of C19 steroids into C18 estrogens. We have generated a mouse model wherein the Cyp19 gene, which encodes aromatase, has been disrupted, and hence, the aromatase knockout (ArKO) mouse cannot synthesise endogenous estrogens. We examined the consequences of estrogen deficiency on accumulation of adipose depots in male and female ArKO mice, observing that these animals progressively accrue significantly more intra-abdominal adipose tissue than their wildtype (WT) litter mates, reflected in increased adipocyte volume and number. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared to WT controls, as were elevated insulin levels, although blood glucose was unchanged. Associated with these changes, the livers of ArKO animals were characterised by a striking accumulation of lipid droplets. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females. Topics: Adipose Tissue; Animals; Aromatase; Blood Glucose; Body Composition; Body Weight; Cell Count; Cholesterol; Energy Metabolism; Estrogens; Fatty Liver; Female; Insulin; Leptin; Lipid Metabolism; Lipoproteins, HDL; Liver; Male; Mice; Mice, Knockout; Physical Exertion; Triglycerides | 2001 |
Effects of 2G exposure on lean and genetically obese Zucker rats.
Changes in the ambient force environment alter the regulation of adiposity, food intake and energy expenditure (i.e., energy balance). Lean (Fa/Fa) and obese (fa/fa) male Zucker rats were exposed to 2G (twice Earth's normal gravity) for eight weeks via centrifugation to test the hypothesis that the Fa/Fa rats recover to a greater degree from the effects of an increased ambient force environment on body mass and food intake, than do the fa/fa rats which have a dysfunctional leptin regulatory system. The rats (lean and obese exposed to either 1G or 2G) were individually housed in standard vivarium cages with food and water provided ad libitum. The acute response to 2G included a transient hypophagia accompanied by decreased body mass, followed by recovery of feeding to new steady-states. In the lean rats, body mass-independent food intake had returned to 1G control levels six weeks after the onset of centrifugation, and body mass increased towards that of the 1G rats. In contrast, food intake and body mass of the 2G obese rats plateaued at a level lower than that of the 1G controls. Although percent carcass fat was reduced more in the 2G leans vs. 2G obese rats, the latter lost significantly more grams of fat than did the leans. Our data suggest that with respect to food intake and body mass, the lean rats recover from the initial effects of 2G exposure to a greater degree than do the fatty rats, a difference that likely reflects the functionality of the leptin regulatory system in the leans. Topics: Adaptation, Physiological; Adipose Tissue; Adrenal Glands; Animals; Body Composition; Body Weight; Centrifugation; Eating; Epididymis; Hypergravity; Leptin; Liver; Male; Obesity; Rats; Rats, Zucker; Retroperitoneal Space | 2000 |
[Effect of chromium gluconate on body weight, serum leptin and insulin in rats].
In order to observe the effect of chromium on rat body weight, serum leptin and insulin, eight groups of rats were randomly fed diets (basal diet or high-fat diet) with different levels of chromium gluconate [proximally Cr(III) 1,2 and 3 mg/kg BW]. All rats were weighted once a week. By the end of the 8th week, all rats were decapitalized and the levels of serum leptin and insulin were tested by RIA method. The ratio of liver, spleen, kidney and testickle to body weight were calculated. The average body weight and the levels of leptin and insulin of high-fat-diet groups were significantly higher than those of the basal-diet group (P < 0.05), but the insulin and leptin of groups with chromium were significantly lower than their corresponding control groups without chromium(P < 0.05). It was concluded that chromium could cause weight loss slightly and reduce the levels of insulin and leptin. Topics: Animals; Body Weight; Chromium; Gluconates; Insulin; Leptin; Male; Random Allocation; Rats; Rats, Wistar | 2000 |
Impact of obesity and leptin treatment on adipocyte gene expression in Psammomys obesus.
We examined the effects of leptin treatment on the expression of key genes in adipocyte metabolism in Psammomys obesus (P. obesus), a polygenic rodent model of obesity. Lean and obese P. obesus were given three daily intraperitoneal injections of either saline or leptin (total of 45 mg/kg per day) for 7 days. In lean animals, leptin treatment led to reductions in food intake, body weight and fat mass. Pair-fed animals matched for the reduction in food intake of the lean leptin-treated animals demonstrated similar reductions in body weight and fat mass. In obese P. obesus, leptin treatment failed to have any effect on body weight or body fat mass, indicating leptin resistance. Lipoprotein lipase, hormone-sensitive lipase and peroxisome proliferator activated receptor gamma 2 mRNA levels were significantly reduced in lean leptin-treated animals, whereas pair-fed animals were similar to lean controls. Uncoupling protein 2 and glycerol phosphate acyltransferase were also reduced in the lean leptin-treated animals, but not significantly so. Obese animals did not show any gene expression changes after leptin treatment. In conclusion, high circulating concentrations of leptin in lean P. obesus resulted in decreased gene expression of a number of key lipid enzymes, independent of changes in food intake, body weight and fat mass. These effects of leptin were not found in obese P. obesus. Topics: Adipocytes; Animals; Body Composition; Body Weight; Eating; Female; Gene Expression; Gerbillinae; Leptin; Lipase; Lipoprotein Lipase; Male; Obesity; Receptors, Cytoplasmic and Nuclear; Transcription Factors | 2000 |
A longitudinal study of leptin during development in the male rhesus monkey: the effect of body composition and season on circulating leptin levels.
The objective of this study was to examine longitudinal changes in serum leptin concentrations during development and to correlate those changes with sexual development in male rhesus monkeys housed under natural environmental conditions. Blood samples were drawn from 8 control animals approximately every other month from 10 to 30 mo of age and thereafter monthly through 80 mo of age. Leptin levels declined through the juvenile period until the onset of puberty and were negatively correlated with body weight. Seven of the eight animals became sexually mature during the breeding season of their fourth year of life. Puberty was delayed in the other animal until the subsequent breeding season. There were no significant fluctuations in leptin levels prior to or in association with the pubertal rise in LH and testosterone (T) secretion. During the peripubertal period, levels of leptin varied between 2 and 3 ng/ml. The animal that exhibited delayed puberty had the lowest body weight and highest leptin levels during this period. With the achievement of sexual maturity, leptin levels varied seasonally, with peak levels in the late winter (Jan-Mar) and a nadir in the late summer (Aug-Sept). A late winter rise in leptin was also evident in most of the animals during Years 2 and 3, but not during Year 4. In the fall of Years 5 and 6, the seasonal rise in leptin concentrations lagged 3-4 mo behind the seasonal increase in LH and T. In the fall of Year 5, but not thereafter, leptin levels were positively related to percent body fat and negatively correlated with lean body mass. The data do not support the hypothesis that increasing leptin concentrations trigger the onset of puberty in the male rhesus monkey. During the juvenile period and after sexual maturation, but not during the peripubertal period, leptin secretion varied with season in the animals; but the environmental factors that cue or drive this rhythm remain to be determined. Topics: Aging; Animals; Body Composition; Body Weight; Leptin; Longitudinal Studies; Luteinizing Hormone; Macaca mulatta; Male; Photoperiod; Seasons; Sexual Maturation; Testis; Testosterone | 2000 |
Differential role of melanocortins in mediating leptin's central effects on feeding and reproduction.
Leptin serves as a humoral link coupling the status of energy reserves to the functional activity of the reproductive system. Leptin is thought to act through melanocortinergic pathways in the brain to regulate ingestive behaviors; however, whether melanocortins mediate leptin's actions on the neuroendocrine-reproductive axis is unknown. We tested this hypothesis first by determining whether the effects of leptin on feeding behavior and reproduction in the ob/ob mouse could be blocked by the melanocortin receptor (MC-R) antagonist SHU9119 and second, by examining the effects of the MC-R agonist MTII on feeding and the endocrine-reproductive system. Administered by intracerebroventricular injections, leptin inhibited food intake, raised plasma gonadotropin levels, and increased seminal vesicle weights compared with controls; SHU9119 (intracerebroventricularly) attenuated leptin's effects on food intake and body weight but did not alter leptin's stimulatory effect on the reproductive axis. MTII (intracerebroventricularly and intraperitoneally) decreased food intake and increased body temperature compared with controls but had no effect on the reproductive-endocrine axis. These results suggest that although leptin acts centrally through melanocortinergic pathways to inhibit ingestive behaviors and stimulate metabolism, leptin's activational effect on the reproductive axis is likely to be mediated by other, unknown neuroendocrine circuits. Topics: alpha-MSH; Animals; Body Temperature; Body Weight; Brain; Eating; Genitalia, Male; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Melanocyte-Stimulating Hormones; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Receptors, Corticotropin; Receptors, Melanocortin; Rectum; Reproduction | 2000 |
Defense of body weight against chronic caloric restriction in obesity-prone and -resistant rats.
Half of Sprague-Dawley rats develop and defend diet-induced obesity (DIO) or diet resistance (DR) when fed a high-energy (HE) diet. Here, adult male rats were made DIO or DR after 10 wk on HE diet. Then half of each group was food restricted for 8 wk on chow to maintain their body weights at 90% of their respective baselines. Rate and magnitude of weight loss were comparable, but maintenance energy intake and the degree of sympathetic activity (24-h urine norepinephrine) inhibition were 17 and 29% lower, respectively, in restricted DR than DIO rats. Restricted DIO rats reduced adipose depot weights, plasma leptin, and insulin levels by 35%. Restricted DR rats reduced none of these. When fed ad libitum, both DR and DIO rats returned to the body weights of their respective chow-fed phenotype controls within 2 wk. This was associated with increased adipose mass and leptin and insulin levels only in DIO rats. Thus DR rats appear to alter primarily their lean body mass, whereas DIO rats primarily alter their adipose mass during chronic caloric restriction and refeeding. Topics: Adipose Tissue; Animals; Body Weight; Circadian Rhythm; Diet; Diet, Fat-Restricted; Disease Susceptibility; Energy Intake; Insulin; Leptin; Male; Norepinephrine; Obesity; Organ Size; Rats; Rats, Sprague-Dawley; Time Factors | 2000 |
Short-term, high-fat diets lower circulating leptin concentrations in rats.
Leptin is produced in proportion to body fat mass and can act on the brain to induce satiety and regulate adipose tissue mass; factors other than adipose tissue mass may influence circulating leptin concentrations.. We explored the possibility that short-term, moderately high-fat diets induce weight gain by producing inappropriately low circulating leptin concentrations.. Female Hooded Wistar rats were fed either a moderately high-fat diet or control diet. Body weight, energy intake, body composition, and fasting plasma leptin were compared after 4 and 14 wk of dietary treatment.. After 4 wk, abdominal fat mass was 38% greater in rats fed the high-fat diet than in those fed the control diet (P < 0.01). However, plasma leptin concentrations were 24% lower in animals fed the high-fat diet (P < 0.05), resulting in significantly lower plasma leptin concentrations per unit abdominal fat mass than in control animals (P < 0.005). From 4 to 14 wk, animals fed the high-fat diet gained twice as much weight and consumed 32 kJ/d more than controls (both P < 0.05). At 14 wk, plasma leptin concentrations per unit abdominal fat mass were 27% lower in rats fed the high-fat diet (P = 0.058) and there was a significant negative association between leptin concentrations per unit abdominal fat mass and body weight (r = 0.44, P < 0.05).. In the short term, a moderately high-fat diet is associated with lower than expected circulating leptin concentrations, which correlate with a higher body weight. A high-fat diet may therefore contribute to weight gain by reducing leptin secretion in adipose tissue. Topics: Adipose Tissue; Animals; Body Weight; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Energy Intake; Female; Insulin; Leptin; Obesity; Rats; Rats, Wistar; Time Factors | 2000 |
Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat.
Pineal melatonin secretion declines with aging, whereas visceral fat, plasma insulin, and plasma leptin tend to increase. We have previously demonstrated that daily melatonin administration at middle age suppressed male rat intraabdominal visceral fat, plasma leptin, and plasma insulin to youthful levels; the current study was designed to begin investigating mechanisms that mediate these responses. Melatonin (0.4 microg/ml) or vehicle was administered in the drinking water of 10-month-old male Sprague Dawley rats (18/treatment) for 12 weeks. Half (9/treatment) were then killed, and the other half were submitted to cross-over treatment for an additional 12 weeks. Twelve weeks of melatonin treatment decreased (P<0.05) body weight (BW; by 7% relative to controls), relative intraabdominal adiposity (by 16%), plasma leptin (by 33%), and plasma insulin (by 25%) while increasing (P<0.05) locomotor activity (by 19%), core body temperature (by 0.5 C), and morning plasma corticosterone (by 154%), restoring each of these parameters toward more youthful levels. Food intake and total body fat were not changed by melatonin treatment. Melatonin-treated rats that were then crossed over to control treatment for a further 12 weeks gained BW, whereas control rats that were crossed to melatonin treatment lost BW, but food intake did not change in either group. Feed efficiency (grams of BW change per g cumulative food intake), a measure of metabolic function, was negative in melatonin-treated rats and positive in control rats before cross-over (P<0.001); this relationship was reversed after cross-over (P<0.001). Thus, melatonin treatment in middle age decreased BW, intraabdominal adiposity, plasma insulin, and plasma leptin, without altering food intake or total adiposity. These results suggest that the decrease in endogenous melatonin with aging may alter metabolism and physical activity, resulting in increased BW, visceral adiposity, and associated detrimental metabolic consequences. Topics: Abdomen; Absorptiometry, Photon; Adipose Tissue; Administration, Oral; Adrenal Glands; Animals; Avoidance Learning; Body Temperature; Body Weight; Choice Behavior; Drinking Behavior; Drug Administration Schedule; Energy Intake; Insulin; Leptin; Male; Melatonin; Motor Activity; Organ Size; Rats; Rats, Sprague-Dawley; Saccharin; Taste; Thymus Gland | 2000 |
Serum leptin concentrations during the menstrual cycle in normal-weight women: effects of an oral triphasic estrogen-progestin medication.
To investigate in normal-weight premenopausal women the relationship between circulating leptin and serum gonadotropins and gonadal steroids, during both spontaneous and pharmacologically induced menstrual cycles.. Clinical longitudinal study.. Two groups of age-matched, normal-weight premenopausal volunteer women (groups I and II) were enrolled in this study. Women in group I were free of any hormonal treatment, while women in group II were taking a triphasic estrogen--progestin contraceptive preparation. Blood samples were collected daily in both groups after an overnight fast throughout a complete menstrual cycle.. In the spontaneously cycling women, serum leptin concentration positively correlated with estradiol (P<0.03) and progesterone (P<0. 05) and was higher in the luteal than in the follicular phase (P<0. 05). However, a significant (P<0.03) short-lasting increase in circulating leptin was present in the late follicular phase of all subjects. In the women using hormonal contraception serum leptin remained unchanged throughout the cycle, along with constantly low values of circulating luteinizing hormone and follicle-stimulating hormone.. In normal-weight premenopausal women serum leptin concentrations differ during the menstrual cycle in line with changes in gonadotropin and gonadal steroid concentrations, increasing in the luteal phase of the cycle after a peri-ovulatory peak. These findings suggest a permissive role for leptin with regard to the functioning of the corpus luteum. Topics: Adult; Body Weight; Contraceptives, Oral; Drug Combinations; Estradiol; Estrogens; Female; Follicle Stimulating Hormone; Follicular Phase; Humans; Leptin; Longitudinal Studies; Luteinizing Hormone; Menstrual Cycle; Osmolar Concentration; Progesterone; Progestins; Reference Values | 2000 |
Lower calorie intake enhances muscle insulin action and reduces hexosamine levels.
Previous studies have demonstrated enhanced insulin sensitivity in calorie-restricted [CR, fed 60% ad libitum (AL) one time daily] compared with AL-fed rats. To evaluate the effects of reduced food intake, independent of temporal differences in consumption, we studied AL (unlimited food access)-fed and CR (fed one time daily) rats along with groups temporally matched for feeding [fed 3 meals (M) daily]: MAL and MCR, eating 100 and 60% of AL intake, respectively. Insulin-stimulated glucose transport by isolated muscle was increased in MCR and CR vs. AL and MAL; there was no significant difference for MCR vs. CR or MAL vs. AL. Intramuscular triglyceride concentration, which is inversely related to insulin sensitivity in some conditions, did not differ among groups. Muscle concentration of UDP-N-acetylhexosamines [end products of the hexosamine biosynthetic pathway (HBP)] was lower in MCR vs. MAL despite unaltered glutamine-fructose-6-phosphate aminotransferase activity (rate-limiting enzyme for HBP). These results indicate that the CR-induced increase in insulin-stimulated glucose transport in muscle is attributable to an altered amount, not timing, of food intake and is independent of lower triglyceride concentration. They further suggest that enhanced insulin action might involve changes in HBP. Topics: 3-O-Methylglucose; Adipose Tissue; Animals; Blood Glucose; Body Weight; Energy Intake; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); Glycogen; Hexosamines; Hexoses; Insulin; Leptin; Liver; Male; Muscle Proteins; Muscle, Skeletal; Organ Size; Rats; Rats, Inbred F344; Triglycerides | 2000 |
Predictive value of serum and follicular fluid leptin concentrations during assisted reproductive cycles in normal women and in women with the polycystic ovarian syndrome.
Leptin is an adipocyte-derived hormone which plays a central role in the regulation of body weight and energy homeostasis and in signalling to the brain that adequate energy stores are available for reproduction. Although leptin may affect reproduction by regulating the hypothalamic-pituitary-gonadal axis, recent in-vitro observations indicate that leptin may also have direct intra-ovarian actions. Leptin concentrations were measured in women who succeeded in becoming pregnant within three cycles of in-vitro fertilization (IVF) or gamete intra-fallopian transfer (n = 53), in women who failed to become pregnant within three cycles (n = 50), and in women with polycystic ovarian syndrome (PCOS) (n = 22). It was found that lower follicular fluid leptin concentrations were a marker of assisted reproduction treatment success in normal women. Women with PCOS had higher leptin concentrations than women without such a diagnosis, but this was due to their higher body mass index (BMI). After adjustment for age and BMI, women with PCOS who became pregnant tended to have lower mean follicular fluid leptin concentrations than women with PCOS who did not succeed at becoming pregnant. Further studies exploiting the strengths of the IVF model are needed to assess whether the prognostic role for follicular fluid leptin in human reproduction is independent of other factors, and to elucidate the underlying mechanisms. Topics: Adult; Biomarkers; Body Weight; Female; Fertilization in Vitro; Follicular Fluid; Humans; Infertility, Female; Leptin; Polycystic Ovary Syndrome; Predictive Value of Tests; Pregnancy; Pregnancy Rate; Reference Values; Reproductive Techniques; Smoking | 2000 |
Hypothalamic neuropeptide Y levels in weaning offspring of low-protein malnourished mother rats.
Maternal low-protein malnutrition during gestation and lactation (LP) is an animal model frequently used for the investigation of long-term deleterious consequences of perinatal growth retardation. Hypothalamic neuropeptides are decisively involved in the central nervous regulation of body weight and metabolism. We investigated neuropeptide Y (NPY) in distinct hypothalamic nuclei in the offspring of LP mother rats at the end of the critical hypothalamic differentiation period (20th day of life). Weanling LP offspring were underweight (P< 0.001) and hypoinsulinaemic (P< 0.05), while leptin levels were unchanged. NPY was significantly increased in the paraventricular hypothalamic nucleus (PVN) (P< 0.01) and lateral hypothalamic area (P< 0.05) in LP offspring. In contrast, NPY was unchanged in the ventromedial hypothalamic nucleus (VMN). These observations indicate a leptin-independent stimulation of the orexigenic ARC-PVN axis in undernourished LP rats at weaning. Furthermore a disturbed NPYergic regulation of the VMN is suggested, possibly contributing to alterations of the hypothalamic regulation of body weight and metabolism in LP offspring during life. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Female; Hypothalamic Area, Lateral; Hypothalamus; Insulin; Leptin; Male; Median Eminence; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Protein-Energy Malnutrition; Rats; Rats, Wistar; Ventromedial Hypothalamic Nucleus; Weaning | 2000 |
Circulating leptin levels during ovulation induction: relation to adiposity and ovarian morphology.
To assess serum leptin levels based on body habitus and ovarian morphology during controlled ovarian hyperstimulation.. Prospective analysis.. University IVF program.. Women undergoing IVF-ET were divided into two groups, obese ovulatory women (n = 6; mean (+/-SD) body mass index, 30.1 +/- 0.6 kg/m(2)) and lean ovulatory women (n = 20); mean (+/- SD) body mass index 22.0 +/- 0.2 kg/m(2)). Lean women were categorized further according to whether they had polycystic-appearing ovaries (n = 8) or normal-appearing ovaries (n = 12).. Controlled ovarian hyperstimulation and IVF.. Serum estradiol, testosterone, and leptin.. Mean (+/- SD) leptin levels were significantly higher before and after GnRH agonist down-regulation in obese women (41.7 +/- 5.2 pg/mL and 36.1 +/- 5.8 pg/mL, respectively) compared with lean women (8.4 +/- 1.0 pg/mL and 6.9 +/- 1.1 pg/mL, respectively). Mean (+/- SD) leptin levels increased significantly in both groups (54.5 +/- 5.1 pg/mL and 11.7 +/- 1.2 pg/mL, respectively), and the mean (+/-SD) percentage increase was similar (55% +/- 18% and 54.8% +/- 17%, respectively). Mean (+/-SD) leptin levels were similar in women with polycystic-appearing and normal-appearing ovaries before controlled ovarian hyperstimulation, but increased significantly in women with polycystic-appearing ovaries afterward (14.7 +/- 1.8 pg/mL and 9.3 +/- 1.0 pg/mL, respectively).. Significant increases in leptin levels occur during controlled ovarian hyperstimulation, suggesting that leptin plays a role in follicular growth and maturation. The exaggerated response in women with polycystic-appearing ovaries reflects either a greater number of recruited follicles or a predisposition of adipocytes to leptin production. Topics: Adult; Body Weight; Case-Control Studies; Estradiol; Female; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Leptin; Menotropins; Obesity; Ovary; Ovulation Induction; Polycystic Ovary Syndrome; Prospective Studies; Testosterone | 2000 |
Cord blood leptin levels: relationship to body weight, body mass index, sex and insulin and cortisol levels of maternal-newborn pairs at delivery.
To investigate leptin and to which factors it is related during the perinatal period, we measured serum leptin levels of 46 mothers at delivery, umbilical cord blood and infants on the third day of life. Maternal leptin was higher than in cord (p < 0.001), and did not correlate with maternal age, body weight, body mass index, weight gain during pregnancy, serum glucose, cholesterol, triglycerides, CPE, cortisol or HbA1c levels, nor any biochemical values or anthropometric data of the newborns (p > 0.05). In cord blood, leptin was significantly higher than in 3 day-old infants (p < 0.05), and correlated only with maternal insulin and glucose (r = 0.5, p < 0.01 and r = 0.4, p < 0.05, respectively). In 3 day-old infants, leptin did not correlate with any clinical data (p > 0.05). Leptin was not different in the two sexes (p > 0.05). Serum leptin levels were not related to adiposity of the mother-infant pairs or neonatal growth, and were not different in the two sexes during the perinatal period. Topics: Adolescent; Adult; Blood Glucose; Body Mass Index; Body Weight; Cholesterol; Female; Fetal Blood; Humans; Hydrocortisone; Infant, Newborn; Insulin; Leptin; Male; Pregnancy; Sex Characteristics | 2000 |
Effects of pregnancy and exercise on concentrations of the metabolic markers tumor necrosis factor alpha and leptin.
Pregnancy and exercise have opposite effects on fat mass and insulin resistance. We therefore designed this study to test the hypotheses that exercise during pregnancy alters the pregnancy- associated increases in the levels of tumor necrosis factor alpha and leptin and that the changes in tumor necrosis factor alpha and leptin concentrations during pregnancy continue to reflect changes in fat mass.. The levels of tumor necrosis factor alpha and leptin were measured longitudinally in a control group of physically active women, a group of women who performed endurance exercises >/=4 times a week throughout pregnancy, and a group of women who initially performed endurance exercises but then stopped exercising during midpregnancy. Exercise was monitored, and longitudinal estimates of maternal total mass and fat mass were obtained.. Tumor necrosis factor alpha levels were lower during pregnancy in the women who exercised, and the same was true for leptin levels. When women stopped exercising, however, both tumor necrosis factor alpha and leptin concentrations rose at rates comparable to those seen in the physically active control group. Changes in leptin concentration but not those in tumor necrosis factor alpha concentration correlated with the pregnancy-associated increases in total body and fat mass.. Regular weight-bearing exercise during pregnancy suppresses the pregnancy-associated changes normally seen in both tumor necrosis factor alpha and leptin. The decrease in leptin reflects decreased fat accretion, and we speculate that the changes in tumor necrosis factor alpha may reflect a change in insulin resistance. Topics: Adult; Body Weight; Educational Status; Enzyme-Linked Immunosorbent Assay; Exercise; Female; Humans; Leptin; Longitudinal Studies; Pregnancy; Prospective Studies; Radioimmunoassay; Skinfold Thickness; Social Class; Tumor Necrosis Factor-alpha; Weight Gain | 2000 |
Modulation of endocrine systems and food intake by green tea epigallocatechin gallate.
Green tea polyphenols, especially the catechin, (-)-epigallocatechin gallate (EGCG), have been proposed as a cancer chemopreventative based on a variety of laboratory studies. For clear assessment of the possible physiological effects of green tea consumption, we injected pure green tea catechins ip into rats and studied their acute effects on endocrine systems. We found that EGCG, but not related catechins, significantly reduced food intake; body weight; blood levels of testosterone, estradiol, leptin, insulin, insulin-like growth factor I, LH, glucose, cholesterol, and triglyceride; as well as growth of the prostate, uterus, and ovary. Similar effects were observed in lean and obese male Zucker rats, suggesting that the effect of EGCG was independent of an intact leptin receptor. EGCG may interact specifically with a component of a leptin-independent appetite control pathway. Endocrine changes induced by parenteral administration of EGCG may relate to the observed growth inhibition and regression of human prostate and breast tumors in athymic mice treated with EGCG as well as play a role in the mechanism by which EGCG inhibits cancer initiation and promotion in various animal models of cancer. Topics: Animals; Blood Cell Count; Blood Chemical Analysis; Body Weight; Catechin; Eating; Endocrine Glands; Female; Genitalia; Gonadal Steroid Hormones; Growth Hormone; Insulin; Insulin-Like Growth Factor I; Leptin; Luteinizing Hormone; Male; Organ Size; Rats; Rats, Sprague-Dawley; Rats, Zucker; Tea; Testosterone | 2000 |
Reduced body weight, adipose tissue, and leptin levels despite increased energy intake in female mice lacking acylation-stimulating protein.
Acylation-stimulating protein (ASP) is a potent lipogenic protein produced by adipocytes. In vitro studies have shown that ASP increases triglyceride synthesis and glucose transport in both murine and human adipocytes. Our initial study indicated that complement C3-deficient (-/-) mice (and, therefore, ASP deficient) demonstrated altered dietary postprandial triglyceride clearance. In the present study we examined the phenotype of female mice longitudinally on different diets. Female C3(-/-) mice on both low (10% of energy) and high (40% of energy) fat diets displayed an average reduction in total body weight of 10.1+/-0.5% (P < 0.0003, by ANOVA) compared with the C3(+/+) littermates. Reductions in white adipose tissue mass accounted for most of this weight difference (59% reduction; P < 0.01 on low fat diet). Plasma leptin levels were significantly reduced in C3(-/-) mice on both high (P < 0.001) and low fat diets (P < 0.01). This reduction was significant even after adjusting for the reduced body weight and body fat (P < 0.001). Leptin reductions in the C3(-/-) were greater on the high fat diet and were associated with increased food intake (18+/-2% increase; P < 0.001). Furthermore, there was a decrease in basal glucose levels and basal insulin levels [12.8% decrease in glucose at 14 weeks (HF; P < 0.05) and 41% decrease in insulin at 26 weeks (HF; P < 0.05)]. These in vivo experiments demonstrate that female mice lacking ASP have marked alterations of body weight, adiposity, plasma leptin, and plasma insulin levels. Decreased adiposity and leptin levels occurred in the ASP-deficient animals despite increased energy intake, suggesting that energy expenditure was elevated in these animals. Thus, ASP appears to have an important role in the regulation of energy balance in mice. Topics: Adipose Tissue; Animals; Area Under Curve; Blood Proteins; Body Weight; Complement C3a; Diet; Eating; Energy Metabolism; Feces; Female; Genotype; Glucose; Glucose Tolerance Test; Leptin; Mice; Mice, Knockout; Organ Size; Reverse Transcriptase Polymerase Chain Reaction; Triglycerides | 2000 |
Diazoxide down-regulates leptin and lipid metabolizing enzymes in adipose tissue of Zucker rats.
We have previously reported that attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, increased insulin sensitivity and reduced body weight in obese Zucker rats. These findings prompted us to investigate the effects of DZ on key insulin-sensitive enzymes regulating adipose tissue metabolism, fatty acid synthase (FAS), and lipoprotein lipase (LPL), as well as on circulating levels of leptin. We also determined the direct effects of diazoxide on FAS in 3T3-L1 adipocytes. Seven-week-old female obese and lean Zucker rats were treated with DZ (150 mg/kg/d) or vehicle (C, control) for a period of 6 wk. Changes in plasma parameters by DZ include significant decreases in triglycerides, free fatty acids, glucose, and insulin, consistent with our previous reports. DZ obese rats exhibited lower plasma leptin levels (P<0.03) compared to their C animals. DZ significantly reduced adipose tissue FAS activity in both lean (P<0.0001) and obese (P<0.01) animals. LPL mRNA content was also decreased significantly in DZ-treated obese animals (P<0.009) as compared to their respective controls without a significant effect on lean animals. The possibility that DZ exerted a direct effect on adipocytes was further tested in cultured 3T3-L1 adipocytes. Although diazoxide (5 microM) alone did not change FAS activity in cultured 3T3-L1 adipocytes, it significantly attenuated insulin's effect on FAS activity (P<0.001). We demonstrate that DZ regulates key insulin-sensitive enzymes involved in regulation of adipose tissue metabolism. These findings suggest that modification of insulin-sensitive pathways can be therapeutically beneficial in obesity management. Topics: 3T3 Cells; Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Diazoxide; Fatty Acid Synthases; Fatty Acids, Nonesterified; Female; Gene Expression Regulation, Enzymologic; Insulin; Leptin; Lipoprotein Lipase; Mice; Obesity; Rats; Rats, Zucker; Thinness | 2000 |
Modulation of leptin sensitivity by short photoperiod acclimation in the Djungarian hamster, Phodopus sungorus.
During seasonal acclimation, Djungarian hamsters spontaneously exhibit a reduction in food intake, body mass and body fat stores, which is externally cued by shortening of day length in autumn and controlled by a sliding set-point. We investigated the function of the leptin adipostatic feedback system in the photoperiodic control of seasonal acclimation. In response to mouse recombinant leptin injections for 10 days, long day photoperiod (LD) and short day photoperiod (SD)-acclimated hamsters decreased food intake and body mass. The reduction of body mass was due to the depletion of body fat, as revealed by carcass composition analysis. In SD hamsters, leptin caused a larger reduction of body fat mass than observed under LD conditions, whereas the anorectic effect was similar in both photoperiods. The serum leptin concentration was 9.3 +/- 1.2 ng/ml in LD-acclimated hamsters and decreased significantly to 4.2 +/- 0.8 ng/ml and 2.1 +/- 0.6 ng/ml in hamsters exposed to SD for 66 days and 116 days, respectively (P < 0.001). A strong positive correlation between total body fat mass and serum leptin concentration was found (rS = 0.935, P < 0.0001, n = 70). Despite the anorectic action of exogenous leptin, higher endogenous leptin levels in LD hamsters were paralleled by higher food intake in LD hamsters as compared to SD hamsters. This paradoxical finding further supports the increased leptin sensitivity in SD hamsters as judged from leptin treatment experiments. We tested the functional significance of leptin for the controlled down-regulation of food intake and body mass induced by short photoperiod. Food restriction for 10 days during the transition phase decreased body mass below the desired sliding set-point, which was recovered in control hamsters following ad libitum refeeding. Treatment with mouse recombinant leptin during ad libitum refeeding inhibited the recovery of body mass and blunted the increase of food intake observed in controls, indicating that the sliding set-point utilizes leptin as a signal for the adjustment of the appropriate body mass level. Topics: Acclimatization; Animals; Body Weight; Climate; Cricetinae; Eating; Leptin; Organ Size; Phodopus; Photoperiod; Regression Analysis; Time Factors | 2000 |
Contrasting obesity phenotypes uncovered by partial leptin receptor gene deletion in transgenic mice.
Non-insulin-dependent diabetes mellitus (type 2 diabetes) is known to be a polygenic and polyfactorial disorder. Here we describe the long-term examination of a transgenic mouse line showing the disruption of the leptin receptor (Lepr, Ob-R) gene caused by transgene insertion. The absence of the expression of the long isoform Ob-Rb uncovered a strong variation of the obesity and diabetes phenotype in the homozygous mutant mice of the outbred strain used. One part of the homozygous mice developed severe persistent early-onset obesity, whereas the other part developed cachexia after having shown initial obesity in the examination period up to 26 weeks p.p. The leptin-receptor-defective mice of this line might serve as a model for the investigation of genes modulating the development and mode of expression of diabetes. Topics: Animals; Body Weight; Carrier Proteins; Diabetes Mellitus, Type 2; Female; Gene Deletion; Homozygote; Leptin; Male; Mice; Mice, Mutant Strains; Mice, Transgenic; Obesity; Phenotype; Receptors, Cell Surface; Receptors, Leptin | 2000 |
Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism.
Heterozygous disruption of Gnas, the gene encoding the stimulatory G-protein alpha subunit (G(s)alpha), leads to distinct phenotypes depending on whether the maternal (m-/+) or paternal (+/p-) allele is disrupted. G(s)alpha is imprinted, with the maternal allele preferentially expressed in adipose tissue. Hence, expression is decreased in m-/+ mice but normal in +/p- mice. M-/+ mice become obese, with increased lipid per cell in white and brown adipose tissue, whereas +/p- mice are thin, with decreased lipid in adipose tissue. These effects are not due to abnormalities in thyroid hormone status, food intake, or leptin secretion. +/p- mice are hypermetabolic at both ambient temperature (21 degrees C) and thermoneutrality (30 degrees C). In contrast, m-/+ mice are hypometabolic at ambient temperature and eumetabolic at thermoneutrality M-/+ and wild-type mice have similar dose-response curves for metabolic response to a beta(3)-adrenergic agonist, CL316243, indicating normal sensitivity of adipose tissue to sympathetic stimulation. Measurement of urinary catecholamines suggests that +/p- and m-/+ mice have increased and decreased activation of the sympathetic nervous system, respectively. This is to our knowledge the first animal model in which a single genetic defect leads to opposite effects on energy metabolism depending on parental inheritance. This probably results from deficiency of maternal- and paternal-specific Gnas gene products, respectively. Topics: Adrenergic beta-Agonists; Alleles; Animals; Body Weight; Dioxoles; Energy Metabolism; Female; Genomic Imprinting; GTP-Binding Protein alpha Subunits, Gs; Histocytochemistry; Leptin; Lipids; Male; Mice; Mice, Knockout; Obesity; Phenotype; Thyroid Hormones; Thyrotropin | 2000 |
BDNF regulates eating behavior and locomotor activity in mice.
Brain-derived neurotrophic factor (BDNF) was studied initially for its role in sensory neuron development. Ablation of this gene in mice leads to death shortly after birth, and abnormalities have been found in both the peripheral and central nervous systems. BDNF and its tyrosine kinase receptor, TrkB, are expressed in hypothalamic nuclei associated with satiety and locomotor activity. In heterozygous mice, BDNF gene expression is reduced and we find that all heterozygous mice exhibit abnormalities in eating behavior or locomotor activity. We also observe this phenotype in independently derived inbred and hybrid BDNF mutant strains. Infusion with BDNF or NT4/5 can transiently reverse the eating behavior and obesity. Thus, we identify a novel non-neurotrophic function for neurotrophins and indicate a role in behavior that is remarkably sensitive to alterations in BDNF activity. Topics: Adipocytes; Animals; Appetite; Body Weight; Brain-Derived Neurotrophic Factor; Carrier Proteins; Feeding Behavior; Female; Heterozygote; Humans; Hypothalamus; Insulin; Leptin; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Motor Activity; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Receptor, trkB; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger | 2000 |
Serum leptin, lipids, free fatty acids, and fat pads in long-term dehydroepiandrosterone-treated Zucker rats.
The obese Zucker rat has a genetically flawed leptin system and is a model of hyperphagia, obesity, hyperlipidemia, and markedly elevated leptin levels. Dehydroepiandrosterone (DHEA) administration reduces hyperphagia, hyperlipidemia, and obesity in Zucker rats. Since serum leptin levels are associated with body fat, we wondered what the effects of fat pad weight reduction from DHEA administration would have on leptin levels. This experiment investigated the effects of DHEA on intra-abdominal fat pads, serum lipids, and peripheral leptin in male lean and obese Zucker rats that were administered DHEA in their food from 4 weeks of age to 20 weeks. Lean and obese rats received plain chow or chow containing DHEA. Additional chow-fed groups of lean and obese weight-matched controls and obese pair-fed rats helped to control for the reduced body weight, food intake, and fat pad weights seen with DHEA administration. DHEA administration to lean Zucker rats reduced body weight and fat pad weights, but leptin levels showed a lower trend. Among obese rats, both DHEA treatment and pair-feeding reduced body weight and fat pad weights, but only DHEA lowered leptin levels. The weight-matched controls had reductions in fat pad weights similar to the DHEA-treated group, but with increased leptin levels. Thus, DHEA may exert a small, independent effect on leptin levels in this animal model, but the reduction is less than what would be expected. Topics: Adjuvants, Immunologic; Animals; Body Weight; Corticosterone; Dehydroepiandrosterone; Energy Intake; Fatty Acids, Nonesterified; Glucose; Insulin; Leptin; Lipids; Male; Rats; Rats, Zucker | 2000 |
Caffeine, carnitine and choline supplementation of rats decreases body fat and serum leptin concentration as does exercise.
The effect of a combination of caffeine, carnitine and choline with or without exercise on changes in body weight, fat pad mass, serum leptin concentration and metabolic indices was determined in 20 male, 7-wk-old Sprague-Dawley rats. They were given free access to a nonpurified diet without or with caffeine, carnitine and choline at concentrations of 0.1, 5 and 11.5 g/kg diet, respectively. In a 2x2 factorial design, one-half of each dietary group was exercised, and the other half was sedentary. Body weight and food intake of all rats were measured every day for 28 d. Rats were killed and blood and tissue samples were collected and analyzed for biochemical markers. Food intake of the groups was not different, but the body weight was significantly reduced by exercise in both dietary groups. Fat pad weights and total lipids of epididymal, inguinal and perirenal regions were significantly reduced by the supplements as well as by exercise. Regardless of exercise, supplements significantly lowered triglycerides in serum but increased levels in skeletal muscle. Serum leptin concentrations were equally lowered by supplements and exercise. Serum leptin was correlated with body weight (r = 0.55, P< or =0.01), fat pad weight (r = 0.82, P< or =0.001) and serum glucose (r = 0.51, P< or =0.05). We conclude that the indices of body fat loss due to dietary supplements were similar to those due to mild exercise, and there were no interactive effects of the two variables. Topics: Adipose Tissue; Analysis of Variance; Animals; Blood Glucose; Body Weight; Caffeine; Carnitine; Choline; Diet; Leptin; Male; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Triglycerides | 2000 |
Genetic dissection of the syndrome X in the rat.
In 1988, Reaven used the term syndrome X to describe a relation between several disorders including hypertension, dyslipidemia, impaired glucose tolerance, obesity, and coronary heart disease. Despite a number of studies dealing with syndrome X, its genetic basis remains poorly understood. Regarding the complexity of this syndrome, it is important to use animal models developing the traits of the disease. Here we show a genetic dissection of syndrome X in the WOKW rat, an animal model of genetically determined syndrome X. We found a major quantitative trait locus (QTL) for glucose metabolism on chromosome 3 and further QTLs influencing obesity and body weight on chromosomes 1 and 5. Genetic determinants of dyslipidemia were mapped to chromosomes 4 and 17. In addition, suggestive linkage for serum insulin was found on chromosome 1 to the region previously shown to be associated with type-1 diabetes mellitus. This is the first study demonstrating independent genetic factors influencing traits of the syndrome X in the rat as well as a possible genetic relationships between syndrome X and diabetes mellitus. Moreover, regarding the close similarities between WOKW rat and human syndrome X, the study could help in a search of genetic factors involved in this complex metabolic disorder in human. Topics: Animals; Body Mass Index; Body Weight; Cholesterol; Cholesterol, HDL; Chromosome Mapping; Crosses, Genetic; Female; Glucose; Humans; Hyperlipidemias; Insulin Resistance; Leptin; Male; Obesity; Quantitative Trait, Heritable; Rats; Rats, Inbred Strains; Rats, Mutant Strains; Triglycerides | 2000 |
In vivo modulation of Hmgic reduces obesity.
The HMGI family of proteins consists of three members, HMGIC, HMGI and HMGI(Y), that function as architectural factors and are essential components of the enhancesome. HMGIC is predominantly expressed in proliferating, undifferentiated mesenchymal cells and is not detected in adult tissues. It is disrupted and misexpressed in a number of mesenchymal tumour cell types, including fat-cell tumours (lipomas). In addition Hmgic-/- mice have a deficiency in fat tissue. To study its role in adipogenesis and obesity, we examined Hmgic expression in the adipose tissue of adult, obese mice. Mice with a partial or complete deficiency of Hmgic resisted diet-induced obesity. Disruption of Hmgic caused a reduction in the obesity induced by leptin deficiency (Lepob/Lepob) in a gene-dose-dependent manner. Our studies implicate a role for HMGIC in fat-cell proliferation, indicating that it may be an adipose-specific target for the treatment of obesity. Topics: Adipose Tissue; Animals; Body Weight; Diet; Dietary Fats; Gene Dosage; Gene Targeting; High Mobility Group Proteins; HMGA2 Protein; Leptin; Mice; Mice, Knockout; Mice, Obese; Obesity | 2000 |
Transient hypophagia in rats switched from high-fat diets with different fatty-acid pattern to a high-carbohydrate diet.
The present study investigates the mechanisms underlying the transient hypophagia occurring when rats adapted to high-fat, carbohydrate-free diets are switched to high-carbohydrate, low-fat diets. The hypophagia after the high-fat, carbohydrate-free to high-carbohydrate, low-fat diet shift seems to depend on the amount of carbohydrate in the diet, since an attenuation of hypophagia was observed when high-fat, carbohydrate-free-adapted rats were switched to a medium-carbohydrate, medium-fat diet. A role of glucose intolerance in the hypophagia is supported by the attenuation of carbohydrate anorexia in rats adapted to a high-fat diet containing n -3 polyunsaturated fatty acids from fish oil (60% of fat as fish oil), which has been shown to improve glucose tolerance in rats. Furthermore, the increased plasma glucose concentration in the high-fat, carbohydrate-free diet to high-carbohydrate, low-fat shifted rats despite the suppression in food intake also suggests an involvement of glucose intolerance in the hypophagia. The failure of the inhibitor of hepatic-fatty-acid oxidation mercaptoacetate (400 micromol/kg, i.p.) to counteract carbohydrate anorexia in the HF-adapted rats argues against an involvement of fatty-acids oxidation in the inhibition of eating after high-fat, carbohydrate-free to high-carbohydrate, low-fat diet shift. This is also supported by the failure to demonstrate a relationship between plasma beta-hydroxybutyrate and the severity of the hypophagia. A role of leptin in the hypophagia seems unlikely, since plasma leptin after diet shift was unchanged. Ingestion of the high-carbohydrate, low-fat diet also produced an aversion towards this diet in high-fat, carbohydrate-free-adapted rats. It is concluded that the transient hypophagia induced by switching rats from a high-fat to a high-carbohydrate diet is not related to fatty acid oxidation but to transiently impaired carbohydrate utilization. Topics: Analysis of Variance; Animals; Blood Glucose; Body Weight; Diet; Dietary Carbohydrates; Dietary Fats; Fatty Acids, Unsaturated; Feeding and Eating Disorders; Leptin; Male; Rats; Rats, Sprague-Dawley; Taste | 2000 |
Cholecystokinin and leptin act synergistically to reduce body weight.
Leptin, the product of the obese gene, reduces food intake and body weight in rats and mice, whereas administration of the gut-peptide CCK reduces meal size but not body weight. In the current experiments, we report that repeated daily combination of intracerebroventricular leptin and intraperitoneal CCK results in significantly greater loss of body weight than does leptin alone. However, leptin plus CCK treatment does not synergistically reduce the size of individual 30-min sucrose meals during this period, and the effect of leptin-CCK combination on daily chow intake, while significant, is small compared with the robust effects on body weight loss. This synergistic effect on body weight loss depends on a peripheral action of CCK and a central action of leptin. These data suggest a previously unsuspected role for CCK in body weight regulation that may not depend entirely on reduction of feeding behavior and suggest a strategy for enhancing the effects of leptin in leptin-resistant obese individuals. Topics: Adipose Tissue; Animals; Body Weight; Brain Chemistry; Carrier Proteins; Dietary Sucrose; Dose-Response Relationship, Drug; Drug Synergism; Eating; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Satiation; Sincalide | 2000 |
Effects of fructose and glucose on plasma leptin, insulin, and insulin resistance in lean and VMH-lesioned obese rats.
To determine the influence of dietary fructose and glucose on circulating leptin levels in lean and obese rats, plasma leptin concentrations were measured in ventromedial hypothalamic (VMH)-lesioned obese and sham-operated lean rats fed either normal chow or fructose- or glucose-enriched diets (60% by calories) for 2 wk. Insulin resistance was evaluated by the steady-state plasma glucose method and intravenous glucose tolerance test. In lean rats, glucose-enriched diet significantly increased plasma leptin with enlarged parametrial fat pad, whereas neither leptin nor fat-pad weight was altered by fructose. Two weeks after the lesions, the rats fed normal chow had marked greater body weight gain, enlarged fat pads, and higher insulin and leptin compared with sham-operated rats. Despite a marked adiposity and hyperinsulinemia, insulin resistance was not increased in VMH-lesioned rats. Fructose brought about substantial insulin resistance and hyperinsulinemia in both lean and obese rats, whereas glucose led to rather enhanced insulin sensitivity. Leptin, body weight, and fat pad were not significantly altered by either fructose or glucose in the obese rats. These results suggest that dietary glucose stimulates leptin production by increasing adipose tissue or stimulating glucose metabolism in lean rats. Hyperleptinemia in VMH-lesioned rats is associated with both increased adiposity and hyperinsulinemia but not with insulin resistance. Dietary fructose does not alter leptin levels, although this sugar brings about hyperinsulinemia and insulin resistance, suggesting that hyperinsulinemia compensated for insulin resistance does not stimulate leptin production. Topics: Animals; Area Under Curve; Blood Glucose; Body Weight; Diet; Dietary Carbohydrates; Female; Fructose; Glucose; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Obesity; Rats; Rats, Sprague-Dawley; Ventromedial Hypothalamic Nucleus | 2000 |
Long-term peripheral treatment of immature coho salmon (Oncorhynchus kisutch) with human leptin has no clear physiologic effect.
The effects of long-term peripheral exposure to recombinant human leptin were tested in immature coho salmon under both fed and fasted conditions. We found that high circulating levels of human leptin did not alter growth, energy stores, gonad weight, pituitary content of follicle-stimulating hormone, or plasma levels of insulin-like growth factor-I, insulin, growth hormone, or thyroxine. Topics: Animals; Body Weight; Drug Implants; Energy Metabolism; Follicle Stimulating Hormone; Growth; Hormones; Humans; Leptin; Liver Glycogen; Oncorhynchus kisutch; Organ Size; Pituitary Gland; Radioimmunoassay; Recombinant Proteins | 2000 |
Longitudinal changes of circadian leptin, insulin and cortisol plasma levels and their correlation during refeeding in patients with anorexia nervosa.
To study the longitudinal changes in plasma levels of leptin, insulin and cortisol during the transition from the state of starvation to the state of refeeding focussing on diurnal secretion characteristics and their temporal relationships.. Leptin, insulin and cortisol were measured every 2h for 24h during acute starvation (T1). Sampling was repeated after reaching half the target-body mass index (BMI) (T2) and again at target-BMI (17. 5kg/m(2); T3). The temporal relationships between the diurnal secretion patterns were assessed by cross-correlation analysis.. Although BMIs at T1 were uniformly low, leptin levels varied widely within a range clearly below normal levels (0.03-1. 7microg/l). With increasing body fat during the course of refeeding, mean leptin levels increased from 0.64microg/l (range: 0.27-1. 73microg/l) (T1) to 1.61microg/l (range: 0.36-4.2microg/l) (T2) and to 3.67microg/l (range: 0.7-9.8microg/l) (T3). Circadian leptin secretion patterns showed maximal values uniformly around 0200h and minimal values around 0800h at all stages of the study. At all three weight levels, plasma leptin levels were highest between midnight and the early morning hours and lowest around the late morning hours. Refeeding neither profoundly changed secretion patterns of leptin nor did it change the positive, time-delayed relationship between leptin and insulin with increments in insulin secretion preceding those of leptin by 6h. A temporal relationship between leptin and cortisol could not be demonstrated in the state of semistarvation but emerged after a substantial weight gain; at that time, leptin increases preceded cortisol increases by 8h.. Absolute leptin, insulin and cortisol levels are profoundly changed during starvation in anorectic patients, while refeeding, paralleled by a BMI gain, reverses these changes. During refeeding the relationship between leptin and cortisol changed profoundly, showing no significant correlation in the state of starvation, whereas at T3 after refeeding a strong inverse relationship could be observed. Leptin and insulin did not correlate significantly at any of the three stages studied. Topics: Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Circadian Rhythm; Cohort Studies; Female; Food; Humans; Hydrocortisone; Insulin; Leptin; Longitudinal Studies; Male; Reference Values; Starvation | 2000 |
Obesity research. Tracing leptin's partners in regulating body weight.
Topics: Adipocytes; alpha-MSH; Animals; Appetite; Body Weight; Carrier Proteins; Humans; Hypothalamic Hormones; Hypothalamus; Leptin; Melanins; Muscles; Neuropeptide Y; Neuropeptides; Obesity; Pituitary Hormones; Pro-Opiomelanocortin; Proteins; Receptors, Cell Surface; Receptors, Leptin; Repressor Proteins; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors | 2000 |
Serum leptin concentrations in children with Prader-Willi syndrome and non-syndromal obesity.
There is limited information on the underlying physiological mechanisms promoting obesity in patients with Prader-Willi syndrome (PWS). The aim of this study was to investigate whether body fat regulation in children with PWS is similar to that in children with non-syndromal obesity and non-obese children. We studied three groups: 1) 72 non-obese children and adolescents; 2) 68 children with non-syndromal obesity; and 3) 11 patients with PWS. Height and weight were measured and body mass index (BMI) and BMI SDS were calculated. Fasting serum leptin concentrations were determined. Median leptin serum concentrations were similar in PWS patients and children with non-syndromal obesity. Median leptin serum concentrations were higher in these two groups than in the non-obese group. Log leptin serum concentrations and BMI SDS showed significant correlations in the three groups of patients; correlation coefficients were 0.525, 0.285 and 0.854, respectively. In conclusion, median leptin serum concentrations are similar in PWS patients and children with non-syndromal obesity. The relationship between log serum leptin concentrations and BMI SDS was different in the three groups of patients studied. Topics: Adolescent; Biliopancreatic Diversion; Body Height; Body Mass Index; Body Weight; Child; Female; Humans; Leptin; Male; Obesity; Prader-Willi Syndrome | 2000 |
Dual regulation of leptin secretion: intracellular energy and calcium dependence of regulated pathway.
Rodent leptin is secreted by adipocytes and acutely regulates appetite and chronically regulates body weight. Mechanisms for leptin secretion in cultured adipocytes were investigated. Acutely, energy-producing substrates stimulated leptin secretion about twofold. Biologically inert carbohydrates failed to stimulate leptin secretion, and depletion of intracellular energy inhibited leptin release. There appears to be a correlation between intracellular ATP concentration and the rate of leptin secretion. Insulin increased leptin secretion by an additional 25%. Acute leptin secretion is calcium dependent. When incubated in the absence of calcium or in the presence of intracellular calcium chelators, glucose plus insulin failed to stimulate leptin secretion. In contrast, basal leptin secretion is secreted spontaneously and is calcium independent. Adipocytes from fatter animals secrete more leptin, even in the absence of calcium, compared with cells from thinner animals. Acute stimulus-secretion coupling mechanisms were then investigated. The potassium channel activator diazoxide and the nonspecific calcium channel blockers nickel and cadmium inhibited acute leptin secretion. These studies demonstrate that intracellular energy production is important for acute leptin secretion and that potassium and calcium flux may play roles in coupling intracellular energy production to leptin secretion. Topics: Adenosine Triphosphate; Adipocytes; Animals; Body Weight; Cadmium; Calcium; Calcium Channel Blockers; Cells, Cultured; Diazoxide; Energy Metabolism; Insulin; Leptin; Male; Nickel; Potassium Channels; Rats; Rats, Sprague-Dawley | 2000 |
Leptin-specific patterns of gene expression in white adipose tissue.
Leptin is a hormone that regulates body weight by decreasing food intake and increasing energy expenditure. ob/ob mice carry leptin mutations and are obese and hyperphagic. Leptin administration to lean and ob/ob mice activates a novel metabolic program that depletes adipose tissue. Although this response is physiologically distinct from that evident after food restriction, the molecular nature of these differences is as yet unknown. Expression monitoring of 6500 genes using oligonucleotide microarrays in wild-type, ob/ob, and transgenic mice expressing low levels of leptin revealed that differences in ambient leptin levels have dramatic effects on the phenotype of white adipose tissue. These data identified a large number of genes that are differentially expressed in ob/ob mice. To delineate the components of the transcriptional program specifically affected by leptin, the level of the same 6500 genes was monitored in wild-type and ob/ob mice at various times after leptin treatment or food restriction. A novel application of k-means clustering identified 8 clusters of adipose tissue genes whose expression was different between leptin treatment and food restriction in ob/ob mice and 10 such clusters in wild-type experiments. One of the clusters was repressed specifically by leptin in both wild-type and ob/ob mice and included several genes known to be regulated by SREBP-1/ADD1. Further studies confirmed that leptin decreases the levels of SREBP-1/ADD1 RNA and transcriptionally active SREBP-1/ADD1 protein in white adipose tissue. Future studies of the molecular basis for the apparent coordinate regulation of the other clusters of leptin-regulated genes may reveal additional mechanisms by which leptin exerts its weight-reducing effects. Topics: Adipose Tissue; Algorithms; Animals; Blotting, Northern; Body Weight; CCAAT-Enhancer-Binding Proteins; Cell Differentiation; Cluster Analysis; DNA-Binding Proteins; Down-Regulation; Female; Food Deprivation; Gene Expression; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Nuclear Proteins; Oligonucleotide Array Sequence Analysis; Sterol Regulatory Element Binding Protein 1; Time Factors; Transcription Factors; Transcription, Genetic; Up-Regulation | 2000 |
Pathophysiological role of leptin in obesity-related hypertension.
To explore the pathophysiological role of leptin in obesity-related hypertension, we examined cardiovascular phenotypes of transgenic skinny mice whose elevated plasma leptin concentrations are comparable to those seen in obese subjects. We also studied genetically obese KKA(y) mice with hyperleptinemia, in which hypothalamic melanocortin system is antagonized by ectopic expression of the agouti protein. Systolic blood pressure (BP) and urinary catecholamine excretion are elevated in transgenic skinny mice relative to nontransgenic littermates. The BP elevation in transgenic skinny mice is abolished by alpha(1)-adrenergic, beta-adrenergic, or ganglionic blockers at doses that do not affect BP in nontransgenic littermates. Central administration of an alpha-melanocyte-stimulating hormone antagonist causes a marked increase in cumulative food intake but no significant changes in BP. The obese KKA(y) mice develop BP elevation with increased urinary catecholamine excretion relative to control KK mice. After a 2-week caloric restriction, BP elevation is reversed in nontransgenic littermates with the A(y) allele, in parallel with a reduction in plasma leptin concentrations, but is sustained in transgenic mice overexpressing leptin with the A(y) allele, which remain hyperleptinemic. This study demonstrates BP elevation in transgenic skinny mice and obese KKA(y) mice that are both hyperleptinemic, thereby suggesting the pathophysiological role of leptin in some forms of obesity-related hypertension. Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; alpha-MSH; Animals; Blood Pressure; Body Weight; Eating; Energy Intake; Ganglionic Blockers; Heart; Heart Rate; Hexamethonium; Hypertension; Kidney; Leptin; Male; Melanocyte-Stimulating Hormones; Mice; Mice, Transgenic; Models, Biological; Obesity; Organ Size; Sympathetic Nervous System; Systole; Urine | 2000 |
An acute i.c.v. infusion of leptin has no effect on hypothalamic histamine and tele-methylhistamine contents in Wistar rats.
The actions of intracerebroventricularly (i.c.v.) infused leptin on food intake, body weight and hypothalamic contents of histamine and tele-methylhistamine, the main histamine metabolite in the mammalian brain, were studied in male Wistar rats. The effect of the histamine H(1) receptor blockade on leptin-induced anorexia was also examined. It was found that leptin at the dose of 10 microg i.c.v. reduced 24-h food intake by 48% as compared with the controls (P<0.01). This leptin dose reduced feeding during 2-4 consecutive days. In spite of the marked changes in food consumption and body weight gain, leptin did not alter the hypothalamic contents of histamine and tele-methylhistamine. Furthermore, the blockade of histamine H(1) receptors by mepyramine did not attenuate the effect of leptin on feeding and body weight. The findings indicate that centrally administered leptin suppresses feeding and promotes weight loss through mechanisms that do not require the direct participation of the brain histaminergic neuron system. Topics: Animals; Anorexia; Body Weight; Eating; Histamine; Histamine H1 Antagonists; Hypothalamus; Leptin; Male; Methylhistamines; Motor Activity; Rats; Rats, Wistar; Receptors, Histamine H1 | 2000 |
Leptin is influenced both by predisposition to obesity and diet composition.
(1) To investigate whether plasma leptin concentrations differ between subjects with and without the genetic predisposistion to obesity, and (2) to investigate the effect of dietary manipulations on plasma leptin in these subjects.. Fasting and postprandial plasma leptin concentrations were measured before and after 14 days' ad libitum intake of a fat-rich (FAT), starch-rich (STARCH) or sucrose-rich (SUCROSE) diet. On day 15 ad libitum breakfast and lunch were given and blood sampled regularly until 6 p.m.. Eight normal-weight, post-obese women and 10 matched controls (body mass index, 23.5+/-0.5 and 22.9 +/- 0.3 kg/m2).. Leptin, glucose, insulin, appetite ratings, dietary intake, body weight and composition.. Fasting leptin concentration on day 1 or 15 did not differ between post-obese and controls. However, after meal intake leptin increased in post-obese compared with controls on all three diets. In both groups fasting and postprandial leptin concentrations were greater after SUCROSE compared with FAT and STARCH.. A larger postprandial leptin concentration was observed in post-obese subjects than in controls. This may be related to greater insulin sensitivity in adipose tissue in the post-obese. Furthermore, increased leptin concentrations were found after a sucrose-rich diet in both groups, possibly related to larger postprandial insulin peaks on this diet. Both contentions should, however, be validated by further studies. Topics: Adult; Appetite; Area Under Curve; Blood Glucose; Body Composition; Body Weight; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Sucrose; Energy Intake; Female; Humans; Insulin; Leptin; Obesity; Starch; Time Factors | 2000 |
Circulating leptin in patients with anorexia nervosa, bulimia nervosa or binge-eating disorder: relationship to body weight, eating patterns, psychopathology and endocrine changes.
A decreased production of leptin has been reported in women with anorexia nervosa (AN) and has been attributed merely to the patients' reduced body fat mass. The extent to which eating patterns, purging behaviors, psychopathology and endocrine changes may contribute to the genesis of leptin alterations has not been deeply investigated. Therefore, we measured plasma levels of leptin, glucose and other hormones in three groups of eating disorder patients with different body weight (BW), eating patterns and purging behaviors. Sixty-seven women, 21 with AN, 32 with bulimia nervosa (BN), 14 with binge-eating disorder (BED) and 25 healthy females volunteered for the study. We found that circulating leptin was significantly reduced in AN and BN patients, but significantly enhanced in women with BED. In anorexics, plasma glucose was decreased, whereas plasma cortisol was enhanced; blood concentrations of 17beta-estradiol and prolactin (PRL) were reduced in both AN, BN and BED patients. In all subject groups, a strong positive correlation emerged between plasma levels of leptin and the subjects' BW or body mass index, but not between leptin and psychopathological measures, plasma glucose, cortisol, PRL and 17beta-estradiol. Since leptin was reduced in both underweight anorexics and normal weight bulimics, but increased in overweight BED women, who compulsively binge without engaging in compensatory behaviors, we suggest that factors other than BW may play a role in the determination of leptin changes in eating disorders. Topics: Adult; Anorexia Nervosa; Body Weight; Bulimia; Estradiol; Feeding Behavior; Female; Hormones; Humans; Hydrocortisone; Hyperphagia; Leptin; Obesity; Prolactin | 2000 |
Chronic intracerebroventricular insulin attenuates the leptin-mediated but not alpha melanocyte stimulating hormone increase in sympathetic and cardiovascular responses.
The co-existence of hyperinsulinemia and hyperleptinemia of obesity is well established. Additionally, both insulin resistance and leptin resistance are also characteristic of these states. Possible central nervous system (CNS) mechanisms could mediate these responses in that leptin receptors are located on hypothalamic neurons that coexpress neuropeptide-Y (NPY) or proopiomelanocortin (POMC) and both peptides that have been implicated as mediators of the CNS action of leptin. Leptin has been demonstrated to decrease or down regulate NPY expression and increase POMC expression. Insulin also has been demonstrated to decrease NPY and insulin insufficiency is associated with an increased POMC. Since both leptin and insulin share and modulate the same effector systems, we investigated the effect of CNS-induced hyperinsulinemia on the subsequent cardiovascular and sympathetic nervous response to leptin. Normal rats were implanted with intracerebroventricular (i.c.v.) cannula and allowed to recover. They were treated with insulin via i.c.v. cannula for 3 days. Following treatment, they were instrumented for the recording of cardiovascular and sympathetic nervous responses. Intracerebroventricular leptin administration in normal animals result in a progressive increase in both lumbar sympathetic nerve activity and mean arterial pressure. However, in animals pretreated with insulin for 3 days the leptin-induced response was completely attenuated. However, insulin treatment did not affect the POMC peptide product, alpha-melanocyte stimulating hormone (alphaMSH), mediated sympathetic nervous and cardiovascular responses. From these studies we conclude that CNS hyperinsulinemia can act to attenuate the leptin-induced increases in sympathetic nervous and cardiovascular system activity. The decreased responsiveness is not due to decreased sensitivity of the melanocortin, alphaMSH, mediated pathway.We suggest that the hyperinsulinemia of obesity may play a role in the obesity-induced leptin resistance. Topics: alpha-MSH; Animals; Blood Pressure; Body Weight; Cerebral Ventricles; Drug Administration Schedule; Heart Rate; Hyperinsulinism; Injections, Intraventricular; Insulin; Leptin; Male; Rats; Rats, Wistar; Sympathetic Nervous System | 2000 |
Increased gene expression of brown fat uncoupling protein (UCP)1 and skeletal muscle UCP2 and UCP3 in MAC16-induced cancer cachexia.
Weight loss in cancer cachexia is attributable to decreased food intake and/or enhanced energy expenditure. We investigated the roles of the uncoupling proteins (UCPs) UCPI, -2, and -3 in a murine model of cachexia, the MAC16 adenocarcinoma. Weight fell to 24% below that of non-tumor-bearing controls (P < 0.01) 18 days after MAC16 inoculation, with significant reductions in fat-pad mass (-67%; P < 0.01) and muscle mass (-20%; P < 0.01). Food intake was 26-60% lower (P < 0.01) than in controls on days 17-18. Non-tumor-bearing mice, pair-fed to match MAC16-induced hypophagia, showed less weight loss (10% below controls, P < 0.01; 16% above MAC-16, P < 0.01) and smaller decreases in fat-pad mass (21% below controls, P < 0.01). Core temperature in MAC16 mice was significantly lower (-2.4 degrees C, P < 0.01) than in controls, and pair-feeding had no effect. MAC16 mice showed significantly higher UCP1 mRNA levels in brown adipose tissue (BAT) than in controls (+63%, P < 0.01), and pair-feeding had no effect. UCP2 and -3 expression in BAT did not differ significantly between groups. By contrast, UCP2 mRNA levels in skeletal muscle were comparably increased in both MAC16 and pair-fed groups (respectively, 183 and 163% above controls; both, P < 0.05), with no significant difference between these two groups. Similarly, UCP3 mRNA was significantly higher than controls in both MAC16 (+163%, P < 0.05) and pair-fed (+253%, P < 0.01) groups, with no significant difference between the two experimental groups. Overexpression of UCP1 in BAT in MAC16-bearing mice may be an adaptive response to hypothermia, which is apparently induced by tumor products; increased thermogenesis in BAT could increase total energy expenditure and, thus, contribute to tissue wasting. Increased UCP2 and -3 expression in muscle are both attributable to reduced food intake and may be involved in lipid utilization during lipolysis in MAC16-induced cachexia. Topics: Adenocarcinoma; Adipose Tissue, Brown; Analysis of Variance; Animals; Blotting, Northern; Body Temperature; Body Weight; Cachexia; Carrier Proteins; Eating; Female; Gene Expression; Ion Channels; Leptin; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Inbred Strains; Mitochondrial Proteins; Muscle, Skeletal; Neoplasms, Experimental; Protein Biosynthesis; Proteins; RNA, Messenger; RNA, Ribosomal, 18S; Time Factors; Tumor Necrosis Factor-alpha; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3 | 2000 |
Cranial irradiation of female rats causes dose-dependent and age-dependent activation or inhibition of pubertal development.
Cranial irradiation in prepubertal children with leukemia or brain tumors can lead to precocious or in high doses to late puberty. To unravel the underlying mechanisms, we developed a rat model with selective cranial Co60-irradiation technique. Infantile (12-16 d old) or juvenile (21-23 d old) female Sprague-Dawley rats received a single dose of 4, 5, 6, 9 or 2 x 9 Gy (at days 21 and 23). Each group consisted of 7-20 animals. High radiation doses (9 Gy and more) caused retardation of sexual development, whereas low radiation doses (5 or 6 Gy) led to accelerated onset of puberty in 20% of infantile irradiated rats animals as determined by vaginal opening. Interestingly, at peripubertal age (postnatal day 32-34), 5 or 6 Gy infantile irradiated rats had significantly higher serum LH levels stimulated by GnRH and estradiol levels (p < 0.05). 2 x 9 Gy irradiated rats had at the age of 3 mo a marked growth retardation and significantly lower GH levels than the controls (p < 0.05) whereas prolactin, FSH, TSH, T4, and corticosterone levels were comparable with controls. These studies demonstrate that the GnRH-pulse generator is very radiosensitive as precocious activation occurred after low dose irradiation (5 or 6 Gy) of infantile rats without any other endocrine disorder. High radiation doses (9 or 2 x 9 Gy) induced retardation of sexual maturation and later on growth hormone deficiency. Moreover this model of cranial irradiation seems to be suitable to study the molecular mechanisms of radiation induced pubertal changes. Topics: Age Factors; Animals; Body Weight; Corticosterone; Cranial Irradiation; Dose-Response Relationship, Radiation; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Growth; Growth Hormone; Growth Hormone-Releasing Hormone; Leptin; Luteinizing Hormone; Prolactin; Rats; Rats, Sprague-Dawley; Sexual Maturation; Thyrotropin; Thyroxine | 2000 |
Weight gain-induced blood pressure elevation.
This study was conducted to evaluate the mechanisms in weight gain-induced blood pressure (BP) elevation focusing, in particular, on the contributions of sympathetic nervous system activity, fasting plasma insulin, and leptin to BP levels. The study design was longitudinal with a cohort of 1897 men. BP, pulse rate, body mass index (BMI), fasting plasma norepinephrine (NE), insulin, and leptin were measured at 6 and 12 months in those 172 lean normotensive, 79 obese normotensive, 64 lean untreated hypertensive, and 38 obese untreated hypertensive men whose BMI increased >10% during the first 6 months. At entry, levels of BP, pulse rate, plasma NE, insulin, and leptin in obese subjects, regardless of BP status, were significantly greater than those in lean subjects. The levels of plasma NE, insulin, and leptin increased with weight gain in the 4 study groups. In the subjects with BP elevation, the increase in pulse rate and plasma NE was significantly greater than that in the subjects without BP elevation at both 6 and 12 months for each of the 4 study groups, although the increase in BMI was similar between the subjects with and without BP elevation. In obese but not lean subjects, whether normotensive or hypertensive, the increases in plasma insulin and plasma leptin with weight gain were greater in the subjects with accompanying BP elevation compared with the subjects without BP elevation. On the other hand, at 6 months in lean subjects, the increase in plasma insulin with weight gain in the subjects with BP elevation was actually lower than that in the subjects without BP elevation. These results suggest that weight gain-induced sympathetic overactivity is more tightly linked to weight gain-induced BP elevation than the changes in plasma insulin and leptin that also accompany weight gain. It is probable that sympathetic nervous activation with weight gain is a major mechanism of blood pressure elevation. Hyperinsulinemia and hyperleptinemia may be ancillary factors that contribute to sympathetic nervous stimulation with weight gain. Topics: Adult; Blood Pressure; Body Weight; Humans; Insulin; Leptin; Male; Middle Aged; Obesity; Sympathetic Nervous System | 2000 |
Partial saturation and regional variation in the blood-to-brain transport of leptin in normal weight mice.
Impaired blood-brain barrier transport of leptin into the arcuate nucleus has been suggested to underlie obesity in humans and outbred aging mice. Here, we used a brain perfusion method in mice to measure transport rates and kinetic parameters for leptin at vascular concentrations between 0.15 and 130 ng/ml. Transport into whole brain was partially saturated at all concentrations, not only those seen in obesity. Leptin entered all regions of the brain, not only the hypothalamus, with entry and saturation rates differing among the brain regions. The value of the Michaelis-Menten constant of the transporter approximates normal serum levels and the maximum velocity value varies significantly among brain regions. These results suggest an important role for low serum levels signaling starvation status to the brain and show that the levels of leptin seen in obesity greatly saturate the transporter. Differences in regional uptake and saturation provide a mechanism by which leptin can control events mediated at the arcuate nucleus and other regions of the central nervous system with different regional thresholds for optimal function. Topics: Animals; Arcuate Nucleus of Hypothalamus; Biological Transport; Blood-Brain Barrier; Body Weight; Kinetics; Leptin; Mice; Recombinant Proteins; Tissue Distribution | 2000 |
The in vivo and in vitro effects of exogenous leptin on ovulation in the rat.
Leptin, a hormonal product of the Lep gene, is expressed by adipocytes and is thought to play a role in regulating food intake and reproduction. The leptin protein has been localized in many reproductive tissues, including the ovary. Several publications indicate that the ovary is directly affected by leptin and that leptin may be a factor linking obesity and reproductive dysfunction. In this study, the effect of systemic leptin administration on ovulation in the rat ovary, both in vivo and in vitro, was investigated. Ip administration of leptin (30 microg at 3 hourly intervals for 15 h) to immature gonadotropin-primed rats caused a decline in ovulation in vivo, from 15.9+/-2.0 oocytes in the control animals to 5.3+/-1.6 oocytes in the leptin-treated animals (P < 0.001). Plasma progesterone and estradiol levels were analyzed immediately before ovulation, and neither was altered significantly in animals receiving the leptin treatment. Food consumption and body weight decreased following leptin treatment; however, a loss in body weight alone (pair-fed controls) was insufficient to explain the decrease in ovulation observed in the leptin-treated animals. In vitro perfusion of FSH-primed whole ovaries showed that treatment with leptin in combination with LH significantly decreased ovulations from 5.7+/-1.6 per ovary perfused with LH alone to 1.3+/-0.6 in those with LH and 1 microg/ml leptin (P < 0.05). Progesterone and estradiol levels in the samples taken during the perfusion period were unaffected by leptin treatment. In summary, leptin administration resulted in fewer ovulations, both in vivo and in vitro, but did not influence steroid levels. Systemic leptin administration at these doses can therefore inhibit ovulation, a process that occurs through a direct effect on the ovary. Topics: Animals; Body Weight; Chorionic Gonadotropin; Eating; Estradiol; Female; Follicle Stimulating Hormone; Humans; Kinetics; Leptin; Luteinizing Hormone; Organ Size; Ovary; Ovulation; Progesterone; Rats; Rats, Sprague-Dawley | 2000 |
Metabolic assessment of female chronic dieters with either normal or low resting energy expenditures.
Chronic dieting syndrome can have negative physiologic and psychological consequences. Metabolic differences between female chronic dieters with normal and with low resting energy expenditures (REEs) have not been fully examined.. To determine whether differences existed between 2 groups (n = 15/group) of female chronic dieters aged 21-49 y with either normal (>/=100% of predicted) and with low (=85% of predicted) REEs based on the equation of Mifflin et al.. The sample was a nonrandomized convenience sample and the 2 groups were compared in an observational study design. Body composition, aerobic fitness, physical activity, glucose and insulin responses, leptin and thyroid hormone status, dietary intake, and dietary restraint were measured.. Both groups were similar with respect to age, height, weight, and body mass index. The normal-REE group had a higher lean body mass and insulin response to a test meal, higher thyroxine and reverse triiodothyronine concentrations, and lower dietary restraint. Within both groups, leptin decreased significantly from baseline to 2 h after an oral-glucose-tolerance test. The groups did not differ significantly with respect to dietary intake, aerobic fitness, or physical activity.. Differences in insulin response were associated with higher ratios of abdominal to gluteal body fat in the normal-REE group. Leptin response appears to be due to normal diurnal variations in leptin production rather than a direct response to food consumption. It appears that a normal REE does not necessarily predict positive metabolic health among chronic dieters. Topics: Adipose Tissue; Adult; Blood Glucose; Body Composition; Body Weight; Diet, Reducing; Energy Metabolism; Exercise; Fasting; Female; Humans; Insulin; Kinetics; Leptin; Middle Aged; Oxygen Consumption; Physical Fitness; Rest | 2000 |
Leptin in postmenopausal women: influence of hormone therapy, insulin, and fat distribution.
Whether use of hormone-replacement therapy (HRT) influences menopause-related changes in body weight is unclear. HRT may affect energy balance by influencing synthesis of the adipocyte-derived hormone leptin. The objectives of this study were to: 1) identify factors influencing circulating leptin in postmenopausal women; 2) determine whether HRT influences serum leptin after adjusting for confounding factors; and, 3) identify potential independent effects of HRT or leptin on resting energy expenditure (REE). Subjects were 54 postmenopausal women, 45-55 yr old, 35 of whom used HRT (estrogen plus progestin). Total and regional body composition and fat distribution were determined by dual-energy x-ray absorptiometry and computed tomography; fasting serum leptin and insulin, by RIA; and REE, by indirect calorimetry. Stepwise multiple linear regression analysis indicated that serum leptin could best be predicted from total fat mass, fasting serum insulin, and total lean mass [log leptin = 1.08 x log fat mass) + (0.46 x log insulin) + (-1.25 x log lean mass) + 1.88; model R2 = 0.78, P < 0.001]. Multiple linear regression analysis indicated that visceral fat was independently related to leptin (parameter estimate = 0.23, P < 0.05), after adjusting for s.c. abdominal fat and leg fat, as well as lean mass and insulin. After adjusting for total fat mass, total lean mass, and fasting insulin, serum leptin did not differ between users and nonusers of HRT (21.7 +/- 1.0 vs. 20.2 +/- 1.3 ng/mL, P = 0.369, adjusted mean +/- SE, respectively). Serum estradiol was inversely correlated with (adjusted) leptin in non-HRT users (r = -0.50), suggesting that ovarian senescence may lead to an increase in leptin. Multiple linear regression analysis indicated that REE (adjusted for fat mass, fat-free mass, and ethnicity) was not associated with leptin (P = 0.298) or hormone use status (P = 0.999; 1323 +/- 31 vs. 1316 +/- 42 kcal/day, adjusted mean +/- SE for users and nonusers, respectively). These results indicate that, in postmenopausal women: 1) total fat mass, lean mass, and fasting insulin, but not HRT, are significant determinants of serum leptin; 2) visceral and s.c. fat contribute to serum leptin; and, 3) neither HRT nor leptin is independently related to REE. Topics: Absorptiometry, Photon; Adipose Tissue; Basal Metabolism; Blood Glucose; Body Composition; Body Weight; Calorimetry, Indirect; Estradiol; Estrogen Replacement Therapy; Estrone; Female; Humans; Insulin; Leptin; Middle Aged; Postmenopause | 2000 |
Plasma leptin concentrations and cardiac autonomic nervous system in healthy subjects with different body weights.
Previous studies have shown that leptin stimulates sympathetic nervous system; heart rate variability (HRV) is a widely used technique for assessing the sympathovagal balance at the cardiac level. The aim of our study was to investigate a possible relationship between plasma leptin levels and the autonomic regulation using spectral analysis of HRV. In 120 healthy nonobese subjects the plasma leptin concentration was determined, and HRV was recorded at baseline and during tilt. All subjects were categorized in quartiles of plasma leptin concentration. Analysis of data showed a significant increase in body mass index, body fat, fasting plasma insulin, triglyceride concentration, and homeostatic model assessment values throughout the different quartiles of plasma leptin concentration. Concerning cardiovascular parameters, heart rate, arterial blood pressures, and RR intervals were not significantly different among the quartiles. Total power and high frequency (HF) in normalized units were significantly decreased, whereas low frequency (LF) normalized units was progressively increased from the first to the fourth quartile. Thus, the LF/HF ratio rose gradually and significantly from the lowest to the highest quartile. Such results were independent of the body fat estimate (P < 0.03 for the trend). The change in the LF/HF ratio was significantly enhanced during tilt (P < 0.001 vs. rest values for all quartiles); the effect was stronger in subjects in the fourth quartile of plasma leptin concentration (P < 0.005 for the trend). The latter parameter was also independent of body fat content and distribution (P < 0.01). Our study shows that increasing fasting plasma leptin concentrations are associated with a shift of the sympathovagal balance toward a progressive increase in sympathetic activation and an increased response to orthostatic stimulus in nonobese subjects with different body fat contents. Topics: Adipose Tissue; Adult; Autonomic Nervous System; Blood Pressure; Body Composition; Body Mass Index; Body Weight; Epinephrine; Heart; Heart Rate; Homeostasis; Humans; Insulin; Leptin; Lipoproteins; Male; Norepinephrine; Triglycerides | 2000 |
Leptin and aging: correlation with endocrine changes in male and female healthy adult populations of different body weights.
Aging is associated with changes in plasma levels of several hormones. There are conflicting reports on whether circulating leptin levels change during aging, the possible explanation for which is that alterations in adiposity and body mass index (BMI) also occur. In this study we measured plasma leptin and other hormonal parameters known to influence leptin in 150 men and 320 women of a wide age (18-77 yr) and BMI (18.5-61.1 kg/m2) range. Subjects of each gender were separated into 2 groups of similar BMI, i.e. nonobese (BMI, <30) and obese (BMI, >30), and treated separately. Statistical analysis was performed, treating each group of subjects as a whole population or divided into age groups (<30, 30-50, and >50 yr). BMI-adjusted leptin levels were progressively lower with increasing age in women, with a consistent fall after menopause (-21%; P < 0.001); in men, leptin levels also tended to be lower in subjects more than 50 yr of age, but the reduction was not significant. Multiple linear regression analysis, performed on subjects treated either as a whole population or divided into obese and nonobese, showed that in both genders BMI and age were independent contributors of leptin levels, and there was an inverse relationship between leptin and age in both obese (standardized coefficient beta = -0.25 in women and -0.23 in men; P < 0.01) and nonobese (-0.22 in women and -0.20 in men; P < 0.05) subjects. The correlation of leptin and age with plasma levels of sex and thyroid hormones, GH, insulin-like growth factor I, PRL, and insulin was also evaluated. The variables that correlated with leptin were included in a multiple regression model that included BMI and age. Testosterone in men (-0.43 in nonobese and -0.19 in obese; P < 0.05) and estradiol in women (0.22 in nonobese and 0.24 in obese; P < 0.05) were important contributors to leptin levels; also, dehydroepiandrosterone sulfate in obese women (-0.16) and sex hormone-binding globulin in obese subjects of both genders (0.15 in women and 0.19 in men) were significant determinants in the model. However, none of the hormonal parameters abolished the negative correlation between leptin and age or the gender difference in leptin levels. In conclusion, our data show that in adult humans of different body weight, serum leptin gradually declines during aging; leptin reduction is higher in women than in men, but it is independent from BMI and other age-related endocrine changes. Topics: Adolescent; Adult; Aged; Aging; Androgens; Blood Glucose; Body Weight; Cross-Sectional Studies; Estradiol; Female; Hormones; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Prolactin; Reference Values; Sex Characteristics; Thyrotropin; Thyroxine; Triiodothyronine | 2000 |
Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice.
To investigate the development of high fat diet-induced obesity and leptin resistance.. Two experiments were carried out in this study. Firstly, we fed the mice with a high- or low-fat diet for up to 19 weeks to examine a progressive development of high fat diet-induced obesity. Secondly, we examined peripheral and central exogenous leptin sensitivity in mice fed high- or low-fat diets for 1, 8 or 19 weeks.. A total of 168 C57BL/6J mice (3 weeks old) were used in this study.. In the first experiment, we measured the body weight, energy intake, adipose tissue mass, tibia bone length, and plasma leptin in mice fed either a high- or low-fat diet for 1, 8, 15 and 19 weeks. In the second experiment, body weight change and cumulative energy intake were measured at 6 h intervals for 72 h after leptin injection in mice fed a high- or low-fat diet for 1, 8 or 19 weeks.. The results from the first experiment suggested that the development of high fat diet-induced obesity in mice could be divided into early, middle and late stages. Compared with the mice fed a low-fat diet, the mice fed a high-fat diet showed a gradually increased body weight (+5.2%), fat storage (epididymal plus perirenal; +6.7%) and plasma leptin (+18%) at 1 week; +11.4%, +68.1%, and +223%, respectively, at 8 weeks; and +30.5%, +141%, and +458%, respectively, at 19 weeks. Energy intake of high fat diet-fed mice was equal to that of low fat diet-fed controls for the first 3 weeks; it fell below control levels over the next 5 week period, but began to increase gradually after 8 weeks of high-fat diet feeding and then increased dramatically from 15 weeks to be 14% higher than that of controls after 19 weeks. The results from our second experiment showed that: (1) after 1 week of feeding, the mice fed a high-fat diet were sensitive to a 2 microg/g (body weight) intraperitoneal (i. p.) injection of leptin, with no differences in body weight change or cumulative energy intake post-injection; (2) after 8 weeks of feeding, the mice fed a high-fat diet were insensitive to 2 microg/g (body weight) i.p. leptin, but were sensitive to a 0.1 microg intracerebroventricular (i.c.v.) injection of leptin; (3) after 19 weeks of feeding, the mice fed a high-fat diet were insensitive to 0. 1 microg i.c.v. leptin, but were sensitive to a high dose of 2 microg i.c.v. leptin.. The present study demonstrated that the development of high fat diet-induced obesity (19 weeks) in C57 B1/6J mice could be divided into three stages: (1) an early stage in response to high-fat diet that mice were sensitive to exogenous leptin; (2) a reduced food intake stage when mice had an increase in leptin production and still retained central leptin sensitivity; and (3) an increased food intake stage, accompanied by a reduction of central leptin sensitivity. Topics: Animals; Body Weight; Dietary Fats; Drug Resistance; Energy Intake; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity | 2000 |
Hypothalamic c-fos-like immunoreactivity in high-fat diet-induced obese and resistant mice.
Some C57Bl/6 mice become obese, whereas others remain lean when raised on a high-fat diet. The mechanisms underlying this interindividual susceptibility to diet-induced obesity remain unknown. Because hypothalamus plays a major role in the regulation of body weight, this study was conducted to identify the differences of hypothalamic neuronal activity between diet-induced obese and diet-resistant mice. Using c-fos as a marker, this study showed that diet-induced obese mice significantly increased c-fos-like immunoreactive neurons in the dorsal part of lateral hypothalamus (+183%) and dorsomedial hypothalamic nucleus (+87.5%) compared with diet-resistant mice. Furthermore, switching from high fat to low fat, or high n-3 polyunsaturated fatty acid diet, significantly decreased body weight gain (-35.7% and -31.0%), overall fat storage (-63.4% and -59.6%), and c-fos-like immunoreactive neurons in the dorsal part of lateral hypothalamus (-76.5% and -64.7%) and dorsomedial hypothalamic nucleus (-73.3% and -56.7%) in diet-induced obese mice, respectively. The present study also showed that the ratio of serum leptin/fat mass was threefold higher in the diet-resistant mice than in the diet-induced obese mice, which may be responsible for the less fat storage in the diet-resistant mice. The current data further confirm that the increased neuronal activity in the key autonomic regulatory centers may contribute to the excessive fat storage in diet-induced obese mice. Moreover, both high-fat diet-induced excessive fat storage and the altered hypothalamic neuronal activity may be largely corrected by reducing dietary fat content or replacing it with non-obesogenic fat. Topics: Animals; Body Weight; Diet, Fat-Restricted; Dietary Fats; Dietary Fats, Unsaturated; Disease Susceptibility; Dorsomedial Hypothalamic Nucleus; Energy Intake; Fatty Acids, Omega-3; Hypothalamus; Leptin; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Neurons; Obesity; Proto-Oncogene Proteins c-fos | 2000 |
Photoperiodic versus metabolic signals as determinants of seasonal anestrus in the mare.
The objectives of this study were to compare the timing and mechanisms controlling the onset of anestrus in young and mature mares treated either continuously with melatonin and in those that remained untreated. Changes in body weight, subcutaneous body fat measured to provide an estimate of total body fat, and circulating concentrations of leptin were compared throughout the 1-yr experimental period. The results demonstrate that in young mares the timing of anestrus occurs significantly earlier in the year than in mature mares and that mature mares are more likely to exhibit continuous reproductive activity during the nonbreeding season. The propensity of mature mares to exhibit this phenomenon is not modified by continuous treatment with melatonin but is associated with higher mean circulating concentrations of leptin, body weight, and estimated percent of body fat. In both young and mature mares, body weight, percent of body fat, and circulating concentrations of leptin are higher during summer than winter months. We conclude that, in the mare, the reproductive response to a decrease in photoperiod or a presumptive inhibitory melatonin signal is modified by energy availability, which may be signaled to the hypothalamus-pituitary axis via a change in the circulating concentration of leptin. An additional observation confirmed that the prolactin axis is responsive to continuous treatment with melatonin but that a suppression of prolactin secretion is limited to the spring months. Topics: Adipose Tissue; Age Factors; Anestrus; Animals; Body Weight; Female; Horses; Leptin; Melatonin; Photoperiod; Prolactin; Seasons | 2000 |
Chronic leptin administration in developing rats reduces stress responsiveness partly through changes in maternal behavior.
In adult rodents, leptin has been shown to significantly alter the activity of several neuroendocrine functions, including the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Leptin is generally believed to be inhibitory to HPA activity in adults. Developing rat pups have high circulating levels of leptin, which begs the question of leptin's physiological role in controlling basal and stress-induced adrenocortical activity in neonatal rats. In this study, we treated rat pups daily from days 2-9 (or 6-10) of life with either vehicle or leptin (1 or 3 mg/kg body wt, ip) and determined the effects on body weight gain, fat pad deposits, and HPA activity in 10-day-old pups. We measured hypothalamic CRF mRNA levels in vehicle- and leptin-treated pups by in situ hybridization and determined plasma ACTH, corticosterone, and leptin concentrations under basal conditions or following exposure to a 3-min ether stress. Because leptin activates sympathetic activity and energy expenditure in adults and possibly also in rat pups, and because litter temperature is an important determinant of maternal behavior, we also investigated whether chronic leptin administration would modify aspects of maternal care that are important for the maintenance of HPA function. Chronic leptin treatment increased circulating levels of leptin and had significant dose-related metabolic effects, including reduced body weight gain and fat pad weight in 10-day-old pups. Basal expression of CRF mRNA in the PVN or secretion of ACTH and corticosterone was not modified by leptin treatment. In contrast, chronically elevated leptin concentrations during the neonatal period significantly lowered CRF expression in the PVN 60 min after stress and reduced the duration of the ACTH response to stress in pups, suggesting that glucocorticoid feedback on the HPA axis might be altered by this treatment. In addition, mothers caring for pups injected with leptin displayed longer bouts of anogenital licking of pups than mothers of vehicle-treated rats. Given that this particular type of pup stimulation has been shown to influence stress responsiveness, it is possible that the maternal response modulates the effects of exogenous leptin treatment. In conclusion, our results demonstrate that the leptin signal is functional during the early developmental period and that leptin can modulate the hormonal response to stress in young rats either by a direct effect on the HPA axis or indirectly through changing Topics: Adipose Tissue; Animals; Animals, Newborn; Behavior, Animal; Body Weight; Corticotropin-Releasing Hormone; Female; In Situ Hybridization; Leptin; Maternal Behavior; Organ Size; Paraventricular Hypothalamic Nucleus; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stress, Psychological | 2000 |
Effects of intracerebroventricular leptin administration on feeding and sexual behaviors in lean and obese female Zucker rats.
Obese Zucker rats (fa/fa) are characterized by inadequate leptin signaling caused by a mutation in the leptin receptor gene. Obese Zucker females are infertile and hyporesponsive to the inductive effects of ovarian hormones on sexual behaviors. Leptin treatment reverses aspects of reproductive dysfunction due to perturbations in energy balance in other animal models. Our first experiment tested the hypothesis that intracerebroventricular (icv) leptin administration would enhance the display of sexual behaviors in obese Zucker females. A second experiment compared lean and obese Zucker females' responses to leptin, during fed and fasted conditions. Ovariectomized (OVX) Zucker rats were implanted with lateral ventricular cannulae. In Experiment 1, fasted, obese females received estradiol benzoate, progesterone, and icv injections of 3, 18, or 36 microg murine leptin or vehicle. Leptin administration reduced food intake, but did not enhance sexual behaviors. In Experiment 2, steroid-replaced, OVX lean and obese females (from a different source than those in Experiment 1) received icv injections of vehicle or 3 or 36 microg leptin under fed and fasted conditions. Leptin treatment reduced food intake and weight gain in the fed, but not the fasted, condition in both genotypes. Sexual receptivity and locomotion were not affected, but icv leptin injections reduced proceptive behaviors in ad libitum-fed rats. These data confirm previous reports that centrally administered leptin decreases food intake and weight gain in obese Zucker rats; results from Experiment 2 suggest that lean and obese females are similarly responsive to these actions of leptin. Contrary to our hypothesis, leptin treatment did not stimulate sexual behaviors; rather, the hormone appears to inhibit the display of sexual proceptivity in ad libitum-fed lean and obese Zucker female rats. Topics: Animals; Body Weight; Eating; Fasting; Feeding Behavior; Female; Injections, Intraventricular; Leptin; Motor Activity; Obesity; Posture; Rats; Rats, Zucker; Sexual Behavior, Animal; Time Factors | 2000 |
Twenty-four-hour profiles of serum leptin in siberian and golden hamsters: photoperiodic and diurnal variations.
Serum leptin concentrations were obtained from male Siberian hamsters (Phodopus sungorus) and golden hamsters (a.k.a. Syrian, Mesocricetus auratus) housed on long [light:dark (LD) 16:8] and short (LD 6:18) photoperiods for 10-11 weeks. Blood samples were collected at 45-min intervals for 24 h from individual animals using an in-dwelling atrial catheter. In Siberian hamsters, exposure to short photoperiods as compared to long photoperiods reduced body weight (32.5 +/- 1.5 vs 47.7 +/- 1.1 g) and leptin (24-h mean: 5.3 +/- 0.4 ng/ml vs 18.6 +/- 2.1 ng/ml). Although photoperiod influenced the temporal distribution of leptin in golden hamsters, the main effect of photoperiod on leptin levels in golden hamsters did not reach significance (24-h mean: 7.1 +/- 1.0 ng/ml vs 5.1 +/- 0.8 ng/ml.). Body weights of golden hamsters did not vary significantly following exposure to short photoperiod for 11 weeks (178.3 +/- 3.6 g in LD 6:18 vs 177.8 +/- 7.3 g in LD 16:8). There was no nocturnal increase in serum leptin in either species. Marked interindividual differences were apparent in individual leptin profiles. Periodogram analysis revealed that only a few animals exhibited 24-h periodicities; the presence of a significant 24-h periodicity was more common in hamsters exposed to short days. Photoperiod-associated differences in the 24-hour profile of leptin secretion may be the result of photoperiod-associated changes in feeding behavior or metabolism. A full understanding of the regulation of leptin secretion in multiple time domains may enhance our understanding of the function of leptin. Topics: Animals; Body Weight; Circadian Rhythm; Cricetinae; Leptin; Male; Mesocricetus; Phodopus; Photoperiod; Radioimmunoassay; Seminal Vesicles; Species Specificity; Testis | 2000 |
Impaired leptin responsiveness in aged rats.
We previously reported that adiposity and serum leptin levels increase with age in male F-344xBN rats and that when physiological levels of serum leptin are manipulated by fasting, there is a corresponding reciprocal change in hypothalamic neuropeptide Y (NPY) mRNA in young rats, but there are no changes in older rats. These findings suggest that the regulation of hypothalamic NPY mRNA by leptin may be impaired with age. To test this hypothesis, we infused saline or leptin for 7 days into ad libitum-fed rats and compared these with saline-infused rats that were pair-fed the amount of food consumed by the leptin-treated rats. We examined daily food consumption, body weight, whole-body oxygen consumption, serum leptin, and NPY mRNA in the hypothalamus. Food consumption decreased by 50% in the leptin-infused compared with the saline-infused young rats but only decreased by 20% in the aged rats. In the leptin-treated young rats, there was a 24% increase in oxygen consumption compared with the pair-fed rats, but there were no changes in oxygen consumption in the aged rats. Leptin infusion diminished hypothalamic NPY levels by nearly 50% compared with pair-fed young rats, whereas there were no changes in the hypothalamic NPY mRNA levels in senescent rats. In summary, aged rats demonstrate a reduced responsiveness to leptin, including a diminished decrease in food intake and no increase in energy expenditure. These diminished responses to leptin were associated with and may be the result of an impaired suppression of hypothalamic NPY mRNA levels. This leptin resistance may be due to either the elevated obesity and serum leptin with age or due to age itself, or both. Topics: Adipose Tissue; Aging; Animals; Body Weight; Eating; Gene Expression; Hypothalamus; Leptin; Male; Neuropeptide Y; Oxygen Consumption; Rats; Rats, Inbred BN; Rats, Inbred F344 | 2000 |
Effects of antidepressants on weight and on the plasma levels of leptin, TNF-alpha and soluble TNF receptors: A longitudinal study in patients treated with amitriptyline or paroxetine.
Leptin, tumor necrosis factor-alpha (TNF-alpha), and soluble TNF receptors are involved in weight regulation. Antipsychotic agents, such as clozapine, induce weight gain and increase circulating levels of these cytokines. To assess whether obesity-inducing antidepressants have a similar effect, we measured plasma cytokine levels in depressive inpatients during the first six weeks of treatment with tricyclic agents (amitriptyline or nortriptyline, n = 12), with paroxetine (n = 10), or without medication (n = 14). There was an increase in the body mass index at week 6 of treatment with the tricyclics, which was preceded by a significant increase in soluble TNF receptor p75 plasma levels. Circulating levels of leptin were not affected. Paroxetine and drug-free treatment did not affect any of these parameters. We conclude that weight gain induced by psychotropic agents may occur without increased circulating levels of leptin. However, activation of the TNF-alpha system might be an early and sensitive marker of ensuing weight gain. Topics: Adult; Aged; Amitriptyline; Antidepressive Agents; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Body Weight; Female; Humans; Leptin; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Nortriptyline; Paroxetine; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha | 2000 |
Monosaccharide-enriched diets cause hyperleptinemia without hypophagia.
To determine the effect of monosaccharide-enriched diets on plasma leptin and food consumption, body weight, food intake, and serum glucose, insulin, and leptin concentrations were measured in rats maintained on a 10-d course of 60% glucose or 60% fructose diet. The serum leptin concentration in rats fed a high-glucose diet (7.60 +/- 0.6 ng/mL) or a high-fructose diet (5.12 +/- 0.8 ng/mL) was significantly increased compared with that in control rats (2.45 +/- 0.10 ng/mL; P < 0.001). To ascertain that the observed effect was related to hyperinsulinemia, a group of rats were infused with exogenous insulin or rendered insulin resistent with a high-fat diet. When hyperinsulinemia was induced with exogenous infusion, the serum leptin was increased (5.56 +/- 0.23 ng/mL; P < 0.001). High-fat feeding was associated with increased serum leptin (12.1 +/- 1.4 ng/mL) and insulin levels. The increased serum leptin concentration was not associated with decreased food intake. We conclude that monosaccharide-enriched diets, probably through hyperinsulinemia or relative or absolute insulin resistance, cause hyperleptinemia, which does not appear to change feeding behavior. Topics: Animals; Blood Glucose; Body Weight; Dietary Carbohydrates; Dietary Fats; Eating; Fructose; Glucose; Insulin; Insulin Resistance; Leptin; Male; Monosaccharides; Rats; Rats, Inbred F344 | 2000 |
Anorexia in rats infected with the nematode, Nippostrongylus brasiliensis: experimental manipulations.
Nippostrongylus brasiliensis induces a biphasic anorexia in laboratory rats, the first phase coincident with lung invasion (ca day 2) and the second when the worms mature in the intestine (ca day 8). Using the anthelminthic, mebendazole (MBZ), N. brasiliensis infections of the rat were eliminated between the first and second anorexic episodes. This intervention prevented the expression of the second phase of anorexia. Rats exposed to a second infection with N. brasiliensis, 3 weeks after the primary infection, exhibited only a first phase anorexic response which was not influenced by MBZ termination of the primary infection. The lower cumulative food intake and weight gain of all infected rats after 8 days of infection were accompanied by elevated plasma insulin and, in some individuals, by elevated plasma leptin, compared with uninfected controls and previously-infected MBZ-treated rats. Messenger RNA levels for neuropeptide Y were higher in the hypothalamic arcuate nucleus of 8-day infected rats than in recovering MBZ-treated animals. Inoculation of rats with heat-killed N. brasiliensis larvae failed to induce anorexia and did not alter the severity of biphasic anorexia on subsequent injection of viable larvae. The first anorexic episode is therefore dependent upon viable migrating larvae. The second phase of anorexia clearly requires the continuing presence of the parasite beyond the lung phase. Viable migrating larvae are also required to confer 'resistance' to reinfection. Topics: Animals; Anorexia; Anthelmintics; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; DNA Primers; DNA, Helminth; Eating; Galanin; Host-Parasite Interactions; Image Processing, Computer-Assisted; Insulin; Leptin; Mebendazole; Neuropeptide Y; Nippostrongylus; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Helminth; Strongylida Infections | 2000 |
Design of a synthetic leptin agonist: effects on energy balance, glucose homeostasis, and thermoregulation.
We have previously reported that a synthetic peptide amide corresponding to amino acid residues 116-130 of mouse leptin, LEP-(116-130), reduces body weight gain, food intake, and blood glucose levels in ob/ob and db/db mice. In the present study we show that the activity of LEP-(116-130) resides in a restricted sequence between amino acid residues 116-122. A synthetic peptide corresponding to this sequence (Ser-Cys-Ser-Leu-Pro-Gln-Thr) has been named OB3. Single point D-amino acid substitution was used to study the structure-function relationship of each residue in OB3. D-Amino acid analogs of OB3 were synthesized by the solid phase method, purified to 98+%, and administered (1 mg/day, ip) for 7 days to female C57BL/6J ob/ob mice. The effects of the peptides on body weight gain, food and water intake, glucose homeostasis, and thermoregulation were assessed. In most cases, the efficacy of OB3 on all parameters tested was reduced by substitution of an L-amino acid with its corresponding D-isoform. A statistically significant increase (2.6-fold) in the weight-reducing effect of OB3, however, was observed by inversion of the configuration of the leucine residue at position 4 (Leu-4) of OB3 by substitution with its D-amino acid isoform [D-Leu-4]. Compared with OB3, mice treated with [D-Leu-4]-OB3 consumed 7.9% less food and 16.5% less water. Blood glucose was normalized to levels comparable to those in wild-type control mice within 2 days after initiation of [D-Leu-4]-OB3 treatment. Unlike native leptin, however, neither OB3 nor any of its D-amino acid-substituted analogs had any apparent effect on thermogenesis. Our results indicate that synthetic peptide strategies may be useful in the development of potent and stabile pharmacophores with potential therapeutic significance in the treatment of human obesity and its related metabolic dysfunctions. Topics: Amino Acid Substitution; Animals; Blood Glucose; Body Temperature Regulation; Body Weight; Drinking; Eating; Energy Metabolism; Epitopes; Female; Glucose; Homeostasis; Leptin; Mice; Mice, Inbred C57BL; Peptide Fragments | 2000 |
Negative regulation of leptin by chronic high-glycemic index starch diet.
The response of plasma leptin to a high-glycemic index (high-GI) starch diet after a short (3 weeks) and prolonged (12 weeks) period was determined in Sprague-Dawley rats. Age-matched rats were fed an identical isocaloric diet except that the carbohydrates were from either mung bean starch (low-GI) or waxy cornstarch (high-GI). After a single test meal of the high-GI starch diet, postprandial plasma glucose (P < .05) and insulin (P < .01) peaks and plasma glucose (P < .014) and insulin (P < .05) areas were higher versus the low-GI starch diet (n = 8 per group). Other age-matched control rats were fed the same diets for a longer period. After 3 weeks, ob mRNA levels were decreased by 50% (P < .005) in the epididymal adipose tissue of high-GI-fed rats versus low-GI-fed rats, without a significant decrease in plasma leptin. After 12 weeks of the high-GI starch diet, both plasma leptin and ob mRNA were decreased by 34% (P < .005) and 41% (P < .05), respectively, compared with the low-GI diet. Both relative epididymal adipose tissue weight (adjusted per 100 g body weight) and total fat mass, as measured by dual-energy x-ray absorptiometry (DEXA), were unchanged by the high-GI starch diet. Basal nonfasting plasma insulin, glucose, and triglycerides were not altered by the high-GI starch diet, whereas free fatty acids were significantly elevated and associated with a trend (P < .13) for increased plasma free glycerol. Plasma leptin levels were negatively correlated with free fatty acid levels (r = .56, P < .05). Despite low leptin, rats fed on the high-GI diet did not increase their food intake, suggesting increased leptin sensitivity. These findings might precede weight gain and the increase in fat mass. Chronic nutritional factors might alter plasma leptin via several overlapping factors independently of energy intake. Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Weight; Dietary Carbohydrates; Eating; Fabaceae; Insulin; Leptin; Male; Plants, Medicinal; Rats; Rats, Sprague-Dawley; RNA, Messenger; Starch; Triglycerides | 2000 |
Starvation, leptin and epithelial cell proliferation in the gastrointestinal tract of the mouse.
Leptin, the ob/ob gene product, is a recently discovered peptide hormone, secreted by adipocytes, which can act as a satiety factor to regulate food intake. Its levels thus will be related to the presence of food in the lumen of the gut, and food intake is one of the most potent stimuli for intestinal epithelial cell proliferation. Leptin has a variety of other actions and the aim of this study was to see if one of these was to stimulate mucosal growth.. Three groups of mice were fed ad libitum, starved for 48 h or starved for 48 h and given twice-daily intraperitoneal injections of recombinant leptin (1 microg/g).. Starvation led to a 20% decrease in body weight and a similar decrease in the weights of the intestines. Starvation also markedly inhibited intestinal epithelial cell proliferation. Leptin had little effect on the small intestine and did not stimulate proliferation. However, in the hind gut it was associated with small but significant decreases in caecal weight, distal colon mitotic counts (p = 0.036) and in colonic crypt area (approximately 20%, p<0.001).. Leptin did not stimulate intestinal cell proliferation, however it did have a paradoxical inhibitory action on the caecum and colon. Topics: Animals; Body Weight; Cell Division; Colon; Epithelial Cells; Injections, Intraperitoneal; Intestinal Mucosa; Intestine, Small; Leptin; Male; Mice; Mice, Inbred C57BL; Organ Size; Recombinant Proteins; Starvation | 2000 |
Differential and genetically separable associations of leptin with obesity-related traits.
The extent to which leptin protects against obesity is unknown. By intercrossing New Zealand obese mice with lean C57BL/6J mice, we have separated the genes controlling leptin and other weight-related phenotypes. This has allowed us to determine whether hyperleptinaemia is associated with reduced food intake and increased physical activity in mice spanning a large range in body weight.. Plasma leptin, glucose and insulin, body weight, food intake, running wheel activity, and four adipose depots were measured in 587 adult F2 and backcross mice. When mice were categorized by adiposity, a plot of food intake vs leptin illustrated a U-shaped curve. Food intake decreased as leptin levels rose to approximately 15 ng/ml, beyond which the relationship reversed. A negative relationship was observed between activity and leptin with a maximal decrease in activity once leptin reached approximately 15 ng/ml.. Leptin has differential responses to food intake and activity, suggesting that it has limited potential to defend against obesity. A genetic defect in leptin sensitivity is unlikely to be the primary cause of obesity in these mice, since hyperleptinaemia was not coinherited with both hyperphagia and inactivity as body weight increased. Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Weight; Eating; Female; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Obesity; Physical Exertion | 2000 |
Body fat distribution and cardiovascular risk in normal weight women. Associations with insulin resistance, lipids and plasma leptin.
To systematically examine the correlations between insulin resistance, plasma leptin concentration, obesity and the distribution of fat assessed by anthropometry and magnetic resonance imaging in Asian women.. A cross sectional study of non-diabetic, normal weight women.. Twenty-one healthy women aged 38.8 y (s.d. 11.7) and BMI 22.6 kg/m2 (s.d. 2.3).. Intraperitoneal, retroperitoneal and subcutaneous abdominal fat volume was assessed by magnetic resonance imaging. Anthropometric data were collected. Total fat mass was assessed by bioelectric impedance analysis. Fasting serum lipids, insulin and plasma leptin were assayed.. Generalized obesity correlated with subcutaneous abdominal fat mass (r=0.83, P<0.001), but not with intra-abdominal fat mass. Both intraperitoneal fat mass and retroperitoneal fat mass increased with age (r=0.58, P=0.005 and r=0. 612, P=0.003, respectively). Abdominal subcutaneous fat mass was the most important determinant of insulin resistance and plasma leptin. Of the serum lipids, only fasting triglyceride correlated significantly with the waist-to-hip ratio.. It is possible that the large size of the subcutaneous depot compared to the intra-abdominal depot overwhelms any metabolic differences between adipose tissue from these two sites, resulting in the stronger correlation between insulin resistance and subcutaneous abdominal fat mass rather than intra-abdominal fat mass. On the other hand, the distribution of fat between subcutaneous fat depots may be important in the metabolic syndrome given the correlation of fasting triglyceride with waist to hip ratio but not with abdominal fat. However, the study population was small, younger and leaner compared to previous studies and we may not be able to generalize these results to all segments of the population. We confirm that subcutaneous fat mass is the major determinant of plasma leptin. Topics: Abdomen; Adipose Tissue; Adult; Body Composition; Body Constitution; Body Weight; Cardiovascular Diseases; Female; Humans; Insulin Resistance; Leptin; Lipids; Magnetic Resonance Imaging; Middle Aged; Risk Factors; Triglycerides | 2000 |
Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice.
Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been implicated in the regulation of insulin action, as well as in other signal transduction pathways. To investigate the role of PTP-1B in vivo, we generated homozygotic PTP-1B-null mice by targeted gene disruption. PTP-1B-deficient mice have remarkably low adiposity and are protected from diet-induced obesity. Decreased adiposity is due to a marked reduction in fat cell mass without a decrease in adipocyte number. Leanness in PTP-1B-deficient mice is accompanied by increased basal metabolic rate and total energy expenditure, without marked alteration of uncoupling protein mRNA expression. In addition, insulin-stimulated whole-body glucose disposal is enhanced significantly in PTP-1B-deficient animals, as shown by hyperinsulinemic-euglycemic clamp studies. Remarkably, increased insulin sensitivity in PTP-1B-deficient mice is tissue specific, as insulin-stimulated glucose uptake is elevated in skeletal muscle, whereas adipose tissue is unaffected. Our results identify PTP-1B as a major regulator of energy balance, insulin sensitivity, and body fat stores in vivo. Topics: Adipose Tissue; Animals; Body Weight; Carrier Proteins; Energy Metabolism; Female; Glucose; Glucose Tolerance Test; Homeostasis; Hyperinsulinism; Insulin Resistance; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mitochondrial Proteins; Muscle, Skeletal; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Proteins; RNA, Messenger; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3 | 2000 |
Lipostat in the lean rat: evidence for a non-causal relationship between glucocorticoids and leptin levels.
In order to assess the long-term impact of a complete depletion of glucocorticoids on plasma leptin levels, we bilaterally adrenalectomized 20 lean rats, and analysed glucocorticoids and leptin levels for 20 consecutive days. Results demonstrate that the adrenalectomy (ADX) significantly lowered the leptin levels, as compared to sham-operated controls. On the other hand, a significant increase in leptin levels was noticeable from day 1 to day 20 of the experiment in the sham-operated controls, even though corticosterone levels remained stable during that same period. Plasma leptin concentration was proportional to body fat content. These results would indicate a non-causal relationship between glucocorticoids and leptin levels in the context of a lipostat in the lean rat. Topics: Adrenalectomy; Animals; Body Weight; Corticosterone; Glucocorticoids; Leptin; Male; Rats; Rats, Sprague-Dawley | 2000 |
Transient effects of long-term leptin supplementation in the prevention of diet-induced obesity in mice.
Low plasma leptin levels have been shown to be associated with the development of obesity in mice as well as in humans. The present study was undertaken to determine if raising plasma leptin levels of obesity-prone C57BL/6J (B6) mice to those seen in obesity-resistant A/J mice would prevent the development of diet-induced obesity. Four-week-old B6 (n = 40) and A/J (n = 10) male mice were weaned onto a low-fat (11% kcal) diet. When the animals weighed 20 g, their diets were changed to a high-fat (HF) diet (58% kcal), and a continuous infusion of leptin (0.4 mg x kg(-1) x day(-1)) or phosphate-buffered saline (control) was started using Alzet minipumps. The A/J mice were not treated but were included to monitor the efficacy of the minipumps in raising plasma leptin in B6 mice. The mice were followed for 12 weeks. Chronic treatment with leptin for 4 weeks raised plasma levels in B6 mice to that of A/J mice. Plasma leptin in B6 control mice remained significantly lower than A/J mice through week 4. By week 8, leptin levels in the B6 control group had risen and were similar to A/J mice. Although there were significant weight differences between B6 treated and B6 control groups for 2-3 weeks after pump implantation, these differences were transient. Ultimately, there were no weight differences between the B6 treated and B6 control groups. There were no differences in plasma glucose between B6 treated and control groups. Plasma insulin values were also not different between the 2 groups. There was no effect of leptin supplementation on locomotor activity or food intake in B6 mice. In summary, this study demonstrates that leptin supplementation in animals that show low plasma leptin levels in response to fat feeding may slow but does not prevent the subsequent development of diet-induced obesity. Topics: Adipose Tissue; Animals; Blood Glucose; Body Temperature; Body Weight; Diet, Fat-Restricted; Dietary Fats; Eating; Infusions, Parenteral; Insulin; Leptin; Male; Mice; Mice, Inbred A; Mice, Inbred C57BL; Motor Activity; Obesity; Organ Size; Time Factors | 2000 |
Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats.
Leptin exerts important effects on the regulation of food intake and energy expenditure by acting in the brain. Leptin is secreted by adipocytes into the bloodstream and must gain access to specific regions in the brain involved in regulating energy balance. Its action is mediated by interaction with a receptor that is mainly expressed in the hypothalamus but is also present in other cerebral areas. To reach these target areas, leptin most likely needs to cross the blood-brain barrier (BBB). In this study, we compared the permeability of leptin at the BBB in homozygous lean (FA/FA), high-fat diet-induced (HFD) obese rats (FA/FA rats on a highfat diet), and genetically obese fa/fa Zucker rats by quantifying the permeability coefficient surface area (PS) product after correction for the residual plasma volume (Vp) occupied by leptin in the vessel bed of different brain regions. The intravenous bolus injection technique was used in the cannulated brachial vein and artery using leptin radioiodinated with 2 isotopes of iodine (125I and 131I) to separately determine the PS and Vp values. The PS for leptin at the BBB in lean FA/FA rats ranged from 11.0 +/- 1.6 at the cortex to 14.8 +/- 1.4 x 10(-6) ml x g(-1) x ml(-1) at the posterior hypothalamus. The PS for leptin in HFD obese FA/FA and obese fa/fa rats ranged from 3.0- to 4.0-fold lower than in lean FA/FA rats. The Vp values were not significantly different among the 3 groups studied. SDS-PAGE analysis of the radioiodinated leptin after 60 min of uptake revealed intact protein in the 8 different brain regions. Plasma leptin levels were significantly higher in both obese rat groups compared with those in lean FA/FA rats. Leptin levels in cerebrospinal fluid were not significantly different among the 3 groups of rats. These findings strongly suggest that the leptin receptor (OB-R) in the BBB can be easily saturated. Saturation of the BBB OB-R in obese individuals would explain the defect in leptin transport into the brain described in this study. Topics: Animals; Blood-Brain Barrier; Body Weight; Brain; Dietary Fats; Homozygote; Iodine Radioisotopes; Leptin; Obesity; Organ Specificity; Radioisotope Dilution Technique; Rats; Rats, Zucker; Thinness | 2000 |
Individual severity of dietary obesity in unselected Wistar rats: relationship with hyperphagia.
We investigated the relative importance of overeating, thermogenesis, and uncoupling protein (UCP) expression in determining the severity of obesity in male Wistar rats fed a highly palatable diet. After 2 wk of feeding, body weight did not differ significantly from controls (248 +/- 4 vs. 229 +/- 3 g; P > 0.3), but rectal temperature, brown adipose tissue (BAT) mass, UCP3 expression in gastrocnemius muscle, and UCP2 expression in white adipose tissue (WAT) were all elevated in diet-fed animals. In a further study, rats fed a palatable diet for 8 wk exhibited higher energy intake and rectal temperature than controls. Dietary-obese rats were divided into high (427-490 g; n = 8) and low (313-410 g; n = 10) weight gainers. The high gainers ate significantly more than the low gainers, and energy intake was positively correlated with weight gain (r(2) = 0.72, P < 0.01). UCP2 and UCP3 mRNA levels in gastrocnemius muscle were significantly increased above lean controls in all diet-fed animals, whereas UCPs in WAT and BAT did not differ significantly from controls. Whereas rats fed palatable food exhibited a thermogenic response, there was no significant difference in core temperature between high and low gain groups (37. 5 +/- 0.1 vs. 37.6 +/- 0.1 degrees C; P > 0.5). We conclude that a higher energy intake is the critical factor determining susceptibility to dietary obesity in unselected Wistar rats. Topics: Adipose Tissue, Brown; Animals; Body Composition; Body Temperature; Body Weight; Carrier Proteins; Diet; Energy Intake; Energy Metabolism; Fatty Acids, Nonesterified; Guanosine Diphosphate; Hyperphagia; Insulin; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mitochondria; Mitochondrial Proteins; Muscle, Skeletal; Obesity; Protein Biosynthesis; Rats; Rats, Wistar; Triglycerides; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3 | 2000 |
Differential regulation of leptin expression and function in A/J vs. C57BL/6J mice during diet-induced obesity.
Obesity-resistant (A/J) and obesity-prone (C57BL/6J) mice were weaned onto low-fat (LF) or high-fat (HF) diets and studied after 2, 10, and 16 wk. Despite consuming the same amount of food, A/J mice on the HF diet deposited less carcass lipid and gained less weight than C57BL/6J mice over the course of the study. Leptin mRNA was increased in white adipose tissue (WAT) in both strains on the HF diet but to significantly higher levels in A/J compared with C57BL/6J mice. Uncoupling protein 1 (UCP1) and UCP2 mRNA were induced by the HF diet in brown adipose tissue (BAT) and WAT of A/J mice, respectively, but not in C57BL/6J mice. UCP1 mRNA was also significantly higher in retroperitoneal WAT of A/J compared with C57BL/6J mice. The ability of A/J mice to resist diet-induced obesity is associated with a strain-specific increase in leptin, UCP1, and UCP2 expression in adipose tissue. The findings indicate that the HF diet does not compromise leptin-dependent regulation of adipocyte gene expression in A/J mice and suggest that maintenance of leptin responsiveness confers resistance to diet-induced obesity. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Carrier Proteins; Dietary Fats; Eating; Energy Intake; Gene Expression; Growth; Ion Channels; Leptin; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Inbred A; Mice, Inbred C57BL; Mitochondrial Proteins; Obesity; Proteins; RNA, Messenger; Species Specificity; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3 | 2000 |
Loss of regulation of lipogenesis in the Zucker diabetic (ZDF) rat.
We present here a study on the role of leptin in the regulation of lipogenesis by examining the effect of dietary macronutrient composition on lipogenesis in the leptin receptor-defective Zucker diabetic fatty rat (ZDF) and its lean litter mate (ZL). Animals were pair fed two isocaloric diets differing in their fat-to-carbohydrate ratio providing 10 and 30% energy as fat. Lipogenesis was measured in the rats using deuterated water and isotopomer analysis. From the deuterium incorporation into plasma palmitate, stearate, and oleate, we determined de novo synthesis of palmitate and synthesis of stearate by chain elongation and of oleate by desaturation. Because the macronutrient composition and the caloric density were controlled, changes in de novo lipogenesis under these dietary conditions represent adaptation to changes in the fat-to-carbohydrate ratio of the diet. De novo lipogenesis was normally suppressed in response to the high-fat diet in the ZL rat to maintain a relatively constant amount of lipids transported. The ZDF rat had a higher rate of lipogenesis, which was not suppressed by the high-fat diet. The results suggest an important hormonal role of leptin in the feedback regulation of lipogenesis. Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Deuterium; Diabetes Mellitus, Experimental; Dietary Carbohydrates; Dietary Fats; Energy Intake; Insulin; Leptin; Lipids; Male; Oleic Acid; Palmitates; Rats; Rats, Zucker; Stearates; Triglycerides | 2000 |
Anthropometric parameters and their relationship to serum growth hormone-binding protein and leptin levels in children with acute lymphoblastic leukemia: a prospective study.
The aim of this study was to follow auxological parameters and their relationship to serum growth hormone-binding protein (GHBP) and leptin levels in children with acute lymphoblastic leukemia (ALL).. In total, 26 prepubertal children with ALL were studied. We report these data at the time of the clinical diagnosis (n=26) and at 6 (n=21), 12 (n=21), 18 (n=21), 24 (n=20), 30 (n=16) and 36 months (n=16) after beginning treatment.. Serum GHBP levels decreased during the first 18 months and returned to normal when therapy was withdrawn. Height SDS increased at 24 months after diagnosis. Weight and the upper arm circumference had increased 6 months after chemotherapy withdrawal, whereas tricipital and subscapular skinfolds had increased both at 6 months after diagnosis and 6 months after therapy had stopped. Therefore, the tendency to become overweight is both an early and a late side-effect of anti-leukemia therapy. A significant positive correlation was found between serum leptin levels and every nutritional anthropometric parameter, with body mass index having the best relationship. However, serum GHBP levels were only correlated with BMI at the end of the study. No correlation was found between leptin and GHBP.. In children with ALL, linear growth is compromised during the acute phase of their illness and therapy; this is probably secondary to a state of partial and transient GH insensitivity. These patients tend to become obese after therapy withdrawal, with leptin being an excellent nutritional marker. Topics: Anthropometry; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Body Weight; Carrier Proteins; Child; Child, Preschool; Female; Humans; Infant; Leptin; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Regression Analysis; Skinfold Thickness | 2000 |
Sources of plasma leptin in infants after feeding.
Topics: Adipose Tissue; Body Weight; Humans; Infant, Newborn; Insulin; Leptin | 2000 |
Leptin prolonged administration inhibits the growth and glucocorticoid secretion of rat adrenal cortex.
Leptin is an adipose-tissue secreted hormone, that acts to decrease caloric intake and to increase energy expenditure. Some of the leptin effects on the energy balance are known to be mediated by the hypothalamo-pituitary-adrenal (HPA) axis, but the role of this cytokine in the regulation of the growth and steroidogenic capacity of adrenal cortex is still controversial. Therefore, the present study was designed to explore the long-term effects of native leptin[1-147] and its biologically active fragment leptin[116-130] (6 daily subcutaneous injection of 20 nmol/kg) on the rat HPA axis. Leptin[1-147] and leptin[116-130] caused a significant adrenal atrophy, which was mainly due to the decrease in the volume of zona fasciculata (ZF) and in the number of its parenchymal cells. Both leptins provoked a marked drop in the plasma concentrations of ACTH and corticosterone, the main hormone produced by ZF cells. The effects of leptin[116-130] were more intense than those of leptin[1-147]. Leptin[1-147], but not its fragment, evoked a clear-cut rise in the plasma concentration of aldosterone. Collectively, these findings indicate that prolonged leptin administration, by inhibiting pituitary ACTH release, exerts a potent suppressive action on the growth and glucocorticoid secretory capacity of the adrenal cortex in the rat. The mechanism(s) underlying the aldosterone secretagogue action of native leptin remain(s) to be investigated. Topics: Adrenal Cortex; Adrenocorticotropic Hormone; Animals; Body Weight; Cell Count; Corticosterone; Female; Glucocorticoids; Leptin; Organ Size; Peptide Fragments; Rats; Rats, Wistar; Zona Fasciculata; Zona Reticularis | 2000 |
Determinants of within-subject variation of fasting serum leptin concentrations in healthy subjects.
The hormone leptin is considered to contribute to body weight regulation through modulation of feeding behavior and energy expenditure. The aim of the present study was 1) to assess the day-to-day within-subject variation (biovariability) of serum leptin concentrations in healthy subjects and 2) to investigate whether this variation is associated with food intake, exercise, anthropometric measurements or various metabolic covariates (insulin, C-peptide and glucagon, glucose, lactate, 3-hydroxybutyrate (3-OHB), triglycerides, non-esterified-fatty acids and glycerol). Serum leptin levels were taken daily on 12 consecutive days after an overnight fast in 12 healthy subjects with a mean (SD) age of 22.7 (1.5) yr. and a BMI of 22.8 (1.6) kg/m2. Food intake, exercise, anthropometric measurements and various metabolic covariates were also determined during this period. The overall mean of serum leptin concentration was 33.3 pmol/L with a within-subject SD range of 27-41 pmol/L and a between-subject SD range of 18-61 pmol/L. The within-subject variance of serum leptin as a proportion of total variance was 9.5%. Within-subject variation of serum leptin concentrations is small in relation to between-subject variation in healthy, normal weight subjects. This has implications for the power of interventional or prospective studies. In men, 6.7% of the variation in serum leptin concentration was associated with body weight measured on the same day (p= 0.037). In women, however, 66% of the variation was negatively associated with 3-OHB measured on both the same and the previous day (p=0.0003 and 0.002), and positively associated with triglyceride concentration measured on the previous day (p=0.0017) and insulin measured on the same day (p=0.0002). Within-subject associations in women could be due to phasic changes in unmeasured variables, possibly related to the menstrual cycle or might suggest that energy balance may exert a delayed influence on serum leptin levels, with plasma 3-OHB and triglycerides acting as markers for the state of the fat stores that regulate leptin secretion. The differences between the genders remain unexplained, however. Topics: 3-Hydroxybutyric Acid; Adult; Alcohol Drinking; Blood Glucose; Body Constitution; Body Weight; C-Peptide; Diet; Exercise; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glycerol; Humans; Insulin; Leptin; Male; Reference Values; Regression Analysis; Reproducibility of Results; Sex Characteristics; Time Factors; Triglycerides | 2000 |
Effects of the oral administration of a beta3-adrenergic agonist on lipid metabolism in alloxan-diabetic rats.
Previous studies have reported that beta3-adrenergic agonists regulate plasma glucose, triglycerides and free fatty acids in situations of hyperglycaemia and dyslipidaemia in rodents. In this study Trecadrine, a novel compound with affinity for beta3-adrenergic receptors, has been tested in an alloxan-induced model of hyperglycaemia in rats. Alloxan-induced hyperglycaemic rats were orally treated with Trecadrine (1 mg/kg/day for 4 days), resulting in an improvement of hyperglycaemia (from 16.6 to 8.3 mmol L(-1), P < 0.001). This effect was not associated with statistical differences in plasma insulin levels, which may be explained by changes in insulin resistance and carbohydrate oxidation in peripheral tissues. Furthermore, a reduction in internal white fat weight (-39%), which was not statistically significant, as well as in plasma triglycerides (from 1.89 to 0.33 mmol L(-1), P < 0.001) and free fatty acids (from 0.70 to 0.39 mmol L(-1), P < 0.001), was found after Trecadrine administration. Trecadrine apparently induced lipolytic activity in adipocytes, as suggested by the increase of oxygen consumption in white adipose tissue (+282%, P < 0.001), while free fatty acids decreased apparently through their utilisation in other tissues. Furthermore, the increase in brown adipose tissue oxygen consumption (+50%, P < 0.01) and in rectal temperature (P < 0.05) suggests that both glucose and fatty acid oxidation may be enhanced in this tissue. These results give support to the possible therapeutic use of beta3-adrenergic compounds in situations of hyperglycaemia, particularly when this is accompanied by hypertriglyceridaemia. Topics: Absorption; Administration, Oral; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Benzyl Alcohols; Body Weight; Carbohydrate Metabolism; Diabetes Mellitus, Experimental; Female; Leptin; Lipid Metabolism; Lipoprotein Lipase; Muscle, Skeletal; Rats; Rats, Wistar | 2000 |
Central exendin-4 infusion reduces body weight without altering plasma leptin in (fa/fa) Zucker rats.
To investigate whether chronic administration of the long-acting glucagon-like peptide-1 receptor agonist exendin-4 can elicit sustained reductions in food intake and body weight and whether its actions require an intact leptin system.. Male lean and obese Zucker (fa/fa) rats were infused intracerebroventricularly with exendin-4 using osmotic minipumps for 8 days.. Exendin-4 reduced body weight in both lean and obese Zucker rats, maximum suppression being reached on Day 5 in obese (8%) and Day 7 in lean (16%) rats. However, epididymal white adipose tissue weight was not reduced, and only in lean rats was there a reduction in plasma leptin concentration. Food intake was maximally suppressed (by 81%) on Day 3 in obese rats but was reduced by only 18% on Day 8. Similarly, in lean rats food intake was maximally reduced (by 93%) on Day 4 of treatment and by 45% on Day 8. Brown adipose tissue temperature was reduced from Days 2 to 4. Plasma corticosterone was elevated by 76% in lean but by only 28% in obese rats.. Chronic exendin-4 treatment reduced body weight in both obese and lean Zucker rats by reducing food intake: metabolic rate was apparently suppressed. These effects did not require an intact leptin system. Neither does the absence of an intact leptin system sensitize animals to exendin-4. Partial tolerance to the anorectic effect of exendin-4 in lean rats may have been due to elevated plasma corticosterone and depressed plasma leptin levels, but other counter-regulatory mechanisms seem to play a role in obese Zucker rats. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Temperature; Body Weight; Brain; Corticosterone; Eating; Epididymis; Exenatide; Glucagon-Like Peptide-1 Receptor; Leptin; Male; Obesity; Organ Size; Peptides; Rats; Rats, Zucker; Receptors, Glucagon; Venoms | 2000 |
Intracerebroventricular injection of murine leptin enhances the postprandial metabolic rate in the rat.
Energy balance is achieved by means of a concomitant control of both food intake and energy expenditure. Leptin, synthesized in the adipose tissue, acts on brain structures and lowers body weight by inhibiting food intake and in parallel by enhancing energy expenditure i.e. metabolism or one of its components. Recording distinctly these components allowed us to assess the effect of an acute intracerebroventricular injection of leptin on both feeding pattern and background metabolism (i.e. energy expenditure free from the part of locomotor activity), respiratory quotient, feeding-related metabolism and locomotor activity-related metabolism. Leptin injection to Sprague-Dawley male rats induced an inhibition of feeding that began 90 min after the treatment and lasted 1 h before to return to the control feeding pattern level. Considering this late behavioral effect, it appeared that leptin may act during the postprandial period so that we recorded the different metabolic parameters following a 3 g calibrated meal itself preceded by leptin vs. artificial cerebrospinal fluid injection. Postprandial respiratory quotient was rapidly lowered in leptin-treated animals and subsequent background metabolism increased for 6 h. Thus it appeared that leptin increased the duration of the postprandial metabolic rate via the recruitment of endogenous fat stores. Enhancement in the thermic effect of food may be the reason for feeding behavior inhibition to be delayed. Topics: Animals; Behavior, Animal; Body Weight; Eating; Injections, Intraventricular; Leptin; Male; Metabolism; Mice; Motor Activity; Postprandial Period; Rats; Rats, Sprague-Dawley; Respiration | 2000 |
Reduced plasma leptin concentrations in bulimia nervosa.
Leptin is a protein produced by the ob-ob gene which inhibits food intake. Plasma levels have previously been reported to be altered in obesity and anorexia nervosa (AN) but not bulimia nervosa (BN). We measured fasting plasma leptin levels by radioimmunoassay in 53 subjects carefully studied at NIMH, including 37 women meeting DSM-III-R criteria for BN [10 with concurrent AN (body mass index (BMI)=14.1+/-1.4), 27 without AN (BMI=20.4+/-1.6)] and 16 normal control women (NCs) (BMI=21.1+/-2.0). Patients were medication-free and abstinent from bingeing and purging for three to four weeks prior to study. Plasma leptin levels were significantly correlated to BMI (r=0.41, P<0.002), weight (kg, r=0.43, P<0.001), and percent average body weight (%ABW, r=0.45, P<0.001) in the total group. Plasma leptin levels were lower in the BN subjects (3.4+/-2.5 ng/ml) compared to the NCs (6.1+/-2.6 ng/ml, P<0.001, ANCOVA) even after controlling for BMI and weight. There was no significant difference between BN subjects with AN (n=10, 2.6+/-2.6 ng/ml) and those without AN (n=27, 3.8+/-2.4 ng/ml), despite lower BMI in BN with AN. Furthermore, leptin levels were decreased in BN without AN compared with healthy controls, even though BMI was comparable in these two subgroups. Plasma leptin concentrations were negatively correlated with baseline plasma cortisol levels (n=49, r=-0.49, P<0.001) and positively correlated with prolactin responses following L-tryptophan (n=49, r=0.37, P<0.009) and m-chlorophenylpiperazine (n=52, r=0.24, P<0.09). This is the first known report of decreased plasma leptin levels in BN. The decrement in leptin concentration is not related to BMI, body weight, or the presence or absence of BN. HPA axis activation as well as serotonin dysregulation may be related to decreased leptin levels, which may in turn contribute to disinhibited eating in BN. Although current leptin levels were not correlated with self-reported previous binge frequency, the role of leptin in the pathophysiology of BN deserves further study. Topics: Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Bulimia; Female; Humans; Hydrocortisone; Leptin; Prolactin; Reference Values | 2000 |
Diurnal variation in circulating leptin is dependent on gender, food intake and circulating insulin in mice.
Leptin is an adipocyte hormone involved in the regulation of energy homeostasis. Its circulating levels show a diurnal rhythm with a nocturnal peak. We examined the influences of gender, feeding state, and plasma insulin and glucose on the diurnal rhythm in normal mice. Plasma was sampled at 4-h interval for 24 h in female (n=80) and male (n=80) mice, which were freely fed or fasted. In both genders, plasma leptin displayed a diurnal rhythm with a nadir at 8 or 10 AM and a nocturnal peak at 10 PM to 2 AM. The nocturnal increase in leptin was higher in females (+160+/-18%) than in males (61+/- 16%; P<0.001), completely abolished by fasting, and correlated significantly to the diurnal variation in plasma insulin both in females (r=0.44, P=0.003) and males (r=0.46, P<0.001). Baseline plasma leptin in non-fasted animals were not different between the genders, whereas during fasting, the reduction in leptin was more pronounced in males than in females, resulting in a higher plasma leptin after fasting in females. Plasma insulin was higher in males under non-fasted conditions (P=0.003), but not significantly different between genders in fasted animals. In conclusion, plasma leptin displays a nocturnal increase in mice, which is more pronounced in female mice than in male mice, is completely abolished by fasting and correlates to the diurnal variation in circulating insulin. It is suggested that the nocturnal rise in leptin shows gender dependency and is caused by the increase in plasma insulin caused by food intake. Topics: Animals; Blood Glucose; Body Weight; Circadian Rhythm; Eating; Fasting; Female; Humans; Insulin; Leptin; Male; Mice; Sex Characteristics; Time Factors | 2000 |
Leptin reduces body weight gain in neonatal rats.
Leptin (OB protein) elicits a neuroendocrine response to starvation and states of nutritional abundance to stabilize the proportion of body fat. Leptin has dramatic effects on food intake and energy expenditure in adult and juvenile rodents. However, whether the neonatal period is associated with the development of an effective leptin feedback system is still not known. In this study, we evaluated the effects of peripherally administered leptin on body weight changes in neonatal rats during the early suckling period (from birth to 10 d). Our results show that daily i.p. injections of leptin (0.3 microg/g and 1.0 microg/g) to neonatal rats led to a significant reduction in weight gain over 10 d compared with the control group (p < 0.01 and p < 0.01, respectively). Concomitant with a reduction in weight gain, retroperitoneal fat pad weight also significantly decreased in the leptin-treated group. Our data indicate that the potential for energy balance regulation by leptin occurs in the first day after birth. In addition, we also observed that 3 d after discontinuing leptin treatment, the body weight as well as the fat pad weight of leptin-treated pups returned to the control level. Our results demonstrate that leptin reduces body weight gain in neonatal rats. Topics: Animals; Animals, Newborn; Body Weight; Body Weight Changes; Injections, Intraperitoneal; Leptin; Rats; Rats, Sprague-Dawley | 2000 |
Age-related changes in plasma leptin binding activity in rats: A comparison of a simple acid-ethanol precipitation technique with column chromatography.
A novel assay for measuring the free leptin fraction was developed and validated against a chromatographic technique. The assay used acid-ethanol extraction (AEE) for separation of bound/free leptin moieties. The interassay coefficient of variation was 3.9%. The specificity for leptin binding was confirmed by incubation with 1 microg of unlabeled rat leptin that effectively competed with radiolabeled leptin whereas human growth hormone and interleukin-6 were ineffective in competing with radiolabeled leptin binding. Scatchard analysis of competitive binding experiments with rat plasma demonstrated a linear relationship with a binding affinity of 0.3-0.6 x 109 M-1. This novel assay was used to determine if age-related insensitivity to leptin action is secondary to altered serum leptin binding. Rats at various age groups were studied for changes in body adiposity and serum total and free leptin concentrations. Serum free leptin concentrations (ng/ml mean +/- SEM) were significantly increased in 24-month-old rats (5.56 +/- 0. 21) compared with 18-month-old rats (4.76 +/- 0.17) (P < 0.01) despite similar body weight and adiposity of the two age groups. The increase in plasma free leptin concentrations in 12-month-old rats (3.86 +/- 0.28) and 6-month-old rats (2.05 +/- 0.06) relative to 3-month-old rats (1.37 +/- 0.06) (P < 0.001) was out of proportion to the increase in body adiposity in aging rats. It is concluded that aging in rats is associated with relative insensitivity to leptin. This change cannot be attributed to increased plasma binding or to a reduction in the leptin free fraction. Topics: Adipose Tissue; Aging; Animals; Binding, Competitive; Body Composition; Body Weight; Carrier Proteins; Chromatography, Gel; Ethanol; Fractional Precipitation; Hydrogen-Ion Concentration; Leptin; Male; Protein Binding; Rats; Rats, Inbred F344; Receptors, Cell Surface; Receptors, Leptin; Reproducibility of Results; Sensitivity and Specificity | 2000 |
Disruption of arcuate/paraventricular nucleus connections changes body energy balance and response to acute stress.
The mediobasal hypothalamus regulates functions necessary for survival, including body energy balance and adaptation to stress. The purpose of this experiment was to determine the contribution of the arcuate nucleus (ARC) in controlling these two functions by the paraventricular nucleus (PVN). Circular, horizontal cuts (1.0 mm radius) were placed immediately above the anterior ARC to sever afferents to the PVN. In shams the knife was lowered to the same coordinates but was not rotated. Food intake and body weight were monitored twice daily, at the beginning and end of the light cycle, for 1 week. On the final day the animals were restrained for 30 min. Lesioned animals had increased food intake in light and dark periods, higher weight gain per day, and more body fat as compared with shams. There was no difference in caloric efficiency. Unlike shams, lesioned rats had no predictable relationship between plasma insulin and leptin. Plasma ACTH was increased at 0 min in lesioned rats but was decreased 15 and 30 min after restraint as compared with shams. There was no difference in plasma corticosterone. Immunostaining revealed that alpha-melanocortin (alphaMSH) and neuropeptide Y (NPY) accumulated below the cuts, and both were decreased in PVN. Food intake and body weight were correlated negatively to alphaMSH, but not NPY in PVN. There was no difference in proopiomelanocortin (POMC) mRNA, but NPY mRNA was reduced in the ARC of lesioned animals. We conclude that ARC controls body energy balance in unstressed rats, possibly by alphaMSH input to PVN, and that ARC also is necessary for PVN regulation of ACTH. Topics: Adrenocorticotropic Hormone; Afferent Pathways; alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Biological Clocks; Body Weight; Circadian Rhythm; Corticosterone; Energy Intake; Energy Metabolism; Insulin; Leptin; Male; Neural Pathways; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stress, Psychological; Transcription, Genetic; Weight Gain | 2000 |
Improved glucose and lipid metabolism in genetically obese mice lacking aP2.
Adipocyte fatty acid-binding protein, aP2, is a member of the intracellular fatty acid binding protein family. Previously, studies have shown increased insulin sensitivity in aP2-deficient mice with dietary obesity. Here, we asked whether aP2-related alterations in lipolytic response and insulin production are features of obesity-induced insulin resistance and investigated the effects of aP2-deficiency on glucose homeostasis and lipid metabolism in ob/ob mice, a model of extreme obesity. ob/ob mice homozygous for the aP2 null allele (ob/ ob-aP2-/-) became more obese than ob/ob mice as indicated by significantly increased body weight and fat pad size but unaltered body length. However, despite their extreme adiposity, ob/ob-aP2-/- animals were more insulin-sensitive compared with ob/ob controls, as demonstrated by significantly lower plasma glucose and insulin levels and better performance in both insulin and glucose tolerance tests. These animals also showed improvements in dyslipidemia and had lower plasma triglyceride and cholesterol levels. Lipolytic response to beta-adrenergic stimulation and lipolysis-associated insulin secretion was significantly reduced in ob/ob-aP2-/- mice. Interestingly, glucose-stimulated insulin secretion, while virtually abolished in ob/ob controls, was significantly improved in ob/ob-aP2-/- animals. There were no apparent morphological differences in the structure or size of the pancreatic islets between genotypes. Taken together, the data indicate that in obesity, aP2-deficiency not only improves peripheral insulin resistance but also preserves pancreatic beta cell function and has beneficial effects on lipid metabolism. Topics: Adipose Tissue; Aging; Animals; Body Weight; Carrier Proteins; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Fatty Acids; Female; Glucose; Homeostasis; Insulin; Islets of Langerhans; Leptin; Lipid Metabolism; Lipolysis; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Myelin P2 Protein; Neoplasm Proteins; Nerve Tissue Proteins; Obesity; Pancreas; Sex Characteristics | 2000 |
Effects of renal denervation on the sodium excretory actions of leptin in hypertensive rats.
Previous studies from this laboratory have reported a marked attenuation of the renal responses to pharmacologic doses of synthetic murine leptin infused in the spontaneously hypertensive rat (SHR) model compared with normotensive Sprague-Dawley and lean Zucker rat models.. In the present study, the hemodynamic and renal excretory effects of an intravenous bolus administration of pharmacologic doses of synthetic murine leptin were examined in groups of anesthetized SHR with unilateral nephrectomy and renal denervation or sham-denervation of the remaining kidney.. In the SHR with acute renal denervation (N = 8), an intravenous bolus of 1600 microg/kg of leptin produced a significant twofold to fourfold elevation in sodium excretion but did not increase natriuresis in the sham-denervated group (N = 6). Chronic renal denervation of one-week duration (N = 8) was associated with qualitatively and quantitatively similar increases of sodium excretion in response to leptin administration. Mean arterial pressure remained unchanged in all groups after the administration of leptin.. Collectively, these results are interpreted to suggest that the blunted natriuretic and diuretic responses to leptin observed in the SHR with intact renal nerves may be partially explained by the antinatriuretic effect of an enhanced baseline efferent renal sympathetic activity and/or leptin's stimulation of the sympathetic nervous system. Topics: Animals; Blood Pressure; Body Weight; Denervation; Hypertension, Renal; Kidney; Leptin; Natriuresis; Rats; Rats, Inbred SHR; Sodium; Sympathetic Nervous System; Urine | 2000 |
Melanocortins and body weight: a tale of two receptors.
Topics: Adipose Tissue; Alleles; alpha-MSH; Animals; Body Weight; Feeding Behavior; Humans; Leptin; Ligands; Mice; Mice, Knockout; Models, Biological; Obesity; Phenotype; Protein Isoforms; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, Peptide; Signal Transduction | 2000 |
Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.
Genetic and pharmacological studies have defined a role for the melanocortin-4 receptor (Mc4r) in the regulation of energy homeostasis. The physiological function of Mc3r, a melanocortin receptor expressed at high levels in the hypothalamus, has remained unknown. We evaluated the potential role of Mc3r in energy homeostasis by studying Mc3r-deficient (Mc3r(-/-)) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. The 4-6-month Mc3r-/- mice have increased fat mass, reduced lean mass and higher feed efficiency than wild-type littermates, despite being hypophagic and maintaining normal metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.) Consistent with increased fat mass, Mc3r(-/-) mice are hyperleptinaemic and male Mc3r(-/-) mice develop mild hyperinsulinaemia. Mc3r(-/-) mice did not have significantly altered corticosterone or total thyroxine (T4) levels. Mice lacking both Mc3r and Mc4r become significantly heavier than Mc4r(-/-) mice. We conclude that Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis. Topics: Adipose Tissue; Age Factors; alpha-MSH; Animals; Blotting, Southern; Body Temperature; Body Weight; Calorimetry; Corticosterone; Feeding Behavior; Female; Genotype; Glucose; Humans; Hyperinsulinism; In Situ Hybridization; Insulin; Leptin; Male; Mice; Mice, Knockout; Models, Genetic; Motor Activity; Obesity; Oligopeptides; Phenotype; Protein Isoforms; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, Peptide; Recombination, Genetic; Thyroxine; Time Factors; Tissue Distribution | 2000 |
Opposite effects of feeding a vitamin A-deficient diet and retinoic acid treatment on brown adipose tissue uncoupling protein 1 (UCP1), UCP2 and leptin expression.
The relationship between interscapular brown adipose tissue (IBAT) thermogenic potential and vitamin A status was investigated by studying the effects of feeding a vitamin A-deficient diet and all-trans retinoic acid (tRA) treatment on body weight and IBAT parameters in mice. Feeding a vitamin A-deficient diet tended to trigger opposite effects to those of tRA treatment, namely increased body weight, IBAT weight, adiposity and leptin mRNA expression, and reduced IBAT thermogenic potential in terms of uncoupling protein 1 (UCP1) mRNA and UCP2 mRNA expression. The results emphasize the importance of retinoids as physiological regulators of brown adipose tissue. Topics: Adipose Tissue, Brown; Animals; Blotting, Northern; Body Temperature Regulation; Body Weight; Carrier Proteins; Hypertrophy; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Inbred Strains; Mitochondrial Proteins; Proteins; RNA, Messenger; Tretinoin; Uncoupling Protein 1; Uncoupling Protein 2; Vitamin A Deficiency | 2000 |
Late effects of postnatal administration of monosodium glutamate on insulin action in adult rats.
Early postnatal administration of monosodium glutamate (MSG) to rats induces obesity, hyperinsulinemia and hyperglycemia in adulthood, thus suggesting the presence of insulin resistance. We therefore investigated the effects of insulin on glucose transport and lipogenesis in adipocytes as well as insulin binding to specific receptors in the liver, skeletal muscle and fat tissues. An increase of plasma insulin, glucose and leptin levels was found in 3-month-old rats treated with MSG during the postnatal period. The attenuation of insulin stimulatory effect on glucose transport was observed in MSG-treated rats. Despite the lower basal and insulin-stimulated glucose uptake, the incorporation of glucose into lipids was significantly higher in MSG-treated rats, suggesting a shift in glucose metabolism towards lipid synthesis in fat tissue. Insulin binding to plasma membranes from the liver, skeletal muscle and adipocytes was decreased in MSG-treated rats. This is in agreement with the lower insulin effect on glucose transport in these animals. Furthermore, a decreased amount of GLUT4 protein was found in adipocytes from MSG-treated obese rats. The results demonstrated an attenuation of insulin effect on glucose transport due to a lower insulin binding and lower content of GLUT4 protein in MSG-treated rats. However, the effect of insulin on lipogenesis was not changed. Our results indicated that early postnatal administration of MSG exerts an important effect on glucose metabolism and insulin action in adipocytes of adult animals. Topics: Adipocytes; Aging; Animals; Animals, Newborn; Biological Transport; Blood Glucose; Body Weight; Cell Membrane; Glucose; Glucose Transporter Type 4; Hepatocytes; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Male; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Organ Size; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Sodium Glutamate | 2000 |
Effect of chronic central infusion of murine and human leptin in lean Zucker rats.
Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Temperature Regulation; Body Weight; Brain; Carrier Proteins; Corticosterone; Eating; Humans; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mitochondrial Proteins; Obesity; Organ Size; Rats; Rats, Zucker; RNA, Messenger; Uncoupling Protein 1 | 2000 |
Role of brain insulin receptor in control of body weight and reproduction.
Insulin receptors (IRs) and insulin signaling proteins are widely distributed throughout the central nervous system (CNS). To study the physiological role of insulin signaling in the brain, we created mice with a neuron-specific disruption of the IR gene (NIRKO mice). Inactivation of the IR had no impact on brain development or neuronal survival. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of luteinizing hormone. Thus, IR signaling in the CNS plays an important role in regulation of energy disposal, fuel metabolism, and reproduction. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Brain; Eating; Female; Hypertriglyceridemia; Insulin; Insulin Resistance; Leptin; Leuprolide; Luteinizing Hormone; Male; Mice; Mice, Knockout; Neurons; Obesity; Ovarian Follicle; Receptor, Insulin; Reproduction; Sex Characteristics; Signal Transduction; Spermatogenesis | 2000 |
Differential expression of hypothalamic neuropeptides in the early phase of diet-induced obesity in mice.
Exposure to high-fat diets for prolonged periods results in positive energy balance and obesity, but little is known about the initial physiological and neuroendocrine response of obesity-susceptible strains to high-fat feeding. To assess responses of C57BL/6J mice to high- and low-fat diets, we quantitated the hypothalamic expression of neuropeptides implicated in weight regulation and neuroendocrine function over a 2-wk period. Exposure to high-fat diet increased food consumption over a 2-day period during which leptin levels were increased when assessed by a frequent sampling protocol [area under the curve (AUC): 134.6 +/- 10.3 vs. 100 +/- 12.3, P = 0.03 during first day and 126.5 +/- 8.2 vs. 100 +/- 5.2, P = 0.02 during second day]. During this period, hypothalamic expression of neuropeptide Y (NPY) and agouti-related protein (AgRP) decreased by approximately 30 and 50%, respectively (P < 0.001). After 1 wk, both caloric intake and hypothalamic expression of NPY and AgRP returned toward baseline. After 2 wk, cumulative caloric intake was again higher in the high-fat group, and now proopiomelanocortin (POMC) was elevated by 76% (P = 0.01). This study demonstrates that high-fat feeding induces hyperphagia, hyperleptinemia, and transient suppression of orexigenic neuropeptides during the first 2 days of diet. The subsequent induction of POMC may be a second defense against obesity. Attempts to understand the hypothalamic response to high-fat feeding must examine the changes as they develop over time. Topics: Agouti-Related Protein; Animals; Area Under Curve; Body Composition; Body Weight; Corticosterone; Dietary Fats; Eating; Energy Intake; Fatty Acids, Nonesterified; Hypothalamus; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Neuropeptides; Obesity; Pro-Opiomelanocortin; Protein Biosynthesis; Proteins; Repressor Proteins; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors | 2000 |
Dissociation of leptin secretion and adiposity during prehibernatory fattening in little brown bats.
Hibernating animals deposit adipose tissue before hibernation to withstand long periods of reduced energy intake. Normally, adiposity is positively correlated with increased secretion from adipose tissue of the satiety hormone, leptin. During the prehibernatory phase of the little brown bat, Myotis lucifugus, body mass and adiposity increased to a maximum within 12 days. Leptin secretion from adipose tissue in vitro and plasma leptin, however, increased before the increase in adiposity, then significantly decreased when adiposity increased. Basal metabolic rate (BMR) decreased when plasma leptin was increasing. This was followed by an increase in nonshivering thermogenic capacity and brown adipose tissue mass. We conclude that in the early prehibernatory phase, BMR decreases despite increasing plasma leptin levels, suggesting a state of relative leptin resistance at that time. At later stages, adiposity increases as BMR continues to decrease, and plasma leptin becomes dissociated from adiposity. Thus, in M. lucifugus, hibernation may be achieved partly by removing the metabolic signal of leptin during the fattening period of prehibernation. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Basal Metabolism; Body Weight; Chiroptera; Female; Hibernation; Leptin; Weight Gain | 2000 |
Diazoxide restores beta3-adrenergic receptor function in diet-induced obesity and diabetes.
We previously demonstrated that the expression and function of the adipocyte-specific beta3-adrenergic receptor (beta3AR) are significantly depressed in single gene and diet-induced rodent models of obesity. Furthermore, these models are relatively unresponsive to the anti-obesity effects of beta3AR agonists. Because all of these models are hyperinsulinemic, we hypothesized that hyperinsulinemia could be responsible for this abnormality in beta3AR function. The goal of this study was to determine whether lowering insulin with the K-ATP channel agonist, diazoxide (Dz) would reverse the depressed expression and function of the beta3AR found in a model of diet-induced diabetes and obesity in C57BL/6J (B6) mice. B6 male mice were placed on either high fat (HF) or low fat experimental diets. After 4 weeks, HF-fed mice were assigned to a group: HF or HF containing disodium (R,R)-5- [2-( [2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl-1,3-benzodioxole-2,2-di carboxylate (CL; 0.001%, wt/wt), Dz (0.32%, wt/wt), or their combination (CLDz). Dz animals exhibited significantly reduced plasma insulin levels as well as increased 3pAR expression and agonist-stimulated adenylyl cyclase activity in adipocytes. CLDz was more effective in reducing percent body fat, lowering nonesterified fatty acids, improving glucose tolerance, and reducing feed efficiency than either treatment alone. Topics: Adipocytes; Adipose Tissue; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diazoxide; Diet; Energy Intake; Glucose; Insulin; Leptin; Lipids; Male; Mice; Mice, Inbred Strains; Muscle, Skeletal; Obesity; Organ Size; Receptors, Adrenergic, beta; Syndrome | 2000 |
Interaction of genetic and environmental programming of the leptin system and of obesity disposition.
Possible adverse interactions between an usually inconspicuous genetic trait and early environmental factors favoring the development of obesity were investigated in rats heterozygous for the leptin receptor defect "fatty" (fa). Pups were exposed to early postnatal overfeeding by reducing litter size from normally 10-12 to only 4. Rearing +/+ and +/fa pups from day 3 to 21 in small litters increased fat-free dry mass and body fat, but only in the latter did a significant interaction with genotype occur. Pronounced differences in the responsiveness of +/+ and +/fa pups to "prophylactic" leptin treatment (from day 1 to 21) were observed, with +/fa females from small litters being nearly as fat and unresponsive as previously reported for normally reared fa/fa pups. Clear heterozygous differences in total hypothalamic leptin binding, but no litter size effect, paralleling the differences in leptin responsiveness, were observed. By early postnatal overfeeding an usually inconspicuous genetic trait may thus become etiologic for the development of obesity via physiological changes other than the decreased leptin binding characterizing the genetic defect. Topics: Adipose Tissue; Analysis of Variance; Animals; Body Composition; Body Weight; Carrier Proteins; Environment; Female; Gene Deletion; Genetic Predisposition to Disease; Heterozygote; Homozygote; Hypothalamus; Least-Squares Analysis; Leptin; Litter Size; Male; Obesity; Rats; Rats, Mutant Strains; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Software | 2000 |
In vivo and in vitro suppression by leptin of glucose-stimulated insulin hypersecretion in high glucose-fed rats.
Chronic feeding to rats of high glycaemic index (GI) diets results in the hypersecretion of insulin in response to an i.v. glucose load. The first aim of this study was to see if this exaggerated insulin response was accompanied by a hypersensitivity to glucose stimulation in isolated islets in vitro. The second aim was to see if the adipocyte factor, leptin, was able to alter insulin secretion in this model both in vivo and in vitro.. Rats were fed for 6 weeks either a high GI diet in which the carbohydrate component was mostly glucose (GLUC diet) or a low GI diet containing mostly amylose (AMOSE diet). Rats then underwent an i.v. glucose tolerance test (ivGTT) (1g/kg) with and without a prior infusion of leptin (133 microg/kg perh). Islets were then isolated from these rats and basal and glucose-stimulated insulin secretion (GSIS) measured in both the absence and presence (100ng/ml) of leptin.. Peak insulin response during the ivGTT was 3-fold greater in GLUC rats (P<0.001). Leptin had no effect on AMOSE rat insulin response but lowered the GLUC rat response to AMOSE rat levels. In vitro, basal insulin secretion was 4-fold greater in GLUC rats (P<0.05). At 20mmol/l glucose, there was no further increase in insulin secretion in GLUC rats but a 2-fold increase in AMOSE rats. Leptin had no effect on basal insulin secretion or GSIS in AMOSE rats but reduced basal insulin secretion and GSIS in GLUC rats. These results show insulin hypersecretion in high GI-fed rats may be reduced by leptin. Topics: Animals; Area Under Curve; Body Weight; Diet; Glucose; Glucose Tolerance Test; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Male; Rats; Rats, Wistar | 2000 |
Development of obesity in transgenic rats with low circulating growth hormone levels: involvement of leptin resistance.
Human growth hormone (hGH) transgenic (TG) rats have been produced in our laboratory. These TG rats are characterized by low circulating hGH levels, virtually no endogenous rGH secretion, and massive obesity.. To elucidate how energy balance and leptin sensitivity contributed to the establishment of this obesity.. Food intake, locomotor activity and leptin concentrations in serum and cerebrospinal fluid were measured in TG rats and their non-transgenic littermates (control). The effect of intraperitoneal and intracerebroventricular injection of leptin on food intake and body weight gain was also examined.. An increase in food intake and a decrease in locomotor activity were observed from 4 and 7 weeks of age, respectively, in the transgenic rats compared with control. Serum leptin concentrations of the transgenic rats were more than twice as high as those of control rats and were associated with an increased white adipose tissue mass and ob gene expression. Intraperitoneal injection of leptin significantly decreased food intake and body weight gain in control rats, but not in transgenic rats. Leptin concentration in the cerebrospinal fluid of transgenic rats was not different from that of control rats, and intracerebroventricular injection of leptin was similarly effective in reducing food intake and body weight gain as it was in control rats.. These results suggest that the transgenic rats, whose GH secretion is suppressed, develop obesity due to early onset of an increase in food intake and a decrease in locomotor activity with leptin resistance resulting from deteriorating leptin transport from peripheral blood to cerebrospinal fluid. Topics: Adipose Tissue; Animals; Animals, Genetically Modified; Blotting, Northern; Body Weight; Eating; Gene Expression Regulation; Human Growth Hormone; Humans; Leptin; Male; Motor Activity; Obesity; Rats | 2000 |
Metabolic variability among disease-resistant inbred rat strains and in comparison with wild rats (Rattus norvegicus).
1. Inbreeding and optimization of environmental conditions for laboratory rats may have led to the survival of mutants with metabolic aberrations but without evident disease phenotype. Therefore, in the present study, we compared metabolic traits between so-called disease-resistant inbred rat strains Dark Agouti (DA), Brown Norway (BN), Lewis (LEW), Wistar-Kyoto (WKY), Fischer 344 (F344) and wild rats (Rattus norvegicus). 2. Twelve males of each strain at 12, 13 and 14 weeks of age were studied for bodyweight, body mass index (BMI), blood glucose, serum triglycerides, total cholesterol, insulin and leptin. 3. In comparison with wild rats, the cholesterol values were significantly increased in all inbred rats studied. Except for DA rats, all rats were also significantly heavier than wild rats. 4. There were also significant differences between the different disease-resistant strains and WKY rats were the biggest animals with the highest bodyweight, BMI and cholesterol values. 5. The strains could be separated into groups with either very high (F344, LEW, WKY) or low values (DA, BN) of serum insulin and leptin levels. 6. Because all rats were studied under the same conditions, the findings suggest a substantial strain dependence in feeding behaviour and energy balance caused by the different genotypes. Topics: Animals; Animals, Wild; Biotransformation; Body Mass Index; Body Weight; Cholesterol; Glucose; Immunity, Innate; Inbreeding; Insulin; Leptin; Lipids; Male; Phenotype; Rats; Rats, Inbred Strains; Triglycerides | 2000 |
Postnatal regulation of hypothalamic neuropeptide expression by leptin: implications for energy balance and body weight regulation.
Leptin is produced mainly by adipose tissue and has been shown to regulate feeding, energy balance and neuroendocrine function. Regulation of energy homeostasis by leptin is thought to be mediated by hypothalamic neuropeptides, at least in adult rodents. The neonatal period is a critical stage of development during which mammals have to optimize caloric intake to support growth and development, as well as maintain body temperature. It is likely that leptin is involved in the transition from preweaning to adult metabolism. To test this hypothesis, we compared the effect of leptin treatment on body weight and adiposity between neonatal and adult mice. We also determined whether well known hypothalamic neuropeptide targets, e.g. neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related peptide (AGRP) and cocaine and amphetamine-regulated transcript (CART) were regulated in a pattern consistent with their presumed roles as mediators of leptin action. Once daily intraperitoneal leptin injection for 7 days did not alter body weight, fat content or expression of hypothalamic neuropeptide mRNAs in 10-day-old mice. In contrast, leptin decreased body weight and adiposity, increased CART and suppressed NPY and AGRP mRNA expression in adult mice. These results are consistent with previous studies showing that the timing of leptin's anorectic action develops after weaning. Furthermore, the association between leptin's ability to influence body weight in adult mice but not in neonates, and the regulation of hypothalamic neuropeptide mRNA expression, is consistent with the view that these peptides mediate leptin's effects on energy balance. Topics: Agouti-Related Protein; Animals; Body Weight; Corticosterone; Energy Metabolism; Fats; Gene Expression Regulation; Hypothalamus; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neuropeptide Y; Pro-Opiomelanocortin; Proteins; RNA, Messenger; Triglycerides | 2000 |
Response of leptin mRNA to 24-h food deprivation and refeeding is influenced by age in rats.
To obtain an insight into the influence of aging on leptin gene expression, the responses of leptin mRNA in retroperitoneal and epididymal adipose tissues and plasma leptin concentrations to 24-h food deprivation and refeeding were examined in 2-, 10- and 24-month-old normal rats. The basal level of leptin gene expression in retroperitoneal adipose tissue was significantly higher in 10- and 24-month-old rats than that in 2-month-old rats, while the level in epididymal adipose tissue was highest in 10-month-old rats for all three age groups. The basal concentrations of plasma leptin was significantly higher in 10- and 24-month-old rats than those in 2-month-old rats. The 24-h food deprivation was followed by a significant reduction in leptin mRNA expression in both retorperitoneal and epididymal adipose tissues for all three age groups. The leptin gene expression was restored to control levels 24 h following refeeding in the 2- and 10-month-old rats, but failed to be restored in the 24-month-old rats. In addition, the time course of recovery for leptin mRNA expression by refeeding to the control levels differed between the retroperitoneal and the epididymal adipose tissue in 2- and 10-month-old rats. The concentrations of plasma leptin 24 h following refeeding were compatible with the leptin mRNA levels in adipose tissues in three age groups. These results suggest that the expression of the leptin gene in response to food-deprivation and refeeding is influenced by an animal's age and that this expression is different for different regions of white adipose tissue. Topics: Adipose Tissue; Aging; Animals; Body Weight; Eating; Food Deprivation; Gene Expression; Leptin; Male; Organ Size; Rats; Rats, Wistar; RNA, Messenger; Time Factors | 2000 |
Single intracerebroventricular bolus injection of a recombinant adenovirus expressing leptin results in reduction of food intake and body weight in both lean and obese Zucker fa/fa rats.
Leptin acts as a satiety factor within the central nervous system by binding to its receptor located in the hypothalamus. A missense mutation of the leptin receptor induces hyperphagia and obesity in the obese Zucker fa/fa rat. Since the CNS is an important target of leptin action, we hypothesized that leptin gene transfer into the lateral cerebral ventricle could efficiently lead to inhibition of food intake and reduction of body weight in obese fa/fa rats as well as in lean animals. A single intracerebroventricular injection of an adenoviral vector containing a cDNA encoding leptin resulted in the expression of leptin in the ependymal cells lining the ventricle and the secretion of leptin into the cerebrospinal fluid (CSF). During the first week after injection, when high concentrations of leptin were produced in the CSF, the reducing effects of leptin on food intake and body weight were comparable in lean and in obese fa/fa rats. The subsequent decline in CSF leptin levels, that was similar in lean and obese fa/fa rats, resulted in the faster resumption of food intake and body weight gain in obese than in lean animals, confirming a reduced sensitivity to leptin in the obese group. The results of this study show that leptin gene delivery into the cerebral ventricles allows for the production of elevated leptin concentrations in CSF, and they support the hypothesis that the impaired sensitivity to leptin may be overcome in obese fa/fa rats. Topics: Adenoviridae; Animals; Body Weight; Cerebral Ventricles; Eating; Female; Gene Expression; Genetic Vectors; Injections, Intraventricular; Leptin; Mice; Obesity; Rats; Rats, Zucker; Recombinant Fusion Proteins | 2000 |
Leptin is a potent stimulator of bone growth in ob/ob mice.
Leptin, the product of the obese gene, is a circulating hormone secreted primarily from adipocytes. The lack of leptin in ob/ob mice, who are homozygous for the obese gene, results in hyperglycemia, hyperinsulinemia, hyperphagia, obesity, infertility, decreased brain size and decreased stature. To this end, we investigated the role of leptin as a hormonal regulator of bone growth. Leptin administration led to a significant increase in femoral length, total body bone area, bone mineral content and bone density in ob/ob mice as compared to vehicle treated controls. The increase in total body bone mass was a result of an increase in both trabecular and cortical bone mass. These results suggest that the decreased stature of the ob/ob mouse is due to a developmental defect that is readily reversible upon leptin administration. Our demonstration that the signalling or long form (Ob-Rb) of the leptin receptor is present in both primary adult osteoblasts and chondrocytes suggests that the growth promoting effects of leptin could be direct. In summary, these results indicate a novel role for leptin in skeletal bone growth and development. Topics: Animals; Body Weight; Bone Development; Carrier Proteins; Eating; Femur; Leptin; Male; Mice; Mice, Obese; Receptors, Cell Surface; Receptors, Leptin | 2000 |
Resistance to the anorexic and thermogenic effects of centrally administrated leptin in obese aged rats.
The aim of the present study was to determine whether the anorexic and thermogenic effects of leptin were attenuated in overweight aged rats following intracerebroventricular (i.c.v.) injection of murine leptin. Male F344/BN rats of two ages (6 months: young (n=20) and 24 months: old (n=18)) were divided into three groups (control, pair-fed and leptin) and were treated with either vehicle (artificial cerebrospinal fluid) or leptin (15.6 microgram/day) for 3 days. There was an age-related increase in basal food intake (20+/-2%), serum leptin levels (363+/-106%) and leptin (OB) mRNA (72+/-16%) in perirenal white adipose tissue (PWAT). In contrast, basal expression of hypothalamic NPY mRNA and brown adipose tissue (BAT) uncoupling protein 1 (UCP1) mRNA was reduced significantly (-35+/-4% and -51+/-5%, respectively) with age. I.c.v. leptin treatment had a significantly greater effect in reducing food intake (-42+/-5% vs. -23+/-4%), serum leptin levels (-55+/-7% vs. 10+/-2%) and PWAT OB mRNA (-46+/-2% vs. 10+/-5%) in young than in old rats. Similarly, central leptin treatment also had a greater effect in suppressing hypothalamic NPY mRNA expression in young (-23+/-4%) than in old (-8+/-4%) rats compared with their age-matched pair-fed treated rats. The stimulatory effect of i.c.v. leptin treatment on BAT UCP1 mRNA expression was also significantly greater in young rats (45+/-8%) than in old rats (10+/-6%) compared with age-matched pair-fed rats. Our previous report indicated that these overweight aged rats were resistant to peripheral administered leptin. The present data extend those findings and demonstrate that the impaired anorexic and metabolic effects of leptin are centrally mediated. This leptin resistance may be due to either the elevated obesity and serum leptin with age or due to age itself or both. The development of leptin resistance with age may contribute to the hyperphagia, hyperleptinemia and impaired energy balance with age. Topics: Adipose Tissue, Brown; Aging; Animals; Anorexia; Body Weight; Carrier Proteins; Eating; Gene Expression Regulation; Hypothalamus; Injections, Intraventricular; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mice; Mitochondrial Proteins; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Inbred BN; Rats, Inbred F344; RNA, Messenger; Thermogenesis; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3 | 2000 |
Long-term differential modulation of genes encoding orexigenic and anorexigenic peptides by leptin delivered by rAAV vector in ob/ob mice. Relationship with body weight change.
We investigated the long-term effects of physiological levels of leptin produced by gene therapy on body weight (BW) and expression of genes that encode orexigenic and anorexigenic peptides in the hypothalamus. Recombinant adeno-associated viral vector (rAAV), a non-pathogenic and non-immunogenic vector, encoding leptin (betaOb) was generated and administered iv to ob/ob mice lacking endogenous leptin. Whereas the lowest dose of rAAV-betaOb (6x10(9) particles) was ineffective, the middle dose (6x10(10) particles) curbed BW gain without affecting food consumption for 75 days of observation. A ten-fold higher dose (6x10(11) particles) resulted in increased blood leptin levels and suppressed both BW gain and food consumption throughout the duration of the experiment. rAAV-betaOb doses that either curbed BW without affecting food consumption or evoked BW loss and reduced food intake, decreased the expression of genes encoding the orexigenic peptides, neuropeptide Y and agouti-related peptide in the ARC, and the two doses were equally effective. Concomitantly, the expression of genes encoding the anorexigenic peptide, alpha-melanocyte stimulating hormone and cocaine-and-amphetamine regulatory transcript, was augmented with the latter gene displaying a dose-dependant response. These results document the efficacy of delivering biologically active leptin for extended periods by an iv injection of rAAV-betaOb and show that physiological leptin concentrations simultaneously exert a tonic inhibitory effect on orexigenic and a stimulatory effect on anorexigenic signaling in the hypothalamus. This intricate dynamic interplay induced by leptin regulates BW with or without an effect on food intake in leptin-deficient ob/ob mice. Further, these results suggest that gene therapy is an effective mode of delivery to the hypothalamus of those therapeutic proteins that cross the blood-brain barrier to ameliorate neuroendocrine disorders. Topics: Agouti-Related Protein; alpha-MSH; Animals; Body Weight; Dependovirus; Gene Expression Regulation; Genetic Vectors; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Obese; Nerve Tissue Proteins; Neuropeptide Y; Pro-Opiomelanocortin; Proteins; Time Factors | 2000 |
Regulation of leptin secretion: effects of aging on daily patterns of serum leptin and food consumption.
We have investigated the effects of age on the daily rise in serum leptin levels during the dark-phase of the light-dark cycle. The results show that in young 7-week-old rats, serum leptin levels increase significantly at 2300 h from the levels at 1500 h in association with increased food consumption. However, in middle-aged rats 25 weeks old, the dark-phase increase in serum leptin is absent despite retention of the daily dark-phase increase in food consumption. When compared to our earlier published results, these finding show that the loss of dark-phase rise in serum leptin occurred despite the daily increase in adipocyte leptin gene expression. These results are in accord with the view that the daily pattern in serum leptin is unlikely to be a contributor to the daily patterning of food consumption. Topics: Adipose Tissue; Aging; Animals; Body Weight; Eating; Gene Expression; Leptin; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2000 |
Chronic leptin administration promotes lipid utilization until fat mass is greatly reduced and preserves lean mass of normal female rats.
Leptin is a hormone synthesized and secreted from adipose tissue. To study the physiologic effects of chronic leptin treatment, normal adult female Sprague-Dawley rats were injected subcutaneously for 35 days. Twice daily injections (250 microgram/day, b.i.d.) resulted in a significant (P<0.05) decrease in food intake that was maintained for 10 days before gradually returning to control level by day 21. Leptin decreased body weight by a maximum of 12% of the initial body weight on day 22 and remained reduced for the duration of the treatment. After 35 days of treatment, visible peritoneal adipose tissue was not detected. Body composition analysis showed that chronic injection of leptin resulted in a dramatic decrease in fat content (28+/-2 to 4+/-2 g, P<0.05; mean+/-SEM) while the lean content remained unchanged. Rats pair-fed to the leptin-treated group but treated with vehicle had the same body composition (23+/-3 g fat mass) as that measured for the ad libitum fed controls. Using indirect calorimetry we observed that leptin decreased respiratory quotient and thus increased fat oxidation. Leptin also prevented energy expenditure reduction typically associated with food restriction. Leptin treatment for 35 days decreased plasma triglyceride (0.75+/-0.07 to 0.30+/-0.03 mM, P<0.05), free fatty acid (0.56+/-0.06 to 0.32+/-0.04 mM) and insulin (3.2+/-0.5 to 1. 4+/-0.4 ng/ml, P<0.05) concentrations despite the fact that food intake was normalized by day 35. Withdrawal of leptin triggered hyperphagia indicating that leptin biology remained throughout the duration of the chronic treatment. These data suggest that leptin reduces fat mass by initially decreasing appetite and by maintaining enhanced fat utilization even when food intake has returned to that of vehicle-treated control. Topics: Animals; Blood Glucose; Body Composition; Body Weight; Eating; Energy Metabolism; Fatty Acids; Female; Humans; Insulin; Leptin; Lipid Metabolism; Rats; Rats, Sprague-Dawley; Triglycerides | 2000 |
Disturbances in leptin metabolism are related to energy imbalance during acute exacerbations of chronic obstructive pulmonary disease.
Previously we reported an impaired energy balance in patients with chronic obstructive pulmonary disease (COPD) during an acute disease exacerbation, but limited data are available on the underlying mechanisms. Experimental and clinical research supports the hypothesis of involvement of the hormone leptin in body weight and energy balance homeostasis. The aim of this study was to investigate the course of the energy balance in relation to leptin and the soluble tumor necrosis factor (TNF) receptors (sTNF-R) 55 and 75, plasma glucose, and serum insulin in patients with severe COPD during the first 7 d of hospitalization for an acute exacerbation (n = 17, 11 men, age mean [SD] 66 [10] yr, FEV(1) 36 [12] %pred). For reference values of the laboratory parameters, blood was collected from 23 (16 men) healthy, elderly subjects. On admission, the dietary intake/resting energy expenditure (REE) ratio was severely depressed (1.28 [0.57]), but gradually restored until Day 7 (1.65 [0. 45], p = 0.005 versus Day 1). Glucose and insulin concentrations were elevated on admission, but on Day 7 only plasma glucose was decreased. The sTNF-Rs were not different from healthy subjects and did not change. Plasma leptin, adjusted for fat mass expressed as percentage of body weight (%FM), was elevated on Day 1 compared with healthy subjects (1.82 [3.85] versus 0.32 [0.72] ng%/ml, p = 0.008), but decreased significantly until Day 7 (1.46 [3.77] ng%/ml, p = 0. 015 versus Day 1). On Day 7, sTNF-R55 was, independently of %FM, correlated with the natural logarithm (LN) of leptin (r = 0.65, p = 0.041) and with plasma glucose (r = 0.81, p = 0.015). In addition, the dietary intake/REE ratio was not only inversely related with LN leptin (-0.74, p = 0.037), but also with sTNF-R55 (r = -0.93, p = 0. 001) on day seven. In conclusion, temporary disturbances in the energy balance were seen during an acute exacerbation of COPD, related to increased leptin concentrations as well as to the systemic inflammatory response. Evidence was found that the elevated leptin concentrations were in turn under control of the systemic inflammatory response, and, presumably, the high-dose systemic glucocorticosteroid treatment. Topics: Acute Disease; Aged; Blood Glucose; Body Weight; Energy Metabolism; Female; Homeostasis; Humans; Leptin; Lung Diseases, Obstructive; Lung Volume Measurements; Male; Middle Aged; Respiratory Insufficiency; Risk Factors; Systemic Inflammatory Response Syndrome | 2000 |
Effects of isoenergetic overfeeding of either carbohydrate or fat in young men.
Ten pairs of normal men were overfed by 5 MJ/d for 21 d with either a carbohydrate-rich or a fat-rich diet (C- and F-group). The two subjects in each pair were requested to follow each other throughout the day to ensure similar physical activity and were otherwise allowed to maintain normal daily life. The increase in body weight, fat free mass and fat mass showed great variation, the mean increases being 1.5 kg, 0.6 kg and 0.9 kg respectively. No significant differences between the C- and F-group were observed. Heat production during sleep did not change during overfeeding. The RQ during sleep was 0.86 and 0.78 in the C- and F-group respectively. The accumulated faecal loss of energy, DM, carbohydrate and protein was significantly higher in the C- compared with the F-group (30, 44, 69 and 51% higher respectively), whereas the fat loss was the same in the two groups. N balance was not different between the C- and F-group and was positive. Fractional contribution from hepatic de novo lipogenesis, as measured by mass isotopomer distribution analysis after administration of [1-(13)C]acetate, was 0.20 and 0.03 in the C-group and the F-group respectively. Absolute hepatic de novo lipogenesis in the C-group was on average 211 g per 21 d. Whole-body de novo lipogenesis, as obtained by the difference between fat mass increase and dietary fat available for storage, was positive in six of the ten subjects in the C-group (mean 332 (SEM 191)g per 21 d). The change in plasma leptin concentration was positively correlated with the change in fat mass. Thus, fat storage during overfeeding of isoenergetic amounts of diets rich in carbohydrate or in fat was not significantly different, and carbohydrates seemed to be converted to fat by both hepatic and extrahepatic lipogenesis. Topics: Adipose Tissue; Adult; Blood Glucose; Body Composition; Body Temperature Regulation; Body Weight; Dietary Carbohydrates; Dietary Fats; Energy Intake; Energy Metabolism; Humans; Hyperphagia; Insulin; Leptin; Lipids; Liver; Male; Nitrogen | 2000 |
Biomedicine. Staying slim with insulin in mind.
Striking the delicate balance between energy intake in the form of food and energy expenditure in the form of metabolic activity keeps the body extremely busy. As Schwartz explains in his enlightening Perspective, the finding that insulin signals the brain to promote weight loss (Brüning et al.) flies in the face of the notion that insulin is involved solely in glucose storage, its conversion to fat, and weight gain. Topics: Adipocytes; Animals; Blood Glucose; Body Weight; Brain; Eating; Female; Insulin; Leptin; Male; Mice; Neurons; Obesity; Receptor, Insulin; Signal Transduction; Weight Loss | 2000 |
Differential expression of lipoprotein lipase gene in tissues of the rat model with visceral obesity and postprandial hyperlipidemia.
Postprandial hyperlipidemia is frequently accompanied with intra-abdominal visceral accumulation in human subjects. We have found that the decreased lipoprotein lipase (LPL) mass and activity is negatively associated with the amount of visceral fat accumulation. Here, we studied the postprandial hyperlipidemia using the OLETF rat, a model with visceral obesity, in order to clarify the molecular mechanism causing postprandial hyperlipidemia accompanied with visceral obesity. At the same age of 32 weeks, the OLETF rats showed obviously higher plasma leptin, total cholesterol, triglyceride, and HDL-cholesterol levels than the control LETO rats, although the plasma glucose level was not significantly different. Fat-loading test revealed the delayed metabolism of exogenous fat in the OLETF rats compared to the LETO rats, similar to human subjects with visceral obesity. In the obese rats, plasma levels of LPL mass and activities were 60 and 49% of control rats. The expression of LPL gene was decreased in subcutaneous adipose tissues and skeletal muscle of OLETF rats to 40 and 52% compared to those of LETO rats. In OLETF rats, plasma tumor necrosis factor-alpha (TNF-alpha) and insulin levels were increased to 2.0- and 2.3-folds compared to those in control rats. Furthermore, plasma insulin and TNF-alpha levels in OLETF rats were negatively correlated with the expression levels of LPL gene in subcutaneous fat and muscle. These results indicate that decreased LPL mass and activity in the animal model with visceral obesity is possibly caused by decreased expression of LPL gene in tissues mediated by the increased levels of insulin and TNF-alpha. The different expression of LPL gene in tissues associated with the increased levels of insulin and TNF-alpha possibly elucidate the underlying mechanisms involving the postprandial hyperlipidemia observed in visceral obesity. Topics: Adipose Tissue; Animals; Blood Glucose; Blotting, Northern; Body Weight; Cholesterol; Cholesterol, HDL; Cloning, Molecular; Disease Models, Animal; Diterpenes; Humans; Hyperlipidemias; Insulin; Leptin; Lipoprotein Lipase; Male; Muscle, Skeletal; Obesity; Rats; Rats, Long-Evans; Retinyl Esters; RNA, Messenger; Time Factors; Tissue Distribution; Triglycerides; Tumor Necrosis Factor-alpha; Vitamin A | 2000 |
Hormonal factors influencing weight and growth pattern in craniopharyngioma.
Patients operated on for craniopharyngioma frequently suffer from hyperphagia and are obese, but their statural growth is normal despite growth hormone (GH) deficiency. We have evaluated the hormonal factors influencing changes in weight and growth in 17 children before and 1, 3-6, 12, and/or 24 months after surgical resection of a craniopharyngioma performed at 7.7 +/- (SE) 1 years of age. Of these, 15 patients had a GH deficiency before surgery, and all had complete pituitary deficiency after it. The plasma fasting insulin concentrations before surgery were positively correlated with body mass index (BMI, kg/m(2); p < 0.05), plasma insulin-like growth factors (IGFI, p = 0.03, and IGFII, p = 0.04), and leptin (p = 0.03). They increased significantly 1 month after surgery and continued to increase thereafter, whereas leptin increased significantly only 3-6 months after surgery, paralleling changes in BMI. The plasma fasting insulin concentrations before surgery were also positively correlated with the weight changes (12.3 +/- 2.3 kg, p < 0.01) during the 12 months after surgery, but not with changes in BMI SDS (3.1 +/- 0.5, p = 0.07). Both expressions of weight change were correlated with the concomitant growth rates (4.8 +/- 0.7 cm, p < 0.01). IGFI was above the 10th percentile for children with idiopathic short stature in 10 of 15 patients with craniopharyngioma-induced GH deficiency and IGF-binding protein 3 in 14 of 15 patients. Craniopharyngioma itself modified the control of insulin secretion, and surgery increased the insulin secretion which continued in the same way in a given patient after surgery. The increased insulin secretion in turn increases weight and keeps IGFI nearly normal. This may explain the normal growth rate despite the complete lack of GH. Topics: Body Mass Index; Body Weight; Child; Craniopharyngioma; Female; Growth; Hormones; Human Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Male; Pituitary Neoplasms | 2000 |
Leptin resistance in obesity is characterized by decreased sensitivity to proopiomelanocortin products.
Obesity in normal animals has been demonstrated to be associated with a decrease in sensitivity to leptin especially as it relates to leptin's capacity to increase sympathetic nerve activity and enhance cardiovascular dynamics. In normal animals leptin has been demonstrated to exert significant regulatory responses by its capacity to increase proopiomelanocortin (POMC) expression and especially the increase in alpha melanocyte stimulating hormone (alphaMSH). These responses to leptin are blocked by a melanocortin-4 (MC-4) receptor antagonist. In this study we investigated the responsiveness of the sympathetic nervous system and cardiovascular system of high fat fed obese animals to the intracerebroventricular (ICV) administration of the POMC products alphaMSH and beta-endorphin (beta-END). We further investigated these responses in obese animals following leptin administration in the presence of MC-4 receptor and opioid receptor blockade. The ICV administration of leptin resulted in an increase in lumbar sympathetic nerve activity (LSNA) and mean arterial pressure (MAP) in normals but decreased it in the obese. The ICV administration of alphaMSH increased the LSNA and MAP in normal animals but to a lesser degree in obese animals. On the other hand beta-endorphin decreased the LSNA and MAP in normal animals but increased it in obese animals. Additionally ICV leptin administration in obese animals in the presence of MC-4 or opioid receptor blockade resulted in an increase in sympathetic activity and a pressor response. From these studies we conclude that obesity in high fat fed animals is characterized by a decreased sensitivity to alphaMSH and a paradoxical response to beta-endorphin and this altered responsiveness may be a factor in the altered leptin resistance characteristic of obese animals. Topics: Agouti Signaling Protein; alpha-MSH; Animals; beta-Endorphin; Blood Pressure; Body Weight; Dietary Fats; Drug Resistance; Electrophysiology; Female; Heart Rate; Injections, Intraventricular; Intercellular Signaling Peptides and Proteins; Leptin; Naloxone; Narcotic Antagonists; Obesity; Pressoreceptors; Pro-Opiomelanocortin; Proteins; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, Opioid; Splanchnic Nerves | 2000 |
CRH and NPY are not decreased in hypophagic, protein-deprived rats.
To test if elevated CRH and decreased NPY might account for pituitary-adrenal activity and hypophagia in dietary protein deprivation, rats received normal or protein-free diet, or were food-or weight-restricted to match effects of protein deprivation. Protein or food restriction increased plasma ACTH. However, hypothalamic CRH mRNA was unchanged by protein deficiency and significantly decreased by food restriction when protein intake was > 50% of normal. Arcuate nucleus NPY mRNA increased in rats given protein-free diet, correlating with leptin rather than decreased feeding. We conclude that CRH and NPY gene expression does not explain adrenocortical axis or feeding activity in protein-deprived rats. Topics: Adrenalectomy; Adrenocorticotropic Hormone; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Diet; Diet, Protein-Restricted; Eating; Food Deprivation; Histocytochemistry; In Situ Hybridization; Leptin; Male; Neuropeptide Y; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2000 |
Serum leptin levels in type 1 diabetic and obese children: relation to insulin levels.
To compare serum leptin levels in type 1 diabetic and obese children.. We studied serum leptin levels in 35 type 1 diabetic, 32 obese, and 35 healthy children. Seven of 35 were new-onset diabetics with ketoacidosis. C-peptide (CPE) levels were used for estimating insulin secretion.. Serum leptin levels were lower in diabetics than in controls (p<0.001). Obese children had higher leptin and CPE levels than diabetics and controls. In new-onset diabetics, 1 month insulin treatment did not cause any change in leptin levels (p>0.05). Leptin was correlated positively with body mass index and CPE (p<0.001) and inversely with glucose (p = 0.001) and HbA1c (p<0.05) in the combined group. HbA1c and gender were the independent predictors of leptin in diabetic children (p<0.01).. Low serum leptin levels in type 1 diabetic children may be due to chronic insulin deficiency related with their metabolic control. Leptin and insulin may have complementary roles in maintaining a stable body weight. Topics: Adolescent; Body Mass Index; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Male; Matched-Pair Analysis; Obesity; Statistics as Topic | 2000 |
Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses.
The aim of this study was to investigate the influence of the antipsychotic agent olanzapine on glucose-insulin homeostasis to explain possible mechanisms behind olanzapine-associated weight gain.. Fourteen patients on treatment with olanzapine (all meeting DSM-IV criteria for schizophrenia or related psychoses) were studied. Fasting blood samples for glucose, insulin, the growth hormone (GH)-dependent insulin-like growth factor I, and the insulin-dependent insulin-like growth factor binding protein-1 (IGFBP-1) were analyzed, as well as GH, leptin, and blood lipid levels and the serum concentrations of olanzapine and its metabolite N-desmethylolanzapine. In addition, body mass index (BMI) was calculated. Moreover, weight change during olanzapine treatment was determined.. Twelve of the 14 patients reported weight gain between 1 and 10 kg during a median olanzapine treatment time of 5 months, whereas data were not available for the other 2 patients. Eight patients (57%) had BMI above the normal limit. Eleven patients were normoglycemic, and 3 showed increased blood glucose values. Most patients (10/14; 71%) had elevated insulin levels (i.e., above the normal limit). Accordingly, the median value of IGFBP-1 was significantly lower for the patients in comparison with healthy subjects. Moreover, 8 (57%) of 14 patients had hyperleptinemia, 62% (8/13) had hypertriglyceridemia, and 85% (11/13) hypercholesterolemia. Weight change correlated positively to blood glucose levels and inversely to the serum concentration level of N-desmethylolanzapine. Additionally, the levels of blood glucose, triglycerides, and cholesterol correlated inversely to the serum concentration of N-desmethylolanzapine.. Olanzapine treatment was associated with weight gain and elevated levels of insulin, leptin, and blood lipids as well as insulin resistance, with 3 patients diagnosed to have diabetes mellitus. Both increased insulin secretion and hyprleptinemia may be mechanisms behind olanzapine-induced weight gain. Moreover, it is suggested that the metabolite N-desmethylolanzapine, but not olanzapine, has a normalizing effect on the metabolic abnormalities. Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Chromatography, High Pressure Liquid; Female; Humans; Insulin; Leptin; Lipids; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia; Triglycerides | 2000 |
Unlike leptin, ciliary neurotrophic factor does not reverse the starvation-induced changes of serum corticosterone and hypothalamic neuropeptide levels but induces expression of hypothalamic inhibitors of leptin signaling.
Leptin mediates neuroendocrine responses to fasting and restores the starvation-induced changes of several hypothalamic neuropeptides. Ciliary neurotrophic factor (CNTF), a cytokine closely related to leptin, reduces food intake and reverses obesity, but its role in restoring the starvation-induced changes of hormones or hypothalamic neuropeptides remains largely unknown. To comparatively assess the roles of CNTF and leptin in reversing the starvation-induced changes of hypothalamic neuropeptides and endocrine function and in inducing expression of hypothalamic inhibitors of leptin and CNTF signaling (suppressor of cytokine signaling 3 [SOCS-3]) and mediators of energy expenditure (cyclo-oxygenase 2 [COX-2]), we studied the effect of CNTF and leptin administered by intraperitoneal injections (1 microg/g twice daily) in C57Bl/6J mice fasted for 48 h. Serum corticosterone levels increased with fasting, and leptin administration partially normalized them, whereas CNTF administration had no effect. Hypothalamic neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expression increased and pro-opiomelanocortin (POMC) decreased in response to fasting. Leptin administration decreased NPY and AgRP and increased POMC mRNA levels toward baseline, but CNTF administration in fasted mice had no effect of comparable significance. Both leptin and CNTF administration in fasted mice resulted in an induction of SOCS-3 mRNA expression. CNTF also induced hypothalamic SOCS-2 mRNA expression. Finally, neither leptin nor CNTF administration in mice fasted for 48 h alters hypothalamic COX-2 expression. Our data suggest that only falling leptin levels mediate the starvation-induced alterations in corticosterone levels and expression of hypothalamic neuropeptides, but inhibitors of leptin signaling are induced by both leptin and CNTF. This may be of clinical importance because both agents are now being evaluated for the treatment of obesity in humans. Topics: Actins; Agouti-Related Protein; Animals; Body Weight; Ciliary Neurotrophic Factor; Corticosterone; Cyclooxygenase 2; DNA-Binding Proteins; Fasting; Gene Expression; Hypothalamus; Intercellular Signaling Peptides and Proteins; Isoenzymes; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Neuropeptides; Pro-Opiomelanocortin; Prostaglandin-Endoperoxide Synthases; Proteins; Repressor Proteins; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Trans-Activators; Transcription Factors | 2000 |
Adrenalectomy reverses obese phenotype and restores hypothalamic melanocortin tone in leptin-deficient ob/ob mice.
In genetically obese leptin-deficient ob/ob mice, adrenalectomy reverses or attenuates the obese phenotype. Relative to lean controls, ob/ob mice also exhibit decreased hypothalamic proopiomelanocortin (POMC) mRNA and increased hypothalamic agouti-related peptide (AGRP) mRNA and neuropeptide Y (NPY) mRNA. It has been hypothesized that this profile of hypothalamic gene expression contributes to the obese phenotype caused by leptin deficiency. To assess if reversal of obese phenotype by adrenalectomy entails normalization of hypothalamic gene expression, male wild-type and ob/ob mice were adrenalectomized (with saline supplementation) or sham adrenalectomized at 2 months of age. Mice were sacrificed 2 weeks after adrenalectomy, during which time food intake and body weight were monitored daily. After sacrifice, hypothalamic gene expression was assessed by Northern blot analysis as well as in situ hybridization. In wild-type mice, adrenalectomy significantly decreased AGRP mRNA but did not significantly influence POMC or NPY mRNA. In ob/ob mice, adrenalectomy reduced the levels of plasma glucose, serum insulin and corticosterone, and food intake toward or below wild-type levels, and it restored hypothalamic POMC and AGRP mRNA but not NPY mRNA to wild-type levels. These studies suggest that adrenalectomy reverses or attenuates the obese phenotype in ob/ob mice, in part by restoring hypothalamic melanocortin tone toward wild-type levels. These studies also demonstrate that factors other than leptin may play a major role in regulating hypothalamic melanocortin function. Topics: Adrenalectomy; Agouti-Related Protein; Animals; Blood Glucose; Blotting, Northern; Body Weight; Corticosterone; Eating; Gene Expression; Hypothalamus; In Situ Hybridization; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Phenotype; Pro-Opiomelanocortin; Proteins | 2000 |
Sibutramine alters the central mechanisms regulating the defended body weight in diet-induced obese rats.
Chronic administration of sibutramine lowers body weight, presumably by altering brain monoamine metabolism. Here the effect of sibutramine on sympathoadrenal function (24-h urine norepinephrine and epinephrine levels) and arcuate nucleus (ARC) neuropeptide Y (NPY) and proopiomelanocortin (POMC) expression was assessed in diet-induced obese rats fed a low-fat diet. Chronic (10 wk) sibutramine [5 mg. kg(-1). day(-1) ip; rats fed ad libitum and injected with sibutramine (AS)] lowered body weight by 15% but only transiently (3-4 wk) reduced intake compared with vehicle-treated controls [rats fed chow ad libitum and injected with vehicle daily (AV)]. Other rats food restricted (RS) to 90% of the weight of AS rats and then given sibutramine restored their body weights to the level of AS rats when allowed libitum food intake. After reequilibration, RS rats were again energy restricted to reduce their weight to 90% of AS rats, and additional vehicle-treated rats (RV) were restricted to keep their body weights at the level of AS rats for 3 wk more. Terminally, total adipose depot weights and leptin levels paralleled body weights (AV > AS = RV > RS), although AS rats had heavier abdominal and lighter peripheral depots than RV rats of comparable body weights. Sibutramine treatment increased sympathetic activity, attenuated the increased ARC NPY, and decreased POMC mRNA levels induced by energy restriction in RV rats. Thus sibutramine lowered the defended body weight in association with compensatory changes in those central pathways involved in energy homeostasis. Topics: Adipose Tissue; Animals; Appetite Depressants; Arcuate Nucleus of Hypothalamus; Body Weight; Cyclobutanes; Energy Intake; Epinephrine; Feeding Behavior; Gene Expression Regulation; Homeostasis; Leptin; Neuropeptide Y; Norepinephrine; Obesity; Organ Size; Pro-Opiomelanocortin; Rats; RNA, Messenger | 2000 |
Effects of leptin on basal and FSH stimulated steroidogenesis in human granulosa luteal cells.
Body weight influences fertility and studies in mice have indicated that leptin is one of the mediators of this effect. Leptin is believed to centrally stimulate the hypothalamic-pituitary axis resulting in increased gonadotropin release. Moreover, leptin is present in follicular fluid and the receptor is expressed in the human ovary. The aim of this study was to evaluate the direct effect of leptin on cultured human granulosa cell steroidogenesis.. Granulosa cells were obtained in connection with IVF procedures, and then cultured in a serum-free medium containing androstenedione (1 microM) for a total of 4 days. After 2 days of culture the medium was changed and the hormones under study were added. We tested the effect of leptin (1, 20, 100 ng/ml) on basal, FSH (10-100 ng/ml), and FSH (10-100 ng/ml)+IGF-I (30 ng/ml) stimulated steroidogenesis.. Leptin (20 ng/ml and 100 ng/ml) significantly reduced basal and FSH-stimulated estradiol secretion (p<0.05). Basal and FSH (10 and 30 ng/ml) stimulated progesterone production was significantly inhibited by leptin 20 ng/ml, whereas leptin 100 ng/ml significantly reduced basal but not FSH stimulated progesterone production. Finally, steroidogenesis stimulated by IGF-I alone and in combination with FSH was not influenced by leptin.. These results suggest that leptin acts directly to inhibit basal and FSH stimulated estradiol and progesterone production in cultured human granulosa cells. This raises the possibility that high circulating leptin levels as seen in obese women may compromise fertility through peripheral mechanisms. Topics: Body Weight; Cell Culture Techniques; Female; Follicle Stimulating Hormone; Granulosa Cells; Humans; Infertility, Female; Leptin; Progesterone | 2000 |
Energy homeostasis and body weight in obesity: new physiopathological and therapeutic considerations.
This paper reviews recent developments and findings regarding the role of the hypothalamus as the main site in the central nervous system (CNS) for regulating appetite. It contains a specific neural network consisting of the main central monoaminergic neurotransmitters (adrenaline, noradrenaline, dopamine, serotonin) and many neuropeptides with orexigenic and anorexigenic functions. The crucial relationship between CNS and obesity and the complex interconnections of CNS and peripheral peptides are becoming clearer. The mechanisms by which these hormones affect energy homeostasis through long and short-term anabolic and catabolic pathways are described. New anti-obesity therapeutic strategies based on drugs or molecules with new mechanisms of action, some not yet available in Italy but will soon be on the market, are considered. Topics: Appetite Depressants; Body Weight; Brain; Cyclobutanes; Energy Intake; Homeostasis; Humans; Leptin; Obesity | 2000 |
Secondary osteoporosis: the potential relevance of leptin and low body weight.
Topics: Body Weight; Female; Humans; Leptin; Male; Osteoporosis | 2000 |
Leptin acts on metabolism in a photoperiod-dependent manner, but has no effect on reproductive function in the seasonally breeding Siberian hamster (Phodopus sungorus).
Leptin may play a role in appetite regulation and metabolism, but its reproductive role is less clear. In photoperiodic Siberian hamsters, seasonal changes in fatness, leptin gene expression, and metabolism occur synchronously with activation or suppression of reproduction, analogous to puberty. Here, we test the hypothesis that seasonal changes in leptin secretion mediate the photoperiodic regulation of reproduction. Mature male and ovariectomized estrogen-treated female Siberian hamsters were kept in long (LD; 16 h of light, 8 h of darkness) or short days (SD; 8 h of light, 16 h of darkness) for 8 weeks, and recombinant murine leptin (15 microg/day) was infused for 2 weeks via osmotic minipumps. SD hamsters exhibited significant weight and fat losses, reduced serum leptin and food intake, and suppressed pituitary LH concentration. Leptin did not suppress food intake over the 2-week treatment on either photoperiod, but significantly reduced fat reserves in SD hamsters. Leptin had no significant effect on pituitary LH concentrations in either sex or photoperiod or on testicular size and testosterone concentrations in males. These results suggest hamsters are more responsive to leptin on SD than on LD and that effects on food intake and fat loss can be dissociated in this species. Our data suggest that leptin does not mediate photoperiodic reproductive changes. Topics: Animals; Body Weight; Cricetinae; Drug Implants; Eating; Estradiol; Female; Hair; Leptin; Luteinizing Hormone; Male; Ovariectomy; Phodopus; Photoperiod; Pituitary Gland; Reproduction; Seasons | 2000 |
Leptin resistance is associated with hypothalamic leptin receptor mRNA and protein downregulation.
It is well known that leptin plays a predominant role in body weight regulation. Leptin receptors are especially abundant in the hypothalamus, where the majority of leptin's biologic activity occurs. In instances where leptin has no or limited activity, it is easy to implicate leptin resistance and speculate as to the multiple levels where resistance may occur. We hypothesize that leptin resistance is associated with hypothalamic leptin receptor downregulation. Rats were randomly divided into 3 groups receiving phosphate-buffered saline (PBS) or low- or high-dose leptin continually over a 28-day period. Body weight and food intake were measured daily. Long-term leptin treatment resulted in a dose-dependent decrease in body weight for the duration of the study. It also resulted in a dose-dependent decrease in food intake, but only for the first half of the study. A test of leptin resistance was performed at week 3 demonstrating the development of resistance to the anorectic effects of leptin in both treatment groups. The results of the resistance test together with the food intake data suggest that resistance to the appetite-regulating effects of leptin developed during the final 2 weeks of the study. In addition, we show a downregulation of leptin receptor mRNA and protein in the hypothalamus, which may be one of the mechanisms by which the food-intake effects of leptin were lost. Topics: Animals; Base Sequence; Blood Glucose; Body Weight; Carrier Proteins; DNA Primers; Down-Regulation; Feeding Behavior; Hypothalamus; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Rats; Rats, Long-Evans; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Triglycerides | 2000 |
Calorigenic actions of leptin are additive to, but not dependent on, those of thyroid hormones.
We examined a possible mechanistic interaction between leptin and thyroid hormones in rats with hypothyroidism induced by thyroidectomy (TX) and propylthiouracil administration. In study 1, the TX rats were treated by vehicle (V, n = 9) or by recombinant murine leptin (L, 0.3 mg. kg(-1). day(-1), n = 9) or were pair-fed (PF, n = 9) against L. In study 2, the TX rats were all given 3, 3'5'-triiodo-L-thyronine (T(3)) replacement (T, 5 microg. kg(-1). day(-1)) to correct hypothyroidism. They were then subdivided into three groups, namely, vehicle (T+V, n = 9), leptin (T+L, n = 10), and pair-feeding (T+PF, n = 9), similar to study 1 except for T(3) (T). Reduced food consumption and weight gain in the TX rats were reversed by T(3) replacement. Leptin suppressed food intake in the TX rats regardless of T(3) replacement. O(2) consumption (VO(2)) and CO(2) production (VCO(2)) were reduced in TX rats (P < 0.05 vs. normal) but were normalized by either T(3) or leptin treatment. T+L additively increased VO(2) and VCO(2) (P < 0.05 vs. TX, T(3), and L). The respiratory exchange ratio was unaltered in TX rats, with and without T(3), but was significantly reduced by L or T+L treatments. These results indicate that the metabolic actions of leptin are not dependent on a normal thyroid status and that the effects of leptin and T(3) on oxidative metabolism are additive. Topics: Animals; Body Weight; Calorimetry, Indirect; Cell Respiration; Drug Interactions; Eating; Energy Metabolism; Hypothyroidism; Leptin; Male; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Thyroidectomy; Triiodothyronine | 2000 |
Editorial: leptin as a therapeutic agent--trials and tribulations.
Topics: Animals; Anti-Obesity Agents; Body Weight; Clinical Trials as Topic; Humans; Lactones; Leptin; Obesity; Orlistat; Recombinant Proteins | 2000 |
Dietary restriction and aging in rhesus monkeys: the University of Wisconsin study.
Dietary restriction (DR) retards aging and extends the maximum lifespan of laboratory mice and rats. To determine whether DR has similar actions in a primate species, we initiated a study in 1989 to investigate the effects of a 30% DR in 30 adult male rhesus monkeys. In 1994, an additional 30 females and 16 males were added to the study. Although the animals are still middle-aged, a few differences have developed between the control and DR animals suggesting that DR may induce physiologic changes in the rhesus monkey similar to those observed in rodents. Fasting basal insulin and glucose concentrations are lower in DR compared to control animals while insulin sensitivity is higher in the restricted animals. DR has also altered circulating LDL in a manner that may inhibit atherogenesis. These results suggest that DR may be slowing some age-related physiologic changes. In addition to measures of glucose and lipid metabolism, the animals are evaluated annually for body composition, energy expenditure, physical activity, hematologic indices, and blood or urinary hormone concentrations. In the next few years, the first animals will reach the average lifespan ( approximately 26 years) of captive rhesus monkeys and it will become possible to determine if DR retards the aging process and extends the lifespan in a primate species. Topics: Aging; Animals; Behavior, Animal; Blood Glucose; Body Composition; Body Weight; Bone Density; Dehydroepiandrosterone; Diet; Energy Metabolism; Female; Hydrocortisone; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Lipids; Macaca mulatta; Male; Melatonin; Physical Exertion; Time Factors; Triiodothyronine | 2000 |
Aging and the neuroendocrine regulation of reproduction and body weight.
Aging in men is associated with a decline in trophic factors such as testosterone (T), alterations in body composition and impaired energy and body weight regulation. We performed studies to investigate the mechanisms underlying age-related changes in the neuroendocrine control of testis function, body composition, food intake and body weight in the Brown Norway (BN) rat. We found that similar to aging men, male BN rats demonstrate both primary and secondary testicular failure with aging without confounding age-related tumors, hormonal changes and systemic illnesses. With aging, these animals have blunted circadian variations in luteinizing hormone (LH) and T, and decreased hypothalamic gonadotropin-releasing hormone (GnRH) synthetic capacity with preserved pituitary gonadotropin responses to GnRH. We found that aging male BN rats have increased peripheral and visceral adiposity associated with increased insulin and leptin levels, and decreased relative lean body mass and muscle mass. We found that these rats exhibit reduced food intake and body weight gain associated with decreased hypothalamic neuropeptide Y (NPY) gene expression in the arcuate nucleus (ARC), both during ad-libitum feeding and after a 72-h fast. Recently, we found that old male BN rats treated chronically with troglitazone, an insulin sensitizer, lowered high insulin and leptin levels, decreased body fat, and corrected the blunted food intake and body weight gain response to fasting without affecting basal ARC NPY gene expression. These findings suggested that hyperinsulinemia and/or hyperleptinemia associated with aging may contribute to the age-related impairment in energy and weight regulation. Our studies suggest that the aging male BN rat is an excellent model to investigate the mechanisms underlying the age-associated changes in the neuroendocrine control of body composition, energy intake and body weight. Topics: Aging; Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Body Weight; Chromans; Eating; Gene Expression Regulation, Developmental; Gonadotropin-Releasing Hormone; Gonadotropins, Pituitary; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Models, Animal; Neuropeptide Y; Neurosecretory Systems; Pituitary Gland; Rats; Rats, Inbred BN; Reproduction; RNA, Messenger; Testis; Thiazoles; Thiazolidinediones; Troglitazone; Weight Gain | 2000 |
Concentrations of leptin in serum and milk collected from lactating sows differing in body condition.
Leptin concentrations in the circulation and milk were determined in sows that differed in body condition at farrowing, and in feed consumption during lactation. Serum concentrations of leptin at farrowing and weaning were highest in sows exhibiting the greatest amount of backfat. Leptin was detected in both skim and whole milk throughout lactation, but levels were not correlated with backfat thickness or circulating leptin concentrations. This report provides the first evidence for the presence of leptin in sow milk; its function in the physiology of suckling pigs remains to be determined. Topics: Adipose Tissue; Animals; Animals, Newborn; Body Weight; Eating; Female; Lactation; Leptin; Milk; Nutritional Status; Radioimmunoassay; Statistics, Nonparametric; Swine | 2000 |
Metabolic features in disease-resistant as well as in spontaneously hypertensive rats and newly established obese Wistar Ottawa Karlsburg inbred rats.
Studies, comparing several disease-prone and disease-resistant rat strains to elucidate the extent and severity of syndromes resembling human diseases are lacking. Therefore we studied the inbred rat strains BB/OK, BN/Crl, LEW/K and WKY/Crl in comparison with SHR/Mol and WOKW/K rats as models of metabolic syndrome.. Body weight and body mass index (BMI) were measured in 12 males of each strain at 14 weeks. In addition blood glucose, serum triglycerides, cholesterol, insulin and leptin were determined at 12, 13 and 14 weeks of age.. In contrast to SHR animals, WOKW rats develop a severe metabolic syndrome including obesity, hyperleptinemia, hyperinsulinemia and dyslipidemia.. We conclude that; (i) the choice of disease-resistant inbred rat strains as 'healthy controls' for a disease-prone strain has to be carefully evaluated; (ii) in comparison with SHR, WOKW rats develop most if not all facets of the metabolic syndrome described in human and (iii) as with the human disease the syndrome in rats is polygenic. Topics: Animals; Blood Glucose; Body Mass Index; Body Weight; Cholesterol; Glucose Intolerance; Hyperlipidemias; Hypertension; Insulin; Insulin Resistance; Leptin; Male; Obesity; Quality Control; Rats; Rats, Inbred BB; Rats, Inbred BN; Rats, Inbred Lew; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Triglycerides | 2000 |
Effects of cafeteria diet feeding on beta3-adrenoceptor expression and lipolytic activity in white adipose tissue of male and female rats.
To investigate the effects of short term (15 days) cafeteria diet feeding on the expression of beta3-AR in vivo and its association with lipolytic stimulation induced by beta3-AR agonist CGP12177A in isolated white adipocytes.. Six female and 6 male Wistar rats (at 4 weeks of age) were fed on a cafeteria diet plus standard diet for 15 days. The remaining 12 age- and sex-matched rats always received standard diet only.. White gonadal adipose tissue was isolated and used for the determination of beta3-AR and leptin expression, and for in vitro studies of lipolytic activity.. Control male rats had higher levels of both beta3-AR and leptin mRNA in white adipose tissue than their female counterparts. Both male and female rats up-regulated the levels of both beta3-AR and leptin mRNA in response to 15 day cafeteria diet feeding. Noradrenaline- and isoprenaline-induced lipolysis were significantly increased in fat cells from control females compared to their male counterparts. CGP12177A stimulation resulted in significantly higher glycerol release in fat cells from cafeteria diet-fed female rats, whereas there were no differences due to dietary treatment in male rats. The maximal lipolytic response of forskolin (stimulating adenylyl cyclase) and dibutyryl cyclic AMP (cyclic AMP analogous) was not affected by sex or cafeteria diet feeding.. Cafeteria diet feeding brings about higher excess body weight and impaired adipose tissue lipolytic activity in female rats compared to male rats. Thus, the higher levels of beta3-AR mRNA induced by cafeteria feeding are not indicative per se of an increase of the lipolytic response of the adipocytes. The changes seen in other adrenoceptor subtypes (beta1 and beta2) may be more determinant of the overall lipolytic response of adipocytes. Topics: Adipocytes; Adipose Tissue; Adrenergic beta-Agonists; Animal Feed; Animals; Blotting, Northern; Body Weight; Cell Size; Diet; Female; Gene Expression; Leptin; Lipolysis; Male; Propanolamines; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3; RNA, Messenger; Sex Factors; Up-Regulation | 2000 |
Leptin receptor expression and suppressor of cytokine signaling transcript levels in high-fat-fed rats.
Several lines of evidence suggest that obese individuals have a higher set point for body weight regulation relative to lean subjects. Since obese rodents and humans have high serum levels of leptin, it has been hypothesized that this may be the result of an insensitivity to this weight reducing hormone. In this experiment we assessed whether feeding of a high-fat diet to rats affects leptin receptor (OB-R) transcript levels or induces up-regulation of the suppressors of leptin/cytokine induced signaling, SOCS-3 and PIAS-3. We found that despite a significant weight gain associated with markedly increased circulating leptin levels neither OB-R gene expression nor SOCS-3 or PIAS-3 mRNA levels were significantly altered in the high-fat fed rats. This was in contrast to control experiments where administration of exogenous leptin induced a several-fold increase in SOCS-3. It is concluded that high-caloric food intake per se is not sufficient to provoke suppression of leptin signaling via these factors in animals without genetic predisposition to obesity. Topics: Adipose Tissue, Brown; Animals; Body Weight; Carrier Proteins; Dietary Fats; DNA Primers; Epididymis; Hypothalamus; Leptin; Male; Proteins; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors | 2000 |
Effect of food deprivation and leptin repletion on the plasma levels of estrogen (E2) and NADPH-d reactivity in the ventromedial and arcuate nuclei of the hypothalamus in the female rats.
The exact role of leptin in fasting has not been completely elucidated. To determine whether leptin can act in fasting to influence plasma estrogen levels and nitric oxide synthase reactivity in food regulating centers of the brain, we fasted female rats for 4 days and treated them i.p. with vehicle or 100 microg of recombinant mouse leptin as 1 ml on the 3rd and 4th day twice daily (10.00 and 17.00 h). Proestrus blood was collected at 10.00, 14.00, 18.00 and at 22.00 h, plasma obtained and assayed for estrogen (E2) and leptin levels. Verification of ovulation occurrence was by examining the oviduct for extruded ovum. The rat brains were removed and processed for nitric oxide synthase reactivity in the ventromedial hypothalamus (VMH) and arcuate nucleus (ARC) using NADPH-diaphorase histochemistry, a marker for neurons expressing NOS enzyme. Leptin effect on dependable variables such as food intake, water intake and body weight gain was also investigated. Four days fasting significantly decreased body weight, estrogen and postfast leptin levels, nitric oxide reactivity in the VMH and ARC nucleus and stopped ovulation in many (4 out of 5) rats fasted and given vehicle. Leptin treatment significantly increased plasma estrogen and postfast leptin levels, restored ovulation in many (4 out of 5) rats and increased nitric oxide reactivity in the VMH and ARC. Leptin significantly inhibited food intake, water intake and gain in body weight during recommenced feeding. These observations suggest that leptin could act in the pituitary-ovarian axis during fasting to improve reproductive function by partly stimulating estrogen secretion. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Drinking; Eating; Estrogens; Female; Food Deprivation; Leptin; Mice; NADPH Dehydrogenase; Nitric Oxide Synthase; Proestrus; Rats; Rats, Wistar; Ventromedial Hypothalamic Nucleus | 2000 |
[Circulating leptin doesn not change in postmenopausal women receiving replacement therapy with tibolone].
After informed consent, blood samples were obtained to measure leptin, FSH, LH, insulin, 17-beta-estradiol, and IGF-1. No differences in serum leptin was observed between the women on Tibolone (8.1 +/- 4.2 ng/mL) and the control group (7.4 +/- 3.7 ng/mL). Women on Tibolone had lower insulin levels (16.4 +/- 1.8) than women without therapy (19.4 +/- 1.3 mU/mL) (p < 0.05). On the contrary IGF-I levels were elevated (150.0 +/- 16.4) as compared with those in non-treated women (121.0 +/- 13.4 ng/mL) (p < 0.05). Body weight was similar between the two groups. From these data it is concluded that Tibolone, as replacement therapy, does not increase circulating leptin and seems to have no effect on body weight. Topics: Aged; Body Weight; Estradiol; Estrogen Replacement Therapy; Follicle Stimulating Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Luteinizing Hormone; Middle Aged; Norpregnenes; Postmenopause; Prodrugs; Selective Estrogen Receptor Modulators | 2000 |
Changes in height, weight and plasma leptin after bone marrow transplantation.
Short stature can be a severe side-effect of bone marrow transplantation (BMT). Because of the effect of weight changes on growth rate and on plasma insulin-like growth factor (IGF I), we analyzed changes in height and body mass index (BMI) in 53 patients given BMT. Group 1 (n = 22) was given 12 Gy total body irradiation (TBI) as six fractions, group 2 (n = 14) 10 Gy TBI (one dose), group 3 (n = 8) 6 Gy total lymphoid irradiation (one dose), and group 4 (n = 9) chemotherapy alone. At the first evaluation, 13/36 patients in groups 1 and 2 had low growth hormone (GH) peaks after stimulation. The mean plasma IGF I concentrations (z score) were similar in groups 1 (-2.9 +/- 0.3) and 2 (-2.5 +/- 0.3), and in groups 3 (-1.4 +/- 0.3) and 4 (-1.4 +/- 0.7), but those of group 1 were lower than those of groups 3 (P < 0.01) and 4 (P < 0.05), and those of group 2 than those of group 3 (P < 0.05). BMI during the 5 years after BMT did not change in groups 1 and 2, decreased in group 3, and increased in group 4. However, these changes were not significant. Most of the patients given TBI had BMI below the mean at 2 (66%) and 5 (57%) years later. Their BMI and leptin concentrations correlated positively with each other (P = 0.005), and negatively with GH peak (P = 0.02 for BMI and 0.007 for leptin). In conclusion, this study suggests that TBI actually decreases GH secretion and is followed by a persistent low BMI. The negative relationship between GH peak and leptin may indicate that both are markers of a TBI-induced hypothalamic-pituitary lesion. Topics: Adolescent; Adult; Body Height; Body Mass Index; Body Weight; Bone Marrow Transplantation; Child; Child, Preschool; Female; Follow-Up Studies; Growth Disorders; Human Growth Hormone; Humans; Infant; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Transplantation Conditioning; Weight Loss; Whole-Body Irradiation | 2000 |
Plasma leptin and thyroxine of mink (Mustela vison) vary with gender, diet and subchronic exposure to PCBs.
Female minks (Mustela vison) fed diets based on freshwater, marine or mixed fish were exposed to 1 mg of polychlorinated biphenyls (PCBs) a day for 21 weeks. The plasma leptin and thyroxine concentrations and the glucose-6-phosphatase and glycogen phophorylase activities in the liver were measured at the end of the experiment. The plasma thyroxine concentrations were significantly higher in the group exposed to PCBs. The mean plasma leptin concentration and glucose-6-phosphatase activity was the highest in the group that had the lowest body-mass index (BMI). The glycogen phophorylase activity was the highest in the freshwater fish-control group. The results suggest that the amount of fat in the body of the female minks is not the only determinant of the plasma leptin levels, but the leptin levels seem to rise with a lowered BMI unlike in rodents or humans. The positive correlation between the leptin levels and the glucose-6-phosphatase activity suggests increased gluconeogenesis with high leptin levels. Subchronic exposure to PCBs seems to have no effect on the plasma leptin levels or the glucose-6-phophatase activities, but it elevates significantly the plasma thyroxine levels with a mechanism that remains unknown. Topics: Adipose Tissue; Animals; Aroclors; Body Weight; Diet; Environmental Pollutants; Female; Fishes; Glucose-6-Phosphatase; Leptin; Liver; Male; Mink; Phosphorylases; Polychlorinated Biphenyls; Sex Characteristics; Thyroxine | 2000 |
Slow recovery of body fat lost during adenovirus-induced hyperleptinemia.
In normal rats, adenovirus-induced hyperleptinemia causes disappearance of visible body fat, downregulation of lipogenic enzymes, and upregulation of oxidative enzymes and thermogenic proteins. In addition, preadipocyte markers replace mature adipocyte markers, suggesting dedifferentiation. In weight loss induced by caloric restriction, by contrast, the lipogenic machinery is essentially intact. To determine if the radical changes induced by leptin would slow the reappearance of body fat, we compared normal lean rats made hyperleptinemic by infusing an adenovirus-leptin construct with diet-matched littermates. Initially, in plasma leptin the hyperleptinemic rats averaged approximately 50x the controls and, although it declined progressively, it was still slightly elevated at 150 days (P < 0.05). In the hyperleptinemics, body fat mass, quantified by magnetic resonance spectroscopy, remained below the pretreatment value for 60 days, while in diet-matched controls it exceeded the pretreatment value. Epididymal fat pad weight in hyperleptinemics was still 28% below paired controls at 150 days posttreatment. Histologic examination revealed adipocytes of hyperleptinemic animals to be smaller 60 days after treatment. At 60 days, adipose tissue UCP-2 gene expression in hyperleptinemics was still above controls, but expression of other lipogenic and oxidative enzymes had returned to baseline expression levels. We conclude that in normal rats recovery of body fat following adenovirus-induced hyperleptinemia is much slower than after caloric restriction, possibly because of persistent upregulation of adipocyte UCP-2. Topics: Adenoviridae; Adipose Tissue; Animals; Body Weight; Fat Body; Gene Expression Profiling; Leptin; Male; Rats; Rats, Zucker; Weight Loss | 2000 |
Hormonal regulation of neonatal weight: placental leptin and leptin receptors.
To examine whether umbilical and maternal leptin levels correlate with birthweight, placental weight, and maternal weight; and to detect membrane-bound leptin receptors in placental tissue as well as soluble leptin receptors in umbilical and maternal blood.. Prospective observational study.. University teaching hospital.. Serum levels of leptin and soluble leptin receptors were analysed in 31 randomly selected mother/newborn pairs at delivery. In addition, placental tissue was assayed for leptin receptors using immunocytochemistry and Western blot.. The mean [SD] leptin level in umbilical cord venous blood (7.1 ng/mL [4.0]) was significantly lower (P<0.001) than in maternal blood (22.5 ng/mL [10.8]). Umbilical cord leptin concentrations correlated significantly with birthweight (P<0.001), placental weight (P<0.005) but not with maternal leptin. Maternal leptin concentrations correlated only with maternal weight (P<0.001). In chorionic villous tissue, trophoblasts stained strongly positive for leptin receptor-like immunoreactivity. Two membrane-bound isoforms of the leptin receptor were also detected in placental tissue. In both umbilical and maternal serum, a soluble leptin receptor was found migrating as broad band at Mr 97,000 D.. The present data strongly reinforce the idea that circulating leptin levels may provide a growth-promoting signal for fetal development during late pregnancy. While membrane-bound leptin receptors may be involved in autocrine regulation of placental leptin production, the soluble receptor form may serve as a transport vehicle for leptin to fetal tissues. Topics: Adult; Birth Weight; Blotting, Western; Body Weight; Carrier Proteins; Embryonic and Fetal Development; Female; Fetal Blood; Humans; Leptin; Placenta; Pregnancy; Prospective Studies; Receptors, Cell Surface; Receptors, Leptin | 2000 |
[Study on the relationships between leptin levels and weights of mothers and infants and the relationships of cord serum leptin to C-peptide, insulin and insulin like growth factor-II].
To determine the relationships between serum leptin levels and maternal weights in late pregnancy and cord blood leptin levels to birth-weights, C-peptide, insulin and insulin like growth factor (IGF-II).. Fifty normal pregnant women at 37-38 weeks and their newborns were studied, and 29 non-pregnant women were set as control. Venous blood was taken from women and from the cord at delivery. Blood leptin and cord blood C-peptide, insulin, and IGF-II were measured by radio-immunoassay.. The average leptin level in maternal sera was (13.62 +/- 3.68) micrograms/L, significantly higher than that in the control (6.60 +/- 3.04) micrograms/L and that in cord blood (8.05 +/- 4.61) micrograms/L. Maternal leptin levels were significantly correlated with maternal weights and body mass index (BMI. r = 0.33, 0.35, P < 0.05), but not with infant birth-weights (r = 0.10, P > 0.05). Cord blood leptin levels were significantly correlated with birth-weights and BMI (r = 0.54, 0.49, P < 0.001) but have no correlation with maternal leptin levels (r = 0.19, P > 0.05). Significant difference of the cord leptin levels was not seen between the males and females. The cord blood C-peptide was (0.86 +/- 0.35) microgram/L, insulin (8.49 +/- 4.76) mU/L and IGF-II (0.218 +/- 0.076) microgram/T. Cord leptin levels were correlated with C-peptide levels (r = 0.37, P < 0.05), but not with insulin and IGF-II levels (r = 0.19, -0.14, P > 0.05).. Maternal leptin levels in late pregnancy were significantly higher than those in normal non-pregnant women and positively correlated with maternal weights and BMI. Cord blood leptin levels were positively correlated with birth-weights and BMI of the newborns. The leptin levels of cord blood were correlated with those of C-peptide but not insulin and IGF-II. Topics: Adult; Birth Weight; Body Weight; C-Peptide; Female; Fetal Blood; Humans; Infant, Newborn; Insulin; Insulin-Like Growth Factor II; Leptin; Pregnancy | 2000 |
Serum leptin and lipids in patients with thyroid dysfunction.
This work was undertaken to examine the relationship between thyroid hormone and serum leptin concentration. This study included 368 Japanese female subjects (27 were affected with pretreatment hyperthyroidism, 68 with hyperthyroidism during treatment, 19 with pretreatment hypothyroidism, 57 with hypothyroidism during treatment and 197 euthyroid control subjects) and 60 control male subjects. In the control group, serum leptin levels in males were lower than those recorded in females (mean +/- SD; 4.6 +/- 4.1 vs 9.5 +/- 6.4 ng/ml, p < 0.001). The leptin values correlated well with body mass index (BMI) and body fat mass (BFM) in both control male and female subjects (p < 0.001 for each). The serum leptin levels in pretreatment female patients with hyperthyroidism were significantly lower than those in the pretreatment patients with primary hypothyroidism and control female subjects (6.4 +/- 3.0 vs 9.7 +/- 6.3, 9.5 +/- 6.4 ng/ml; p < 0.05, 0.02, respectively), but after adjusting for BMI and BFM, the difference was mainly due to the significantly different BMI and BFM. Furthermore, serum leptin did not change significantly during the treatment in hyper and hypothyroidism. There was no correlation between serum leptin and thyroid hormones or lipids levels in female patients with thyroid disorders. Adiposity and gender were the major determinants of leptin concentration, but thyroid hormones did not appear to play any relevant role in leptin synthesis and secretion in human. Topics: Adolescent; Adult; Aged; Aged, 80 and over; Body Weight; Case-Control Studies; Female; Humans; Hyperthyroidism; Hypothyroidism; Leptin; Lipids; Middle Aged; Reference Values; Thyroid Diseases; Thyroid Hormones | 2000 |
Cloning of Chinese obese cDNA and its expression in E. coli.
To obtain the sequence of Chinese obese (OB) cDNA and establish a method of leptin production in China.. Han Chinese OB cDNA fragment was obtained by reverse transcriptase-polymerase chain reaction (RT-PCR) with total RNA extracted from human adipocytes and was inserted into the expressing vector pBV220. Then the constructed recombinant plasmid pBV220-OB was transformed to E. coli DH5 alpha for leptin expression. The recombinant expressing system was confirmed by restriction endonuclease digestion, DNA sequencing and protein expression. E. coli cells were lysed by high-pressure homogenization. After cell membrane was extracted, the inclusion bodies were mainly renatured and purified primarily by precipitation with ammonium sulfate and gel chromatography through a Sephadex G75 column. The activity of recombinant leptin was determined by its influence on the satiety and weight gain of mice.. Analysis of DNA sequence showed that Han Chinese OB cDNA included the glutamine codon at 49. The amount of recombinant leptin expressed in E. coli accounted for 31%-47% of total cellular proteins. From 1 L of fermentative bacteria about 40 mg of pure recombinant human leptin was isolated with a purity of being above 95%. The recombinant human leptin could reduce food intake and inhibit weight gains in mice.. The glutamine codon at 49 is not missing in Chinese OB gene. The biologically active human leptin can be obtained by a relatively simple method of recombinant DNA technology. Topics: Animals; Body Weight; Cloning, Molecular; DNA, Complementary; Eating; Escherichia coli; Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mutation; Recombinant Proteins | 2000 |
[Focus on leptin studies in the field of obstetrics].
Topics: Animals; Body Weight; Embryonic and Fetal Development; Female; Humans; Hypertension; Infertility; Leptin; Pregnancy; Pregnancy Complications, Cardiovascular | 2000 |
[Exploration of weight-reducing effect of Kintop in obese rats and its mechanism].
To investigate the weight-reducing effect of Kintop and its probable mechanism in obese rats.. Body weight, Lee's index, total weight of celiac fat tissue, adipocyte size, blood glucose, blood lipid, expression of leptin in adipocyte (by ABC method), level of serum leptin (by RIA) of obese rats were chosen as the indexes to compare the weight-reducing effect of different dosages of Kintop. The administration of Kintop lasted 1 month.. Good effect could be obtained by administration of medium dose Kintop (40 mg/100 g body weight per day) in simple obese rats. At the same time of reducing body weight, blood cholesterol and sugar levels also decreased in a certain degree. The adipocyte leptin expression reduced and serum leptin elevated in those rats with body weight reduced effectively by Kintop.. Medium dose of Kintop administration for 1 month shows evident weight-reducing effect in simple obese rats, the effect might be related to raising the serum leptin level. Kintop also has the effect in lowering blood cholesterol level, and it could lower the blood sugar in obesity complicated with hyperglycemia by increasing the dosage appropriately. Topics: Animals; Body Weight; Cholesterol; Drugs, Chinese Herbal; Leptin; Male; Obesity; Rats; Rats, Sprague-Dawley | 2000 |
[Effects of ob genotype on early development in mice].
To study the effects and the extent of dominance of ob gene on early development in mice.. ob genotypes, wild type (+/+), hybrid type (ob/+) and mutant type (ob/ob), were detected by polymerase chain reaction and restrict endonuclease technique. Body weight of mice was recorded daily for the first seventh weeks of life. Their wet weight of white adipose tissue (WAT) and brown adipose tissue (BAT) was compared at the 7th, 14th and 24th days after birth.. Body weight of ob/ob mice increased rapidly two weeks after birth and reached two times of that of +/+ and ob/+ mice seven weeks after birth. WAT of ob/ob mice was significantly higher than that of +/+ and ob/+ mice 24 days after birth. Effect of ob genotype on BAT was earlier than that on WAT. Body weight and WAT of ob/+ mice ranged between those of +/+ and ob/ob mice. Dominance index, reflecting the effect of ob gene on body weight, ranged from 1.0 - 0.5 within the first two weeks after birth, appearing co-dominance. And, dominance index approximated to 0.0 six weeks after birth, appearing almost complete recession.. Effect of ob gene on body weight and WAT initiated two weeks after birth and increased with age, developing gradually from co-dominance to recession in their early life. Topics: Adipose Tissue, Brown; Adipose Tissue, White; Aging; Animals; Body Weight; Female; Genotype; Heterozygote; Leptin; Male; Mice; Mice, Inbred C57BL; Organ Size | 2000 |
Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats.
Electrolytic lesions placed in the ventromedial hypothalamus (VMH) of rats induce instant hyperphagia and excessive weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal, and leptin secreted by adipocytes regulates NPY output, we tested the hypothesis that altered NPYergic-leptin signaling may underlie hyperphagia in VMH-lesioned rats. VMH-lesioned rats exhibiting hyperphagia and excessive weight gain in a time-related fashion were sacrificed on days 2, 7, and 21 post-surgery. Quite unexpectedly, NPY concentrations in the hypothalamic paraventricular nucleus (PVN), a major site of NPY release for stimulation of feeding, and in other sites, such as the dorsomedial nucleus, lateral hypothalamic area and median eminence-arcuate nucleus decreased, with the earliest diminution occurring on day 2 in the PVN only. In vitro basal and K+-evoked NPY release from the PVN of VMH-lesioned rats was significantly lower than that of controls. Analysis of hypothalamic NPY gene expression showed that although the daily decrease in NPY mRNA from 0800 to 2200 h occurred as in control rats, NPY mRNA concentrations were markedly reduced at these times in the hypothalami of VMH-lesioned rats. Leptin synthesis in adipocytes as indicated by leptin mRNA levels was also profoundly altered in VMH-lesioned rats. The daily pattern of increase in adipocyte leptin mRNA at 2200 h from 0800 h seen in controls was abolished, higher levels of leptin gene expression at 2200 h were maintained at 0800 h. The pattern of increase in serum leptin and insulin levels diverged in VMH-lesioned rats. Serum insulin concentration increased to maximal on day 2 and remained at that level on day 21-post-lesion; serum leptin levels on the other hand, increased slowly in a time-related fashion during this period. These results demonstrate that hyperphagia and excessive weight gain in VMH-lesioned rats are associated with an overall decrease in hypothalamic NPY and augmented leptin signaling to the hypothalamus. The divergent time course of increases in serum leptin and insulin levels suggest independent mechanisms responsible for their augmented secretion, and neither these hormones nor VMH lesions altered the daily rhythm in NPY gene expression. These observations underscore the existence of an independent mechanism controlling the daily rhythm in hypothalamic NPY gene expression and suggest that leptin feedback action requires an intact VMH. Topics: Adipocytes; Animals; Body Weight; Circadian Rhythm; Dorsomedial Hypothalamic Nucleus; Eating; Gene Expression; Hypothalamic Area, Lateral; In Vitro Techniques; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Time Factors; Ventromedial Hypothalamic Nucleus | 1999 |
Induction of uncoupling protein expression in brown and white adipose tissue by leptin.
Deposition of excess body fat occurs when energy intake chronically exceeds energy expenditure. In ob/ob mice, the absence of leptin affects both components of the energy balance equation, and the mice become morbidly obese after weaning. Treatment of ob/ob mice with exogenous leptin reduces body weight by decreasing food intake and stimulating energy utilization, but even when saline- and leptin-injected ob/ob mice are pair-fed, mice receiving leptin lose significantly more weight. Therefore, the purpose of the present study was to test the hypotheses that uncoupling protein-1 (UCP1) expression is reduced in adipose tissue from ob/ob mice and is restored by treatment with exogenous leptin. Lean and ob/ob mice (5-6 weeks old) were housed at 23 C and treated with leptin (20 microg/g BW x day) for 3 days before they were killed. Compared with levels in lean littermates, UCP1 messenger RNA (mRNA) and protein levels were lower in brown adipose tissue (BAT) and retroperitoneal white adipose tissue (WAT) from ob/ob mice. Treatment of ob/ob mice with leptin reduced body weight and produced a 4- to 5-fold increase in UCP1 mRNA levels in both interscapular BAT and retroperitoneal WAT. The increases in UCP1 mRNA were accompanied by comparable increases in UCP1 protein in mitochondrial preparations from each tissue. Given that the sole known function of UCP1 is to uncouple oxidative phosphorylation, the present results are consistent with the conclusion that leptin stimulates energy utilization in ob/ob mice by increasing thermogenic activity and capacity (UCP1). In addition, the present results suggest that decreased UCP1 expression in BAT and WAT of ob/ob mice is in part responsible for their increased metabolic efficiency and propensity to become obese. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Blotting, Western; Body Weight; Carrier Proteins; Energy Metabolism; Epididymis; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Proteins; Obesity; Peritoneum; Protein Biosynthesis; Proteins; RNA, Messenger; Uncoupling Protein 1; Uncoupling Protein 2 | 1999 |
Glucocorticoid replacement, but not corticotropin-releasing hormone deficiency, prevents adrenalectomy-induced anorexia in mice.
There is considerable evidence that CRH can suppress food intake. As hypothalamic CRH, a main site of CRH expression, is also negatively regulated by glucocorticoids, it is unclear whether anorexia and weight loss in adrenal insufficiency are attributable to elevated CRH or to decreased glucocorticoid levels. To distinguish these possibilities, we have measured food intake and body weight in wild-type and CRH-deficient mice after sham adrenalectomy (Sham ADX) or adrenalectomy (ADX) with and without corticosterone (B) replacement. CRH deficiency neither increased basal food intake and body weight nor attenuated decreases in food intake after ADX or Sham ADX. B replacement producing plasma levels above the circadian peak completely blocked ADX-induced decreases in feeding and body weight in all mice and frequently stimulated food intake in CRH-deficient mice. Plasma levels of insulin and leptin, two other hormones involved in appetite regulation, did not differ between genotypes; however, the relationship between food intake and circulating leptin was significantly less negative at B doses that preserved appetite. B replacement levels slightly below circadian peak concentrations did not prevent hypophagia after ADX. We conclude that factors other than or in addition to CRH are more important in mediating appetite responses to adrenalectomy. Topics: Adrenalectomy; Animals; Anorexia; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Energy Intake; Genotype; Glucocorticoids; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Proteins | 1999 |
Effect of the genetic background on the reproduction of leptin-deficient obese mice.
Obesity is often associated with an impairment of the hypothalamic-pituitary-gonadal axis. The leptin-deficient ob/ob mouse model is characterized by a morbid obesity with a sterility in males and females that is corrected by continuous leptin treatment. Since ob/ob mice are maintained on the C57BL/6J inbred genetic background, we sought to determine whether their infertility can be corrected without leptin treatment but via the effect of modifier genes brought into the obese-sterile phenotype by a different genetic background. Thus, we generated via an F2 intercross ob/ob mice on a mixed C57BL/6J-BALB/cJ genetic background and assayed them for fertility by mating with wild-type C57BL/6J mice. Whereas genetically heterogeneous F2 obese females remained sterile like male and female C57BL/6J ob/ob mice, 41% of F2 C57BL/6J-BALB/cJ obese males were capable of reproducing despite a morbidly obese state. Therefore, the sterility of the original C57BL/6J ob/ob mouse model was genetically corrected independently of its obese state via the effects of modifier genes. Unlike testosterone levels, triglyceride levels, and testes weight-to-body weight ratios, which were all higher in fertile vs. sterile mice, glucose levels were similar in both groups, indicating that the underlying hyperglycemia of ob/ob mice was not an impediment to the onset of fertility. A genome-wide scan in F2 ob/ob males resulted in the localization of four modifier loci on chromosomes 1, 3, 5, and 14 with respective quantitative traits consisting of number of pregnancies, testes weights normalized to body weights, body weight at 8 weeks of age, and circulating testosterone. We conclude that the inheritance of modifier genes at the identified loci acts to promote fertility of otherwise sterile leptin-deficient obese male mice. Topics: Animals; Body Weight; Chromosome Mapping; Female; Infertility; Leptin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Obesity, Morbid; Pregnancy; Proteins; Reproduction | 1999 |
Plasma insulin rise precedes rise in ob mRNA expression and plasma leptin in gold thioglucose-obese mice.
Circulating leptin levels are strongly related to the degree of adiposity, with hyperleptinemia being associated with hyperinsulinemia. In the gold thioglucose-injected mouse (GTG), hyperinsulinemia is an early abnormality in the development of insulin resistance and obesity. In this study, hyperinsulinemia occurred 1 wk post-GTG [GTG, 199 +/- 43; age-matched controls (CON), 53 +/- 5 microU/ml; P < 0.001], with leptin levels not rising until 2 wk post-GTG (CON, 3.2 +/- 0.3; GTG, 9.9 +/- 1.7 ng/ml; P < 0.001) in parallel with increases in the size of different fat pads and increased expression of ob mRNA. The ratio of serum leptin to fat pad weight was significantly higher in GTG mice 12 wk postinjection. Starvation-induced reductions in serum leptin (50%), glucose (50%), and insulin (74%) were greater than decreases in fat pad weight (18%). Adrenalectomy decreased both adiposity and serum leptin within 1 wk in both CON and GTG and altered the serum leptin level-to-fat pad weight ratio in CON. Thus hyperinsulinemia preceded increased ob expression and hyperleptinemia, which occurred in parallel with increasing adiposity, consistent with the role of leptin as an indicator of energy supplies. Changes in hormonal and nutritional status may modify this relationship. Topics: Adipose Tissue; Adrenalectomy; Animals; Aurothioglucose; Blood Glucose; Body Weight; Epididymis; Fasting; Glucose Tolerance Test; Insulin; Leptin; Male; Mice; Mice, Inbred CBA; Obesity; Organ Size; Proteins; Reference Values; RNA, Messenger | 1999 |
Effect of diet on the response to leptin in the marsupial Sminthopsis crassicaudata.
The aim of this study was to determine in the marsupial Sminthopsis crassicaudata 1) the effect of leptin on food intake, body fat stores, and metabolism and 2) whether leptin can prevent a diet-induced increase in adiposity. In response to 21 days of feeding with mealworms (2.99 kcal/g, 30% fat), body weight (P < 0. 0001) and tail width (P < 0.0001) increased, compared with control animals fed with laboratory diet (1.01 kcal/g, 20% fat). Subsequently, S. crassicaudata were randomly allocated to receive either laboratory diet or a choice between laboratory diet and mealworms. For 13 days, one-half of the animals in each dietary group received intraperitoneal human leptin (2.5 mg/kg twice daily), while the other one-half received phosphate-buffered saline. In animals receiving laboratory diet alone, leptin induced a decrease in body weight (P < 0.0001), tail width (P < 0.0001), and energy intake (P < 0.01). In animals receiving both laboratory diet and mealworms, leptin had no effect on body weight or tail width, although the proportion of laboratory diet eaten was reduced (P = 0. 0001), and there was a nonsignificant fall in overall energy intake (P = 0.07). We conclude that in S. crassicaudata, 1) a high-calorie, higher-fat diet induces an increase in adiposity and 2) leptin induces weight loss, but 3) an increase in dietary calories and fat content is associated with resistance to the actions of leptin. Topics: Animals; Body Temperature; Body Weight; Diet; Energy Intake; Food Preferences; Humans; Injections, Intraperitoneal; Leptin; Male; Marsupialia; Proteins; Tail; Time Factors | 1999 |
Body weight and leptin plasma levels during treatment with antipsychotic drugs.
Leptin is produced by fat cells and is presumed to signal the size of the adipose tissue to the brain. The authors investigated whether antipsychotic drugs that often induce weight gain affect circulating levels of leptin.. Weight, body mass index, and leptin plasma level were measured weekly over 4 weeks in psychiatric inpatients who received clozapine (N = 11), olanzapine (N = 8), haloperidol (N = 13), or no psychopharmacological treatment (N = 12).. In patients receiving clozapine or olanzapine, significant increases in weight, body mass index, and leptin level were found, whereas these measures remained stable in patients who received haloperidol or no pharmacological treatment.. Weight gain induced by clozapine or olanzapine appears to be associated with an increase in leptin level that cannot be attributed to dietary changes upon hospitalization. Topics: Adipose Tissue; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Haloperidol; Hospitalization; Humans; Leptin; Mental Disorders; Olanzapine; Pirenzepine; Proteins; Weight Gain | 1999 |
Serum leptin and weight gain over 8 years in African American and Caucasian young adults.
There is considerable interest in how to prevent weight gain in adulthood. Leptin, a peptide hormone expressed in adipose tissue, is believed to signal the central nervous system about the level of body fat stores, and thereby may control appetite. Little information exists on whether the serum leptin concentration influences long-term weight changes in the free-living population.. From an ongoing cohort study of young African American and white adults, we selected a sample of participants (n=492), stratified on sex, race, and weight changes over 8 years. Serum leptin was measured on stored specimens using a radioimmunoassay. Weight change was modeled in relation to baseline leptin concentrations.. Cross-sectionally, leptin concentration was associated positively with body mass index, negatively with physical activity level, and was higher in women than men. These variables explained 72% of the variance in serum leptin. Over the 8 years, the sample gained an average of 7.8 kg (standard deviation = 10.8). There was no evidence that 8-year weight change was associated with initial leptin concentration: 8-year weight change was only 0.5 kg less (95% confidence interval =-1.8 to 0.8, p = 0.47) per each 10 ng/ mL increment (approximately one standard deviation) of baseline leptin. In contrast, leptin change correlated highly (r=0.62) with weight change.. Our data corroborate evidence that adiposity determines leptin levels but do not support the hypothesis that leptin deficiency plays an important role in obesity in the general population. Topics: Adipose Tissue; Adolescent; Adult; Age Factors; Black People; Body Constitution; Body Mass Index; Body Weight; Cross-Sectional Studies; Exercise; Female; Humans; Leptin; Male; Obesity; Prospective Studies; Proteins; Radioimmunoassay; Regression Analysis; Sex Factors; Surveys and Questionnaires; Weight Gain; White People | 1999 |
Divergent effects of intracerebroventricular and peripheral leptin administration on feeding and hypothalamic neuropeptide Y in lean and obese (fa/fa) Zucker rats.
Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express neuropeptide Y, a powerful inducer of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb leptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and neuropeptide Y neuronal activity is not fully known. We compared the effects of three doses of leptin given intracerebroventricularly and three doses of leptin injected intraperitoneally on food intake and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In lean rats, 4-h food intake was reduced in a dose-related fashion (P<0.01) by all intracerebroventricular leptin doses and by intraperitoneal doses of 300 and 600 microg/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21% after the highest intracerebroventricular and intraperitoneal doses respectively (P<0. 01 for both). In fatty rats, only the highest intracerebroventricular leptin dose reduced food intake (by 22%; P<0. 01). Neuropeptide Y mRNA levels were 100% higher in fatty rats than in lean animals, and were reduced by 18% (P<0.01) after the highest intracerebroventricular leptin dose. Intraperitoneal injection had no effect on food intake and neuropeptide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin given intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neurons and its transport into the central nervous system. Obesity in the fa/fa Zucker rat may be partly due to the inability of leptin to inhibit hypothalamic neuropeptide Y neurons. Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Hypothalamus; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Zucker | 1999 |
Leptin is suppressed during infusion of recombinant human insulin-like growth factor I (rhIGF I) in normal rats.
To examine whether insulin-like growth factor I (IGF I) or growth hormone (GH) influences leptin in vivo we measured leptin mRNA in epididymal fat pads and serum leptin of normal rats infused subcutaneously for 6 days with recombinant human (rh)IGF I (1 mg/day), rhGH (200 mU/day), or vehicle. In addition, we determined fat pad weight and food consumption as well as IGF I, insulin, glucose, non-esterified fatty acid (NEFA), glycerol, beta-hydroxybutyrate and triglyceride (TG) serum concentrations. Food intake was identical during all three treatments. RhIGF I but not rhGH raised IGF I serum concentrations, reduced fat pad weight (60.3 +/- 7.4% of control rats, p = 0.019), and suppressed leptin mRNA (38.8 +/- 11.9% of control rats, p = 0.002), serum leptin (51.6 +/- 10.5% of control rats, p = 0.0028) and serum triglycerides (39.3 +/- 8.0% of control rats, p = 2.6 x 10(-6)). Both rhIGF I and rhGH reduced non-esterified fatty acids (NEFA) (p = 0.00001 and 0.0007, respectively), whereas serum glycerol, beta-OH butyrate and glucose concentrations remained unchanged. Serum insulin concentrations during rhIGF I were lower than during rhGH infusion and correlated with leptin mRNA (r = 0.589, p = 0.016) and fat pad weight (r = 0.643, p = 0.007). Reduction of adipose tissue mass and suppression of leptin by IGF I appear to be due to reduced circulating insulin leading to enhanced fat mobilization and NEFA oxidation as well as to increased gluconeogenesis from glycerol. In contrast, decreased NEFA concentrations during rhGH in the presence of unchanged fat pad weight, serum glycerol and triglycerides might result from more efficient re-esterification of released fatty acids within the triglyceride-fatty acid cycle. The results also show that exogenously infused IGF I and GH act on lipid metabolism by different mechanisms and suggest an IGF-independent, probably direct, metabolic effect of GH. Finally, in agreement with previous studies in GH-infused hypophysectomized rats, it appears unlikely that GH regulates leptin in the rat. Topics: 3-Hydroxybutyric Acid; Adipose Tissue; Animals; Blood Glucose; Body Weight; Fatty Acids, Nonesterified; Glycerol; Human Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Organ Size; Proteins; Rats; Recombinant Proteins; RNA, Messenger; Triglycerides | 1999 |
Effect of leptin deficiency on metabolic rate in ob/ob mice.
Reduced metabolic rate may contribute to weight gain in leptin-deficient (ob/ob) mice; however, available studies have been criticized for referencing O2 consumption (VO2) to estimated rather than true lean body mass. To evaluate whether leptin deficiency reduces energy expenditure, four separate experiments were performed: 1) NMR spectroscopy was used to measure fat and nonfat mass, permitting VO2 to be referenced to true nonfat mass; 2) dietary manipulation was used in an attempt to eliminate differences in body weight and composition between ob/ob and C57BL/6J mice; 3) short-term effects of exogenous leptin (0.3 mg. kg-1. day-1) on VO2 were examined; and 4) body weight and composition were compared in leptin-repleted and pair-fed ob/ob animals. ob/ob animals had greater mass, less lean body mass, and a 10% higher metabolic rate when VO2 was referenced to lean mass. Dietary manipulation achieved identical body weight in ob/ob and C57BL/6J animals; however, despite weight gain in C57BL/6J animals, percent fat mass remained higher in ob/ob animals (55 vs. 30%). Exogenous leptin increased VO2 in ob/ob but not control animals. Weight loss in leptin-repleted ob/ob mice was greater than in pair-fed animals (45 vs. 17%). We conclude, on the basis of the observed increase in VO2 and accelerated weight loss seen with leptin repletion, that leptin deficiency causes a reduction in metabolic rate in ob/ob mice. In contrast, these physiological studies suggest that comparison of VO2 in obese and lean animals does not produce useful information on the contribution of leptin to metabolism. Topics: Animals; Body Composition; Body Weight; Diet; Leptin; Mice; Mice, Inbred C57BL; Obesity; Oxygen Consumption; Proteins; Reference Values; Time Factors | 1999 |
The quantitative trait locus on chromosome 2 for serum leptin levels is confirmed in African-Americans.
Topics: Black or African American; Black People; Body Weight; Chromosome Mapping; Chromosomes, Human, Pair 2; Female; Genetic Linkage; Humans; Leptin; Male; Mexican Americans; Obesity; Proteins; Quantitative Trait, Heritable; United States | 1999 |
A role for leptin in brain development.
Leptin, the product of the obese gene, is a circulating hormone involved in feeding behavior and energy homeostasis. Ob/ob mice which are leptin deficient have many phenotypic abnormalities including brains that are smaller in both weight and cortical volume. To this end, we monitored the effects of leptin administration on brain growth. Intraperitoneal administration of leptin for 2 weeks daily to 4-week-old ob/ob mice resulted in a maximal 10% increase in both wet and dry brain weights. This increase appears to be partially the result of increased cell number as indicated by a 19% increase in total brain DNA. In summary, our data suggest that the decreased brain size of the ob/ob mouse is due to a developmental defect that can be corrected upon leptin administration and therefore leptin plays a role in brain growth and development. Topics: Animals; Body Weight; Brain; Brain Chemistry; Carrier Proteins; Cell Count; DNA; Eating; Leptin; Male; Mice; Mice, Obese; Organ Size; Proteins; Receptors, Cell Surface; Receptors, Leptin; Thinness; Water | 1999 |
Effects of leptin on melanin-concentrating hormone expression in the brain of lean and obese Lep(ob)/Lep(ob) mice.
The effect of leptin on the expression of melanin-concentrating hormone (MCH) was investigated in lean and genetically obese Lepob/Lepob mice. Murine leptin was subcutaneously infused using osmotic minipumps. The treatment period extended to 7 days and the daily dose of leptin delivered was 100 microgram/kg of body weight. In situ hybridization was used to assess the effects of leptin infusion on the expression of MCH mRNA. MCH levels in the brain (hypothalamus/thalamus and the remaining part), spleen and testis were measured by radioimmunoassay coupled to HPLC of selected tissue extracts. Leptin significantly reduced final body weight, weight of brown adipose tissue, daily food intake in obese mice but not in lean animals. In obese mice, leptin led to a rapid reduction in food intake which reached statistical significance after only 24 h and which led to a significant reduction in the body weight after 3 days of treatment. Leptin restored the normal circulating levels of glucose and insulin in obese mice. The present results mainly provide evidence for a stimulating effect of leptin infusion on the MCH neuronal system. The hypothalamic/thalamic levels of MCH mRNA and peptide were higher in mice treated with leptin than in mice infused with phosphate-buffered saline. The stimulation of MCH neurons appeared particularly intense in obese mice, in which the effects of leptin infusion led to the reduction in MCH content of neuron fibers and terminals. Leptin did not affect spleen and testis MCH contents. In the light of the acknowledged orexigenic effects of MCH, the results of this study questioned the direct role of MCH in the action of leptin on energy balance. The increase in MCH expression following leptin could occur as a mechanism to compensate the decrease in energy deposition led to by leptin. It may also indicate that MCH mediates the metabolic actions of leptin indirectly or else that leptin influences actions of MCH other than those related to the regulation of energy balance. Topics: Adipose Tissue, Brown; Animals; Blood Glucose; Body Weight; Brain; Chromatography, High Pressure Liquid; Eating; Gene Expression; Hypothalamic Hormones; Insulin; Leptin; Male; Melanins; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Pituitary Hormones; Recombinant Proteins; RNA, Messenger; Spleen; Testis | 1999 |
Leptin and the hypothalamus: neuroendocrine regulation of food intake.
Topics: Adipose Tissue; Animals; Body Weight; Energy Intake; Homeostasis; Humans; Hypothalamus; Leptin; Mice; Mice, Knockout; Neurosecretory Systems; Proteins | 1999 |
Plasma leptin and insulin in C57BI/6J mice on a high-fat diet: relation to subsequent changes in body weight.
It has been proposed that leptin and insulin through central effects are involved in the regulation of energy balance and body weight. Whether circulating leptin or insulin levels predict subsequent changes in body weight is, however, not known. We examined plasma leptin and insulin at 2, 3, 6, 9 and 12 months of age in C57BI/6J mice given a normal diet (n = 12) or a high-fat diet (58% fat on a caloric base; n = 15). Plasma leptin levels increased by age and correlated with body weight in the entire material (r = 0.81, P < 0.001). Also plasma insulin increased by high-fat diet and correlated across all age periods with body weight (r = 0.56, P < 0.001). In mice, given normal diet, plasma leptin or insulin did not correlate to subsequent changes in body weight at any of the time points studied. However, in mice given the high-fat diet, plasma leptin at 6 (r = -0.57, P = 0.027) and 9 months of age (r = -0.56, P = 0.042) as well as plasma insulin at 6 (r = - 0.51, P = 0.049) and 9 months (r = -0.58, P = 0.037) correlated inversely to the change in body weight during the subsequent 3-month period. Hence, both leptin and insulin are negative predictors for future weight gain in high-fat fed mice. This suggests that when the regulation of body weight is challenged by a high-fat diet, leptin and insulin act to restrain or prevent future weight gain. This in turn may suggest that impairment of these (probably central) actions of leptin and insulin might underlie excessive increase in body weight under such conditions. Topics: Animals; Biomarkers; Body Weight; Dietary Fats; Female; Follow-Up Studies; Insulin; Leptin; Mice; Mice, Inbred C57BL; Obesity; Predictive Value of Tests; Proteins; Radioimmunoassay | 1999 |
Leptin resistance in a polygenic, hyperleptinemic animal model of obesity and NIDDM: Psammomys obesus.
To investigate the effects of leptin administration to Psammomys obesus, a polygenic animal model of obesity and type 2 diabetes mellitus.. Longitudinal intervention study utilising three separate leptin treatment protocols lasting 7-14 d.. Body weight and food intake were measured daily, body fat and muscle content were estimated by carcass analysis on completion of the study. Blood glucose, plasma insulin, leptin, triglycerides and cholesterol were measured at baseline and twice each week during the study.. Relatively high doses of leptin were required to significantly reduce food intake and body fat content in lean Psammomys obesus, but had no discernible effect on their obese littermates.. As a species, Psammomys obesus appear to be relatively insensitive to the effects of leptin administration, compared with other rodents. Obese Psammomys obesus are leptin resistant relative to their lean littermates. Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Energy Intake; Gerbillinae; Insulin; Leptin; Obesity; Proteins; Triglycerides | 1999 |
Reproducibility of fasting plasma leptin concentration in lean and obese humans.
We determined the reproducibility of plasma leptin levels in 20 healthy subjects (10 men, 10 women; 10 lean, 10 obese) at stable body weight. Blood samples were obtained, after an overnight fast, between 0700 and 0800 on days 1, 2, 3, 4, 5, 12, 19, and 26. Body weights were recorded on the same days. Plasma leptin was measured using a specific radioimmunoassay. The mean +/- SE baseline body weights (kg) were 65.8 +/- 3.6 (lean) and 96.4 +/- 7.1 (obese). The body mass indices (BMI) were 22.9 +/- 2.8 kg/m2 (lean) and 32.7 +/- 2.2 kg/m2 (obese). The mean daily fasting plasma glucose level was 98.7 +/- 3.7 mg/dl. Baseline plasma leptin levels (ng/ml) were 5.3 +/- 0.75 in lean men, 14.9 +/- 4.6 in obese men, 11.2 +/- 2.8 in lean women, and 27.1 +/- 8.4 in obese women. Fasting leptin levels on days 2 to 26 were highly correlated with the baseline levels on day 1 (r2 = 0.9, P<0.0001). Body weights remained within 98%-102% of baseline, whereas intra-individual leptin levels fluctuated between 80% and 120% of baseline values, throughout the 26 days of study. We conclude that fasting plasma leptin levels are reproducible, with a maximum day-to-day variation of approximately 20%, in healthy, free-living, lean and obese persons who maintain a stable body weight. Topics: Adult; Body Weight; Fasting; Female; Humans; Leptin; Male; Obesity; Osmolar Concentration; Proteins; Reference Values; Reproducibility of Results | 1999 |
Cross-sectional and longitudinal analysis of age-associated changes in body composition of male Brown Norway rats: association of serum leptin levels with peripheral adiposity.
Aging-associated alterations in body composition are accompanied by changes in the endocrine system. We evaluated, in male Brown Norway rats, the effects of aging on body composition and the association with serum levels of leptin, insulin, and testosterone. Body composition was assessed cross-sectionally in male rats (3, 8, 17, and 29 months) by a combination of dual energy x-ray absorptiometry (DEXA) and dissection of specific muscles and adipose depots. Longitudinal changes in body composition were quantified by DEXA before and after 3 months of ad-libitum feeding. Body weight, lean mass, absolute and percentage fat increased with age, whereas percentage of lean mass decreased. Leptin and insulin levels increased with age in proportion to adiposity; the increase in leptin with age was related to increased total and peripheral, but not visceral, fat. Testosterone decreased with age, and was associated with decreased lean and skeletal muscle mass. These findings suggest that alterations in body composition with age may be due to decreased trophic and increased lipogenic hormones. Relative to other rodent models, Brown Norway rats undergo shifts in body composition and in the hormonal milieu that are consistent with changes seen in aging humans. Topics: Absorptiometry, Photon; Adipose Tissue; Aging; Analysis of Variance; Animals; Blood Glucose; Body Composition; Body Mass Index; Body Weight; Bone Density; Cross-Sectional Studies; Disease Models, Animal; Dissection; Endocrine Glands; Insulin; Leptin; Longitudinal Studies; Male; Muscle, Skeletal; Proteins; Rats; Rats, Inbred BN; Testosterone | 1999 |
A study in the relationships between leptin, insulin, and body fat in Asian subjects.
To study the relationship of leptin concentrations with indices of obesity, fasting insulin, insulin resistance and lipid profiles (total cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)- cholesterol and triglyceride) in an Asian cohort.. Cross sectional study.. A total of 133 healthy volunteers were enrolled (64 female: age: 25-61 y, body mass index (BMI): 18.7-45.1 kg/m2 and 69 male: age: 25-61 y, BMI: 19.3-35.0 kg/m2).. Weight, height, waist and hip circumferences, blood pressure, lean body mass (by bioelectric impedence analysis (BIA)), plasma leptin and lipid profiles were taken after a 10 h fast.. Percentage of body fat measured by bioelectric impedance was the strongest determinant of plasma leptin (r = 0.844, P < 0.0001). Females had higher leptin concentrations than males for the same fat mass. In a multiple linear regression model, body fat percentage, (percentage body fat* gender), hip circumference and fasting insulin were significant determinants of leptin concentration (r = 0.882, P < 0.0001).. Leptin concentration correlated closely with percentage body fat in Asian subjects. Hip circumference as a corollary for peripheral obesity, was better associated with leptin than waist circumference or waist-to-hip ratio (WHR). Distribution of fat in females tended to be peripheral and may partly explain the gender difference. Fasting insulin level and central obesity were correlated with HDL-cholesterol, triglyceride and blood pressure, while fasting leptin had little correlation with these metabolic parameters. Therefore, insulin resistance was a better guide to cardiovascular risk assessment than plasma leptin. Topics: Adipose Tissue; Adult; Blood Pressure; Body Composition; Body Constitution; Body Height; Body Mass Index; Body Weight; Electric Impedance; Fasting; Female; Humans; Insulin; Leptin; Lipids; Male; Middle Aged; Proteins; Singapore | 1999 |
Plasma leptin levels and triglyceride secretion rates in VMH-lesioned obese rats: a role of adiposity.
To explore the role of adiposity on hypertriglyceridemia associated with obesity, we examined the relation between triglyceride secretion rate (TGSR) and plasma leptin, insulin, or insulin resistance in ventromedial hypothalamus (VMH)-lesioned rats in the dynamic and static phases (2 and 14 wk after lesions, respectively). VMH-lesioned rats gained body weight (BW) at fivefold higher rates in the dynamic phase compared with sham-operated control (sham) rats, and BW gain reached a plateau in the static phase. Parametrial fat pad mass was increased 2.5-fold in VMH-lesioned rats compared with sham rats in both phases. Leptin levels were sixfold higher in VMH-lesioned rats of the dynamic phase and even higher in the static phase. Insulin levels were twofold higher in VMH-lesioned rats than in sham rats in both phases. In the dynamic phase, VMH-lesioned rats had 2-fold higher plasma triglyceride (TG) levels and 2.6-fold higher TGSRs, whereas steady-state plasma glucose (SSPG) values, an indicator of insulin resistance, were lower. SSPG values became significantly higher in VMH-lesioned rats in the static phase, but TGSR was not further accelerated. TGSR was significantly associated with leptin, independent of insulin. Leptin was highly correlated with BW, fat mass, and nonesterified fatty acids (NEFA). These results suggest that adiposity itself plays a critical role in TGSR probably through increased NEFA flux from enlarged adipose tissues. Insulin resistance is not associated with the overproduction of TG in this animal model for obesity. Topics: Adipose Tissue; Animals; Body Weight; Female; Insulin; Insulin Resistance; Leptin; Obesity; Proteins; Rats; Rats, Sprague-Dawley; Regression Analysis; Triglycerides; Ventromedial Hypothalamic Nucleus | 1999 |
Long-term CCK-leptin synergy suggests a role for CCK in the regulation of body weight.
The gut peptide CCK is a nutrient-related signal important to the control of food intake. In the present studies, we observed that a single intraperitoneal injection of CCK (1-2 microgram/kg) given 2-3 h after intracerebroventricular leptin (2-5 microgram) reduced body weight and chow intake over the ensuing 48 h more than did leptin alone. CCK alone had no effect on either 48-h chow intake or body weight but significantly reduced feeding during a 30-min sucrose test. However, reduction of 30-min sucrose intake by CCK was not enhanced by prior intracerebroventricular leptin. The present data suggest that CCK can contribute to the regulation of body weight when central leptin levels are elevated. Topics: Animals; Body Weight; Cholecystokinin; Drinking; Drug Synergism; Eating; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Proteins; Rats; Rats, Sprague-Dawley; Solutions; Sucrose; Time Factors | 1999 |
Conjugated linoleic acid rapidly reduces body fat content in mice without affecting energy intake.
Recent reports have demonstrated that conjugated linoleic acid (CLA) has effects on body fat accumulation. In our previous work, CLA reduced body fat accumulation in mice fed either a high-fat or low-fat diet. Although CLA feeding reduced energy intake, the results suggested that some of the metabolic effects were not a consequence of the reduced food intake. We therefore undertook a study to determine a dose of CLA that would have effects on body composition without affecting energy intake. Five doses of CLA (0.0, 0.25, 0.50, 0.75, and 1.0% by weight) were studied in AKR/J male mice (n = 12/group; age, 39 days) maintained on a high-fat diet (%fat 45 kcal). Energy intake was not suppressed by any CLA dose. Body fat was significantly lower in the 0.50, 0.75, and 1.0% CLA groups compared with controls. The retroperitoneal depot was most sensitive to the effects of CLA, whereas the epididymal depot was relatively resistant. Higher doses of CLA also significantly increased carcass protein content. A time-course study of the effects of 1% CLA on body composition showed reductions in fat pad weights within 2 wk and continued throughout 12 wk of CLA feeding. In conclusion, CLA feeding produces a rapid, marked decrease in fat accumulation, and an increase in protein accumulation, at relatively low doses without any major effects on food intake. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Dose-Response Relationship, Drug; Eating; Insulin; Leptin; Linoleic Acid; Liver; Male; Mice; Mice, Inbred AKR; Proteins; Spleen; Time Factors; Vacuoles | 1999 |
Divergency of leptin response in intestinal inflammation.
Topics: Animals; Anorexia; Body Weight; Humans; Hypothalamus; Inflammatory Bowel Diseases; Leptin; Mice; Proteins | 1999 |
Leptin levels in lines of mice developed by long-term divergent selection on fat content.
The mouse lines were developed by long-term selection for fatness, after which the fat line (F) had about a 5-fold (23% vs 4%) higher fat percentage than the lean (L) line at 14 weeks; but the lines differed little in fat-free body weight. To assess the contribution of genetic changes in leptin hormone level to the selection response, plasma leptin levels were assayed in these lines in generation 60 and in an unselected control (C) from the same base population. With access to food prior to assay, the F, C and L lines had 16.5, 0.91 and 0.26 ng/ml leptin, respectively. In fasted animals these levels were much lower: 2.98, 0.171 and 0.0087 ng/ml, respectively. Thus the leptin levels differ greatly between the lines, with the fattest mice showing the highest level: almost 20 times higher than the control and 60-300 times higher than the L line. These correlated selection effects are an order of magnitude greater than the direct selection response, and believed to be much larger than seen for any hormonal or other trait. Correlations between leptin level and fat amount were high (over 0.86) in fed or fasted animals of the F line, indicative of leptin resistance. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Cholesterol; Leptin; Male; Mice; Mice, Inbred CBA; Obesity; Proteins; Triglycerides | 1999 |
Leptin mRNA expression and serum leptin concentrations as influenced by age, weight, and estradiol in pigs.
Two experiments (EXP) were conducted to determine the roles of age, weight and estradiol (E) treatment on serum leptin concentrations and leptin gene expression. In EXP I, jugular blood samples were collected from gilts at 42 to 49 (n = 8), 105 to 112 (n = 8) and 140 to 154 (n = 8) d of age. Serum leptin concentrations increased (P < 0.05) with age and averaged 0.66, 2.7, and 3.0 ng/ml (pooled SE 0.21) for the 42- to 49-, 105- to 112-, and 140- to 154-d-old gilts, respectively. In EXP II, RNase protection assays were used to assess leptin mRNA in adipose tissue of ovariectomized gilts at 90 (n = 12), 150 (n = 11) or 210 (n = 12) d of age. Six pigs from each age group received estradiol (E) osmotic pump implants and the remaining animals received vehicle control implants (C; Day 0). On Day 7, back fat and blood samples were collected. Estradiol treatment resulted in greater (P < 0.05) serum E levels in E (9 +/- 1 pg/ml) than C (3 +/- 1 pg/ml) pigs. Serum leptin concentrations were not affected by age, nor E treatment. Leptin mRNA expression was not increased by age in C pigs nor by F in 90- and 150-d-old pigs. However, by 210 d of age, leptin mRNA expression was 2.5-fold greater (P < 0.01) in E-treated pigs compared to C animals. Serum insulin concentrations were similar between treatments for 210-d-old pigs. However, insulin concentrations were greater (P < 0.05) in E than C pigs at 90 d and greater in C than E animals at 150 d. Plasma glucose and serum insulin-like growth factor-I concentrations were not influenced by treatment. These results demonstrate that serum leptin concentrations increased with age and E-induced leptin mRNA expression is age- and weight-dependent. Topics: Adipose Tissue; Animals; Body Weight; Estradiol; Leptin; Ovariectomy; Proteins; RNA, Messenger; Swine; Time Factors | 1999 |
Hypothalamic hypocretin/orexin and neuropeptide Y: divergent interaction with energy depletion and leptin.
The aim of this study was to measure the effects of chronic leptin treatment on two orexigenic peptides present in the hypothalamus namely hypocretin/orexin and neuropeptide Y (NPY). For this purpose, recombinant murine leptin (0.2 mg/rat/day) or saline were injected intraperitoneally in Long-Evans rats for 7 consecutive days. Food intake (-8%; p < 0.002) and body weight gain (23.7 +/- 1 vs 31.5 +/- 1.3 g; p < 0.003) were significantly lower in leptin-treated rats than the saline-treated rats. NPY concentrations did not change significantly in any of the microdissected brain areas including the arcuate and paraventricular nuclei. Orexin A concentration in the lateral hypothalamus was significantly decreased by the leptin treatment (-68%; p < 0.01). A smaller decrease (-46%; p < 0.04) was also noted in saline-treated rats pairfed to the level of the leptin-treated rats. We conclude that orexin/hypocretin could be considered as a new relay for leptin in the central nervous system. Its variation in case of lower energy supply observed in pairfed rats could constitute an alerting system for the brain and therefore considered as the first step in the establishment of defense mechanisms against energy depletion. Topics: Animals; Body Weight; Carrier Proteins; Feeding Behavior; Hypothalamus; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Neuropeptides; Neurotransmitter Agents; Orexins; Proteins; Rats; Rats, Long-Evans | 1999 |
Leptin effects on the expression of type-2 CRH receptor mRNA in the ventromedial hypothalamus in the rat.
The product of the ob gene, leptin, is thought to act in the hypothalamus to reduce food intake and body weight (b.w.) in rats and mice; however, the mechanisms of leptin action in the brain have not been fully elucidated. Corticotropin-releasing hormone (CRH) is a potent anorectic neuropeptide, and its type-2 receptor (CRHR-2) in the ventromedial hypothalamus (VMH) appears to play an important role in the expression of this anorectic effect. We explored here the impact of systemic leptin administration on CRH mRNA expression in the hypothalamic paraventricular nucleus (PVN) and CRHR-2 mRNA expression in the VMH in male rats, using in-situ hybridization histochemistry. The expression of CRH mRNA in the PVN and CRHR-2 mRNA in the VMH were increased at 2 h and 6 h, respectively, after a single intraperitoneal injection of leptin (1.0 mg/kg). Continuous subcutaneous infusion of leptin (1.2 mg/kg/day) via an osmotic minipump for 5 days increased the expression of CRHR-2 mRNA in the VMH, but not the expression of CRH mRNA in the PVN, compared with vehicle treatment. The rats that received the single or continuous administration of leptin showed reductions of food intake and b.w. compared with vehicle-treated rats. These results are consistent with our previous findings that the expression of CRHR-2 mRNA in the VMH is positively correlated with plasma leptin concentrations under various conditions, and highlight the importance of circulating leptin for the regulation of VMH CRHR-2 mRNA. The present results also raise the possibility that leptin reduces food intake and b.w. at least partially due to the enhancement of the anorectic effect of CRH via increased PVN CRH expression and/or VMH CRHR-2 expression. Topics: Animals; Body Weight; Corticotropin-Releasing Hormone; Feeding Behavior; Humans; Hypothalamus, Middle; In Situ Hybridization; Leptin; Male; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Proteins; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Receptors, Leptin; Recombinant Proteins; RNA, Messenger | 1999 |
Reproductive, metabolic, and endocrine responses to feed restriction and GnRH treatment in primiparous, lactating sows.
The current experiment was carried out to determine whether exogenous GnRH treatment in primiparous, lactating sows undergoing feed restriction would improve reproductive performance after weaning. Sows were allocated to one of three treatments: AA sows (n = 8) were fed to appetite throughout a 28-d lactation, AR (n = 12) and AR + GnRH (n = 12) sows were fed as AA sows from farrowing to d 21 of lactation, and feed intake was reduced to 50% of the ad libitum intakes from d 22 to 28. The AR + GnRH sows received 800 ng of GnRH i.v. every 6 h from d 22 to 28 of lactation, and AA and AR sows received saline. Sow weight, backfat, and litter weight were recorded weekly. Within 2 d after farrowing, litter size was standardized to 8 to 10. At d 17 of lactation, an indwelling jugular catheter was surgically implanted in each sow. Blood samples were taken for characterization of plasma LH, FSH, insulin, IGF-I, and leptin by RIA at d 21 and before and after weaning on d 28 of lactation. After weaning, all sows were given ad libitum access to feed, checked for onset of standing estrus twice daily with mature vasectomized boars, and inseminated 12 and 24 h after onset of standing estrus with pooled semen from the same fertile boars (3 x 10(9) sperm/AI). After breeding, feed allowance was reduced to NRC (1988) requirements for gestation. At d 28 +/- 3 of gestation, sows were killed and ovulation rate and embryo survival were determined. Restricted sows lost more weight during lactation than AA sows (P < .02). During the period of feed restriction, plasma IGF-I and postprandial insulin and leptin in AR and AR + GnRH sows, and LH pulse frequency in AR sows, were lower than those in AA sows (P < .04). Associations (P < .004) between plasma insulin and leptin and between leptin and mean LH concentrations were established. The LH pulse frequency in AR + GnRH sows did not differ from that in AA sows before weaning. After weaning, maximum, mean, and minimum LH concentrations in the AA and AR sows, and FSH concentrations in AR sows, increased (P < .05) in response to weaning. Paradoxically, GnRH treatment in lactation seemed to suppress the expected LH and FSH responses to weaning. Ovulation rate and embryo survival were not different among the three groups. In conclusion, although exogenous GnRH therapy restored LH secretion in feed-restricted sows, it did not improve overall reproductive performance. Topics: Adipose Tissue; Animals; Body Weight; Female; Follicle Stimulating Hormone; Food Deprivation; Gonadotropin-Releasing Hormone; Insulin; Insulin-Like Growth Factor I; Lactation; Leptin; Litter Size; Luteinizing Hormone; Ovulation; Parity; Progesterone; Proteins; Reproduction; Swine | 1999 |
Regulation of serum leptin levels by gonadal function in rats.
The aim of this study was to investigate the regulation of serum leptin levels by gender and gonadal steroid milieu. Thus, we measured serum leptin levels by radioimmunoassay in (a) intact male and female rats, (b) female rats at different stages of the estrous cycle and (c) ovariectomized or orchidectomized rats. Gonadectomized groups were or were not implanted with silastic capsules (10 or 30 mm in length, 1.519mm internal diameter; 3.06 mm external diameter) containing estradiol or testosterone and decapitated two weeks later. We found (i) intact female rats weighing 50 g, 250 g and 300 g exhibited higher serum leptin concentrations than intact male rats of similar body weight; (ii) leptin concentrations were not affected by the phase of the estrous cycle; (iii) two weeks after gonadectomy serum leptin concentrations increased in both male (from 4.47+/-1.87 to 8.76+/-1.24 ng/ml) and female (from 1.97+/-0.46 to 5.29+/-0.51 ng/ml) rats. The ovariectomy-induced increase in serum leptin levels was not dependent, at least completely, on changes in body weight since it could be observed when comparisons were made between ovariectomized rats and intact rats in estrus matched for body weight. In contrast the effect of orchidectomy on serum leptin levels appears to be dependent on changes in body weight since it was no longer observed when comparisons were made with a group of intact male rats matched for body weight. In conclusion, these results suggest that serum leptin concentrations are controlled by gonadal function either directly or as a consequence of changes in body weight. Topics: Animals; Body Weight; Estradiol; Estrus; Female; Gonads; Hormone Replacement Therapy; Leptin; Male; Orchiectomy; Ovariectomy; Proteins; Rats; Rats, Wistar; Sex Characteristics; Testosterone | 1999 |
STZ-induced diabetes decreases and insulin normalizes POMC mRNA in arcuate nucleus and pituitary in rats.
Effects of streptozotocin (STZ)-induced diabetes and insulin on opioid peptide gene expression were examined in rats. In experiment 1, three groups were administered STZ (75 mg/kg ip single injection). Two groups were killed at either 2 or 4 wk. In the third group, insulin treatment (7.0 IU/kg x 1 day for 3 wk) was initiated 1 wk after STZ injection. STZ induced hyperphagia and reduced weight gain. Insulin decreased food intake and increased body weight relative to diabetes. Proopiomelanocortin (POMC) mRNA in arcuate nucleus (Arc) and pituitary decreased in diabetes and normalized after insulin treatment. Prodynorphin (proDyn) mRNA increased in diabetes and normalized in the pituitary after insulin but not in the Arc. Diabetes did not alter proenkephalin (proEnk) expression in the Arc or pituitary, nor dynorphin A1-17 or beta-endorphin in paraventricular nucleus (PVN). alpha-Melanocyte-stimulating hormone (alpha-MSH) peptide levels were decreased in the PVN and normalized following insulin treatment. Diabetes increased Arc neuropeptide Y mRNA, and insulin suppressed this increase. In experiment 2, insulin (2.5 IU/kg sc) daily for 1 wk in normal rats increased Arc POMC mRNA, but not proDyn and proEnk mRNA. These results suggest that Arc POMC expression and PVN alpha-MSH peptide levels decrease in diabetes. Also, insulin may influence Arc and pituitary POMC activity in neurons that regulate energy metabolism. Topics: alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Eating; Energy Metabolism; Enkephalins; Gene Expression; Hypoglycemic Agents; Insulin; Leptin; Male; Melanocytes; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pituitary Gland; Pro-Opiomelanocortin; Protein Precursors; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger | 1999 |
Metabolic, gastrointestinal, and CNS neuropeptide effects of brain leptin administration in the rat.
To investigate whether brain leptin involves neuropeptidergic pathways influencing ingestion, metabolism, and gastrointestinal functioning, leptin (3.5 micrograms) was infused daily into the third cerebral ventricular of rats for 3 days. To distinguish between direct leptin effects and those secondary to leptin-induced anorexia, we studied vehicle-infused rats with food available ad libitum and those that were pair-fed to leptin-treated animals. Although body weight was comparably reduced (-8%) and plasma glycerol was comparably increased (142 and 17%, respectively) in leptin-treated and pair-fed animals relative to controls, increases in plasma fatty acids and ketones were only detected (132 and 234%, respectively) in pair-fed rats. Resting energy expenditure (-15%) and gastrointestinal fill (-50%) were reduced by pair-feeding relative to the ad libitum group, but they were not reduced by leptin treatment. Relative to controls, leptin increased hypothalamic mRNA for corticotropin-releasing hormone (CRH; 61%) and for proopiomelanocortin (POMC; 31%) but did not reduce mRNA for neuropeptide Y. These results suggest that CNS leptin prevents metabolic/gastrointestinal responses to caloric restriction by activating hypothalamic CRH- and POMC-containing pathways and raise the possibility that these peripheral responses to CNS leptin administration contribute to leptin's anorexigenic action. Topics: Animals; Arousal; Blood Glucose; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Digestive System; Eating; Fats; Gene Expression; Glycogen; Grooming; Hypothalamus; In Situ Hybridization; Insulin; Leptin; Male; Oxidation-Reduction; Pro-Opiomelanocortin; Proteins; Rats; Rats, Long-Evans; Rest; RNA, Messenger; Sympathetic Nervous System; Triglycerides | 1999 |
Leptin and tumor growth in rats.
We have examined the role of leptin in tumor-induced anorexia in 2 different tumor models. In rats bearing the Yoshida AH-130 ascites hepatoma, the reduction in food intake becomes important from day 6 after tumor inoculation. Interestingly, at day 4, when the animals do not show any anorectic behavior, circulating leptin levels were already reduced. Indeed, in all the tumor-bearing groups studied the levels of leptin were lower than in control animals. Moreover, the changes in the circulating levels paralleled changes in adipose tissue leptin mRNA expression, even at early stages following tumor inoculation when neither food intake nor fat stores were modified by the presence of a tumor. Interestingly, 7-day pair-fed controls showed changes similar to those present in tumor-bearing rats. These results agree with previous observations relating fasting to decreased leptin expression. Similar results were observed in another tumor model, the mouse Lewis lung carcinoma; i.e., at day 8 after tumor inoculation (when the animals did not show anorexia) both the circulating levels and the adipose leptin mRNA expression were also reduced. Our results suggest that experimental cancer-induced anorexia is not related to leptin changes. Topics: Adipose Tissue; Animals; Anorexia; Body Weight; Cachexia; Carcinoma, Lewis Lung; Female; Gene Expression; Insulin; Leptin; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Organ Size; Proteins; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Tumor Cells, Cultured | 1999 |
Does estradiol mediate leptin's effects on adiposity and body weight?
The role of estradiol in mediating leptin's effects on body weight was assessed in ovariectomized (OVX) mice before and after the onset of obesity. Ovariectomy did not alter leptin levels before the onset of obesity, and estradiol adminstration (0.05-17 microgram/day for 14 days) did not significantly alter leptin levels if they were corrected for the estradiol-induced reduction in body fat. The converse was also true, in that leptin administration (0.4-140 microgram/day) did not alter estradiol levels in intact mice. Furthermore, neither estradiol reduction (via ovariectomy) nor addition (via exogenous administration) significantly altered leptin's ability to reduce fat mass. Leptin was equally effective in reducing body weight in lean or obese OVX mice and intact controls. Finally, estradiol did not change the magnitude of leptin's effect on fat mass reduction when it was given in combination with leptin to lean intact or OVX mice. Estradiol may have indirectly affected leptin efficacy, because leptin did not produce as large a change in fat mass at lower doses in lean OVX mice as it did in intact counterparts. Taken together, these data suggested that 1) estradiol does not directly regulate leptin secretion or its effects on fat mass and 2) leptin does not directly regulate estradiol secretion or its effects on fat mass. Leptin and estradiol, however, may interact in an indirect fashion to affect fat utilization. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Estradiol; Female; Leptin; Mice; Obesity; Ovariectomy; Proteins; Recombinant Proteins | 1999 |
Serum leptin levels, body fat deposition, and weight in females with anorexia or bulimia nervosa.
The objective of this retrospective study was to investigate the relation between serum leptin level and fat deposition in patients with eating disorders. 40 female inpatients with anorexia (n=24) or bulimia nervosa (n=16) were assessed for leptin level, body mass index (BMI), and percentage body fat by dual-energy X-ray absorbometry (DXA). The results show that percentage body fat is a better predictor for leptin level and clinical findings in eating disordered patients than BMI. We discuss the necessity for DXA measurements in anorectic patients for prognostic and research purposes. Topics: Absorptiometry, Photon; Adipose Tissue; Adolescent; Adult; Anorexia; Body Composition; Body Mass Index; Body Weight; Bulimia; Female; Humans; Leptin; Prognosis; Proteins; Retrospective Studies | 1999 |
Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat.
It has been claimed that factors favoring the development or maintenance of animal or human obesity may include increases in glucocorticoid production or hyperresponsiveness of the hypothalamic-pituitary-adrenal axis. In normal rats, glucocorticoids have been shown to be necessary for chronic intracerebroventricular infusion of neuropeptide Y to produce obesity and related abnormalities. Conversely, glucocorticoids inhibited the body weight-lowering effect of leptin. Such dual action of glucocorticoids may occur within the central nervous system, since both neuropeptide Y and leptin act within the hypothalamus. The aim of this study was to determine the effects of glucocorticoids (dexamethasone) given intracerebroventricularly to normal rats on body weight homeostasis and hypothalamic levels of neuropeptide Y and corticotropin-releasing hormone. Continuous central glucocorticoid infusion for 3 days resulted in marked sustained increases in food intake and body weight relative to saline-infused controls. The infusion abolished endogenous corticosterone output and produced hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, three salient abnormalities of obesity syndromes. Central glucocorticoid infusion also produced a marked decrease in the expression of uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and UCP-3 in muscle. Finally, chronic central glucocorticoid administration increased the hypothalamic levels of neuropeptide Y and decreased those of corticotropin-releasing hormone. When the same dose of glucocorticoids was administered peripherally, it resulted in decreases in food intake and body weight, in keeping with the decrease in hypothalamic neuropeptide Y levels. These results suggest that glucocorticoids induce an obesity syndrome in rodents by acting centrally and not peripherally. Topics: Animals; Body Weight; Brain; Carrier Proteins; Corticosterone; Corticotropin-Releasing Hormone; Dexamethasone; Eating; Glucocorticoids; Homeostasis; Hyperinsulinism; Hypertriglyceridemia; Hypothalamus; Injections, Intraperitoneal; Ion Channels; Leptin; Membrane Proteins; Mitochondrial Proteins; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Zucker; Uncoupling Protein 1 | 1999 |
A detailed study on the role of sex steroid milieu in determining plasma leptin concentrations in adult male and female rats.
We examined the effects of sex steroid milieu on plasma leptin levels in adult male and female rats. Since the body weight is known to influence leptin concentrations, the hormone was measured in rats with a very similar body weight (about 250 g) throughout this study. Plasma leptin levels were significantly higher in female than in male rats. Orchidectomy (ODX) caused a significant rise in leptin, and replacement of a physiological dose of testosterone (T) completely abolished the effect of ODX. Since the effect of tamoxifen (estrogen antagonist) coadministered with T on leptin levels in ODX rats was the same as that of T alone, it was suggested that the suppressive effect of T on leptin may be mediated by the androgenic potency of T, but not by its aromatized product, estradiol. In female rats, plasma leptin concentrations did not change significantly during the estrous cycle. Furthermore, leptin levels were not affected either by ovariectomy alone or by the administration after ovariectomy of physiological doses of estradiol, progesterone, or both. This is the first study to demonstrate in rats with a very similar body weight the existence of a clear sexual difference in plasma leptin levels, and also a suppressive action of T on the adipocyte hormone concentrations. Topics: Animals; Body Weight; Estradiol; Estrus; Female; Gonadal Steroid Hormones; Leptin; Male; Orchiectomy; Ovariectomy; Progesterone; Proteins; Rats; Rats, Wistar; Sex Factors; Tamoxifen; Testosterone | 1999 |
Increased uncoupling protein2 mRNA in white adipose tissue, and decrease in leptin, visceral fat, blood glucose, and cholesterol in KK-Ay mice fed with eicosapentaenoic and docosahexaenoic acids in addition to linolenic acid.
The effects of n-3 polyunsaturated fatty acids (n-3PUFA) on obesity and diabetes were examined using KK-Ay mice fed with perilla oil (P), soybean oil (S), or lard (L), and those containing 30% fish oil (PF, SF, or LF), containing eicosapentaenoic acid (EPA = 9.9%) and docosahexaenoic acid (DHA = 18.0%). Perilla oil contained the largest proportion of linolenic acid (LNA = 61.9%). Computerized tomography (CT) scans showed narrower areas of visceral fat in the abdominal cross sections of groups given fish oil (PF, SF, and LF) and lower leptin levels (p < 0.05-p < 0.001) compared with controls (P, S, and L), without significant changes in energy intake and body weight. The highest plasma n-3PUFA content (21.31 +/- 0.35%) was attained with PF. This group contained 2.6-fold more plasma DHA (p < 0.001), and expressed 2.7-fold more UCP2 mRNA in white adipose tissue (p < 0.01) than in the P group. The epididymal fat pad (p < 0.05) weighed less, and levels of blood glucose (p < 0.05) and total cholesterol (p < 0.01) were reduced in PF compared with P. Topics: Adipose Tissue; alpha-Linolenic Acid; Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus; Diet; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Ion Channels; Leptin; Male; Membrane Transport Proteins; Mice; Mice, Inbred Strains; Mitochondrial Proteins; Obesity; Organ Size; Proteins; RNA, Messenger; Tomography, X-Ray Computed; Uncoupling Protein 2 | 1999 |
Lack of leptin suppression in response to hypersecretion of catecholamines in pheochromocytoma patients.
Leptin is a major regulator of body weight and energy balance and is subject to a variety of regulatory inputs. From several previous studies, catecholamines have been suggested to exert an inhibitory influence on leptin production in animals. In the present study, we analyzed leptin levels in relation to catecholamine hypersecretion in 27 human pheochromocytoma patients. A 10-fold increase in circulating norepinephrine (P < .0001) did not result in suppression of plasma leptin in the patients compared with normal controls (median and interquartile range, 4.3 ng/mL [2.4 to 6.8] v 2.2 ng/mL [1.9 to 3.0] in men and 18.6 [12.3 to 27.0] v 11.4 [10.1 to 15.9] in women). Correlation analysis indicated a significant association of leptin with epinephrine in normal subjects (r = -.81, P < .0001), but not in pheochromocytoma patients. Leptin was not related to norepinephrine in either group. In conclusion, our data suggest that a chronic elevation of catecholamines does not cause suppression of leptin secretion in patients with pheochromocytoma. This lack of effect may be attributable to the development of tolerance of adipose tissue leptin production to catecholamines. Topics: Adrenal Gland Neoplasms; Adult; Body Mass Index; Body Weight; Epinephrine; Female; Humans; Leptin; Male; Middle Aged; Norepinephrine; Pheochromocytoma; Proteins; Reference Values | 1999 |
Chronic leptin administration increases insulin-stimulated skeletal muscle glucose uptake and transport.
Leptin, the product of the ob gene, has been shown to reduce fat mass, food intake, hyperglycemia, and hyperinsulinemia and to increase whole-body glucose disposal. However, it is unknown if leptin improves insulin action in skeletal muscle. Therefore, the purpose of this investigation was to determine if chronic leptin administration increases insulin-stimulated skeletal muscle glucose uptake and transport. Sixty-nine female Sprague-Dawley rats (240 to 250 g) were randomly assigned to one of three groups: (1) control, (2) pair-fed, and (3) leptin. All animals were subcutaneously implanted with miniosmotic pumps that delivered 0.5 mg leptin/kg/d to the leptin animals and vehicle to the control and pair-fed animals for 14 days. Following this 14-day period, all animals were subjected to hindlimb perfusion to determine the rates of skeletal muscle glucose uptake and 3-O-methyl-D-glucose (3-MG) transport under basal, submaximal (500 microU/mL), and maximal (10,000 microU/mL) insulin concentrations. Chronic leptin treatment significantly increased (P < .05) the rate of glucose uptake across the hindlimb by 27%, 32%, and 47% under basal, submaximal, and maximal insulin, respectively, compared with the control and pair-fed condition. However, when the submaximal rate of glucose uptake was expressed as a percentage of maximal insulin-stimulated glucose uptake, no differences existed among the groups, indicating that leptin treatment does not increase insulin sensitivity. Rates of 3-MG transport in the soleus, plantaris, and white and red portions of the gastrocnemius (WG and RG) were significantly increased (P < .05) in leptin animals under all perfusion conditions. 3-MG transport was not different between control and pair-fed animals. Collectively, these findings suggest that improvements in insulin-stimulated skeletal muscle glucose uptake and transport following chronic leptin treatment result from increased insulin responsiveness. Topics: 3-O-Methylglucose; Animals; Biological Transport; Body Weight; Eating; Female; Glucose; Hindlimb; Insulin; Leptin; Muscle, Skeletal; Organ Size; Proteins; Rats; Rats, Sprague-Dawley; Time Factors | 1999 |
Lipolysis, fatness, gender and plasma leptin concentrations in healthy, normal-weight subjects.
Relationship between plasma leptin and adiposity and gender has been reported in adults. Effects of age on plasma leptin is unclear and regulation of leptin production by white adipose tissue is still poorly understood.. To study if age and parameters of lipolysis are related to plasma leptin concentrations.. Seventy-seven healthy, normal-weight subjects (age range 19-82 y.) had measurements of body composition (18oxygen dilution technique) and of fasting plasma levels of leptin, glycerol, and nonesterified fatty acids (NEFA).. Plasma leptin was correlated to NEFA (r = 0.28) and glycerol (r = 0.48) concentrations. The relationship between %fat and plasma leptin was best fitted by an exponential (r2 = 0.82). In multiple regression %fat, body mass index, glycerol, and gender, but not fat mass, age or NEFA contributed independently to the variation in log plasma leptin. Log plasma leptin was higher in women than in men for a given glycerol concentration.. Adiposity, lipolysis, and gender are related to plasma leptin in healthy humans. Topics: Adipose Tissue; Adult; Age Factors; Aged; Aged, 80 and over; Aging; Body Mass Index; Body Weight; Fatty Acids, Nonesterified; Female; Glycerol; Humans; Leptin; Lipolysis; Male; Middle Aged; Proteins; Reference Values; Regression Analysis; Sex Characteristics | 1999 |
Oleoyl-estrone treatment affects the ponderostat setting differently in lean and obese Zucker rats.
To determine whether the slimming effects of treatment with oleoyl-estrone (OE) in liposomes of normal and obese rats are permanent, or disappear as soon as the treatment with the drug ceased. This study was devised to gain further knowledge on the postulated role of OE as a ponderostat signal, evaluating whether (in addition) it can lower the ponderostat setting of the rat.. The rats were infused for 14d (using osmotic minipumps) with oleoyl-estrone in liposomes at a dose of 3.5 micromol/kg x d, and were studied up to one month after the treatment ceased.. Young adult lean controls (CL) or treated (TL) and obese controls (CO) or treated (TO) Zucker rats.. Energy balance, blood glucose, liver glycogen, plasma insulin, leptin corticosterone, ACTH and estrone (free and total) concentrations, and expression of the OB gene in white adipose tissue (WAT).. The loss of body weight caused by OE was recovered quickly in the TO, which gained weight at the same rate as the CO. TL rats, however remained at the low weight attained for one month after the treatment ceased. However, no differences were observed in calculated energy expenditure (EE) between the TL and TC rats once treatment had stopped. In TL and TO rats, liver glycogen concentrations decreased to normal shortly after treatment ceased, and leptin expression and concentrations remained normal and unchanged after the end of OE treatment. In TO rats, plasma glucose, insulin and leptin were lower than in the CO. Total estrone concentrations decreased rapidly in TL rats and more slowly in the TO, and free estrone followed a similar pattern.. Continuous infusion of liposomes loaded with OE resulted in a decreased energy intake (EI), maintenance of EE and the utilization of body fat reserves in lean and obese rats alike. This process ended in obese rats as soon as the infusion ceased, so that even when the levels of free and total estrone in plasma remained high, there was a marked (and relatively fast) shift toward the basal situation, which translated into an increase in EI, maintenance of estimated EE and a marked buildup of energy stores. In lean rats, the effects of OE on leptin concentrations and OB gene expression persisted after infusion ended. Topics: Adrenocorticotropic Hormone; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Energy Intake; Energy Metabolism; Estrone; Female; Glycogen; Insulin; Leptin; Liposomes; Liver; Obesity; Oleic Acids; Proteins; Rats; Rats, Zucker; Urea | 1999 |
Daily changes in hypothalamic gene expression of neuropeptide Y, galanin, proopiomelanocortin, and adipocyte leptin gene expression and secretion: effects of food restriction.
The participation of hypothalamic neuropeptide Y (NPY)-, galanin (GAL)-, and opioid-producing neurons in the restraint on food intake exerted by adipocyte leptin has recently been recognized. To further understand the interplay between the central appetite-stimulating- and peripheral appetite-inhibiting signals in the management of daily food intake, we have examined the daily patterns in expression of the hypothalamic neuropeptides and leptin receptor (R) and adipocyte leptin gene expression and secretion in freely feeding (FF) rats. These analyses were extended to determine the impact of food restriction (FR) to 4 h daily for 4 weeks. Groups of FF and FR rats were killed at 4-h intervals during a 24-h period, and hypothalamic NPY, GAL, POMC, and leptin-R gene expression and leptin gene expression were evaluated by RNase protection assays and serum leptin and corticosterone (CORT) levels were estimated by RIA. The following new findings emerged: 1) In FF rats, hypothalamic NPY messenger RNA (mRNA) levels fluctuated during the course of 24 h with high levels at 0700 h and 1100 h followed by a decrease at 1500 h during the lights-on phase that was sustained throughout the dark phase (1900 h-0500 h) of the light-dark cycle. Hypothalamic GAL and POMC mRNA also displayed daily patterns but with a different time course; GAL and POMC gene expression were elevated 4 h later than NPY mRNA at 1100 h and 1500 h. 2) Although FR to 4 h between 1100 h and 1500 h resulted in maintenance of body weight compared with a steady weight gain in FF rats, the daily patterns of fluctuations in hypothalamic neuropeptide gene expression were abolished. 3) In FF rats, hypothalamic leptin-R and adipocyte leptin gene expression and serum leptin levels displayed a daily pattern temporally different from that of hypothalamic neuropeptide gene expression. Adipocyte leptin mRNA remained low during the lights-on phase but increased at the onset of the lights-off phase (1900 h) and remained elevated through the dark phase. 4) Hypothalamic leptin-R gene expression, like that of adipocyte leptin gene expression, rose abruptly at the onset of nocturnal feeding behavior but receded progressively to low range thereafter. 5) On the other hand, a dichotomy in the daily rise in adipocyte leptin gene expression and leptin secretion was observed in FF rats. Unlike adipocyte leptin mRNA, serum leptin increased at 2300 h, 4 h after initiation of ingestive behavior. 6) In FR rats, adipocyte leptin gen Topics: Adipocytes; Animals; Body Weight; Carrier Proteins; Corticosterone; Eating; Galanin; Gene Expression; Hypothalamus; Leptin; Male; Neuropeptide Y; Pro-Opiomelanocortin; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin | 1999 |
Role of glucocorticoids in the response of the hypothalamo-corticotrope, immune and adipose systems to repeated endotoxin administration.
The present study was designed to determine whether the glucocorticoid inhibitory feedback mechanism plays a role in the well-known tolerance of the neuroendocrine-immune axis response to repeated endotoxemia. Adult male rats underwent adrenalectomy (ADX) and were implanted with a subcutaneous corticosterone (compound B, CB, 75 mg) pellet, or sham operated and implanted with a placebo pellet. On the morning of day 8 after surgery (experimental day, D1), all rats received an intravenous injection of lipopolysaccharide (LPS) (25 microg/kg body weight) which was repeated daily until D5. Blood was drawn via intravenous indwelling catheters before (sample time zero) as well as 1, 2, 3 and 4 h after LPS treatment on D1, 3 and 5 for measurements of corticotropin (ACTH), CB, tumor necrosis factor-alpha (TNF-alpha) and leptin. In sham animals, tolerance to repeated LPS administration was complete by D5 for the corticotrope axis and the immune response. In addition, LPS was found to stimulate leptin secretion on day 1 in intact rats, an effect that also disappeared thereafter. ADX + CB rats showed only a partial tolerance of the corticotrope axis on D5, whereas tolerance of the immune response was similar to that found in sham animals. Interestingly, the acute stimulation of leptin secretion by LPS in ADX + CB rats was qualitatively similar to that of intact controls on D1, but plasma leptin levels were significantly reduced on D3 and 5 compared to controls. Our results demonstrate that the adrenal response tolerance of the hypothalamo-pituitary-adrenal axis to repeated endotoxemia. In addition, our finding that TNF-alpha secretion follows the same pattern in sham-operated and in adrenalectomized animals suggests that unlike the corticotrope axis, tolerance of the immune response does not depend upon stimulated CB levels. The decrease in circulating levels of leptin following ADX is consistent with the stimulatory effects of glucocorticoids on leptin secretion. However, our finding of an acute stimulation of leptin secretion by LPS in ADX + CB animals demonstrates that this effect of endotoxemia is at least partially glucocorticoid independent. Topics: Adipose Tissue; Adrenalectomy; Adrenocorticotropic Hormone; Animals; Body Weight; Corticosterone; Cytokines; Dose-Response Relationship, Drug; Drug Implants; Electroshock; Endotoxins; Glucocorticoids; Hypothalamo-Hypophyseal System; Immune System; Leptin; Lipopolysaccharides; Male; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha | 1999 |
The presence of the "fa" gene in heterozygous (FA/fa) lean female rats, effects on body weight, body fat and serum leptin.
In previous studies, suckling lean heterozygous (FA/fa) pups had higher body fat levels in comparison to lean homozygous (FA/FA) pups. However, in older male rats fed either low- or high-fat diets, we found no effects of the "fa" gene in heterozygous lean rats compared to homozygous lean rats. Other studies have reported effects of the "fa" gene on aspects of insulin metabolism for lean heterozygous female rats compared to their homozygous counterparts. In the present study, the effect of the "fa" gene on body weight and body fat in lean female rats was investigated.. Homozygous lean female rats were obtained by mating homozygous lean male and female rats. Heterozygous lean female rats were obtained by mating homozygous obese male rats with heterozygous lean female rats. Following weaning, rats were maintained on a standard laboratory diet until 10 weeks of age when they were killed after an overnight fast.. Body weight (p<0.03) and inguinal (p = 0.01) and combined retroperitoneal+parametrial (p = 0.06) fat pad weights were heavier in heterozygous lean compared to homozygous lean female rats. Combined fat pad-to-body weight ratio (p = 0.05) and fat cell sizes (p = 0.06) were also higher in the heterozygous lean compared to homozygous lean rats. No differences in serum triacylglycerol, cholesterol, glucose, or insulin concentrations were found between the two groups, but serum leptin levels were significantly higher (p<0.004) in heterozygous lean rats.. These results indicate that effects of the "fa" gene are present during the postweaning period in lean female rats. Implications for increased body fat and leptin with respect to sexual maturation and fertility are discussed. Topics: Adipose Tissue; Animals; Animals, Newborn; Blood Glucose; Body Composition; Body Weight; Cholesterol; Female; Heterozygote; Insulin; Leptin; Liver; Male; Obesity; Proteins; Radioimmunoassay; Rats; Rats, Zucker; Triglycerides | 1999 |
Effect of leptin on cytochrome P-450, conjugation, and antioxidant enzymes in the ob/ob mouse.
Leptin is a hormone that is secreted by adipocytes and regulates body weight through its effect on satiety and energy metabolism. The ob/ob mouse is deficient in this protein and is characterized by obesity and other metabolic disorders. This study investigated the alterations of several hepatic cytochrome P-450 (CYP), conjugation, and antioxidant enzymes in lean and ob/ob mice and the role leptin plays in the modulation of these enzymes. Lean and ob/ob male mice were injected with leptin (100 microg) or PBS for 15 days. Liver microsomes from ob/ob mice, when compared with lean controls, displayed significantly reduced chlorzoxazone 6-hydroxylation activity (27%); however, 7alpha- and 16alpha- testosterone hydroxylation and pentoxyresorufin O-dealkylation activities were significantly higher (47%, 22%, and 39%, respectively). Leptin administration corrected alterations seen with all P-450 activities. Dealkylation of ethoxyresorufin and omega-hydroxylation of lauric acid activities from ob/ob and lean mice were not statistically different; however, leptin exposure significantly increased ethoxyresorufin activity in lean mice (14%) and decreased the activity in ob/ob mice (36%). UDP-glucuronosyl-transferase and glutathione S-transferase activities were not altered. The antioxidant enzymes, catalase (11%) and glutathione peroxidase (26%), as well as glutathione reductase (17%), were lower in the ob/ob mice and leptin treatment corrected these alterations. The results of this study demonstrate alterations in constitutive expression of CYP2B, CYP2E, CYP2A, catalase, glutathione peroxidase, and glutathione reductase in ob/ob mice that were restored to lean control values following leptin treatment. Additionally, CYP3A activity was increased following leptin treatment in ob/ob mice. The mechanism for the observed alterations may be due to direct leptin effects or via indirect alterations in insulin, corticosterone, and/or growth hormone. Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Corticosterone; Cytochrome P-450 Enzyme System; Cytosol; Glucuronosyltransferase; Glutathione; Glutathione Peroxidase; Hydroxylation; Insulin; Leptin; Liver; Male; Mice; Mice, Obese; Microsomes, Liver; Proteins; Testosterone | 1999 |
Urocortin reduces food intake and gastric emptying in lean and ob/ob obese mice.
Gastric emptying plays an important role in regulating food intake. This study was designed to investigate whether intraperitoneally injected urocortin reduces gastric emptying, feeding, and body weight in lean and ob/ob obese mice.. Food intake and body weight were measured after intraperitoneal injections of one of the following: urocortin, deamidated form of urocortin (urocortin OH), corticotropin-releasing factor (CRF), CRF6-33, cholecystokinin octapeptide (CCK-8), and leptin in 16-hour food-deprived animals. Gastric emptying was assessed 2, 4, or 8 hours after intraperitoneal injection. Repeated injections of urocortin were continued for 5 days in ob/ob mice.. Urocortin (0.003-3 nmol) dose-dependently and potently decreased food intake and body weight gain in lean mice. The ranking order of potency was urocortin > urocortin OH >/= CRF > CCK-8 > CRF6-33 > leptin. Gastric emptying was also potently reduced by urocortin with a similar ranking order of potency of urocortin > CRF > urocortin OH > CCK-8. Simultaneous administration of urocortin and CRF receptor antagonist, alpha-helical CRF9-41, blocked the effects of urocortin. Urocortin reduced food intake and body weight gain, as well as the rate of gastric emptying, in ob/ob mice, which was significantly faster than that of lean mice. Five daily injections of urocortin significantly lowered body weight and improved glycemic control in ob/ob mice.. The urocortin-induced decrease in food intake and body weight in lean and ob/ob mice is closely related to gastric emptying and opens new possibilities for the treatment of obesity. Topics: Animals; Blood Glucose; Body Weight; Corticotropin-Releasing Hormone; Dose-Response Relationship, Drug; Eating; Gastric Emptying; Injections, Intraperitoneal; Leptin; Male; Mice; Obesity; Proteins; Reference Values; Sincalide; Urocortins | 1999 |
Are circulating leptin and luteinizing hormone synchronized in patients with polycystic ovary syndrome?
Animal and human studies suggest that leptin modulates hypothalamic-pituitary-gonadal axis functions. Leptin may stimulate gonadotrophin-releasing hormone (GnRH) release from the hypothalamus and luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion from the pituitary. A synchronicity of LH and leptin pulses has been described in healthy women, suggesting that leptin probably also regulates the episodic secretion of LH. In some pathological conditions, such as polycystic ovarian syndrome (PCOS), LH-leptin interactions are not known. The aim of the present investigation was to assess the episodic fluctuations of circulating LH and leptin in PCOS patients compared to regularly menstruating women. Six PCOS patients and six normal cycling (NC) women of similar age and body mass index (BMI) were studied. To assess episodic hormone secretion, blood samples were collected at 10-min intervals for 6 h. LH and leptin concentrations were measured in all samples. For pulse analysis the cluster algorithm was used. To detect an interaction between LH and leptin pulses, an analysis of copulsatility was employed. LH concentrations were significantly higher in the PCOS group in comparison to NC women, however serum leptin concentrations and leptin pulse characteristics for PCOS patients did not differ from NC women. A strong synchronicity between LH and leptin pulses was observed in NC women; 11 coincident leptin pulses were counted with a phase shift of 0 min (P = 0.027), 18 pulses with a phase shift of -1 (P = 0.025) and 24 pulses with a phase shift of -2 (P = 0.028). PCOS patients also exhibited a synchronicity between LH and leptin pulses but weaker (only 20 of 39 pulses) and with a phase shift greater than in normal women, leptin pulses preceding LH pulses by 20 min (P = 0.0163). These results demonstrate that circulating leptin and LH are synchronized in normal women and patients with PCOS. The real significance of the apparent copulsatility between LH and leptin must be elucidated, as well as the mechanisms that account for the ultradian leptin release. Topics: Adult; Body Weight; Female; Humans; Insulin; Leptin; Luteinizing Hormone; Menstrual Cycle; Periodicity; Polycystic Ovary Syndrome; Proteins; Sex Hormone-Binding Globulin; Testosterone | 1999 |
Cyclical variations in the abundance of leptin receptors, but not in circulating leptin, correlate with NPY expression during the oestrous cycle.
We have demonstrated previously that pharmacological doses of oestradiol decreased leptin receptor expression in the hypothalamus. We therefore analysed leptin receptor expression during the oestrous cycle in the rat, to establish if acute changes in oestradiol affect leptin receptor expression under physiological conditions. Radioactive in situ hybridization histochemistry was used to measure the gene expression under investigation. Total leptin receptor transcript levels were lowest in pro-oestrus in the choroid plexus, these changes correspond inversely with levels of circulating oestradiol in the rat 4-day oestrous cycle. In contrast full-length leptin receptor levels in both arcuate and ventromedial nuclei did not correspond to the levels of total leptin receptor in the same areas of the hypothalamus or serum levels of oestradiol. Full-length leptin receptor expression in the arcuate nucleus was negatively correlated with neuropeptide Y (NPY) expression (r = 0.447, p < 0. 05) in the same nucleus. Arcuate nucleus NPY expression did not correlate significantly with the expression of total leptin receptors in the arcuate nucleus (r = 0.080) or serum leptin levels (r = 0.251). Our results demonstrate that leptin receptor expression is regulated during the oestrous cycle. The unchanged serum leptin levels during the oestrous cycle together with the correlation between the expression of leptin-RL and NPY provide circumstantial evidence that regulation of leptin receptor abundance in the hypothalamus governs the biological actions of leptin. Topics: Animals; Body Weight; Brain Chemistry; Carrier Proteins; DNA, Complementary; Estradiol; Estrus; Female; In Situ Hybridization; Leptin; Neuropeptide Y; Progesterone; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger | 1999 |
The effect of thyroid hormone on size of fat depots accounts for most of the changes in leptin mRNA and serum levels in the rat.
The physiological consequences and mechanism(s) for thyroid hormone-induced alterations in serum leptin are not known. To address this, leptin expression in rats was evaluated in relationship to food intake, fat mass, and body temperature in rats with pharmacologically altered thyroid status. Total body weight, food intake, and temperature were decreased in hypothyroid rats. Fat weight was decreased in both chronically hypothyroid and hyperthyroid rats (n = 6/group). Serum leptin was linearly correlated with fat weight, epididymal and retroperitoneal fat leptin mRNA concentration, but not total body weight. Serum leptin was decreased in the chronically hyperthyroid rats. When fat weight was used as a covariant, serum leptin was not different between the three groups. Epididymal fat leptin mRNA was higher in euthyroid (n = 7) than in hypothyroid and hyperthyroid rats. Retroperitoneal fat leptin mRNA was not affected by thyroid status. A positive linear relationship between food intake and free triiodothyronine (FT3) index was observed, but not between food intake and serum leptin alone. In a time course study, serum leptin, epididymal fat leptin mRNA content, and fat weight did not change within 24 hours of high-dose triiodothyronine (T3) (n = 6/group), but both temperature and epididymal fat S14 mRNA content rapidly increased. These findings demonstrate that thyroid state influences circulating leptin levels, but primarily does so indirectly through the regulation of fat mass. Leptin does not influence core body temperature across thyroidal state. Finally, thyroid state is more important to regulate food intake, through an as yet undefined mechanism, than are thyroid state-associated changes in serum leptin. Topics: Adipose Tissue; Animals; Body Temperature; Body Weight; Energy Intake; Humans; Hyperthyroidism; Hypothyroidism; Leptin; Male; Organ Size; Proteins; Rats; Rats, Sprague-Dawley; Regression Analysis; RNA, Messenger; Thyroid Gland; Transcription, Genetic; Triiodothyronine | 1999 |
The effect of moxonidine on feeding and body fat in obese Zucker rats: role of hypothalamic NPY neurones.
The antihypertensive agent moxonidine, an imidazoline Ii-receptor agonist, also induces hypophagia and lowers body weight in the obese spontaneously hypertensive rat, but the central mediation of this action and the neuronal pathways that moxonidine may interact with are not known. We studied whether moxonidine has anti-obesity effects in the genetically-obese and insulin-resistant fa/fa Zucker rat, and whether these are mediated through inhibition of the hypothalamic neuropeptide Y (NPY) neurones. Lean and obese Zucker rats were given moxonidine (3 mg kg(-1) day(-1)) or saline by gavage for 21 days. Moxonidine decreased food intake throughout by 20% in obese rats (P<0.001) and by 8% in lean rats (P<0.001), and reduced weight gain that final body weight was 15% lower in obese (P<0.001) and 7% lower in lean (P<0.01) rats than their untreated controls. Plasma insulin and leptin levels were decreased in moxonidine-treated obese rats (P<0.01 and P<0.05), but unchanged in treated lean rats. Uncoupling protein-1 gene expression in brown adipose tissue was stimulated by 40-50% (P< or =0.05) in both obese and lean animals given moxonidine. Obese animals given moxonidine showed a 37% reduction in hypothalamic NPY mRNA levels (P = 0.01), together with significantly increased NPY concentrations in the paraventricular nucleus (P<0.05), but no changes in the arcuate nucleus or other nuclei; this is consistent with reduced NPY synthesis in the arcuate nucleus and blocked release of NPY in the paraventricular nucleus. In lean animals, moxonidine did not affect NPY levels or NPY mRNA. The hypophagic, thermogenic and anti-obesity effects of moxonidine in obese Zucker rats may be partly due to inhibition of the NPY neurones, whose inappropriate overactivity may underlie obesity in this model. Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Antihypertensive Agents; Blood Glucose; Body Weight; Carrier Proteins; Eating; Feeding Behavior; Hormones; Hypothalamus; Imidazoles; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Neurons; Neuropeptide Y; Obesity; Protein Biosynthesis; Rats; Rats, Zucker; RNA, Messenger; Uncoupling Protein 1 | 1999 |
Effects of cigarette smoking and its cessation on body weight and plasma leptin levels.
Smokers weigh less than age-matched nonsmokers, and most smokers gain weight after smoking cessation due to an increase in food intake and a decrease in energy expenditure. Leptin is an endocrine signal thought to regulate body fat stores through hypothalamic control of energy intake and expenditure. To determine whether the "weight-reducing" effects of smoking may be mediated by leptin, we measured plasma leptin concentrations in 22 middle-aged and older male smokers (body mass index [BMI], 28 +/- 1 kg/m2, mean +/- SEM) and 22 nonsmokers matched to the smokers for age (64 +/- 1 years) and BMI (28 +/- 1 kg/m2). The body weight and leptin concentration were remeasured at 3 and 6 months in 13 of the smokers who successfully stopped smoking. The leptin concentration correlated positively with the BMI in both smokers (r = .74, P < .001) and nonsmokers (r = .76, P < .001). However, the intercept of the regression line was higher for smokers versus nonsmokers (P < .05), with no difference in the slope. Thus, male smokers have a higher leptin level for a given BMI than nonsmokers. Following 6 months of smoking cessation, body weight increased by 7% (6.0 +/- 0.1 kg, n = 13, P < .01). Despite this weight gain, the mean leptin concentration did not increase with smoking cessation. On average, leptin levels were 25% lower than would be expected for the amount of weight gained after smoking cessation. These findings suggest that cigarette smoking directly elevates circulating plasma leptin concentrations, and this increase may be one mechanism for the lower body weight of smokers compared with nonsmokers. Topics: Aged; Body Mass Index; Body Weight; Eating; Energy Metabolism; Humans; Leptin; Male; Middle Aged; Proteins; Smoking; Smoking Cessation; Time Factors | 1999 |
Treatment with the NO-synthase inhibitor, methylene blue, moderates the decrease in serum leptin concentration in streptozotocin-induced diabetes.
It was previously reported that serum leptin concentrations were decreased in rats with streptozotocin-induced diabetes. Also, simultaneous nitric oxide (NO)-synthase inhibitor treatment is known to partially attenuate streptozotocin-induced diabetes development. The aim of our study was to investigate the influence of the NO-synthase inhibitor, methylene blue, on serum leptin concentration and diabetes development. Body weight, blood glucose, glycated hemoglobin and leptin concentration were measured in a control group, diabetic (streptozotocin 70 mg/kg i.p.) group, methylene blue (40 mg/kg in the food) treated group and a diabetic group treated with methylene blue. After six weeks of experiments, blood glucose and glycated hemoglobin increased significantly in the diabetic group vs controls (27.31 vs 5.49 mmol.l(-1), 14.11 vs 6.79%, respectively) and this increase was partially attenuated by simultaneous methylene blue treatment (16.8 vs 27.31 mmol/l, p < 0.05). Body weight and serum leptin fell in diabetic rats vs controls (248.9 vs 342.8 g, 0.57 vs 3.46 ng.ml(-1)). Treatment with methylene blue significantly suppressed the drop of body weight and the increase in blood glucose and glycated hemoglobin concentrations in the diabetic group. The decrease of serum leptin levels was significantly inhibited by methylene blue in the first experiment (1.1 vs 0.57 ng. ml(-1), p < 0.05); the same trend was found in a second experiment but the differences did not reach statistical significance. We conclude that the drop of serum leptin levels in diabetic rats is probably mainly due to streptozotocin-induced insulin deficiency, which is partially attenuated by NO-synthase inhibitor treatment. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Enzyme Inhibitors; Glycated Hemoglobin; Leptin; Male; Methylene Blue; Nitric Oxide Synthase; Proteins; Rats; Rats, Wistar | 1999 |
Selective dependence of intracerebroventricular neuropeptide Y-elicited effects on central glucocorticoids.
It has been reported that hyperphagia and excessive body weight gain of genetically obese rodents were abolished by adrenalectomy. High hypothalamic levels of neuropeptide Y (NPY) were found in obese rodents. A chronic intracerebroventricular (icv) infusion of NPY in normal rats was shown to produce most hormono-metabolic abnormalities of genetically obese animals, and to be inefficient in doing so in adrenalectomized (ADX) rats. The combined presence of NPY and of glucocorticoids thus appeared to be necessary for inducing obesity. This study, therefore, was aimed at determining the consequences of a chronic i.c.v. NPY infusion in ADX rats receiving or not i.c.v. glucocorticoids. It was found that the combined i.c.v. infusion of NPY and dexamethasone in ADX rats increased food intake, body weight, plasma insulin, leptin, and triglyceride levels relative to vehicle-infused ADX controls. The infusion of NPY alone, or of dexamethasone alone in ADX rats failed to produce these effects. In contrast, the icv infusion of NPY alone greatly decreased the expression of brown adipose tissue uncoupling protein-1 and -3. This was not modified by the superimposed infusion of dexamethasone. It is concluded that, although many of centrally elicited NPY effects require the central presence of glucocorticoids, those bearing on the inhibition of uncoupling proteins expression (energy dissipation) do not require central glucocorticoids. Topics: Adipose Tissue, Brown; Adrenalectomy; Animals; Body Weight; Brain; Carrier Proteins; Dexamethasone; Drug Combinations; Eating; Female; Glucocorticoids; Injections, Intraventricular; Insulin; Ion Channels; Leptin; Membrane Proteins; Mitochondrial Proteins; Neuropeptide Y; Proteins; Rats; Rats, Sprague-Dawley; Triglycerides; Uncoupling Protein 1 | 1999 |
Uncoupling protein-3 mRNA levels are increased in white adipose tissue and skeletal muscle of bezafibrate-treated rats.
Fibrates are hypolipidemic drugs that are also able to improve glucose tolerance in animals and diabetic patients through an unknown mechanism. Since uncoupling proteins (UCP) seem to play an important role in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether treatment of rats with bezafibrate for 3, 7, or 15 days modified UCP mRNA levels. Using RT-PCR, we observed a weak ectopic expression of UCP-1 and a 2-fold increase in UCP-3 mRNA levels in white adipose tissue after 7 and 15 days of treatment. Moreover, bezafibrate administration caused a 1. 7-fold induction in UCP-3 mRNA levels in skeletal muscle on day 7. Since UCP-3 mRNA levels are reduced in skeletal muscle of diabetic patients, this effect may be involved in the improvement of insulin sensitivity caused by bezafibrate in NIDDM. Topics: Adipose Tissue; Animals; Base Sequence; Bezafibrate; Body Weight; Carrier Proteins; Diabetes Mellitus, Type 2; DNA Primers; Hypolipidemic Agents; Insulin Resistance; Ion Channels; Leptin; Male; Mitochondria; Mitochondrial Proteins; Muscle, Skeletal; Organ Size; Proteins; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uncoupling Protein 3 | 1999 |
The effect of continuous ambulatory peritoneal dialysis on change in serum leptin.
Elevated serum leptin can contribute to anorexia and poor nutrition in patients with chronic renal failure, because leptin is elevated in chronic renal failure patients with or without dialysis, especially in chronic ambulatory peritoneal dialysis (CAPD) patients. The aim of this study was to find whether leptin can be removed by peritoneal dialysis (PD) and to analyze factors that can affect serum leptin after start of CAPD by observing the change in serum leptin shortly after start of CAPD and its correlation with body mass index (BMI), with serum insulin, and with residual renal function.. Twenty patients who started CAPD during the observation period were studied. Serum leptin was measured by radioimmunoassay before start of CAPD, 3-5 days after start of CAPD, and 1 month and 3 months after start of CAPD. Simultaneously, body weight, serum insulin, and residual renal function were measured. To compensate for the circardian rhythm of leptin, removal of leptin was assessed by measuring dialysate leptin divided by average serum leptin before and after a peritoneal equilibration test (PET).. Leptin was eliminated by PD with a dialysate-to-serum ratio of 0.16+/-0.07, which was comparable to removal of beta2-microglobulin (0.14+/-0.06). The mean serum leptin concentrations did not decrease after 3-5 days of CAPD (8.4+/-13.1 ng/mL-->11.9+/-18.0 ng/mL) despite its removal by PD, and levels increased markedly to 189% of basal serum leptin 1 month after start of PD and to 260% of basal serum leptin 3 months after start of PD. Correlation coefficients (Spearman's rho) between change of serum leptin and change of BMI, of serum insulin, of glomerular filtration rate (average of urine creatinine clearance and urine urea clearance) were 0.267 (p > 0.05, n = 20), 0.441 (p > 0.05, n = 16), 0.706 (p > 0.05, n = 8) respectively.. Leptin is removed by peritoneal dialysis. Serum leptin did not decrease in 5 days after the start of PD despite its removal by PD, but increased markedly thereafter, within 3 months after start of PD. We could not find a significant correlation between the change in leptin and the change in BMI. Factors other than fat-mass gain can stimulate leptin increase shortly after start of PD. Topics: Adipose Tissue; Body Weight; Female; Humans; Insulin; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Proteins | 1999 |
Distinct patterns of neuropeptide gene expression in the lateral hypothalamic area and arcuate nucleus are associated with dehydration-induced anorexia.
We have investigated the hormonal and hypothalamic neuropeptidergic substrates of dehydration-associated anorexia. In situ hybridization and hormone analyses of anorexic and paired food-restricted rats revealed two distinct profiles. First, both groups had the characteristic gene expression and endocrine signatures usually associated with starvation: increased neuropeptide Y and decreased proopiomelanocortin and neurotensin mRNAs in the arcuate nucleus (ARH); increased circulating glucocorticoid but reduced leptin and insulin. Dehydrated animals are strongly anorexic despite these attributes, showing that the output of leptin- and insulin-sensitive ARH neurons that ordinarily stimulate eating must be inhibited. The second pattern occurred only in anorexic animals and had two components: (1) reduced corticotropin-releasing hormone (CRH) mRNA in the neuroendocrine paraventricular nucleus (PVH) and (2) increased CRH and neurotensin mRNAs in the lateral hypothalamic (LHA) and retrochiasmatic areas. However, neither corticosterone nor suppressed PVH CRH gene expression is required for anorexia after dehydration because PVH CRH mRNA in dehydrated adrenalectomized animals is unchanged from euhydrated adrenalectomized controls. We also showed that LHA CRH mRNA was strongly correlated with the intensity of anorexia, increased LHA CRH gene expression preceded the onset of anorexia, and dehydrated adrenalectomized animals (which also develop anorexia) had elevated LHA CRH gene expression with a distribution pattern similar to intact animals. Finally, we identified specific efferents from the CRH-containing region of the LHA to the PVH, thereby providing a neuroanatomical framework for the integration by the PVH of neuropeptidergic signals from the ARH and the LHA. Together, these observations suggest that CRH and neurotensin neurons in the LHA constitute a novel anatomical substrate for their well known anorexic effects. Topics: Adrenalectomy; Adrenocorticotropic Hormone; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Axonal Transport; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Dehydration; Food Deprivation; Gene Expression Regulation; Hypothalamic Area, Lateral; Insulin; Leptin; Male; Neuropeptide Y; Neuropeptides; Neurotensin; Paraventricular Hypothalamic Nucleus; Phytohemagglutinins; Pro-Opiomelanocortin; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thymus Gland; Time Factors; Transcription, Genetic | 1999 |
Leptin increases circulating glucose, insulin and glucagon via sympathetic neural activation in fasted mice.
A number of recent studies suggest that leptin has effects on glucose metabolism and pancreatic hormone secretion. Therefore, the effect of leptin administration on circulating glucose, insulin and glucagon in fed and fasted mice was investigated. The potential contribution of the sympathetic nervous system to the effects of leptin was also examined.. Recombinant human or murine leptin was administered intraperitoneally (300 microg/mouse per 12 h over 24 h) to fed or fasted, normal or chemically sympathectomized NMRI mice. Blood samples were collected at baseline and after 24 h.. Plasma concentrations of glucose, insulin and glucagon.. In the fed state (n = 24), leptin administration did not affect glucose, insulin or glucagon concentrations after 24 h. Fasting (n = 24) reduced body weight by 2.2+/-0.4 g, plasma glucose by 3.7+/-0.4 mmol/l, plasma insulin by 138+/-35 pmol/l, and plasma glucagon by 32+/-7 pg/ml. In fasted mice, human leptin (n = 24) increased plasma glucose by 1.5+/-0.2 mmol/l (P = 0.041), plasma insulin by 95+/-22 pmol/l (P = 0.018), and plasma glucagon by 16+/-3 pg/ml (P = 0.025), relative to saline-injected control animals. Murine leptin exerted similar stimulating effects on circulating glucose (+1.0+/-0.2 mmol/l, P = 0.046), insulin (+58+/-17 pmol/l, P = 0.038) and glucagon (+24+/-9 pg/ml, P = 0.018) as human leptin in fasted mice (n = 12) with no significant effect in fed mice (n = 12). Human leptin did not affect circulating glucose, insulin or glucagon in fasted mice after chemical sympathectomy with 6-hydroxydopamine (40 mg/kg iv 48 h prior to fasting; n = 12).. Leptin increases circulating glucose, insulin and glucagon in 24 h fasted mice by a mechanism requiring intact sympathetic nerves. Topics: Animals; Blood Glucose; Body Weight; Eating; Fasting; Glucagon; Injections, Intraperitoneal; Insulin; Leptin; Mice; Mice, Inbred Strains; Obesity; Proteins | 1999 |
The effect of fasting and physical exercise on plasma leptin concentrations in high-fat fed rats.
The aim of our study was to estimate the effect of fasting and physical exercise on a treadmill on plasma leptin concentrations in high-fat fed rats. Male Wistar rats were injected a low dose of streptozotocin (STZ) or buffer at 2 days of age and later fed a standard or high-fat diet (HFD). Plasma leptin was measured by RIA method in all the groups studied in basal conditions, after 48h fasting, a single bout of exhaustive exercise, and 4 weeks of exercise training. Plasma leptin concentrations were markedly elevated in the HFD and STZ/HFD groups compared to the control group. The significant correlation between plasma leptin and body weight was noted. Fasting and exercise training decreased plasma leptin in similar percentage in all the groups studied. The observed decrease was greater than expected from changes in body weight. We conclude that high-fat feeding results in an increase in plasma leptin levels in rats independently of plasma insulin or daily calorie intake. High-fat fed rats have maintained leptin response to fasting and exercise training. The reduction in plasma leptin after exercise training is partly independent on changes in body weight or plasma insulin. Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Fasting; Insulin; Islets of Langerhans; Leptin; Male; Obesity; Physical Conditioning, Animal; Proteins; Rats; Rats, Wistar | 1999 |
Neuropeptide Y gene expression in lines of mice subjected to long-term divergent selection on fat content.
Lines of mice have been developed in our laboratory by divergent long-term selection for body fat content. This has resulted in a fivefold (23% vs 4%) higher fat percentage in the Fat line at 14 weeks of age, with little difference between the Fat and Lean lines in fat-free body weight. As part of an approach to characterize the physiological mechanisms underlying these different phenotypes, neuropeptide Y (NPY) mRNA levels in the hypothalamus and cerebral cortex of ad libitum-fed and fasted mice of the Fat and Lean selected lines were measured. Significant differences in NPY gene expression were confined to the hypothalamus. Under ad libitum-fed conditions, hypothalamic NPY mRNA levels did not differ significantly between the Fat and Lean lines. After an overnight fast of 18-20 h, hypothalamic NPY mRNA levels were increased significantly (P<0.05) by 31% in Lean animals relative to fed mice from the same line. However, fasting did not significantly stimulate NPY gene expression in the Fat line. Most plasma leptin measurements in the Lean line fell below the sensitivity threshold of the assay (0.1 ng/ml), but levels in the Fat line were at least 30 to 50 times higher under fasted and fed conditions respectively. After fasting, plasma leptin levels in the Fat line decreased significantly (P<0. 05) by 48%. Thus, unlike the situation in other rodent models, obesity in the Fat line is not associated with increased hypothalamic NPY mRNA levels in the ad libitum-fed state. The decreased sensitivity of hypothalamic NPY gene expression to fasting in the Fat line is consistent with an inhibitory effect of higher circulating leptin levels. Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Female; Gene Expression; Genetic Variation; Leptin; Male; Mice; Mice, Inbred CBA; Mice, Inbred Strains; Neuropeptide Y; Obesity; Proteins; RNA, Messenger; Selection, Genetic; Time Factors | 1999 |
Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal yellow agouti mutation: usefulness of leptin for the treatment of obesity-associated diabetes.
Leptin acts as an adipocyte-derived blood-borne satiety factor that can increase glucose metabolism. To elucidate the therapeutic implications of leptin for obesity-associated diabetes, we crossed transgenic skinny mice overexpressing leptin (Tg/+), which we have developed recently, and lethal yellow KKAy mice (Ay/+), a genetic model for obesity-diabetes syndrome, and examined the metabolic phenotypes of F1 animals. At 6 weeks of age, plasma leptin concentrations in Tg/+ mice with the Ay allele (Tg/+:Ay/+) were significantly higher than those in Ay/+ mice. Although no significant differences in body weight were noted among Tg/+:Ay/+ mice, Ay/+ mice, and their wild-type lean littermates (+/+), glucose and insulin tolerance tests revealed increased glucose tolerance and insulin sensitivity in Tg/+:Ay/+ compared with Ay/+ mice. However, at 12 weeks of age, when plasma leptin concentrations in Ay/+ mice were comparable to those in Tg/+:Ay/+ mice, Tg/+:Ay/+ mice developed obesity-diabetes syndrome similar to that of Ay/+ mice. Body weights of 12-week-old Tg/+:Ay/+ and Ay/+ mice were reduced to those of +/+ mice by a 3-week food restriction; when plasma leptin concentrations remained high in Tg/+:Ay/+ mice but were markedly reduced in Ay/+ and +/+ mice, glucose tolerance and insulin sensitivity in Tg/+:Ay/+ mice were markedly improved as compared with Ay/+ and +/+ mice. The present study demonstrates that hyperleptinemia can delay the onset of impaired glucose metabolism and accelerate the recovery from diabetes during caloric restriction in Tg/+:Ay/+ mice, thereby suggesting the potential usefulness of leptin in combination with a long-term caloric restriction for the treatment of obesity-associated diabetes. Topics: Aging; Animals; Body Weight; Diabetes Mellitus; Eating; Female; Food Deprivation; Glucose; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Mutation; Obesity; Proteins | 1999 |
Effects of intravenously infused leptin on insulin sensitivity and on the expression of uncoupling proteins in brown adipose tissue.
Centrally administered leptin has been shown to increase insulin-stimulated glucose utilization and to favor the expression of uncoupling proteins (UCPs). To study if leptin also has direct peripherally mediated effects on these processes, this hormone (1 mg/day) or its vehicle was infused i.v. for 4 days to lean rats and insulin-stimulated glucose utilization in skeletal muscle and adipose tissue as well as the expression of UCP messenger RNAs (mRNAs) in brown adipose tissue were measured. I.v. leptin administration resulted in decreases in food intake (31%), body weight gain, and plasma insulin levels (45%), in increases in overall (23%) as well as brown adipose tissue and muscle glucose utilization, and in decreases in white adipose tissue glucose uptake. Most of these changes were mimicked, in control rats, by giving them the same amount of food as that consumed by the leptin-infused group (pair-feeding). I.v. leptin infusion also favored the expression of UCPs in brown adipose tissue, either by increasing their expression or preventing the fall occurring during the pair-feeding regimen. Relative UCP expression levels were 100, 104, and 33 for UCP1, 100, 191, and 125 for UCP2 and 100, 107, and 29 for UCP3 in ad libitum fed control rats, in leptin-treated rats and in pair-fed control rats, respectively. These results suggest that the overall effect of leptin on glucose utilization and on the expression of UCPs may be mediated through central mechanism. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Blood Glucose; Body Weight; Carrier Proteins; Energy Intake; Feeding Behavior; Gene Expression Regulation; Glucose; Glucose Clamp Technique; Hyperinsulinism; Infusions, Intravenous; Insulin; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mitochondrial Proteins; Muscle, Skeletal; Proteins; Rats; Rats, Zucker; Recombinant Proteins; RNA, Messenger; Thinness; Transcription, Genetic; Uncoupling Agents; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3; Weight Gain | 1999 |
Targeted deletion of the Vgf gene indicates that the encoded secretory peptide precursor plays a novel role in the regulation of energy balance.
To determine the function of VGF, a secreted polypeptide that is synthesized by neurons, is abundant in the hypothalamus, and is regulated in the brain by electrical activity, injury, and the circadian clock, we generated knockout mice lacking Vgf. Homozygous mutants are small, hypermetabolic, hyperactive, and infertile, with markedly reduced leptin levels and fat stores and altered hypothalamic proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti-related peptide (AGRP) expression. Furthermore, VGF mRNA synthesis is induced in the hypothalamic arcuate nuclei of fasted normal mice. VGF therefore plays a critical role in the regulation of energy homeostasis, suggesting that the study of lean VGF mutant mice may provide insight into wasting disorders and, moreover, that pharmacological antagonism of VGF action(s) might constitute the basis for treatment of obesity. Topics: Aggression; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Catecholamines; Circadian Rhythm; Energy Metabolism; Fasting; Female; Fertility; Gene Deletion; Gene Expression; Gonadotropins; Homeostasis; In Situ Hybridization; Leptin; Male; Mammary Glands, Animal; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Growth Factors; Neurons; Neuropeptides; Ovary; Oxygen Consumption; Phenotype; Pituitary Gland; Protein Precursors; Proteins; RNA, Messenger; Thyrotropin | 1999 |
Body fat, caloric intake, and plasma leptin levels in women with anorexia nervosa.
To measure serum leptin concentrations in women with anorexia nervosa (AN) and to identify independent predictors of leptin levels, thereby allowing hormone levels to be modeled using regression analysis.. A cross-sectional study of 15 AN inpatients and 16 healthy control subjects. Age, height, weight, percent body fat, total caloric intake, fat intake, and fasting plasma leptin levels were recorded. Stepwise forward regression analysis was carried out to identify predictors of leptin levels.. Circulating leptin concentrations in AN were 3.5+/-0.5 versus 7.6+/-1.2 ng/ml in control subjects. Percent body fat correlated best with leptin levels in anorexic and control subjects (r =.63; p =.0002), with caloric intake showing only a moderate correlation (r = .47; p = .008). Only percent body fat was a significant predictor of plasma leptin levels in our regression model.. Leptin levels are proportionately lower in AN as compared to healthy controls. It appears that physiological regulation of plasma levels with respect to percent body fat is maintained in individuals with little body fat. Topics: Adipose Tissue; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Cross-Sectional Studies; Energy Intake; Female; Humans; Leptin; Middle Aged | 1999 |
Decreased visceral adiposity accounts for leptin effect on hepatic but not peripheral insulin action.
Leptin decreases visceral fat (VF) and increases peripheral and hepatic insulin action. Here, we generated similar decreases in VF using leptin (Lep), beta(3)-adrenoreceptor agonism (beta3), or food restriction (FR) and asked whether insulin action would be equally improved. For 8 days before the in vivo study, Sprague-Dawley rats (n = 24) were either fed ad libitum [control (Con)], treated with Lep or beta3 (CL-316,243) by implanted osmotic mini-pumps, or treated with FR. Total VF was similarly decreased in the latter three groups (Lep, 3.11 +/- 0.96 g; beta3, 2.87 +/- 0.48 g; and FR, 3.54 +/- 0.77 g compared with 6.91 +/- 1.41 g in Con; P < 0.001) independent of total fat mass (by (3)H(2)O) and food intake. Insulin (3 mU. kg(-1). min(-1)) clamp studies were performed to assess hepatic and peripheral insulin sensitivity. Decreased VF resulted in similar and marked improvements in insulin action on glucose production (GP) (Lep, 1.19 +/- 0.51; beta3, 1.46 +/- 0.68; FR, 2.27 +/-0.71 compared with 6.06 +/- 0.70 mg. kg(-1). min(-1) in Con; P < 0.001). By contrast, reduction in VF by beta3 and FR failed to reproduce the stimulation of insulin-mediated glucose uptake ( approximately 60%), glycogen synthesis ( approximately 80%), and glycolysis ( approximately 25%) observed with Lep. We conclude that 1) a moderate decrease in VF uniformly leads to a marked increase in hepatic insulin action, but 2) the effects of leptin on peripheral insulin action are not due to the associated changes in VF or beta3 activation. Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Body Weight; Energy Intake; Food Deprivation; Gluconeogenesis; Glycogen; Glycolysis; Insulin; Leptin; Liver; Male; Proteins; Rats; Rats, Sprague-Dawley; Viscera | 1999 |
Analysis of a 762-bp proximal leptin promoter to drive and control regulation of transgene expression of growth hormone receptor in mice.
Transgenic (TG) mice expressing porcine GH receptor (pGHR) directed by a 762-bp proximal leptin promoter were used to analyze the capability of the promoter to drive and regulate pGHR expression in vivo. Transgene expression occurred in inguinal, retroperitoneal, and epididymal/parametrial fat depots in both male and female TG mice, but not in wild type (WT) mice. pGHR transgene was also expressed in liver, heart, kidney, muscle, lung, and brain. Levels of pGHR transgene mRNA were higher in tissues other than adipose tissue. Fasting reduced leptin mRNA levels in adipose; however, pGHR transgene expression was not affected in either adipose or muscle. These results suggest (1) the region between +3 and -759 bp of the leptin promoter is able to drive gene expression in vivo, (2) this region may not be responsible for adipose tissue specificity of leptin expression, and (3) this region may not be responsible for negative regulation of leptin gene expression during fasting. Topics: Adipose Tissue; Animals; Body Weight; Dietary Fats; Fasting; Female; Gene Expression Regulation; Leptin; Male; Mice; Mice, Transgenic; Muscles; Organ Size; Organ Specificity; Promoter Regions, Genetic; Proteins; Receptors, Leptin; Receptors, Somatotropin; RNA, Messenger; Swine; Transgenes | 1999 |
Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy.
Obstructive sleep apnea syndrome (OSAS) is a common disorder in obese subjects. Visceral fat accumulation (VFA) is a better predictor of coronary heart disease than body mass index. Leptin is a hormone involved in the control of body weight and fat distribution. The effect of nasal continuous positive airway pressure (NCPAP) treatment on VFA and serum leptin levels in OSAS patients has not been known.. VFA and subcutaneous fat accumulation (SFA) were assessed by CT before and after NCPAP treatment in 22 OSAS patients (mean apnea and hypopnea index >50 episodes/h). Serum leptin levels of another 21 OSAS patients were measured before and after 3 to 4 days of NCPAP to gain insight into the mechanism by which NCPAP affects fat distribution. VFA and SFA decreased significantly after 6 months of NCPAP treatment (236+/-16 to 182+/-14cm(2), P=0.0003 and 215+/-21 to 189+/-18 cm(2), P=0.003, respectively). VFA decreased significantly in the body weight reduction group (n=9, P<0.01) and the no body weight reduction group (n=13, P<0.03). In contrast, SFA changed significantly in the body weight reduction group only (P<0.01). Leptin levels decreased significantly following 3 to 4 days of NCPAP (P<0.01), whereas body weight, fasting insulin, and cortisol levels did not change significantly.. Correction of sleep disordered breathing by NCPAP may be used to reduce VFA in OSAS patients. OSAS may have significant effects on the serum leptin levels. Topics: Adipose Tissue; Blood Glucose; Body Weight; Cholesterol, LDL; Glucose Tolerance Test; Leptin; Positive-Pressure Respiration; Proteins; Sleep Apnea Syndromes; Triglycerides; Viscera; Weight Loss | 1999 |
Effects of simmondsin on food intake, growth, and metabolic variables in lean (+/?) and obese (fa/fa) Zucker rats.
Incorporation of 2.5 g/kg of the anorexigen, simmondsin, in the diet resulted in food intake reduction in both lean and obese Zucker rats; however, the obese rats were much more sensitive to the food intake-reducing activity of simmondsin. In both obese and lean simmondsin-treated Zucker rats, growth was slower than in control rats, but was the same as that in pair-fed animals. The 24 h heat production pattern showed a smaller diurnal variation and a lower mean in obese rats than in lean rats. Food intake reduction, as a result of either simmondsin treatment or pair feeding, caused a decrease in mean heat production. Simmondsin treatment, but not pair feeding, caused a decrease in the diurnal variation of heat production. Plasma total cholesterol levels were increased in both simmondsin-treated and pair-fed obese and lean Zucker rats compared with control animals; this increase was mainly due to an increase in HDL-cholesterol levels. Blood leptin levels in both obese and lean rats decreased with decreased food intake and decreased fat deposition, but in obese rats, simmondsin treatment resulted in an additional decrease in leptin levels. It is concluded that the food intake-reducing effect of simmondsin is more pronounced in obese Zucker rats than in their lean littermates, and except for the simmondsin-specific effects on leptin and total cholesterol values in obese littermates, the effects of simmondsin are related to food intake restriction in obese and lean Zucker rats. Topics: Acetonitriles; Adipose Tissue; Animals; Appetite Depressants; Body Temperature Regulation; Body Weight; Cholesterol; Cyclohexanes; Eating; Glucosides; Growth; Leptin; Male; Obesity; Proteins; Rats; Rats, Zucker; Time Factors | 1999 |
Plasma plasminogen activator inhibitor-I is associated with plasma leptin irrespective of body mass index, body fat mass, and plasma insulin and metabolic parameters in premenopausal women.
Leptin, the satiety hormone expressed almost exclusively in adipose tissue, is a marker of body fat accumulation in humans. Recent studies have shown that plasminogen activator inhibitor-1 (PAI-1), a prothrombotic factor associated with atherosclerosis complications, is also produced in adipose tissue. The objective of the present study was to determine whether PAI-1 antigen plasma concentrations are associated with leptin plasma levels or the body fat mass (FM) independently of the variables known to influence PAI-1 production. Sixty-one nondiabetic women aged 18 to 45 years with a wide range of values for the body mass index ([BMI] 18.1 to 37.7 kg/m2) were evaluated for (1) body FM and fasting plasma levels of (2) PAI-1 antigen, (3) PAI-1 activity, (4) leptin, (5) insulin, (6) blood glucose, and (7) lipids (cholesterol, high-density lipoprotein [HDL]-cholesterol, and triglycerides [TG]). Body FM and fat-free mass (FFM) were estimated during fasting conditions by the bioimpedance analysis (BIA) method using a tetrapolar device. Body fat distribution was evaluated by the waist circumference and the waist to hip ratio (WHR). FM was directly associated with both PAI-1 antigen (r = .585, P < .001) and PAI-1 activity (r = .339, P < .001). Seemingly, leptin was positively related to both PAI-1 antigen (r = .630, P < .001) and PAI-1 activity (r = .497, P < .001). Moreover, both PAI-I antigen and PAI-1 activity were directly correlated with FFM (r = .285, P < .05, and r = .336, P < .01, respectively), BMI (r = .594, P < .001, and r = .458, P < .001, respectively), and WHR (r = .510, P < .001, and r = .391, P < .005, respectively). Insulin was directly related to PAI-1 antigen (r = .540, P < .001), PAI-1 activity (r = .259, P < .05), leptin (r = .447, P < .001), and FM (r = .435, P < .001). The association between PAI-1 antigen (dependent variable) and leptin or FM was tested by a stepwise regression model simultaneously including leptin, FM, BMI, WHR, age, FFM, and fasting insulin, blood glucose, TG, cholesterol, and HDL-cholesterol as independent variables. PAI-1 antigen maintained a significant positive independent relationship only with leptin (t = 2.923, P < .01), insulin (t = 3.489, P < .001), and fasting blood glucose (t = 2.092, P < .05), and a negative independent relationship with HDL-cholesterol (t = -2.634, P < .05). In conclusion, the strong relationship between PAI-1 antigen and leptin irrespective of other variables known to influence these factors Topics: Adipose Tissue; Adolescent; Adult; Body Mass Index; Body Weight; Female; Humans; Insulin; Leptin; Middle Aged; Plasminogen Activator Inhibitor 1; Premenopause; Proteins | 1999 |
Body fat distribution with long-term dietary restriction in adult male rhesus macaques.
Dietary restriction (DR) is the only intervention that has been shown to increase average and median life span in laboratory rodents. The effect of long-term, moderate DR on body composition and fat distribution was evaluated in male rhesus monkeys. Thirty animals (8-14 years of age)fed either 30% less than baseline intake (R, n = 15) or allowed to eat to satiety (C, n = 15), have been assessed semiannually using somatometrics and dual-energy alpha-ray absorptiometry (DXA)for 7.5 years. R subjects have reduced body weight (p <.0001), total body fat (p < .0001), and percentage body fat located in the abdominal region (p < .05). In addition, there has been a sustained reduction in plasma leptin concentrations (p <.001). These findings suggest reduced risk for common morbidities, such as insulin resistance, dyslipidemia, and type 2 diabetes mellitus, that are associated with advancing age and increased levels of bodyfat, especially in the visceral depot. Topics: Absorptiometry, Photon; Adipose Tissue; Animals; Body Composition; Body Weight; Diet; Leptin; Macaca mulatta; Male; Obesity; Proteins | 1999 |
Starvation: early signals, sensors, and sequelae.
To identify the sequences of changes in putative signals, reception of these and responses to starvation, we sampled fed and starved rats at 2- to 6-h intervals after removal of food 2 h before dark. Metabolites, hormones, hypothalamic neuropeptide expression, fat depots, and leptin expression were measured. At 2 h, insulin decreased, and FFA and corticosterone (B) increased; by 4 h, leptin and glucose levels decreased. Neuropeptide Y messenger RNA (mRNA) increased 6 h after food removal and thereafter. Adrenal and plasma B did not follow ACTH and were elevated throughout, with a nadir at the dark-light transition. Leptin correlated inversely with adrenal B. Fat stores decreased during the last 12 h. Leptin mRNA in perirenal and sc fat peaked during the dark period, resembling plasma leptin in fed rats. We conclude that 1) within the first 4 h, hormonal and metabolic signals relay starvation-induced information to the hypothalamus; 2) hypothalamic neuropeptide synthesis responds rapidly to the altered metabolic signals; 3) catabolic activity quickly predominates, reinforced by elevated B, not driven by ACTH, but possibly to a minor extent by leptin, and more by adrenal neural activity; and 4) leptin secretion decreases before leptin mRNA or fat depot weight, showing synthesis-independent regulation. Topics: Adipose Tissue; Animals; Body Weight; Eating; Hormones; Hypothalamo-Hypophyseal System; Hypothalamus; Leptin; Male; Neuropeptides; Organ Size; Pituitary-Adrenal System; Proteins; Rats; Starvation | 1999 |
Leptin and neuropeptide Y (NPY) modulate nitric oxide synthase: further evidence for a role of nitric oxide in feeding.
Recent studies have suggested a role for nitric oxide in the regulation of food intake. Neuropeptide Y (NPY) is one of the most potent orexigenic agents. Chronic administration of leptin decreases food intake. This study examined the effects of NPY and leptin on nitric oxide synthase (NOS) in the hypothalamus. Previously it has been demonstrated that obese (ob/ob) mice have elevated NOS levels in the hypothalamus. In this study we demonstrated that the administration of leptin (6 microg/day) subcutaneously (SC) for 3 days decreased body weight (P < 0.001) and food intake P < 0.001) in obese (ob/ob) mice as expected. In addition, leptin decreased NOS in the hypothalamus nu 37% (P < 0.01) and in brown adipose tissue by 69% (P < 0.01) but not in white adipose tissue. NPY was administered intracerebroventricularly to CD-1 mice at doses of 0.25 and 0.50 microg. Mice were sacrificed 15 min after injection and NOS was measured in their hypothalami. NPY at the lower dose increased NOS in the hypothalamus by 147%. These results, taken together, with previously published studies support the concept that nitric oxide may play a role as a mediator of the effects of NPY and leptin on food intake. The alterations of NOS in brown adipose tissue following leptin administration could result in changes in blood flow or metabolism in the brown fat. Topics: Adipose Tissue; Animals; Body Weight; Eating; Hypothalamus; Injections, Intraventricular; Injections, Subcutaneous; Leptin; Male; Mice; Mice, Obese; Neuropeptide Y; Nitric Oxide Synthase | 1999 |
Leptin serum concentrations in healthy neonates within the first week of life: relation to insulin and growth hormone levels, skinfold thickness, body mass index and weight.
Leptin, the ob gene product, plays a key role in the regulation of body fat mass and weight in adult life. The mechanisms by which maternal and fetal/neonatal weight are regulated during human pregnancy and in early postnatal life are poorly understood. High leptin levels are observed in women during gestation and in cord blood at term. We have hypothesized that high leptin levels at term could represent an important feed-back indicator of nutrient supply. Subsequently, leptin could signal adipose tissue status during late gestation and during early neonatal life.. 51 healthy newborns were studied. Clinical and auxological data (birth length, weight, and iliac, subscapular, biceps and triceps skinfold thickness) were recorded using a standardized data sheet. Venous cord blood was obtained immediately after birth in all neonates. Subsequently, capillary blood was obtained from the heel from some of the newborns when blood had to be obtained because of signs or symptoms of particular problems such as hypoglycaemia or hyperbilirubinaemia, at the following time points: two to four hours after birth in 51 infants, 56-79 h after birth in 47 infants and 99-128 h after birth in 23 of the newborns. The ratio between the sexes (girls/boys) was similar at all time points. The infants that were included in the study were subsequently found to be normal and healthy after analysis of the clinical and biochemical data. A specific ultrasensitive radioimmunoassay was used to measure leptin, while growth hormone and insulin were measured using commercially available immunoassays.. Gestational age was 38-42 weeks, maternal age was 21-42 years. Birth weights ranged from 2480 to 4400 g. All newborns and mothers were subsequently found to be healthy. Leptin levels in venous cord blood was 0.16-6.80 microg/l, median 3. 47 microg/l and in capillary blood shortly after birth 0.26-7.03 microg/l, median 3.89 microg/l. 56-79 h after birth leptin levels had fallen dramatically, range 0.02-1.69 microg/l, median 0.26 microg/l, while 99-128 h after birth, leptin concentrations in capillary blood (0.05-2.61 microg/l, median 0.59 microg/l) had significantly increased when compared to the levels at 56-79 h (P < 0.001). There was a significant correlation between leptin levels in umbilical vein and birth weight of the neonates (r = 0.57, P < 0.03). Multistep regression analysis revealed that weight and skinfold thickness accounted for approximately 35-70% of the variation of leptin levels. Insulin and growth hormone, and glucose and bilirubin however, had no major impact on leptin levels.. High leptin levels are present in cord blood at birth and in capillary blood shortly after birth. Since leptin levels in cord blood correlate with birth weight it is tempting to speculate that in the fetus as in later life leptin is signalling expansion of fat stores. Most importantly, we now report that leptin levels are high in the fetus but decline rapidly and dramatically after birth in healthy neonates. This may be important for the stimulation of feeding behaviour and the acquisition of energy homeostasis in the neonate. Topics: Body Mass Index; Body Weight; Female; Fetal Blood; Growth Hormone; Humans; Infant, Newborn; Insulin; Leptin; Male; Regression Analysis; Skinfold Thickness; Statistics, Nonparametric | 1999 |
Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin.
Excess of body fat, or obesity, is a major health problem and confers a higher risk of cardiovascular and metabolic disorders such as diabetes, hypertension, and coronary heart disease. Leptin is an adipocyte-derived satiety factor that plays an important role in the regulation of energy homeostasis, and its synthesis and secretion are markedly increased in obese subjects. To explore the metabolic consequences of an increased amount of leptin on a long-term basis in vivo, we generated transgenic skinny mice with elevated plasma leptin concentrations comparable to those in obese subjects. Overexpression of leptin in the liver has resulted in complete disappearance of white and brown adipose tissue for a long period of time in mice. Transgenic skinny mice exhibit increased glucose metabolism accompanied by the activation of insulin signaling in the skeletal muscle and liver. They also show small-sized livers with a marked decrease in glycogen and lipid storage. The phenotypes are in striking contrast to those of recently reported animal models of lipoatrophic diabetes and patients with lipoatrophic diabetes with reduced amount of leptin. The present study provides evidence that leptin is an adipocyte-derived antidiabetic hormone in vivo and suggests its pathophysiologic and therapeutic implications in diabetes. Topics: Animals; Body Weight; Female; Glucose; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Liver Glycogen; Male; Mice; Mice, Transgenic; Obesity; Protein Biosynthesis; Signal Transduction | 1999 |
Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area.
Recent studies have reinforced the view that the lateral hypothalamic area (LHA) regulates food intake and body weight. We identified leptin-sensitive neurons in the arcuate nucleus of the hypothalamus (Arc) that innervate the LHA using retrograde tracing with leptin administration. We found that retrogradely labeled cells in the Arc contained neuropeptide Y (NPY) mRNA or proopiomelanocortin (POMC) mRNA. Following leptin administration, NPY cells in the Arc did not express Fos but expressed suppressor of cytokine signaling-3 (SOCS-3) mRNA. In contrast, leptin induced both Fos and SOCS-3 expression in POMC neurons, many of which also innervated the LHA. These findings suggest that leptin directly and differentially engages NPY and POMC neurons that project to the LHA, linking circulating leptin and neurons that regulate feeding behavior and body weight homeostasis. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Cell Count; Eating; Homeostasis; Hypothalamic Area, Lateral; Immunohistochemistry; In Situ Hybridization; Leptin; Male; Neural Pathways; Neurons; Neuropeptide Y; Pro-Opiomelanocortin; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Repressor Proteins; RNA, Messenger; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors | 1999 |
Sparing effect of leptin on liver glycogen stores in rats during the fed-to-fasted transition.
The effect of moderate hyperleptinemia ( approximately 20 ng/ml) on liver and skeletal muscle glycogen metabolism was examined in Wistar rats. Animals were studied approximately 90 h after receiving recombinant adenoviruses encoding rat leptin (AdCMV-leptin) or beta-galactosidase (AdCMV-betaGal). Liver and skeletal muscle glycogen levels in the fed and fasted (18 h) states were similar in AdCMV-leptin- and AdCMV-betaGal-treated rats. However, after delivery of a glucose bolus, liver glycogen levels were significantly greater in AdCMV-leptin compared with AdCMV-betaGal rats (P < 0.05). To investigate the mechanism(s) of these differences, glycogen levels were measured immediately after the cessation of a 3- or 6-h glucose infusion or 3, 6, and 9 h after the cessation of a 6-h glucose infusion. Similar increases in liver and skeletal muscle glycogen occurred in hyperleptinemic and control rats in response to glucose infusions. However, 3 and 6 h after the cessation of a glucose infusion, liver glycogen levels were approximately twofold greater (P < 0.05) in AdCMV-leptin-treated compared with AdCMV-betaGal-treated animals. Skeletal muscle glycogen levels were similar in AdCMV-leptin-treated and AdCMV-betaGal-treated animals at the same time points. Glycogen phosphorylase, phosphodiesterase 3B, and glycogen synthase activities were unaltered by hyperleptinemia. We conclude that moderate increases in plasma leptin levels decrease liver glycogen degradation during the fed-to-fasted transition. Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adipose Tissue; Animals; beta-Galactosidase; Body Weight; Cyclic Nucleotide Phosphodiesterases, Type 3; Eating; Epididymis; Fasting; Glycogen; Glycogen Synthase; Leptin; Liver; Male; Muscle, Skeletal; Organ Size; Phosphorylases; Rats; Rats, Wistar | 1999 |
Neuropeptide Y receptor alterations in the hypothalamus of lactating rats.
Hypothalamic neuropeptide Y (NPY) neurons are influenced by circulating levels of insulin and leptin and are thought to be involved in mediating hunger following underfeeding. We have investigated hypothalamic NPY receptor subtypes in lactating rats, which are markedly hyperphagic throughout the day and night. NPY receptors were measured by using [125I] peptide YY, a high-affinity ligand, and Y1 receptors were masked by using the highly specific antagonist BIBP 3226. Freely fed lactating rats showed no changes in the densities of Y1, or non-Y1, NPY binding sites in whole hypothalamic homogenates or in individual hypothalamic regions (measured by quantitative autoradiography) examined during the day or night (P > 0.05; n = 10/group, and n = 6/group, respectively). However, reducing food intake by 35% had a more profound effect on NPY receptor density in lactating than in control rats, producing down-regulation of non-Y1 receptors in the ventromedial, dorsomedial, and perifornical lateral areas (all P < 0.05; n = 7/group) and reduction of plasma insulin and leptin levels (both P < 0.01). Thus, although the NPY system may not have a major role in the hyperphagia of freely fed lactating rats, it appears to have an important function in the response to undernutrition in such animals. Topics: Animals; Body Weight; Down-Regulation; Feeding Behavior; Female; Hypothalamus; Insulin; Lactation; Leptin; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Neuropeptide Y | 1999 |
Rats with hypothalamic obesity are insensitive to central leptin injections.
Genetically determined obesities, involving leptin- and melanocortin-signaling pathways, have focused attention on the four medial hypothalamic nuclei as primary sources of feeding- and metabolically-based obesity. All four medial cell groups contain leptin receptors. To determine which of these cell groups normally mediates the effects of leptin on food intake and body weight gain, we injected colchicine bilaterally into each nucleus and determined the pathophysiological effects of disruption and responsivity to leptin injected intracerebroventricularly. Intracerebroventricular injections of leptin in sham-lesioned rats decreased food intake during the dark period, but not during the light period. Lesions of the arcuate (ARC), paraventricular (PVN), and ventromedial (VMN) nuclei all resulted in leptin insensitivity; by contrast, lesions of the dorsomedial nuclei (DMN) augmented sensitivity to leptin on feeding and body weight gain. Although rats with ARC and PVN lesions were obese, they were still capable of reducing caloric efficiency over the 5 days of study and increasing uncoupling protein content in interscapular brown adipose tissue. Caloric efficiency and uncoupling protein content were unchanged in rats with VMN and DMN lesions. Finally, the slope of the relationship between leptin and mesenteric white adipose tissue was increased in rats with VMN lesions and abolished in rats with ARC lesions. Thus, lesions of the ARC, PVN, and VMN produced obesity via separate pathways. We conclude that the medial hypothalamic cell groups, each with a different role in energy balance, are all necessary for normal leptin responsiveness. Topics: Animals; Body Weight; Colchicine; Dorsomedial Hypothalamic Nucleus; Eating; Hypothalamic Diseases; Injections, Intraventricular; Leptin; Male; Obesity; Proteins; Rats; Rats, Sprague-Dawley; Ventromedial Hypothalamic Nucleus | 1999 |
Fasting regulates hypothalamic neuropeptide Y, agouti-related peptide, and proopiomelanocortin in diabetic mice independent of changes in leptin or insulin.
Fasting increases hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AGRP) messenger RNA (mRNA) and reduces hypothalamic POMC mRNA, and is also characterized by a reduction in plasma leptin, insulin, and glucose, each of which has been implicated in the regulation of hypothalamic gene expression. To further evaluate the roles of leptin, insulin, and glucose in mediating effects of fasting, we examined hypothalamic gene expression in nondiabetic and streptozotocin (STZ)-induced diabetic mice both under ad lib fed and 48-h fasted conditions. In both diabetic and nondiabetic mice, fasting stimulated hypothalamic NPY and AGRP mRNA and inhibited hypothalamic POMC mRNA and adipose leptin mRNA. However, in diabetic mice fasting had no effect on plasma leptin and insulin while decreasing plasma glucose, whereas in nondiabetic mice fasting decreased plasma leptin, insulin, and glucose. Furthermore, in nondiabetic fasted mice, NPY and AGRP mRNA were higher, and POMC mRNA and plasma glucose were lower, than in diabetic ad lib fed mice, even though insulin and leptin were similar in these two groups. These data are consistent with the hypothesis that although leptin and insulin regulate hypothalamic gene expression, glucose or other factors may have independent effects on hypothalamic and adipose gene expression under conditions of low insulin and leptin. Topics: Adipose Tissue; Agouti-Related Protein; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Epididymis; Fasting; Gene Expression; Hypothalamus; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Organ Size; Pro-Opiomelanocortin; Proteins; RNA, Messenger | 1999 |
Norepinephrine is required for leptin effects on gene expression in brown and white adipose tissue.
Exogenous leptin enhances energy utilization in ob/ob mice by binding its hypothalamic receptor and selectively increasing peripheral fat oxidation. Leptin also increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), but the neurotransmitter that mediates this effect has not been established. The present experiments sought to determine whether leptin regulates UCP1 expression in BAT and its own expression in white adipose tissue (WAT) through the long or short forms of leptin receptor and modulation of norepinephrine release. Mice lacking dopamine beta-hydroxylase (Dbh-/-), the enzyme responsible for synthesizing norepinephrine and epinephrine from dopamine, were treated with leptin (20 microg/g body weight/day) for 3 days before they were euthanized. UCP1 messenger RNA (mRNA) and protein expression were 5-fold higher in BAT from control (Dbh+/-) compared with Dbh-/- mice. Leptin produced a 4-fold increase in UCP1 mRNA levels in Dbh+/- mice but had no effect on UCP1 expression in Dbh-/-. The beta3-adrenergic agonist, CL-316,243 increased UCP1 expression and established that BAT from both groups of mice was capable of responding to beta-adrenergic stimulation. Similarly, exogenous leptin reduced leptin mRNA in WAT from Dbh+/- but not Dbh-/- mice. In separate experiments, leptin produced comparable reductions in food intake in both Dbh+/- and Dbh-/- mice, illustrating that norepinephrine is not required for leptin's effect on food intake. Lastly, db/db mice lacking the long form of the leptin receptor failed to increase UCP1 mRNA in response to exogenous leptin but increased UCP1 mRNA in response to CL-316,243. These studies establish that norepinephrine is required for leptin to regulate its own expression in WAT and UCP1 expression in BAT and indicate that these effects are likely mediated through the centrally expressed long form of the leptin receptor. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Carrier Proteins; Diabetes Mellitus; Dopamine beta-Hydroxylase; Eating; Gene Expression; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Norepinephrine; Proteins; RNA, Messenger; Uncoupling Protein 1 | 1999 |
Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor.
Neuropeptide Y (NPY), a 36-amino-acid peptide widely expressed in the brain is involved in many physiological responses, including hypothalamic control of food intake and cardiovascular homeostasis. NPY mediates its effects through binding to the Y1, Y2 and Y5 G-protein-coupled receptors. Little is known of the role of the Y2 receptor in mediating the different NPY effects. We inactivated the Y2 receptor subtype in mice and found that these mice developed increased body weight, food intake and fat deposition. The null mutant mice showed an attenuated response to leptin administration but a normal response to NPY-induced food intake and intact regulation of re-feeding and body weight after starvation. An absence of the Y2 receptor subtype also affected the basal control of heart rate, but did not influence blood pressure. These findings indicate an inhibitory role for the Y2 receptor subtype in the central regulation of body weight and control of food intake. Topics: Adipose Tissue; Animals; Blood Pressure; Body Weight; Feeding Behavior; Female; Heart Rate; Leptin; Mice; Mice, Mutant Strains; Neuropeptide Y; Protein Binding; Proteins; Receptors, Leptin; Receptors, Neuropeptide Y | 1999 |
Neuropeptide Y expression and endogenous leptin concentrations in a dietary model of obesity.
To determine how leptin concentrations and neuropeptide (NPY) are regulated in a model of dietary obesity in relation to relative growth (RG) and relative food consumption (RFC).. Sprague-Dawley rats were fed a moderately high-fat diet for 14 weeks over which time animals diverged into obesity-prone (OP) and obesity-resistant (OR) populations. RG rates and RFC were calculated weekly. Following the study, an adiposity index was calculated and arcuate nucleus (ARC) NPY expression was determined by in situ hybridization (ISH) or ribonuclease protection (RPA) assays.. Body weights were greater in OP rats after 2 weeks on the diet compared to OR rats and remained different throughout the study. RG and RFC were greater in OP rats compared to OR rats only during the first 2 weeks of the study. Leptin concentrations rose in both groups during the experiment, but the increase was greater in OP rats than in OR rats. Insulin changes paralleled those for leptin. ARC NPY mRNA expression was not different between OP and OR rats as measured by ISH and RPA.. Although NPY expression has been reported to be different initially in OP and OR rats, this difference dissipates following divergence of body weight. RFC and RG data suggest the initial NPY elevation may contribute to increased weight gain of OP rats during the first 2 weeks of the diet. Higher relative leptin concentrations in OP rats may be necessary to normalize differences in adiposity and apparent leptin and insulin resistance of OP rats. Topics: Animals; Body Composition; Body Weight; Dietary Fats; Disease Models, Animal; Eating; Energy Intake; Gene Expression; Hypothalamus; In Situ Hybridization; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; RNA, Messenger | 1999 |
Seasonal regulation of food intake and body weight in the male Siberian hamster: studies of hypothalamic orexin (hypocretin), neuropeptide Y (NPY) and pro-opiomelanocortin (POMC).
The aim of these experiments was to investigate the relationship between hypothalamic expression of orexin (also called hypocretin), neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA and seasonal cycles of body weight and food intake in the Siberian hamster. Adult males were transferred from long days of 16 h light and 8 h dark to short days of 8 h light and 16 h dark, a procedure known to induce major reductions in food intake and body weight in this species. After 8 weeks of exposure to short days, while body weight was declining, hypothalamic NPY mRNA levels as assessed by in situ hybridization were slightly lower (P < 0.05) than in age-matched controls exposed to long days. After 12 weeks with short days, when body weight would be expected to have reached its seasonal nadir, POMC mRNA levels were lower (P < 0.05) than in hamsters under long days. At no stage did orexin mRNA levels in hamsters under short days differ significantly from levels in those under long days. To investigate further the role of these peptide systems in seasonal changes in body weight and food intake, two provocative tests were carried out. Firstly, a 48-h fast induced a significant increase (P < 0.025) in hypothalamic NPY mRNA levels in both long- and short-day conditions, but did not change hypothalamic POMC or orexin mRNA levels. Secondly, systemic (intraperitoneal) treatment with recombinant murine leptin (5 mg/kg body weight) significantly decreased (P < 0.01) food intake over a 6-h post-treatment period in both long- and short-day conditions. However, this acute leptin treatment did not induce significant changes in hypothalamic orexin, NPY or POMC mRNA abundance. The increase in NPY expression in both long- and short-day conditions following food restriction and the suppression of food intake by leptin in both conditions suggests that acute homeostatic mechanisms operate in both long-day (obese) and short-day (nonobese) conditions. The lack of major changes in orexin, NPY and POMC in such different metabolic states suggest that other central systems must play a greater role in generating these states. Such findings are consistent with the 'sliding set-point' hypothesis, that is, seasonal cycles in food intake and fat metabolism are brought about by as yet unknown central mechanisms that chronically alter the level ('set point') around which homeostasis occurs, rather than resulting from changes in the potency of the acute feedback mechanisms themselves. Topics: Animals; Autoradiography; Body Weight; Carrier Proteins; Cricetinae; Eating; Fasting; Food Deprivation; Hypothalamus; In Situ Hybridization; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Neuropeptides; Oligonucleotide Probes; Orexins; Phodopus; Pro-Opiomelanocortin; RNA, Messenger; Seasons | 1999 |
Rapid increase in circulating leptin in ventromedial hypothalamus-lesioned rats: role of hyperinsulinemia and implication for upregulation mechanism.
The mechanisms of marked increase in plasma leptin soon after ventromedial hypothalamus (VMH) lesions were investigated. Although rats did not gain body weight or parametrial fat-pad mass 24 h after the operation, the acute VMH-lesioned rats exhibited substantial five- and fourfold increases in plasma leptin levels compared with sham-operated control rats in fed (22.6 +/- 3.2 vs. 5.8 +/- 1.2 ng/ml) and fasted (8.8 +/- 2.0 vs. 2.3 +/- 0.3 ng/ml) states, respectively. Plasma insulin concentration was doubled in VMH-lesioned rats compared with sham-operated controls in both fed and fasting states. Northern blot analysis revealed that mRNA of ob gene was not increased in parametrial fat pad of animals 24 h after the creation of VMH lesions. However, leptin content in the fat pad was significantly increased in VMH-lesioned rats compared with sham-operated controls (32.2 +/- 4.7 vs. 17.4 +/- 2.3 ng/g wet tissue). The leptin content in parametrial fat pad was highly correlated with plasma leptin concentrations (r = 0.898, P < 0.001). To define the effect of hyperinsulinemia on their hyperleptinemia, a small dose of streptozotocin (STZ) (25 mg/kg body wt) was intravenously administered into rats 5 days before the creation of VMH lesions. Plasma insulin levels were not increased after VMH lesions in STZ-pretreated rats. Plasma leptin levels were halved in the absence of hyperinsulinemia, but still remained twofold higher than those in their sham-operated counterparts (9.9 +/- 1.3 vs. 4.8 +/- 0.7 ng/ml). These results indicate that the destruction of VMH rapidly promotes leptin production before obesity develops through an enhanced translational process in which hyperinsulinemia occurring after VMH lesioning plays an important role. The present study also suggests that there are other mechanisms that rapidly upregulate leptin production in adipocytes in VMH-lesioned rats in which the target organ of this hormone has been destroyed. Topics: Animals; Blotting, Northern; Body Weight; Female; Hyperinsulinism; Hypothalamus, Middle; Insulin; Leptin; Obesity; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Up-Regulation | 1999 |
Decreased type 2 corticotropin-releasing hormone receptor mRNA expression in the ventromedial hypothalamus during repeated immobilization stress.
Chronic or repeated stress results in reduction of food intake and body weight in rats. Stress-induced anorexia has been attributed to increased corticotropin-releasing hormone (CRH) function in the central nervous system. To explore possible roles of other neuropeptides and peripheral hormones involved in food intake and energy utilization during continuing stress, we examined the impact of repeated immobilization stress on expression of mRNAs coding for CRH, neuropeptide Y (NPY), galanin and pro-opiomelanocortin (POMC) mRNAs in such hypothalamic nuclei as the paraventricular nucleus (PVN), arcuate nucleus (ARC) and dorsomedial hypothalamus (DMH), as well as plasma insulin and leptin concentrations. Changes in type 2 CRH receptor (CRHR-2) mRNA in the ventromedial hypothalamus (VMH), a possible target of anorectic CRH effect, were also examined. Rats were immobilized for 2 h daily for 6 days and sacrificed 24 h after the last immobilization. Immobilized rats had lower food intake and body weight and higher levels of PVN CRH mRNA than controls. Repeated immobiliza tion also lowered plasma insulin and leptin concentrations and VMH CRHR-2 mRNA levels. These results provide additional evidence linking VMH CRHR-2 mRNA levels to plasma leptin concentration. ARC NPY and DMH galanin mRNAs increased following repeated immobilization, while ARC POMC mRNA decreased. DMH NPY mRNA and ARC galanin mRNA were unaltered by immobilization. Since NPY and galanin are considered orexigenic, while the POMC-melanocortin-4 receptor system is apparently anorexigenic, the changes in neuropeptide mRNAs and VMH CRHR-2 mRNA may play counterregulatory roles against anorectic CRH effects. Topics: Adrenocorticotropic Hormone; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Corticotropin-Releasing Hormone; Cortisone; Eating; Galanin; Gene Expression; Homeostasis; In Situ Hybridization; Insulin; Leptin; Male; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pro-Opiomelanocortin; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Restraint, Physical; RNA, Messenger; Stress, Physiological; Ventromedial Hypothalamic Nucleus | 1999 |
Leptin concentrations in maternal serum and cord blood: relationship to maternal anthropometry and fetal growth.
To determine 1. the relationship between maternal serum leptin concentrations and maternal anthropometry and 2. the relationship between cord serum leptin concentrations at birth and neonatal anthropometry.. Prospective cohort study of fetal growth in low-risk pregnancies.. University teaching hospital.. Thirty-nine women and their babies taking part in a fetal growth study.. Blood was taken from the women between 10-20 weeks of gestation and from the umbilical cord of their babies at delivery. Serum leptin was measured by radio-immunoassay. Maternal anthropometric measurements were recorded at booking. Neonatal anthropometric measurements were recorded within 48 hours after delivery. Linear regression analysis was used to explore the relationship between serum leptin concentrations and anthropometric measures and multiple regression analysis then applied to determine which variables remained independently associated with leptin.. The median (range) leptin concentration in maternal serum was 11.8 ng/mL (1.7-39.7) and in cord blood was 4.2 ng/mL (0.6-21.4). Maternal leptin levels correlated with maternal weight, body mass index, midarm circumference and skinfold thickness, but not with birthweight, placental weight or maternal height. Body mass index and midarm circumference remained significant after multiple regression analysis. Cord leptin levels correlated with birthweight, birthlength, placental weight and skinfold thickness but not with ponderal index. Birthweight and subscapular skinfold thickness remained significant after multiple regression analysis. Cord leptin concentrations did not correlate with maternal leptin concentrations.. We suggest that there are very strong associations between maternal leptin and maternal adiposity in pregnancy, and between cord leptin at delivery and birthweight, as well as other anthropometric markers of fetal growth. Topics: Adult; Birth Weight; Body Height; Body Weight; Cohort Studies; Embryonic and Fetal Development; Female; Fetal Blood; Gestational Age; Humans; Leptin; Organ Size; Placenta; Pregnancy; Prospective Studies | 1999 |
Fasting insulin and leptin serum levels are associated with systolic blood pressure independent of percentage body fat and body mass index.
To examine the relationship between leptin and insulin serum levels and systolic and diastolic blood pressure in young men.. Kobe University of Mercantile Marine, Kobe, Japan.. One hundred and ninety-eight male students aged 18-20 years (comprising 100% of those eligible).. A cross-sectional survey of a sample of male college students was performed, with measurements to include anthropometry, blood pressure and blood tests after overnight fasting.. Compared with 90 men with an optimal blood pressure, 56 men with high-normal and high blood pressure had an increase in body mass index (23.7 +/- 5.2 versus 20.4 +/- 2.2 kg/m2), percentage body fat (21.7 +/- 8.0 versus 16.3 +/- 4.2%) and serum leptin (3.7 +/- 4.7 versus 1.5 +/- 0.8 ng/ml). In addition, they had greater serum insulin (59 +/- 31 versus 43 +/- 12 pmol/l) despite there being no differences in plasma glucose, resulting in a reduction of the ratio of glucose to insulin (x 10(6)) (107 +/- 43 versus 126 +/-, which is an estimate of insulin sensitivity in a nondiabetic population. Furthermore, the 56 men had higher serum triglyceride levels, although there was no difference in low density lipoprotein-cholesterol and high density lipoprotein-cholesterol between men with optimal and high-normal plus high blood pressure. Similar differences were found between men in a top versus low tertile of systolic and diastolic blood pressure. In multiple regression analysis, both log leptin and log insulin emerged as determinants for systolic blood pressure independent of body mass index and percentage body fat, but an association with diastolic blood pressure was only shown for log leptin.. Hyperleptinemia and hyperinsulinemia may be regulators of arterial pressure, independent of body mass index or percentage body fat. Topics: Adipose Tissue; Adult; Blood Pressure; Body Mass Index; Body Weight; Cross-Sectional Studies; Fasting; Humans; Insulin; Leptin; Male | 1999 |
The future of weight management.
Topics: Adolescent; Adult; Animals; Appetite Depressants; Behavior Therapy; Body Mass Index; Body Weight; Child; Diet, Reducing; Exercise; Female; Humans; Leptin; Male; Mice; Middle Aged; Neuropeptide Y; Obesity; Rats; Sex Factors; United States; Weight Loss | 1999 |
Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia.
Leptin acts on specific populations of hypothalamic neurons to regulate feeding behavior, energy expenditure, and neuroendocrine function. It is not known, however, whether the same neural circuits mediate leptin action across its full biologic dose-response curve, which extends over a broad range, from low levels seen during starvation to high levels characteristic of obesity. Here, we show that the characteristic fall in leptin with fasting causes a rise in neuropeptide Y (NPY) messenger RNA (mRNA), as well as a fall in POMC and cocaine and amphetamine-regulated transcript (CART) mRNAs. Sc infusion of leptin sufficient to maintain plasma levels within the physiologic range during the fast prevents changes in the expression of these peptides, as well as changes in neuroendocrine function, demonstrating that multiple neural circuits are highly sensitive to small changes in leptin within its low physiologic range. In contrast, a modest elevation of plasma leptin above the normal fed range by constant sc infusion, which produced marked reduction in food intake and body weight, decreased NPY mRNA in the arcuate hypothalamic nucleus but did not affect the levels of mRNAs encoding the anorexigenic peptides alpha-MSH, CART or CRH. These results suggest that the dose response characteristics of leptin on hypothalamic target neurons at the level of mRNA expression are variable, with some neurons (e.g. NPY) responding across a broad dose range and others (e.g. POMC and CART) showing a limited response within the low range. These results further suggest that the central targets of leptin that mediate the transition from starvation to the fed state may be distinct from those that mediate the response to overfeeding and obesity. Topics: alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Corticotropin-Releasing Hormone; Eating; Fasting; Gene Expression Regulation; Hypothalamus; Leptin; Male; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Rats; Rats, Sprague-Dawley; RNA, Messenger | 1999 |
PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance.
Agonist-induced activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) is known to cause adipocyte differentiation and insulin sensitivity. The biological role of PPAR gamma was investigated by gene targeting. Homozygous PPAR gamma-deficient embryos died at 10.5-11.5 dpc due to placental dysfunction. Quite unexpectedly, heterozygous PPAR gamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. These phenotypes were abrogated by PPAR gamma agonist treatment. Heterozygous PPAR gamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPAR gamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPAR gamma. Topics: Adipocytes; Animals; Blood Glucose; Body Weight; Cell Differentiation; Cell Size; Diet; Eating; Energy Metabolism; Fats; Fetal Viability; Hypoglycemic Agents; Insulin Resistance; Leptin; Mice; Mice, Knockout; Myocardium; Pioglitazone; Placenta; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors | 1999 |
Neuropeptide Y overexpression in the preweanling Zucker (fa/fa) rat.
Hypothalamic preproNPY overexpression in the Zucker fatty (fa/fa) rat was examined. In situ hybridization was used to determine the relative level of preproNPY mRNA in the arcuate nucleus of +/+, +/fa, and fa/fa pups aged postnatal day 2 (P2), 5, 9, 12, or 25. The relative optical density (ROD) of probe hybridization in the arcuate, the area of hybridization (A), and the product of ROD x A (a measure of total arcuate preproNPY mRNA hybridization) were measured. Values were normalized to the mean +/fa value within each litter. Initial analysis showed that preproNPY mRNA hybridization (ROD x A) in fa/fa pups was significantly higher than +/fa and +/+ pups on P9, 12, and 25, and significantly higher than +/fa on P5. No significant difference between lean (+/+ and +/fa) genotypes, however, were observed at any age tested. Values from the lean genotypes were, therefore, pooled, and data were normalized to the mean value of lean animals for analysis. This analysis revealed that preproNPY mRNA hybridization in fa/fa pups was higher than lean littermates as early as P2. Topics: Aging; Animals; Animals, Suckling; Body Weight; Energy Metabolism; Female; Genotype; Hypothalamus; In Situ Hybridization; Leptin; Male; Neuropeptide Y; Protein Precursors; Rats; Rats, Zucker; RNA, Messenger | 1999 |
Hypoleptinemia in female and male elite gymnasts.
Elite gymnasts favour low body fat mass as the current aesthetic ideal required for complex movements in this sports discipline. Pubertal development and growth are retarded in juvenile gymnasts. Leptin, the protein product of the ob-gene, is secreted by fat cells. Besides its role in regulation of body weight, leptin also stimulates the reproductive axis. We investigated various serum hormones including leptin, body composition and nutrition in cohorts of female and male elite gymnasts to elucidate if there is a relationship between leptin levels and delayed puberty in elite gymnasts.. Twenty-two female and 18 male elite gymnasts were enrolled in this study. Pubertal stage, various hormonal levels and body composition were determined and nutritional intake was assessed. Leptin was analysed using a specific RIA.. Pubertal development and growth were delayed in the study group, especially in girls. The percentage of body fat was reduced as compared to a normal age-matched population: 14.4% versus 21.9% in girls and 10.4% versus 15.1% in boys. Serum leptin levels were decreased, especially in pubertal girls, and did not show the normal developmental pattern with a steady increase in girls and a peak in boys of pubertal stage 2. In all gymnasts leptin levels correlated with the amount of fat mass (r = 0.6, P = 0.005 in girls; r = 0.44, P = 0.038 in boys). When leptin levels were transformed into standard deviation scores (SDS) it became obvious that the gymnasts, especially pubertal females, had significantly lower values than normal controls of the same sex, pubertal stage and body mass index (BMI): leptin SDS (BMI) = -1.21 and -3.99 in prepubertal and pubertal girls, - 0.94 and -0.91 in prepubertal and pubertal boys, respectively. When leptin SDS were based on % body fat instead of BMI, mean values were still significantly decreased compared to normal controls: -1.05 in girls (P < 0.001) and -0.60 in boys (P = 0. 025).. Adjustment of serum leptin levels in elite gymnasts for gender, pubertal stage and BMI or % body fat reveals inappropriately low values. The reason for this hypoleptinemia is most probably insufficient caloric intake. The data suggest that hypoleptinemia in turn causes delayed puberty and growth in this particular group of athletes. Topics: Adipose Tissue; Adolescent; Body Height; Body Mass Index; Body Weight; Child; Estradiol; Female; Gymnastics; Hormones; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Prolactin; Puberty; Regression Analysis; Testosterone | 1999 |
Effects of ethanol on leptin secretion and the leptin-induced luteinizing hormone (LH) release from late juvenile female rats.
Chronic ethanol (EtOH) exposure lowers serum insulin-like growth factor-1 (IGF-1) and luteinizing hormone (LH) levels and also delays female puberty, similar to the deficits in the reproductive system that occur during leptin deficiency. Leptin administration restores fertility and gonadotropin secretion in the ob/ob mouse and can induce recovery of reproductive function in food-restricted animals. This study assessed the effects of EtOH on serum leptin levels, and whether exogenous leptin administration could restore IGF-1 and LH levels in the EtOH-treated animals.. In the first study, 29-day-old female rats were divided into control and EtOH-treated groups, each of which received their respective diet regimen for 5 consecutive days. The EtOH-treated animals were subdivided and received an intraperitoneal injection of either leptin (100 microg/0.1 ml) or saline twice daily. Control animals also received intraperitoneal saline injections twice daily. On day 34, animals were killed, and serum leptin, LH, and IGF-1 were measured by RIA. In a second study we assessed the acute effects of a single 3 g/kg dose of EtOH on the ability of leptin to act centrally to induce LH release. For this, leptin (1 microg) was administered via a third ventricular (3V) cannula and blood sampling via jugular cannula. In a third experiment, animals were again subjected to a chronic feeding regimen. When 34 days old, they were killed and the anterior pituitaries removed and incubated in a static incubation system for 60 min to establish basal LH release, then for an additional 60 min in medium containing leptin (10(-7) M).. Chronic EtOH exposure lowered serum leptin (p < 0.01), IGF-1 (p < 0.01), and LH (p < 0.05) levels. Leptin administration to EtOH-treated animals did not restore serum IGF-1 levels. This peptide did, however, effectively restore LH levels to normal, but did not advance the timing of puberty. Acute EtOH administration was found to block leptin-induced LH release following central administration of the peptide. Conversely, anterior pituitaries from control and 5-day EtOH-treated animals that were incubated in vitro released (p < 0.01) equal amounts of LH in response to leptin (10(-7) M).. These data demonstrate that EtOH administration not only can suppress peripheral levels of leptin, but also blocks its central action to facilitate LH secretion. Although replacement of leptin can reverse the EtOH-induced suppression of LH by a direct action at the level of the pituitary, it cannot elevate serum IGF-1; a peripheral signal that acts centrally to stimulate LH releasing-hormone (LHRH)/LH release during the juvenile-peripubertal transition period, and thus accelerates the initiation of female puberty. These results demonstrate further the complex actions and interactions of multiple hormones involved in the pubertal process and the vulnerability of their actions to the toxic effects of EtOH. Topics: Age Factors; Animals; Body Weight; Central Nervous System Depressants; Ethanol; Female; Insulin-Like Growth Factor I; Leptin; Luteinizing Hormone; Rats; Rats, Sprague-Dawley; Sexual Maturation | 1999 |
Initiation of hyperinsulinemia and hyperleptinemia is diet dependent in C57BL/6 mice.
C57BL/6 female mice were fed high fat diets containing different types of carbohydrate (sucrose or corn starch) and contents of cholesterol (0.03 % or 1 %) to identify early metabolic changes leading to increases in leptin levels and eventual insulin resistance. Under identical dietary fat conditions, type of carbohydrate and cholesterol content contributed to the timing of leptin increases. Mice fed a high-fat, high-sucrose diet showed early (4 weeks) and robust increases in circulating insulin and leptin levels (2-fold and 5-fold, respectively). In contrast, mice fed this diet with added cholesterol or with sucrose substituted by corn starch led to marked delays (8-10 weeks) in the elevations of insulin and leptin, although body weight gains were nearly identical among test diet groups. Thus, sucrose in combination with saturated fat played a specific role in initiating early metabolic changes associated with elevated leptin and insulin levels. Because leptin levels were most reflective of changes in insulin, our data support a role for insulin in determining plasma leptin levels in mice. Topics: Animals; Body Weight; Cholesterol; Cholesterol, Dietary; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Sucrose; Female; Hyperinsulinism; Insulin; Insulin Resistance; Leptin; Lipoproteins; Liver; Mice; Mice, Inbred C57BL; Organ Size; Triglycerides | 1999 |
Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy and haemodilution.
1. The blood glucose-lowering efficacy of rosiglitazone (RSG) and the mechanisms of associated weight gain were determined in dietary obese rats (DIOs). DIO and chow-fed rats received RSG 0.3-30 mg kg-1 daily for 21 days. 2. In DIOs, plasma glucose and insulin concentrations were reduced by RSG at dosages of 3 and 10 mg kg-1, respectively. Homeostasis model assessment (HOMA) indicated the threshold for a reduction of insulin resistance was 1 mg kg-1. Neither glucose nor insulin levels were affected by treatment in chow-fed rats. 3. RSG 0.3 mg kg-1 lowered free fatty acids (FFAs) in DIOs, whereas for plasma triglycerides (TGs), the threshold was 3 mg kg-1. By contrast, the threshold for reducing packed red cell volume (PCV) and increasing cardiac mass was 10 mg kg-1. Thus, the therapeutic index for RSG in DIOs was >3 and < or = 10. 4. Energy intake and weight gain increased in treated DIOs (by 20% and 50 g, at 30 mg kg-1) and chow-fed rats (by 25% and 35 g, at 30 mg kg-1). In DIOs, these increases coincided with falls in plasma leptin (40% lower at 30 mg kg-1) and insulin (43% lower at 30 mg kg-1). By contrast, in chow-fed rats, weight gain and hyperphagia occurred without changes in either leptin or insulin. However, reductions in FFAs below 0.4 - 0.3 mM were associated with hyperphagia and weight gain in DIO and chow-fed rats. 5. We conclude that increased energy intake and body weight did not attenuate the improved metabolism evoked by RSG in DIO rats, and that insulin action was enhanced at a dose >3 fold below the threshold for causing haemodilution and cardiac hypertrophy in DIO rats. Topics: Animals; Body Weight; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Hemodilution; Hemodynamics; Hypoglycemic Agents; Insulin; Leptin; Male; Obesity; Rats; Rats, Wistar; Rosiglitazone; Thiazoles; Thiazolidinediones | 1999 |
Weight relapsers, maintainers, and controls: metabolic and behavioural differences.
The present investigation was undertaken to describe selected factors associated with the maintenance of body weight in three groups of women: relapsers (regained weight after losing weight), maintainers (maintained weight loss), and controls (weight stable). The following physiological variables were also assessed: resting energy expenditure (REE), serum glucose, insulin, leptin, triiodothyronine (T3), and body composition. As well, participants completed the interviewer-administered Weight Maintenance Questionnaire (WMQ). Overall, relapsers were older and heavier than maintainers and controls. As well, BMI, sum-of-four skinfolds, waist and arm circumference, serum leptin, and insulin levels were significantly greater for relapsers than for maintainers and controls. There were no differences between maintainers and controls in any of the parameters measured. Although relapsers revealed a history of weight cycling, the weight loss strategies and exercise habits of maintainers and relapsers did not differ. The data suggest that the higher body mass and fat mass in relapsers may explain the physiological differences between relapsers and maintainers. Topics: Adipose Tissue; Adult; Age Factors; Analysis of Variance; Blood Glucose; Body Composition; Body Constitution; Body Mass Index; Body Weight; Energy Metabolism; Exercise; Female; Health Behavior; Humans; Insulin; Leptin; Skinfold Thickness; Surveys and Questionnaires; Triiodothyronine; Weight Gain; Weight Loss | 1999 |
Epitope mapping of secreted mouse leptin utilizing peripherally administered synthetic peptides.
We have recently reported that intraperitoneal (i.p.) administration of synthetic peptide amides corresponding to amino acids 106-140 of mouse leptin significantly reduced food intake and body weight gain in female C57BL/6J ob/ob mice. These results suggested that leptin activity was localized in domains toward its C-terminus between residues 106-140. In the present study, 14 overlapping peptides encompassing the complete sequence of secreted mouse leptin were synthesized, and their effects on body weight and food intake in female C57BL/6 J ob/ob mice were assessed. When given as seven daily 1-mg i.p. injections, only peptides corresponding to amino acids 106-120, 116-130 and 126-140 caused significant reductions in body weight and food intake. These results confirmed our earlier study and suggest that in contrast to the domain encompassed by amino acids 106-140, the N-terminal of mouse leptin between amino acids 21-105 may not contain functional epitopes that can be utilized as lead compounds in the development of peripherally administered bioactive peptide analogs or nonpeptide mimetics of leptin, which may have potential usefulness in treatment of the energy imbalance associated with obesity. Topics: Amino Acid Sequence; Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Epitope Mapping; Female; Injections, Intraperitoneal; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Sequence Data; Obesity; Peptide Fragments; Protein Structure, Tertiary | 1999 |
The effect of hypoxia on plasma leptin and insulin in newborn and juvenile rats.
Hypoxia leads to a decrease in food intake and attenuated weight gain in rats. The purpose of this study was to measure plasma leptin and insulin in young rats exposed to hypoxia for 7 d as compared to a normoxic control group of the same age. One group was exposed from birth to 7 d of age; the other was exposed from 28 to 35 d of age (weaned at 21 d of age). As expected, body weight was significantly lower in rats of either age exposed to hypoxia for 7 d. Plasma leptin was significantly lower in hypoxic (2.0+/-0.2 ng/mL; n = 41) compared with normoxic (2.6+/-0.3 ng/mL; n = 30) 7-d-old rats. Plasma leptin was also significantly lower in hypoxic (1.1+/-0.1 ng/mL; n = 20) as compared to normoxic (1.5+/-0.1 ng/mL; n = 20) 35-d-old rats. Seven-day-old rats exposed to hypoxia demonstrated significant increases in plasma glucose and insulin whereas 35-d-old rats exhibited a decrease in both variables. We conclude that exposure to hypoxia for 7 d leads to a decrease in body weight and plasma leptin in infant and juvenile rats. The decrease in leptin may be an attempt to reverse hypoxia-induced anorexia. Topics: Aging; Animals; Animals, Newborn; Blood Glucose; Body Weight; Female; Hypoxia; Insulin; Leptin; Pregnancy; Rats; Rats, Sprague-Dawley | 1999 |
Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice.
Recent advances in understanding the neuroendocrine pathways regulating appetite, metabolism and body weight afford an opportunity to explore further the mechanisms by which obesity influences arterial pressure. ob/ob(Lep(ob)/Lep(ob)) mice have a mutation in the ob gene and are leptin-deficient. Leptin possesses pressor actions and has been shown to increase arterial pressure when infused chronically or over-expressed transgenically. In contrast, agouti yellow obese(Ay) mice have overexpression of an agouti peptide that blocks melanocortin receptors. Stimulation of melanocortin receptors by alpha-melanocyte-stimulating hormone decreases arterial pressure.. This study measured arterial pressure in leptin-deficient ob/ob mice, agouti yellow obese mice and their lean controls to test the hypothesis that the effects of obesity on arterial pressure are importantly influenced by the genetic and neuroendocrine mechanisms causing the obesity. We measured arterial pressure directly in conscious ob/ob mice (n = 14), agouti yellow obese mice (n = 6) and the same number of lean littermates.. Body weight was nearly twice as high in ob/ob mice as in their lean controls, but mean arterial pressure was significantly lower in ob/ob mice (92+/-3 mmHg) compared with their lean controls (106+/-2 mmHg; P = 0.00017). In contrast, mean arterial pressure was significantly higher in agouti yellow obese mice (124+/-3 mmHg) than in their lean controls (99+/-1 mmHg; P = 0.000002) despite the fact that the agouti mice had milder obesity.. This study prompts three conclusions: (1) leptin-deficient ob/ob mice and agouti yellow obese mice have contrasting blood pressure responses to obesity, (2) obesity does not invariably increase arterial pressure in mice, and (3) the arterial pressure response to obesity may depend critically on the underlying genetic and neuroendocrine mechanisms. Topics: Animals; Blood Pressure; Body Weight; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Reference Values | 1999 |
Effect of resistance exercise (body building) training on serum leptin levels in young men. Implications for relationship between body mass index and serum leptin.
Available data about the influence of exercise on leptin level are controversial, and there are no studies concerning leptin levels in trained men with low fat mass plus large increase of muscle. 65 healthy young male matched for age were separated in three groups. 1) 25 non-professional body builders; 2) 21 mild overweight sedentary subjects; 3) 19 normal weight sedentary controls. Body composition was determined by bioelectrical impedance. Serum leptin was measured in duplicate by RIA.. Student's t and Pearson's test. Athletes showed similar BMI than overweight subjects: 26.98+/-0.49 vs 27.12+/-0.41 but lower fat mass: 12.53+/-0.96 vs 16.16+/-1.01 % (p=0.0064) and lower leptin: 4.66+/-0.51 vs 7.31+/-0.76 microg/l (p=0.014). Athletes showed higher BMI than controls: 26.98+/-0.49 vs 23.08+/-0.30 (p<0.0001) but similar fat mass: 12.53+/-0.96 vs 12.48+/-0.73% and leptin: 4.66+/-0.51 vs 4.79+0.58 microg/l. Overweight subjects showed higher BMI than controls: 27.12+/-0.41 vs 23.08+/-0.30 (p<0.0001), higher fat mass: 16.16+/-1.01 vs 12.48+/-0.73% (p=0.0064) and higher leptin: 7.31+/-0.76 vs 4.79+/-0.589 microg/l (p=0.014). When leptin was calculated by fat mass no differences were observed between the three groups. There was a significant correlation between leptin and fat mass in all groups. Leptin correlated with BMI in overweight subjects (r=0.438, p=0.0463), but this correlation was not observed either in athletes or in controls. In conclusion 1) regardless of the high BMI characteristic of body builders, no correlation was observed with leptin; 2) trained state induced by resistance exercise does not influence leptin production independently of variations in body composition. Topics: Adipose Tissue; Adult; Body Composition; Body Mass Index; Body Weight; Electric Impedance; Humans; Leptin; Male; Weight Lifting | 1999 |
Leptin changes in normal weight and obese women in pre- and post-menopausal conditions.
Topics: Adolescent; Adult; Aged; Body Mass Index; Body Weight; Child; Female; Humans; Leptin; Middle Aged; Obesity; Postmenopause; Premenopause; Reference Values | 1999 |
Early pubertal development and overweight in girls.
Topics: Adipose Tissue; Basal Metabolism; Body Weight; Child; Energy Intake; Energy Metabolism; Female; Gonadal Steroid Hormones; Humans; Leptin; Obesity; Physical Exertion; Puberty | 1999 |
Interactions among chronic cold, corticosterone and puberty on energy intake and deposition.
We have shown that chronic cold stress strongly interacts with corticosterone (B) to determine subsequent regulation of the hypothalamo-pituitary-adrenal (HPA) axis responses to novel stress. These studies, using the same 2 sets of rats, show that chronic cold also interacts with B and testosterone on signals of energy balance. The two groups of rats differed in weight by 20% and in age by 2 weeks (44-59 days of age). Adrenalectomized rats, replaced with varying doses of B, were exposed to cold or served as controls. Food intake and body weight during the experiments and hormones, metabolites and fat depots were measured on day 5. B, but not cold, affected food intake in the younger rats; by contrast, cold, but not B, affected food intake in the older rats. Testosterone was higher in older control rats and was markedly depressed by cold; younger rats had lower testosterone that was minimally affected by cold. Weight gain decreased in all rats at room temperature with increasing B, whereas they all lost weight in cold independently of B. Cold stimulated and B inhibited interscapular brown adipose tissue DNA content (reflecting sympathetic stimulation of thermogenesis). B stimulated insulin, whereas cold inhibited leptin and insulin; B also increased white adipose tissue weight gain in controls and inhibited its loss in cold. Leptin was unrelated to white adipose tissue depots in older control rats but was strongly related to these stores in younger rats and in all rats in cold. We conclude that: 1. By decreasing signals that act centrally to inhibit food intake (insulin, leptin and testosterone) cold allows B to stimulate food intake; 2. B inhibits weight gain although it causes accrual of fat; 3. Cold, probably through sympathetic stimulation of white adipose tissue, causes fat loss which is modulated by the inhibitory effect of B on sympathetic outflow; and, 4. The slope of the relationship between fat depot size and leptin becomes flatter in cold, possibly because of increased sympathetic outflow to these depots. Topics: Adipose Tissue, Brown; Adrenalectomy; Animals; Blood Glucose; Body Weight; Cold Temperature; Corticosterone; Eating; Energy Metabolism; Glucagon; Hypothalamo-Hypophyseal System; Insulin; Leptin; Male; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Sexual Maturation; Stress, Physiological; Testosterone; Triglycerides | 1999 |
Relation of leptin and tumor necrosis factor alpha to body weight changes in patients with pulmonary tuberculosis.
In this study we investigated whether leptin and TNFalpha levels change with improvement in body weight with antituberculotic therapy in active tuberculosis patients. 30 patients (8 females and 22 males) with active pulmonary tuberculosis formed the patient group, and 25 sex- and age-matched healthy subjects (8 females and 17 males) served as the control group. Body weight, body mass index (BMI) and serum leptin and plasma TNFalpha levels are measured before and in the sixth month of therapy in all patients. Before the initiation of therapy, BMI of the patients was significantly lower than BMI of the controls (20.2 +/- 1.6 vs. 25.2 +/- 2.7 kg/m(2), respectively; p < 0.05). After treatment, BMI of the patients increased significantly to 21.4 +/- 1.9 kg/m(2) (p < 0.05), but was still lower than that of the controls (p < 0.05). Pretreatment serum leptin (4.5 +/- 0.9 vs. 2.1 +/- 0.2 ng/ml, respectively; p < 0.05) and plasma TNFalpha (27.9 +/- 3.4 vs. 23.9 +/- 3.0 pg/ml, respectively; p < 0.05) levels of the patients were significantly higher than those of the controls. After treatment, serum leptin levels increased to 6.7 +/- 2.2 ng/ml, but this rise was not statistically significant (p > 0.05). Treatment did not result in any significant change in TNFalpha levels, either. Delta leptin was highly related to Delta BMI in patients with tuberculosis (r = 0.68, p = 0.02). In the pretreatment period, there was a significant correlation between leptin and TNFalpha levels in the whole patient group (r = 0.78, p < 0.001), and in female (r = 0.74, p < 0.001) and male patients separately (r = 0.74, p = 0.035). In conclusion, leptin and TNFalpha may be responsible for the weight loss in pulmonary tuberculosis patients, but their levels do not change with improvement in body weight with antituberculotic treatment. Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Body Mass Index; Body Weight; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Leptin; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha | 1999 |
The effect of high-fat diet on the development of obesity and serum leptin level in rats.
Ten male Wistar-albino rats were overfed with high-fat diet (margarine at the dose 40 g/kg body weight/day in addition to standard rat diet) during six months from the age of between 8-12 weeks. Ten male rats received a standard chow for the same period. The body weights of the overfed rats increased time dependently (basal 171.5 +/- 5, at sixth month 268 +/- 19 g), whereas those of the rats fed with standard chow did not increase significantly (basal 177 +/- 6.4, at sixth month 220 +/- 10 g). At the sixth month, mean body fat percentages were 36.3 +/- 6.7% and 24.2 +/- 5.4% respectively. Both total cholesterol-triglyceride levels and mean serum leptin levels were also higher than in the overfed rats (p < 0.01 and p < 0.05 respectively). The livers of all rats were histopathologically normal.. High-fat diet resulting in an increased body fat percentage in rats is associated with hyperleptinemia, hypercholesterolemia and hypertriglyceridemia. Topics: Animals; Body Composition; Body Weight; Cholesterol; Dietary Fats; Energy Intake; Leptin; Male; Obesity; Rats; Rats, Wistar; Triglycerides | 1999 |
Obesity and hyperleptinemia in metallothionein (-I and -II) null mice.
Metallothionein (MT) has several putative roles in metal detoxification, in Zn and Cu homeostasis, in scavenging free radicals, and in the acute phase response. Mice of mixed 129/Ola and C57BL/6J background with targeted disruption of MT-I and MT-II genes are more sensitive to toxic metals and oxidative stress. We noted that these animals were larger than most strains of mice, and we systematically studied aspects of their physiology and biochemistry relating to energy metabolism. During the first 2 weeks after weaning, the growth rates of MT-null and C57BL/6J mice were similar, but the transgenic mice became significantly heavier at age 5-6 weeks. At age 14 weeks, the body weight and food intake of MT-null mice was 16 and 30% higher, respectively, compared with C57BL/6J mice. Most 22- to 39-week-old male MT-null mice were obese, as shown by increased fat accretion, elevated obese (ob) gene expression, and high plasma leptin levels, similar to those recorded in Zucker fatty (fa/fa) rats. Seven-week-old MT-null mice also had significantly higher levels of plasma leptin and elevated expression of ob, lipoprotein lipase, and CCAAT enhancer binding protein alpha genes as compared with age-matched C57BL/6J mice. These observations indicate that abnormal accretion of body fat and adipocyte maturation is initiated at 5-7 weeks of age, possibly coincident with sexual maturation. Targeted disruption of MT-I and MT-II genes seems to induce moderate obesity, providing a new obese animal model. A link between MT and the regulation of energy balance is implied. Topics: Adipose Tissue; Animals; Body Weight; CCAAT-Enhancer-Binding Proteins; DNA-Binding Proteins; Eating; Energy Metabolism; Insulin; Leptin; Liver; Liver Glycogen; Male; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins; Obesity; Proteins; Rats; RNA, Messenger; Transcription Factors | 1998 |
A leptin dose-response study in obese (ob/ob) and lean (+/?) mice.
This experiment determined the amount of leptin required to correct different abnormalities in leptin-deficient ob/ob mice. Baseline food intakes and body weights of lean (+/?) and obese (ob/ob) C57B1/6J Topics: Animals; Biogenic Monoamines; Body Temperature; Body Weight; Brain Chemistry; Dose-Response Relationship, Drug; Eating; Female; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Ovary; Proteins | 1998 |
Dysregulation of leptin in response to fasting in insulin-resistant Psammomys obesus (Israeli sand rats).
Leptin is thought to play a significant role in energy balance as an afferent signal to the hypothalamus that reflects body fat content. In addition, leptin may also act as an acute sensor of energy balance independent of body fat mass, since ob gene expression and plasma leptin concentrations are decreased in lean animals and humans in response to short-term caloric deprivation. However, in obese animals and humans, the acute response of leptin to fasting is less clear. We investigated the effects of a 24-hour fast on circulating plasma leptin concentrations in lean and obese Psammomys obesus (Israeli sand rats). In the lean, insulin-sensitive group (n = 25) a 24-hour fast caused a 44% decrease in plasma leptin, whereas in the obese, insulin-resistant group (n = 24) plasma leptin increased by 18% after fasting (P < .003). There was no difference between the two groups regarding the effect of a 24-hour fast on body weight, blood glucose, or plasma insulin. Within the insulin-resistant group, there was no difference in the response of leptin to fasting between hyperglycemic and normoglycemic animals. We conclude that there is a dysregulation of leptin in response to acute caloric deprivation in obese, insulin-resistant but not in lean, insulin-sensitive P obesus. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Fasting; Gerbillinae; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Obesity; Proteins; Rats | 1998 |
Anorectic effects of the cytokine, ciliary neurotropic factor, are mediated by hypothalamic neuropeptide Y: comparison with leptin.
Although ciliary neurotropic factor (CNTF) is a tropic factor in nervous system development and maintenance, peripheral administration of this cytokine also causes severe anorexia and weight loss. The neural mechanism(s) mediating the loss of appetite is not known. As hypothalamic neuropeptide Y (NPY) is a potent orexigenic signal, we tested the hypothesis that CNTF may adversely affect NPYergic signaling in the hypothalamus. Intraperitoneal administration of CNTF (250 microg/kg) daily for 4 days significantly suppressed 24-h food intake in a time-dependent manner and decreased body weight. The loss in body weight was similar to that which occurred in pair-fed (PF) rats. As expected, hypothalamic NPY gene expression, determined by measurement of steady state prepro-NPY messenger RNA by ribonuclease protection assay, significantly increased in PF rats in response to energy imbalance. However, despite a similar loss in body weight, there was no increase in NPY gene expression in CNTF-treated rats. Daily administration of CNTF intracerebroventricularly (0.5 or 5.0 microg/rat) also produced anorexia and body weight loss. In this experiment, negative energy balance produced by both PF and food deprivation augmented hypothalamic NPY gene expression. However, despite reduced intake and loss of body weight, no similar increment in hypothalamic NPY gene expression was observed in CNTF-treated rats. In fact, in rats treated with higher doses of CNTF (5.0 microg/rat), NPY gene expression was reduced below the levels seen in control, freely fed rats. Furthermore, CNTF treatment also markedly decreased NPY-induced feeding. These results suggested that anorexia in CNTF-treated rats may be due to a deficit in NPY supply and possibly in the release and suppression of NPY-induced feeding. The possibility that CNTF-induced anorexia may be caused by increased leptin was next examined. Daily intracerebroventricular injections of leptin (7 microg/rat) decreased food intake, body weight, and hypothalamic NPY gene expression in a manner similar to that seen after CNTF treatment. Leptin administration also suppressed NPY-induced feeding. However, peripheral and central CNTF injections markedly decreased leptin messenger RNA in lipocytes, indicating a deficiency of leptin in these rats; thus, leptin was unlikely to be involved in appetite suppression. Thus, these results show that a two-pronged central action of CNTF, causing diminution in both NPY availability and the NPY-induce Topics: Adipocytes; Animals; Anorexia; Body Weight; Ciliary Neurotrophic Factor; Cytokines; Eating; Gene Expression; Hypothalamus; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Nerve Tissue Proteins; Neuropeptide Y; Proteins; Rats; Rats, Sprague-Dawley | 1998 |
Hyperphagia in cold-exposed rats is accompanied by decreased plasma leptin but unchanged hypothalamic NPY.
Chronic cold exposure stimulates sympathetically driven thermogenesis in brown adipose tissue (BAT), resulting in fat mobilization, weight loss, and compensatory hyperphagia. Hypothalamic neuropeptide Y (NPY) neurons are implicated in stimulating food intake in starvation, but may also suppress sympathetic outflow to BAT. This study investigated whether the NPY neurons drive hyperphagia in rats that have lost weight through cold exposure. Rats exposed to 4 degrees C for 21 days weighed 14% less than controls maintained at 22 degrees C (P < 0.001). Food intake increased after 3 days and remained 10% higher thereafter (P < 0.001). Increase BAT activity was confirmed by 64, 96, and 335% increases in uncoupling protein-1 mRNA at 2, 8, and 21 days. Plasma leptin decreased during prolonged cold exposure. Cold-exposed rats showed no significant changes in NPY concentrations in any hypothalamic regions or in hypothalamic NPY mRNA at any time. We conclude that the NPY neurons are not activated during cold exposure. This is in contrast with starvation-induced hyperphagia, but is biologically appropriate since enhanced NPY release would inhibit thermogenesis causing potentially lethal hypothermia. Other neuronal pathways must therefore mediate hyperphagia in chronic cold exposure. Topics: Acclimatization; Animals; Body Temperature Regulation; Body Weight; Cold Temperature; Feeding Behavior; Hyperphagia; Hypothalamus; Leptin; Male; Neurons; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Transcription, Genetic | 1998 |
Central infusion of melanocortin agonist MTII in rats: assessment of c-Fos expression and taste aversion.
Like leptin (OB protein), central infusion of the nonspecific melanocortin agonist MTII reduces food intake for relatively long periods of time (i.e., 12 h; W. Fan, B. A. Boston, R. A. Kesterson, V. J. Hruby, and R. D. Cone, Nature; 385: 165-168, 1997). To test the hypothesis that MTII may influence ingestive behavior via mechanisms similar to those that mediate the effects of leptin, we infused a single dose of MTII into the third ventricle (i3vt) of Long-Evans rats and examined three dependent measures that have been studied following i3vt infusion of leptin: 1) effects on long-term food intake and body weight (48 h), 2) patterns of c-Fos expression in the brain, and 3) conditioned taste aversion learning. Similar to leptin, MTII reduced 48-h food intake (1.0 nmol dose), reduced body weight at 24 and 48 h (0.1 and 1.0 nmol doses, respectively), and induced c-Fos expression in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala. In contrast to leptin, MTII was found to produce conditioned taste aversions. These results are consistent with the hypothesis that MTII may influence regulatory behavior via mechanisms similar to those that mediate the effects of leptin. Topics: Administration, Oral; alpha-MSH; Amygdala; Animals; Avoidance Learning; Body Weight; Cerebral Ventricles; Feeding Behavior; Infusions, Parenteral; Leptin; Male; Melanocyte-Stimulating Hormones; Obesity; Paraventricular Hypothalamic Nucleus; Proteins; Proto-Oncogene Proteins c-fos; Rats; Saccharin; Taste | 1998 |
A genetic polymorphism of the peroxisome proliferator-activated receptor gamma gene influences plasma leptin levels in obese humans.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor implicated in adipocyte differentiation, lipid and glucose metabolism. A polymorphism corresponding to a silent C-->T substitution was detected in exon 6 of the PPAR gamma gene. We analysed the relationships between this genetic polymorphism and various markers of the obesity phenotype (body weight, body mass index, waist:hip ratio and plasma leptin levels) in a representative sample of 820 men and women living in northern France. The frequencies of the C and T alleles were 0.860 and 0.140 respectively. In the whole sample no association of the polymorphism with the markers tested was observed but a statistically significant interaction ( P < 0.03) existed between this polymorphism and body mass index for plasma leptin levels. This result suggested that the impact of the PPAR gamma gene polymorphism on plasma leptin levels differed according to the BMI of the subjects. Indeed, obese subjects (BMI >30 kg/m2) bearing at least one T allele ( CT + TT ) had higher plasma leptin levels than subjects who did not (35.0 +/- 17.4 ng/ml versus 28.3 +/- 14.8 ng/ml respectively; P < 0.001). This effect existed in both genders, despite the higher plasma leptin levels observed in women. The plasma leptin level increase was not associated with elevation of body mass index, even though these two variables were highly correlated. Thus for a given leptin level the BMI was relatively lower in obese subjects carrying at least one T allele than in obese CC homozygotes. Our results show that in obese subjects variability within the PPAR gamma gene locus is associated with circulating leptin levels and may modify the relationship between leptin levels and adipose tissue mass. Topics: Adult; Age Factors; Alleles; Blood Pressure; Body Mass Index; Body Weight; Exons; Female; France; Humans; Leptin; Male; Middle Aged; Nuclear Proteins; Obesity; Patient Selection; Phenotype; Point Mutation; Polymorphism, Genetic; Proteins; Receptors, Cytoplasmic and Nuclear; Reference Values; Regression Analysis; Transcription Factors | 1998 |
Defense of differing body weight set points in diet-induced obese and resistant rats.
Among outbred Sprague-Dawley rats, approximately one-half develop diet-induced obesity (DIO) and one-half are diet resistant (DR) on a diet relatively high in fat and energy content (HE diet). Here we examined the defense of body weight in these two phenotypes. After HE diet for 13 wk, followed by chow for 6 wk, DR rats gained weight comparably but their plasma leptin levels fell to 54% of chow-fed controls. When a palatable liquid diet (Ensure) was added for 13 wk, other DR rats became obese. But when switched to chow, their intakes fell by 60%, and body and retroperitoneal (RP) fat pad weights and plasma leptin and insulin levels all declined for 2 wk and then stabilized at control levels after 6 wk. In contrast, comparably obese DIO rats decreased their intake by only 20%, and their weights plateaued when they were switched to chow after 13 wk on HE diet. When a subgroup of these DIO rats was restricted to 60% of prior intake, their weights fell to chow-fed control levels over 2 wk. But their leptin and insulin levels both fell disproportionately to 30% of controls. When no longer restricted, their intake and feed efficiency rose immediately, and their body and RP pad weights and leptin and insulin levels rose to those of unrestricted DIO rats within 2 wk. Thus diet and genetic background interact to establish high (DIO) or low (DR) body weight set points, which are then defended against subsequent changes in diet composition and/or energy availability. If leptin affects energy homeostasis, it does so differentially in DIO vs. DR rats since comparably low and high levels were associated with differing patterns of weight change between the two phenotypes. Topics: Animals; Body Weight; Diet; Dietary Fats; Energy Intake; Leptin; Male; Obesity; Proteins; Rats; Rats, Sprague-Dawley; Weight Gain; Weight Loss | 1998 |
Serum leptin levels increase rapidly after initiation of clozapine therapy.
Weight gain is a major side-effect of treatment with clozapine. In order to investigate the influence of the atypical neuroleptic clozapine on leptin secretion, serum leptin levels were measured in 12 patients at baseline and for a 10-week period after initiation of treatment. Serum clozapine levels and levels of its metabolites were simultaneously assessed. Alterations of body weight and body composition were determined. During the 10-week observation period leptin levels differed significantly from the levels determined at baseline (P < 0.0001). During the first 2 weeks of treatment serum leptin levels at least doubled in eight of the 12 patients. The maximal relative increase over baseline was 536%. Low doses of clozapine were sufficient to induce this effect. Within a 10-week period mean body weight, mean body mass index, mean fat mass and mean lean body mass all increased. Based on the results we suggest that in predisposed individuals clozapine induces an increased appetite; overeating and weight gain can ensue, which in turn underlie elevated leptin secretion. Topics: Adipose Tissue; Antipsychotic Agents; Body Composition; Body Mass Index; Body Weight; Clozapine; Humans; Leptin; Proteins; Schizophrenia; Time Factors; Weight Gain | 1998 |
Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats.
Troglitazone (CS-045) is one of the thiazolidinediones that activate the peroxisome proliferator-activated receptor gamma (PPARgamma), which is expressed primarily in adipose tissues. To elucidate the mechanism by which troglitazone relieves insulin resistance in vivo, we studied its effects on the white adipose tissues of an obese animal model (obese Zucker rat). Administration of troglitazone for 15 d normalized mild hyperglycemia and marked hyperinsulinemia in these rats. Plasma triglyceride level was decreased by troglitazone in both obese and lean rats. Troglitazone did not change the total weight of white adipose tissues but increased the number of small adipocytes (< 2,500 micron2) approximately fourfold in both retroperitoneal and subcutaneous adipose tissues of obese rats. It also decreased the number of large adipocytes (> 5,000 micron2) by approximately 50%. In fact, the percentage of apoptotic nuclei was approximately 2.5-fold higher in the troglitazone-treated retroperitoneal white adipose tissue than control. Concomitantly, troglitazone normalized the expression levels of TNF-alpha which were elevated by 2- and 1.4-fold in the retroperitoneal and mesenteric white adipose tissues of the obese rats, respectively. Troglitazone also caused a dramatic decrease in the expression levels of leptin, which were increased by 4-10-fold in the white adipose tissues of obese rats. These results suggest that the primary action of troglitazone may be to increase the number of small adipocytes in white adipose tissues, presumably via PPARgamma. The increased number of small adipocytes and the decreased number of large adipocytes in white adipose tissues of troglitazone-treated obese rats appear to be an important mechanism by which increased expression levels of TNF-alpha and higher levels of plasma lipids are normalized, leading to alleviation of insulin resistance. Topics: Adipocytes; Adipose Tissue; Animals; Apoptosis; Blood Glucose; Blotting, Northern; Body Weight; Chromans; DNA; DNA, Complementary; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Mesentery; Polymerase Chain Reaction; Proteins; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear; Retroperitoneal Space; RNA; RNA, Messenger; Thiazoles; Thiazolidinediones; Transcription Factors; Triglycerides; Troglitazone; Tumor Necrosis Factor-alpha | 1998 |
Leptin selectively increases energy expenditure of food-restricted lean mice.
To find out whether leptin can attenuate hypometabolic torpor-like states of metabolic rate (MR) in adult lean animals, as it attenuates the morning suppression of thermoregulatory thermogenesis in suckling-age rat pups.. Leptin effects on MR and food intake were studied in mice aged 4-7 months, in which a high incidence of exaggerated circadian reductions of MR had been induced by chronic food-restriction and, for comparison, in free-feeding mice.. Continuous recordings of MR, for a group of seven mice maintained at an ambient temperature of 24 degrees C, while they were repeatedly-with pauses of at least six days-treated for three consecutive days with either recombinant murine leptin (20, 200 or 600 pmol x g(-1) x d[-1]) or saline.. Leptin treatment caused dose-dependent 5-15% increases in energy expenditure by moderating the decreases in MR during the circadian minima, without affecting either the MR during the circadian maxima or food intake. Similar treatment of free-feeding mice caused dose-dependent decreases of food intake without changing MR.. Leptin controls thermoregulatory energy expenditure when food supplies are scarce and changes food intake, rather than energy expenditure, when food is abundant. Topics: Animal Nutritional Physiological Phenomena; Animals; Body Weight; Circadian Rhythm; Cohort Studies; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Female; Food Deprivation; Injections, Subcutaneous; Leptin; Mice; Mice, Inbred BALB C; Oxygen Consumption; Proteins; Random Allocation; Recombinant Proteins; Time Factors | 1998 |
Efficient secretion of biologically active recombinant OB protein (leptin) in Escherichia coli, purification from the periplasm and characterization.
The genes encoding the mature forms of mouse (mOB) and human OB (hOB) protein (also called leptin) were fused to the secretion signal coding sequence of the Escherichia coli outer membrane protein A (sOMP A). The hybrid genes were preceded by a ribosome binding site (RBS) and were expressed under transcriptional control of both the lipoprotein promoter (Plpp) and the lac promoter-operator (POlac). The recombinant fusion proteins were efficiently expressed and exported into the periplasmic compartment of E. coli cells from where they were recovered by osmotic shock as soluble mature polypeptides with the sOMP A precisely removed. Recombinant mOB and hOB proteins were also produced in Sf9 insect cells using the baculovirus expression system. Milligram quantities of both proteins were purified to homogeneity using ion-exchange, hydrophobic interaction chromatography and gel filtration and were found to be biologically active and to have antiobesity effects upon testing in genetically obese ob/ob mice. Topics: Animals; Body Weight; Cell Line; Chromatography, Gel; Chromatography, Ion Exchange; Chromatography, Liquid; Disease Models, Animal; Eating; Electrophoresis, Polyacrylamide Gel; Escherichia coli; Female; Humans; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Mice; Mice, Obese; Obesity; Periplasm; Proteins; Recombinant Proteins; Spodoptera | 1998 |
Increased plasma leptin levels are associated with fat accumulation in Japanese Americans.
Although the hormone leptin seems to play a role in ensuring the maintenance of adequate energy stores and thereby protects against starvation, its role in the regulation of body weight and adiposity under normal circumstances is unclear. Overweight individuals have markedly elevated circulating leptin levels, suggesting that leptin's effect on food intake and thermogenesis is diminished or absent in obesity. Recent evidence, though, indicates that weight gain in Pima Indians is associated with relatively decreased levels of the hormone. Because it is important to understand whether a deficiency in circulating leptin contributes to the development of obesity, we sought to determine whether there is a relationship between leptin levels and subsequent changes in adiposity in a more typical population. We compared baseline plasma leptin concentrations to changes over 5 years in body weight, BMI, and computed tomography-determined total fat in 492 second- and third-generation Japanese Americans. Subjects were of 100% Japanese ancestry; male subjects had a mean BMI at baseline of 25.4 kg/m2 and a mean age of 54 years; female subjects had a mean BMI of 23.1 kg/m2 and a mean age of 53 years. Changes in weight (men: r = 0.17, P < 0.05; women: r = 0.20, P < 0.05), BMI (men: r = 0.17, P < 0.05; women: r = 0.18, P < 0.05), and total fat (men: r = 0.19, P < 0.05; women: r = 0.20, P < 0.01) were positively correlated with baseline leptin levels adjusted for baseline adiposity, fasting insulin, and age. In Japanese Americans, then, relatively increased leptin levels are associated with greater subsequent gains in weight and adiposity. We concluded that in this population, fat accumulation is associated not with leptin deficiency but possibly with leptin resistance and is preceded by increased leptin levels. Topics: Adipose Tissue; Aging; Asian; Body Composition; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Insulin; Japan; Leptin; Male; Middle Aged; Proteins; United States | 1998 |
Effects of leptin on corticotropin-releasing factor (CRF) synthesis and CRF neuron activation in the paraventricular hypothalamic nucleus of obese (ob/ob) mice.
The effects of leptin on the levels of CRF messenger RNA (mRNA) in the paraventricular hypothalamic nucleus (PVN), on the activation of the PVN CRF cells, and on the plasma levels of corticosterone were investigated in lean (+/?) and obese (ob/ob) C57BL/6J male mice. Murine leptin was s.c. infused using osmotic minipumps. The treatment period extended to 7 days, and the daily dose of leptin delivered was 100 microg/kg. The mice were killed either in a fed state or following 24 h of total food deprivation. The starvation paradigm was employed to enhance the activity of the hypothalamic-pituitary-adrenal axis in obese mice. In situ hybridization histochemistry was performed to determine the PVN levels of CRF mRNA and the arcuate nucleus levels of neuropeptide Y mRNA. The activity of the PVN CRF cells was estimated from the number of PVN cells colocalizing CRF mRNA and the protein Fos. Leptin led to a reduction in body weight gain and fat deposition. These effects were seen in both +/? and ob/ob mice and were observed to be particularly striking in obese mutants, in which leptin also caused an important reduction in food intake. Leptin also was found to affect plasma levels of corticosterone. It lowered the high corticosterone levels of obese mutants, an effect that appeared more evident in food-deprived than in fed mice. Finally, leptin prevented the induction of CRF synthesis in the PVN and the activation of the PVN CRF neurons observed in food-deprived ob/ob mice and hindered the elevation of arcuate nucleus neuropeptide Y synthesis in ob/ob mice. Together these results suggest a role for leptin in the excessive response of the hypophysiotropic CRF system of the ob/ob mouse. Topics: Adipose Tissue; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Eating; Gene Expression; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neurons; Neuropeptide Y; Obesity; Organ Size; Paraventricular Hypothalamic Nucleus; Proteins; RNA, Messenger | 1998 |
Chronic effects of a nonpeptide corticotropin-releasing hormone type I receptor antagonist on pituitary-adrenal function, body weight, and metabolic regulation.
CRH, the principal regulator of the hypothalamic-pituitary-adrenal axis and modulator of autonomic nervous system activity, also participates in the regulation of appetite and energy expenditure. Antalarmin, a pyrrolopyrimidine compound, antagonizes CRH type 1 receptor-mediated effects of CRH, including pituitary ACTH release, stress behaviors, and acute inflammation. We administered antalarmin chronically to evaluate its effects on hypothalamic-pituitary-adrenal axis function and metabolic status. Adult male rats were treated twice daily with 20 mg/kg of i.p. antalarmin or placebo over 11 days. The animals were weighed; plasma ACTH, corticosterone, leptin, and blood glucose levels were determined; and morphometric analyses were performed to determine adrenal size and structure, including sizing, histochemistry, immunohistochemistry, and electron microscopy. Leptin messenger RNA expression in peripheral fat was analyzed by Northern blot. Antalarmin decreased plasma ACTH (mean +/- SD, 2.62 +/- 0.063 pg/ml) and corticosterone concentrations (10.21 +/- 1.80 microg/dl) compared with those in vehicle-treated rats [respectively, 5.3 +/- 2.0 (P < 0.05) and 57.02 +/- 8.86 (P < 0.01)]. Antalarmin had no significant effect on body weight, plasma leptin, or blood glucose concentrations or fat cell leptin messenger RNA levels. The width of the adrenal cortex of animals treated with antalarmin was reduced by 31% compared with that in controls without atrophy of the gland. On the ultrastructural level, adrenocortical cells were in a hypofunctional state characterized by reduced vascularization, increased content of lipid droplets, and tubulovesicular mitochondria with fewer inner membranes. The apoptotic rate was increased in the outer zona fasciculata of animals treated with the antagonist (26.6 +/- 3.58%) compared with that in placebo-treated controls (6.8 +/- 0.91%). We conclude that chronic administration of antalarmin does not affect body weight, carbohydrate metabolism, or leptin expression, whereas it reduces adrenocortical function mildly, without anatomical, clinical, or biochemical evidence of causing adrenal atrophy. These results are promising for future uses of such an antagonist in the clinic. Topics: Adipose Tissue; Adrenal Glands; Adrenocorticotropic Hormone; Animals; Apoptosis; Blotting, Northern; Body Weight; Corticosterone; Leptin; Male; Metabolism; Microscopy, Electron; Pituitary Gland; Proteins; Pyrimidines; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; RNA, Messenger | 1998 |
Plasma leptin concentrations in newborns of diabetic and nondiabetic mothers.
Leptin plays an important role in regulating body composition through modulation of appetite and energy expenditure. We hypothesized that leptin levels in umbilical cord blood correlate with newborn body weight and habitus. We also hypothesized that infants of diabetic mothers would demonstrate altered leptin metabolism. Venous blood was sampled at birth from the umbilical cords of 105 infants (74 infants of nondiabetic mothers, and 31 infants of diabetic mothers). Thirty-nine mothers had plasma leptin concentrations measured. Analysis was done using Student's t-test, Pearson's correlation, and Spearman's correlation. Univariate/multivariate regression was used for analysis of factors associated with leptin concentration in umbilical cord plasma. Maternal and newborn characteristics were correlated with log leptin levels in umbilical venous plasma. Leptin concentration in umbilical cord plasma correlated best with birth weight for newborns of both nondiabetic and diabetic mothers (p < 0.01 for either). Umbilical cord plasma concentration of leptin was higher in infants of diabetic mothers than in infants of nondiabetic mothers (2.53 +/- 1.09 vs. 1.76 +/- 0.82; p < 0.001). Multiple regression analysis revealed a significant (p < 0.01) relationship between umbilical cord leptin level and newborn birth weight, as well as maternal DM, but not with gestational age. Similarly, there was no significant correlation with maternal plasma leptin concentration. The strong correlation of leptin concentration in umbilical cord plasma with newborn birth weight, and the lack of significant correlation with maternal leptin plasma levels, suggest that normal fetal leptin metabolism reflects fetal size and/or body habitus independent of maternal leptin metabolism. On the other hand, the higher umbilical plasma levels in infants of diabetic mothers may reflect an influence of altered fetal insulin homeostasis on fetal leptin metabolism, and suggests that maternal diabetes may influence fetal leptin metabolism. Topics: Adolescent; Adult; Body Weight; Cohort Studies; Female; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Leptin; Linear Models; Male; Pregnancy; Pregnancy in Diabetics; Proteins; Reference Values | 1998 |
Acute and chronic effects of leptin on glucose utilization in lean mice.
Experiments described here show that in vivo glucose uptake is impaired in mice given 30 micrograms leptin by intraperitoneal injection 2 hours before an oral glucose tolerance test (GTT). When mice were infused for 7 days with 10 micrograms/day leptin, the 4-fold increase in circulating leptin caused a transient hypophagia, a sustained weight loss and significantly inhibited insulin release in response to an oral GTT. Adipocytes from these mice were not insulin responsive whereas insulin-stimulated muscle and liver glycogen synthesis were increased. In contrast, leptin added to 2 hour in vitro incubations had an insulin-like effect on muscle glucose utilization and augmented insulin stimulation of adipocyte lipid synthesis. Thus, normal mice treated chronically with leptin develop tissue specific changes in insulin sensitivity and compensate for inhibition of glucose-stimulated insulin release. The contrasting response to acute leptin exposure suggests these changes are not a direct effect of the protein. Topics: Adipocytes; Animals; Blood Glucose; Body Weight; Eating; Female; Glucose; Glucose Tolerance Test; Glycogen; Insulin; Leptin; Liver; Mice; Mice, Inbred Strains; Muscles; Organ Size; Proteins | 1998 |
Temperature-dependent feeding: lack of role for leptin and defect in brown adipose tissue-ablated obese mice.
The objective was to characterize the ability of control and transgenic brown adipose tissue (BAT)-ablated uncoupling protein diphtheria toxin A chain (UCP-DTA) mice to adjust food intake in relation to changes in environmental temperature and to assess the involvement of leptin in this adjustment. We measured serum leptin in mice from a previous study of UCP-DTA mice raised at thermoneutrality (35 degrees C) or at the usual rearing temperature (24 degrees C) from weaning [Melnyk, A., M. -E. Harper, and J. Himms-Hagen. Am. J. Physiol, 272 (Regulatory Integrative Comp. Physiol. 41): R1088-R1093, 1997] and extended the study by acclimating control and obese UCP-DTA mice at 18 wk of age to cold (14 degrees C) for up to 14 days. Leptin levels did not change in control mice at 14 degrees C; however, food intake increased threefold within 1 day and remained at this level. Serum leptin level was elevated in UCP-DTA mice at 24 degrees C compared with control mice at 24 degrees C; this elevated level decreased within 1 day at 14 degrees C and was not different from the level in control mice by 14 days. Food intake of UCP-DTA mice that were hyperphagic at 24 degrees C did not change during 7 days at 14 degrees C, then increased slowly. Similar low leptin levels were present in control mice raised at 24 or 35 degrees C and in UCP-DTA mice raised at 35 degrees C. Food intake of control mice raised at 24 degrees C was two times that of control mice raised at 35 degrees C. UCP-DTA mice raised at 35 degrees C ate the same low amount as control mice raised at 35 degrees C. UCP-DTA mice at 24 degrees C were hyperphagic relative to control mice at 24 degrees C yet had elevated leptin levels in their serum. Two principal conclusions are drawn. First, adjustment of food intake over a fourfold range by control mice acclimated to temperatures from 35 down to 14 degrees C is independent of changes in serum leptin levels. Second, this adjustment of food intake in relation to temperature is defective in the UCP-DTA mouse; the defect leads to hyperphagia at 24 degrees C and a failure to increase food intake as rapidly as control mice when exposed to 14 degrees C. Because lack of UCP-1-mediated thermogenesis in BAT of knockout mice is known not to induce hyperphagia, we propose that deficiency of UCP-1-expressing brown adipocytes in BAT of UCP-DTA mice results in lack of a satiety factor, secreted by these cells in BAT of control mice in inverse relationship to sympathetic nervous Topics: Adipose Tissue, Brown; Animals; Body Weight; Eating; Feeding Behavior; Female; Leptin; Mice; Mice, Inbred Strains; Obesity; Osmolar Concentration; Proteins; Temperature | 1998 |
Plasma leptin in diabetic and insulin-treated diabetic and normal rats.
Adipose tissue leptin mRNA levels are decreased by food deprivation or induction of insulin-deficient diabetes. To determine whether plasma leptin concentrations are similarly affected, whether treatment of diabetes with insulin restores plasma leptin, and whether this requires restoration of body weight (lost as a result of diabetes) and/or normalization of glycemia, we measured plasma leptin concentrations in control, untreated streptozotocin (STZ)-diabetic, and insulin-treated STZ-diabetic rats. Plasma leptin was markedly reduced in untreated STZ-diabetic rats. Insulin treatment for 4 to 17 days increased plasma leptin approximately twofold above control levels. However, despite the hyperleptinemia, insulin-treated diabetic rats gained weight at a rate equal to that of sham-treated controls. Epididymal adipose tissue leptin mRNA levels in 17-day insulin-treated diabetic rats were equal to but did not exceed sham-control levels, unlike plasma leptin. Plasma glucose concentrations in insulin-treated STZ-diabetic rats were lower than in sham controls. Therefore, to determine whether hypoglycemia may be important in increasing plasma leptin, we measured plasma leptin levels in diabetic rats infused with insulin for 3 hours along with a variable-rate glucose infusion targeting glycemia to 200 or 40 mg/100 mL. Plasma leptin rapidly increased in these rats irrespective of target glycemia. Plasma leptin also increased rapidly in normal rats infused with insulin and glucose (target glycemia, 200 mg/100 mL). We conclude that plasma leptin concentrations are markedly reduced under conditions of insulin deficiency and rapidly increased by insulin treatment. The increase in plasma leptin does not require restoration of body weight and, under glucose clamp conditions, does not depend on target glycemia. Hyperleptinemia in insulin-treated diabetic rats is not explained on the basis of steady-state leptin mRNA levels, at least as reflected in epididymal fat. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Experimental; Epididymis; Glucose; Hypoglycemic Agents; Insulin; Leptin; Male; Obesity; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Streptozocin | 1998 |
Increase in plasma leptin and Lep mRNA concentrations by food intake is dependent on insulin.
Obese (Lep) gene expression and leptin secretion are regulated by changes in food intake. However, the mechanism by which leptin concentrations are altered by fasting and feeding is unclear. Since these changes occur in parallel with changes in plasma insulin, it is possible that the changes observed are mediated by insulin. To test this hypothesis, we studied the role of insulin in the regulation of Lep gene expression in epididymal fat and leptin secretion during feeding. As shown previously, fasted animals showed significant reductions in Lep mRNA, plasma leptin, and plasma insulin concentrations. Conversely, feeding increased plasma insulin, Lep mRNA, and plasma leptin. In streptozotocin (STZ)-treated animals, plasma insulin concentrations were low. This was associated with low Lep mRNA and plasma leptin concentrations. Changes in food intake, whether fasting or feeding, did not significantly alter plasma insulin levels in STZ-treated animals. Under these circumstances, Lep mRNA and plasma leptin concentrations also remained low. Our results demonstrate that the decrease in Lep mRNA and plasma leptin during fasting and the increase with feeding are dependent on changes in the plasma insulin concentration. Topics: Animal Feed; Animals; Anti-Bacterial Agents; Blood Glucose; Body Weight; Data Interpretation, Statistical; Energy Intake; Food; Gene Expression; Insulin; Leptin; Male; Obesity; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Streptozocin | 1998 |
Leptin secretion from subcutaneous and visceral adipose tissue in women.
Upper body obesity is a risk factor for type 2 diabetes. Little is known about the regulation of body fat distribution, but leptin may be involved. This study examined the secretion of leptin in subcutaneous and omental fat tissue in 15 obese and 8 nonobese women. Leptin secretion rates were two to three times higher in subcutaneous than in omental fat tissue in both obese and nonobese women (P < 0.0001 and P < 0.001, respectively). There was a positive correlation between BMI and leptin secretion rates in both subcutaneous (r = 0.87, P < 0.0001) and omental (r = 0.74, P < 0.0001) fat tissue. Furthermore, leptin secretion rates in subcutaneous and omental fat tissue correlated well with serum leptin levels (r = 0.84, P < 0.0001 and r = 0.73, P = 0.001, respectively), although in multivariate analysis, the subcutaneous leptin secretion rate was the major regressor for serum leptin (F = 42). Subcutaneous fat cells were approximately 50% larger than omental fat cells, and there was a positive correlation between fat cell size and leptin secretion rate in both fat depots (r = 0.8, P < 0.01). Leptin (but not gamma-actin) mRNA levels were twofold higher in subcutaneous than in omental fat tissue (P < 0.05). Thus the subcutaneous fat depot is the major source of leptin in women owing to the combination of a mass effect (subcutaneous fat being the major depot) and a higher secretion rate in the subcutaneous than in the visceral region, which in turn could be due to increased cell size and leptin gene expression. Topics: Adipose Tissue; Adult; Body Mass Index; Body Weight; Female; Humans; Kinetics; Leptin; Middle Aged; Obesity; Omentum; Polymerase Chain Reaction; Protein Biosynthesis; Proteins; Reference Values; Regression Analysis; RNA, Messenger; Skin; Viscera | 1998 |
A new paradigm for type 2 diabetes mellitus: could it be a disease of the foregut?
We previously reported, in a study of 608 patients, that the gastric bypass operation (GB) controls type 2 diabetes mellitus in the morbidly obese patient more effectively than any medical therapy. Further, we showed for the first time that it was possible to reduce the mortality from diabetes; GB reduced the chance of dying from 4.5% per year to 1% per year. This control of diabetes has been ascribed to the weight loss induced by the operation. These studies, in weight-stable women, were designed to determine whether weight loss was really the important factor.. Fasting plasma insulin, fasting plasma glucose, minimal model-derived insulin sensitivity and leptin levels were measured in carefully matched cohorts: six women who had undergone GB and had been stable at their lowered weight 24 to 30 months after surgery versus a control group of six women who did not undergo surgery and were similarly weight-stable. The two groups were matched in age, percentage of fat, body mass index, waist circumference, and aerobic capacity.. Even though the two groups of patients were closely matched in weight, age, percentage of fat, and even aerobic capacity, and with both groups maintaining stable weights, the surgical group demonstrated significantly lower levels of serum leptin, fasting plasma insulin, and fasting plasma glucose compared to the control group. Similarly, minimal model-derived insulin sensitivity was significantly higher in the surgical group. Finally, self-reported food intake was significantly lower in the surgical group.. Weight loss is not the reason why GB controls diabetes mellitus. Instead, bypassing the foregut and reducing food intake produce the profound long-term alterations in glucose metabolism and insulin action. These findings suggest that our current paradigms of type 2 diabetes mellitus deserve review. The critical lesion may lie in abnormal signals from the gut. Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glycated Hemoglobin; Humans; Insulin; Leptin; Obesity, Morbid; Proteins | 1998 |
Leptin produces anorexia and weight loss without inducing an acute phase response or protein wasting.
The ob gene product leptin is known to produce anorexia and loss of body fat when chronically administered to both lean and genetically obese mice. The current study was undertaken to examine whether administration of recombinant leptin in quantities sufficient to produce decreases in food intake and body weight and alterations in body composition would elicit either an hepatic acute phase protein response or preferential loss of carcass lean tissue. Mice were administered increasing quantities of recombinant human leptin or human tumor necrosis factor-alpha as a positive control. Although leptin (at 10 mg/kg body wt) produced significant anorexia and weight loss (both P < 0.05), human leptin administration did not appear to induce an hepatic acute phase protein response in either lean or genetically obese mice, as determined by protein synthetic rates in the liver or changes in the plasma concentration of the murine acute phase protein reactants, amyloid A, amyloid P, or seromucoid (alpha1-acid glycoprotein). In addition, human leptin administration did not induce a loss of fat-free dry mass (protein) in lean or obese animals. The findings suggest that at doses adequate to alter food intake and body weight leptin is not a significant inducer of the hepatic acute phase response nor does leptin promote the preferential loss of somatic protein characteristic of a chronic inflammatory process. Topics: Acute-Phase Reaction; Animals; Anorexia; Body Weight; Cachexia; Female; Humans; Leptin; Mice; Mice, Inbred C57BL; Proteins; Time Factors | 1998 |
Mechanisms contributing to angiotensin II regulation of body weight.
Previous studies in our laboratory have implicated adipose tissue as a potential site for local angiotensin II (ANG II) synthesis. However, functions of ANG II in adipose tissue and the impact of ANG II on body weight regulation are not well defined. To study the effect of ANG II on body weight, a chronic ANG II infusion model was used. In study 1, a low dose of ANG II (175 ng.kg-1.min-1) was infused into rats for 14 days. Plasma ANG II levels were not elevated after 14 days of infusion. ANG II-infused rats did not gain weight over the 14-day protocol and exhibited a lower body weight than controls on day 8. Food intake was not altered, but water intake was increased in ANG II-infused rats. Blood pressure gradually increased to significantly elevated levels by day 14. Thermal infrared imaging demonstrated an increase in abdominal surface temperature. Measurement of organ mass demonstrated site-specific reductions in white adipose tissue mass after ANG II infusion. In study 2, the dose-response relationship for ANG II infusion (200, 350, and 500 ng.kg-1.min-1) was determined. Body weight (decrease), blood pressure (increase), white adipose mass (decrease), plasma ANG II levels (increase), and plasma leptin levels (decrease) were altered in a dose-related manner after ANG II infusion. In study 3, the effect of ANG II infusion (350 ng.kg-1.min-1) was examined in rats treated with the vasodilator hydralazine. Hydralazine treatment normalized blood pressure in ANG II-infused rats. The effect of ANG II to decrease body weight was augmented in hydralazine-treated rats. These results demonstrate that low levels of ANG II infusion regulate body weight through mechanisms related to increased peripheral metabolism and independent of elevations in blood pressure. Topics: Adipose Tissue; Angiotensin II; Animals; Blood Pressure; Body Temperature; Body Weight; Dose-Response Relationship, Drug; Drinking; Hydralazine; Leptin; Male; Organ Size; Proteins; Rats; Rats, Sprague-Dawley; Vasodilator Agents | 1998 |
Marked and rapid decreases of circulating leptin in streptozotocin diabetic rats: reversal by insulin.
Evidence for regulation of circulating leptin by insulin is conflicting. Diabetes was induced in rats with streptozotocin (STZ; 40 mg.kg(-1).day(-1) x 2 days) to examine the effect of insulin-deficient diabetes and insulin treatment on circulating leptin. After 12 wk, plasma leptin concentrations in untreated rats were all < 0.4 ng/ml versus 4.9 +/- 0.9 ng/ml in control animals (P < 0.005). In rats treated with subcutaneous insulin implants for 12 wk, which reduced hyperglycemia by approximately 50%, plasma leptin was 2.1 +/- 0.6 ng/ml, whereas leptin concentrations were 6.0 +/- 1.6 ng/ml in insulin-implanted rats receiving supplemental injections of insulin for 4 days to normalize plasma glucose (P < 0.005 vs. STZ untreated). In a second experiment, plasma leptin was monitored at biweekly intervals during 12 wk of diabetes. In rats treated with insulin implants, plasma leptin concentrations were inversely proportional to glycemia (r = -0.64; P < 0.0001) and unrelated to body weight (P = 0.40). In a third experiment, plasma leptin concentrations were examined very early after the induction of diabetes. Within 24 h after STZ injection, plasma insulin decreased from 480 +/- 30 to 130 +/- 10 pM (P < 0.0001), plasma glucose increased from 7.0 +/- 0.2 to 24.8 +/- 0.5 mM, and plasma leptin decreased from 3.2 +/- 0.2 to 1.2 +/- 0.1 ng/ml (delta = -63 +/- 3%, P < 0.0001). In a subset of diabetic rats treated with insulin for 2 days, glucose decreased to 11.7 +/- 3.9 mM and leptin increased from 0.5 +/- 0.1 to 2.9 +/- 0.6 ng/ml (P < 0.01) without an effect on epididymal fat weight. The change of leptin was correlated with the degree of glucose lowering (r = 0.75, P < 0.05). Thus insulin-deficient diabetes produces rapid and sustained decreases of leptin that are not solely dependent on weight loss, whereas insulin treatment reverses the hypoleptinemia. We hypothesize that decreased glucose transport into adipose tissue may contribute to decreased leptin production in insulin-deficient diabetes. Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Eating; Hypoglycemic Agents; Insulin; Leptin; Male; Proteins; Rats; Rats, Sprague-Dawley; Streptozocin | 1998 |
Evidence that dark-phase hyperphagia induced by neurotoxin 6-hydroxydopamine may be due to decreased leptin and increased neuropeptide Y signaling.
Hyperphagia and obesity can be experimentally induced in rodents by microinjection of 6-hydroxydopamine (6-OHDA) into the ventral noradrenergic bundle (VNAB) to interrupt efferent catecholaminergic pathways to the hypothalamus. Since hypothalamic neuropeptide Y (NPY) is implicated in the control of ingestive behavior, we evaluated hypothalamic NPY activity in this model of obesity. Adult male rats injected bilaterally with 12 microg of 6-OHDA in the VNAB displayed an enhanced rate of body weight gain and selective dark-phase hyperphagia that started at about 10 days postinjection and persisted for the entire duration of the experiment. NPY gene expression, assessed by ribonuclease protection assay, was significantly higher in the hypothalami of 6-OHDA-treated hyperphagic rats during the dark phase (p < 0.01 vs. levels during the light phase and in control, vehicle-injected rats). We also evaluated gene expression of NPY Y and Y5 receptors, receptor subtypes reported to mediate NPY-induced feeding. The dark-phase increase in NPY mRNA was accompanied by the concomitant upregulation of NPY Y5R gene expression, but not of Y1R mRNA levels. Leptin, the peripheral hormone secreted by adipocytes, is believed to maintain body weight and inhibit food intake, most likely by suppressing hypothalamic NPY activity. Evaluation of leptin gene expression in the epididymal fat revealed that the upregulation of leptin mRNA noted during the dark phase in control rats did not occur in 6-OHDA-treated rats. These observations implied that the normal restraint on NPY and feeding exercised by leptin in control rats may be abrogated in 6-OHDA-treated hyperphagic rats due to insufficient levels of leptin. If so, administration of leptin should inhibit food intake in these rats. Indeed, injection of leptin (2 mg/kg, intraperitoneally (i.p.)) on 2 consecutive days reduced 24-h food intake by 25% and significantly reduced body weight. These results suggest that the nocturnal hyperphagia and resultant obesity induced by 6-OHDA injected into the VNAB may be attributed to leptin deficiency concomitant with increased hypothalamic NPY. Topics: Adrenergic Agents; Animals; Body Weight; Circadian Rhythm; Eating; Efferent Pathways; Gene Expression Regulation; Hypothalamus; Leptin; Male; Microinjections; Neuropeptide Y; Neurotoxins; Norepinephrine; Oxidopamine; Proteins; Rats; Rats, Sprague-Dawley; Signal Transduction | 1998 |
Role of the Y5 neuropeptide Y receptor in feeding and obesity.
Neuropeptide Y (NPY), a 36-amino-acid neuromodulator abundantly expressed in the brain, has been implicated in the regulation of food intake and body weight. Pharmacological data suggest that NPY's stimulatory effect on appetite is transduced by the G-protein-coupled NPY Y5 receptor (Y5R). We have inactivated the Y5R gene in mice and report that younger Y5R-null mice feed and grow normally; however, they develop mild late-onset obesity characterized by increased body weight, food intake and adiposity. Fasting-induced refeeding is unchanged in younger Y5R-null mice and they exhibit normal sensitivity to leptin. Their response to intracerebroventricular (i.c.v.) administration of NPY and related peptides is either reduced or absent. NPY deficiency attenuates the obesity syndrome of mice deficient for leptin (ob/ob), but these effects are not mediated by NPY signaling through the Y5R because Y5R-null ob/ob mice are equally obese. These results demonstrate that the Y5R contributes to feeding induced by centrally administered NPY and its analogs, but is not a critical physiological feeding receptor in mice. Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Feeding Behavior; Female; Genotype; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Mutant Strains; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Neuropeptide Y; Obesity; Pancreatic Polypeptide; Peptide YY; Peptides, Cyclic; Phenotype; Proteins; Receptors, Neuropeptide Y; RNA, Messenger; Time Factors | 1998 |
Serum leptin levels and energy expenditure in normal weight women.
To investigate whether circulating leptin levels are associated with energy expenditure in healthy humans, doubly labeled water energy measurements and food intake assessment were carried out in 27 women (mean age, 48.6 years; weight, 61.9 kg; body mass index, 23.2). Energy expenditure was determined over 13 days. Food intake was measured by 7-day food records. Leptin was measured by radioimmunoassay. Leptin level was strongly associated with percentage body fat (r = 0.59; p < 0.001), fat mass (r = 0.60; p < 0.001), and body mass index (r = 0.41; p = 0.03), but no correlation was observed with energy expenditure (r = 0.02; p = 0.93). After controlling for percentage body fat, a positive association of leptin level with energy expenditure of marginal significance (p = 0.06) was observed. There were no significant univariate associations of age, physical activity, lean body mass, height, or dietary variables with leptin level. When controlling for body fat, a significant positive correlation was observed for percent energy from carbohydrate and negative correlations with dietary fat and alcohol intake. These findings confirm previous associations between leptin and body fat content and suggest a relationship between serum leptin and energy expenditure level in healthy humans. Topics: Body Weight; Diet; Energy Metabolism; Female; Humans; Leptin; Middle Aged; Proteins; Reference Values | 1998 |
Chronic central leptin infusion enhances insulin-stimulated glucose metabolism and favors the expression of uncoupling proteins.
Continuous (4 days) intracerebroventricular leptin infusion (12 microg/day) was performed in lean rats, and its hormonometabolic effects were determined. Intracerebroventricular leptin administration did not result in leakage of the hormone into the peripheral circulation. Thus, its effects were elicited by its presence within the central nervous system. Intracerebroventricular leptin infusion produced marked decreases in food intake and body weight gain relative to vehicle-infused fed ad libitum rats. Because decreases in food intake alter hormonometabolic homeostasis, additional control rats pair-fed to the amount of food consumed by leptin-infused ones were included in the study. Intracerebroventricular leptin-infused and vehicle-infused pair-fed rats were characterized, relative to vehicle-infused ad libitum-fed animals, by decreases in body weight and insulinemia and by increases in insulin-stimulated overall glucose utilization and muscle and brown adipose tissue glucose utilization index. Brown adipose tissue uncoupling protein (UCP)1, UCP2, and UCP3 mRNA levels were markedly decreased in pair-fed animals relative to those of fed ad libitum control animals, as were liver and white adipose tissue UCP2 and muscle UCP3 mRNA levels. In marked contrast, intracerebroventricular leptin administration was accompanied by the maintenance of high UCP1, UCP2, and UCP3 expression in all these tissues. Thus, despite analogies between leptin's effects and those of pair-feeding with regard to glucose handling, their respective underlying mechanisms differ. While leptin maintains or favors energy-dissipating mechanisms (UCP1, UCP2, and UCP3), the latter are markedly depressed in pair-fed rats. This effect of leptin may prevent subsequent excessive storage processes, thereby maintaining normal body homeostasis. Topics: Adipose Tissue, Brown; Animals; Blood Glucose; Body Weight; Brain; Carrier Proteins; Eating; Gene Expression; Glucose; Glucose Clamp Technique; Insulin; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mitochondrial Proteins; Muscles; Proteins; Rats; Rats, Zucker; RNA, Messenger; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3 | 1998 |
The influence of ovariectomy on ob gene expression in rats.
Ovarian steroid hormones exert major influences on eating behaviour and body weight regulation of female rats. Ovariectomy (OVX) results in an increase in food intake and a concomitant increase in body weight, while estradiol (E2) replacement reverses these effects. In this study, we examined the influence of OVX on obese (ob) gene expression in rat adipose tissues and serum leptin concentration. Female Wistar rats, 10 weeks old, were divided into three groups: sham-operated control rats receiving corn oil (group 1, n = 4), ovariectomized rats receiving corn oil (group 2, n = 5), and ovariectomized rats receiving 17beta-E2 (10 microg/kg/day) replacement (group 3, n = 4). After 4 weeks, the rats and food consumption were weighed and serum E2 and leptin levels were measured by radioimmunoassays. Furthermore, the expression levels of ob mRNA obtained from the bilateral perimetric fat pads were estimated by Northern blot analysis. The mean weight and food consumption in group 2 were significantly (p < 0.01) heavier than those in group 1. But there were no significant differences between group 1 and group 3. The expression levels of ob mRNA in group 2 were lower than those in group 1, however, the levels of group 3 were restored to the level of group 1. On the other hand, no significant differences among the 3 groups as to serum levels of leptin were observed. The data herein clearly indicate that ovarian steroid hormones may be one of the factors involved in the regulation of ob gene. Topics: Adipose Tissue; Animals; Body Weight; Eating; Estradiol; Female; Gene Expression; Leptin; Obesity; Ovariectomy; Proteins; Rats; Rats, Wistar; RNA, Messenger | 1998 |
Serum leptin and body weight in females with anorexia and bulimia nervosa.
In this study we hypothesized that there is a correlation between serum leptin levels and body mass indices within patients with anorexia nervosa or bulimia nervosa during a twelve weeks' course of in-patient treatment. We evaluated leptin levels weekly in female in-patients with anorexia (n = 17) or bulimia nervosa (n = 18). Only patients with anorexia nervosa were therapeutically encouraged to gain weight throughout the treatment episode. For the whole cohort, body mass indices and serum leptin levels were highly correlated upon admission (r = 0.89, p < 0.001). The median intra-individual correlation in the anorexia group was higher than in the bulimia group (0.63 and 0.39, respectively). The intra-individual correlations were higher in those anorexia nervosa patients who showed increments of their body mass index within the observation span. This dynamic aspect is important specifically in patients with anorexia nervosa during therapeutically induced weight gain. Topics: Adolescent; Adult; Anorexia; Body Mass Index; Body Weight; Bulimia; Female; Humans; Leptin; Proteins | 1998 |
Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake.
Leptin is a protein encoded by the ob gene and expressed in adipocytes. A sensitive marker of nutritional status, leptin is known to correlate with fat mass and to respond to changes in caloric intake. Leptin may also be an important mediator of reproductive function, as suggested by the effects of leptin infusions to restore ovulatory function in an animal model of starvation. We hypothesized that leptin levels are decreased in women with hypothalamic amenorrhea and that leptin may be a sensitive marker of overall nutritional status in this population. We, therefore, measured leptin levels and caloric intake in 21 women with hypothalamic amenorrhea (HA) and 30 age-, weight-, and body fat-matched eumenorrheic controls. Age (24 +/- 5 vs. 24 +/- 3 yr), body mass index (20.6 +/- 1.3 vs. 21.1 +/- 1.5 kg/m2), percent ideal body weight (94.9 +/- 5% vs. 96.3 +/- 6.3%), and fat mass (14.2 +/- 3.6 vs. 15.5 +/- 2.9 kg, determined by dual energy x-ray absortiometry) did not differ between the groups. Leptin levels were significantly lower in the HA subjects compared with those in the controls (7.1 +/- 3.0 vs. 10.6 +/- 4.9 micrograms/L; P = 0.005). Total caloric intake (1768 +/- 335 vs. 2215 +/- 571 cal/day; P = 0.003), fat intake (333 +/- 144 vs. 639 +/- 261 cal/day; P < 0.0001), and insulin levels (5.6 +/- 1.2 vs. 7.4 +/- 3.2 microU/mL; P = 0.015) were lower in the women with HA than in the eumenorrheic controls. The difference in leptin levels remained significant after controlling for insulin (P = 0.023). These data are the first to demonstrate hypoleptinemia, independent of fat mass, in women with HA. The hypoleptinemia may reflect inadequate calorie intake, fat intake, and/or other subclinical nutritional disturbances in women with HA. The mechanism and reproductive consequences of low leptin in this large population of women remain unknown. Topics: Adult; Amenorrhea; Body Composition; Body Weight; Case-Control Studies; Female; Humans; Hypothalamic Diseases; Leptin; Nutritional Status; Obesity; Ovulation; Proteins; Regression Analysis | 1998 |
Effect of a high-fat diet on food intake and hypothalamic neuropeptide gene expression in streptozotocin diabetes.
Insulin-deficient diabetic rats are markedly hyperphagic when fed a high-carbohydrate (HC) diet, but normophagic when fed a high-fat (HF) diet. When maintained on a HC diet, diabetic rats also exhibit increased gene expression of the orexigenic peptide neuropeptide Y (NPY) in the hypothalamic arcuate nucleus, and reduced expression of the anorectic peptide corticotropin-releasing hormone (CRH) in the paraventricular nucleus, and these changes are hypothesized to contribute to diabetic hyperphagia. In this experiment we assessed whether the normophagia displayed by HF-fed diabetic rats is associated with the opposite profile of NPY and CRH expression. Our results show that relative to diabetic rats on the HC diet, the diabetic rats on the HF diet exhibited significantly reduced caloric intake (-40%), NPY expression in the arcuate nucleus (-27%), and elevated CRH expression in the paraventricular nucleus (+37%). Insulin and corticosterone, which are known to affect hypothalamic NPY and CRH expression, were not different between these two groups, making it unlikely that they can account for the differences in either feeding behavior or hypothalamic peptide expression. There was a small but significant increase in plasma leptin levels in the diabetic animals maintained on the HF, and large differences in parameters associated with elevated fat oxidation. These observations support the hypothesis that the normalization of food intake observed in diabetic rats consuming a HF diet may in part be mediated by reductions in NPY expression and elevations in CRH expression. Topics: Animals; Blood Glucose; Body Weight; Corticotropin-Releasing Hormone; Diabetes Mellitus, Experimental; Dietary Fats; Eating; Fatty Acids; Gene Expression; Hypothalamus; Insulin; Leptin; Male; Neuropeptide Y; Proteins; Rats; Streptozocin | 1998 |
Role of neuropeptide Y in diet-, chemical- and genetic-induced obesity of mice.
The goal of this study was to ascertain whether neuropeptide Y (NPY) is required in mice for the development of obesity induced by a high-fat diet (HFD), chemical lesions of the hypothalamus caused by monosodium glutamate (MSG) or gold thioglucose (GTG), impaired brown adipose tissue (BAT) due to a diphtheria toxin transgene driven by the uncoupling protein 1 promoter (UCP-DTA) or the lethal yellow agouti mutation (Ay).. The obesity syndrome of the leptin-deficient (ob/ob) mouse can be partially reversed by the genetic removal of NPY. In the murine models of obesity examined in this study, the animals become obese despite increased serum leptin levels, indicating that they are resistant to the weight-limiting actions of leptin. The role of NPY in these obesity models with elevated leptin levels is unknown.. Mice lacking NPY due to genetic disruption of the gene and wildtype littermates were made obese by allowing them access to a highly palatable HFD, by treatment with MSG, or GTG, or by inheriting the dominant UCP-DTA or Ay alleles. Food consumption, body weight and dissectable fat pad weights were measured and compared to values obtained from non-obese littermates.. In each model of obesity tested, NPY-deficient mice achieved the same food intake, body weight and fat content as wildtype littermates.. NPY is not necessary for the progressive development of obesity exhibited by multiple murine models with leptin resistance. Topics: Adipose Tissue, Brown; Agouti Signaling Protein; Animals; Aurothioglucose; Body Composition; Body Weight; Carrier Proteins; Diet; Diphtheria Toxin; Eating; Female; Hypothalamus; Intercellular Signaling Peptides and Proteins; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondrial Proteins; Mutation; Neuropeptide Y; Obesity; Proteins; Sodium Glutamate; Uncoupling Protein 1 | 1998 |
Plasma leptin in relation to regional body fat in older New Zealand women.
Leptin is the protein product of the obesity (ob) gene and is produced in adipose tissue. Plasma leptin values are highly correlated with total body fat mass but less is known concerning relationships of leptin with regional adiposity.. To investigate associations between leptin and dual energy X-ray absorptiometry (DEXA) measures of regional body fat deposition in older New Zealand women.. Body composition was measured in 80 women aged 40 to 79 years (20 in each decade) using DEXA. Height and weight were measured by conventional anthropometry. Plasma leptin concentrations were assayed by radioimmunoassay.. Leptin was strongly correlated (p < 0.001) with weight (r = 0.751), body mass index (r = 0.782), total fat mass (r = 0.854) and % fat mass (r = 0.813). A statistical model with trunk fat (kg) and leg fat (kg) as the independent variables showed that trunk fat accounted for 72.1% of the variance in plasma leptin with leg fat explaining only a further 1.6% of the variance. No relationships were found between leptin and age, height, lean tissue mass or menopausal status (p > 0.05).. We conclude that trunk fat explains more of the variance in circulating leptin concentrations than leg fat, suggesting that the propensity to leptin resistance may be increased in women with higher central adiposity. Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Aged; Aging; Body Composition; Body Weight; Energy Metabolism; Female; Humans; Leptin; Middle Aged; New Zealand; Proteins; Reference Values | 1998 |
Lactation suppresses diurnal rhythm of serum leptin.
Rats consume most of their daily food intake at night; serum leptin levels and adipose tissue leptin mRNA content are elevated at night in non-lactating rats fed ad libitum. Lactation induces massive hyperphagia with most food still consumed at night, but the nocturnal increase in leptin secretion was not observed in lactating rats. Thus the link between nocturnal food intake and increased serum leptin is broken during lactation and the hypoleptinaemia may be an important factor promoting the hyperphagia of lactation. Topics: Adipocytes; Analysis of Variance; Animals; Blood Glucose; Body Weight; Circadian Rhythm; Darkness; Fatty Acids; Fatty Acids, Nonesterified; Female; Insulin; Lactation; Leptin; Light; Proteins; Rats; Rats, Wistar; RNA, Messenger | 1998 |
Satiety effect and sympathetic activation of leptin are mediated by hypothalamic melanocortin system.
Leptin is an adipocyte-derived blood-borne satiety factor that decreases food intake and increases energy expenditure, thereby leading to a substantial decrease in body weight. To explore the possible roles of the hypothalamic melanocortin system in leptin action, we examined the effects of intracerebroventricular (i.c.v.) injection of leptin with or without SHU9119, a potent antagonist of alpha-melanocyte stimulating hormone, on food intake, body weight, and mitochondrial uncoupling protein-1 (UCP-1) mRNA expression in the brown adipose tissue (BAT) in rats. A single i.c.v. injection of leptin decreased cumulative food intake and body weight gain, and increased UCP-1 mRNA expression during 3 h at the onset of the dark phase. Inhibition of food intake and body weight change with leptin was reversed by co-injection of SHU9119 in a dose-dependent manner. Co-injection of SHU9119 also inhibited completely the leptin-induced increase in UCP-1 mRNA expression in the BAT. Treatment with SHU9119 alone did not affect food intake, body weight, and UCP-1 mRNA expression in rats. The present study provides evidence that the hypothalamic melanocortin system plays a central role in both satiety effect and sympathetic activation of leptin. Topics: Adipose Tissue, Brown; alpha-MSH; Animals; Blotting, Northern; Body Weight; Carrier Proteins; Dose-Response Relationship, Drug; Eating; Hypothalamus; Injections, Intraventricular; Ion Channels; Leptin; Male; Melanocyte-Stimulating Hormones; Membrane Proteins; Mitochondrial Proteins; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin; Recombinant Proteins; RNA, Messenger; Satiety Response; Uncoupling Protein 1 | 1998 |
Effect of leptin on energy balance does not require the presence of intact adrenals.
The present study was conducted to assess the effects of leptin on food intake and energy balance in the presence or absence of corticosterone. Three cohorts of C57BL/6 mice differing in their corticosterone status [nonadrenalectomized (intact), adrenalectomized (ADX), and ADX with corticosterone replacement] were infused with either saline or leptin at a dose of 150 microg . kg-1 . day-1. Throughout the study, mice had free access to both a high-starch and a high-fat diet. At the end of the experimental period, mice were decapitated and their carcasses were processed for the determination of energy, protein, and lipid contents. Leptin significantly reduced body gains in weight, fat, and energy, whereas corticosterone therapy significantly promoted all of these gains. Leptin and ADX significantly reduced food intake and gross energetic efficiency, whereas corticosterone therapy significantly increased these variables. The effects of leptin, ADX, and corticosterone on food intake were accounted for by changes in the intake of the high-fat diet. Leptin also attenuated the preference for fat that developed quickly in mice simultaneously exposed to the high-starch and high-fat regimen. Altogether, the results of this study 1) emphasize the abilities of leptin and corticosterone to, respectively, decrease and increase energy deposition and ingestion of fat, 2) do not substantiate any leptin-corticosterone interaction in the regulation of energy balance, and 3) demonstrate that leptin can produce its effect on energy and fat gains in the absence of an intact hypothalamic-pituitary-adrenal axis. Topics: Adipose Tissue; Adrenal Glands; Adrenalectomy; Analysis of Variance; Animals; Blood Glucose; Body Weight; Corticosterone; Energy Metabolism; Infusions, Intravenous; Leptin; Male; Mice; Mice, Inbred C57BL; Proteins; Recombinant Proteins; Regression Analysis; Weight Gain | 1998 |
Chronic administration of OB protein decreases food intake by selectively reducing meal size in male rats.
The potent hypophagic effect of OB protein (OB) is well established, but the mechanism of this effect is largely unknown. We investigated the effects of chronic administration of a novel modified recombinant human OB (Mod-OB) with a prolonged half-life (>48 h) on ad libitum food intake, spontaneous meal patterns, and body weight in 24 adult, male Sprague-Dawley rats (body weight at study onset: 292 g). Single daily subcutaneous injections of Mod-OB (4 mg/kg daily) for 8 consecutive days significantly reduced ad libitum food intake compared with vehicle injections from injection day 3 through postinjection day 3. Mod-OB-injected rats ate between 4.5 and 7.1 g (or 13-20%) per day less than controls, with the reduction primarily occurring during the dark period. Body weight gain was significantly decreased in response to Mod-OB from injection day 8 until postinjection day 4, with a maximum difference of 24 g on postinjection day 3. The reduction of food intake by Mod-OB was mainly due to a 21-34% decrease in nocturnal spontaneous meal size. There was no significant effect of Mod-OB on nocturnal meal frequency or duration. Mod-OB also did not reliably affect the size, duration, or frequency of diurnal meals. Mod-OB-injected rats displayed no compensatory hyperphagia after the injection period. These results indicate that chronically administered OB selectively affects the mechanisms controlling meal size in male rats. Topics: Animals; Appetite; Body Weight; Drug Administration Schedule; Energy Intake; Humans; Injections, Subcutaneous; Leptin; Male; Obesity; Proteins; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Time Factors | 1998 |
Chronic administration of OB protein decreases food intake by selectively reducing meal size in female rats.
The mechanisms by which OB protein controls food intake and energy balance are unknown. Therefore, we investigated the effects of a novel modified human recombinant OB protein (Mod-OB) on spontaneous feeding patterns, body weight, running wheel activity, and ovarian cycling in female rats. Mod-OB or vehicle was injected (4 mg . kg-1 . day-1 sc) for 2 ovarian cycles (8 days) using a within-subjects design. Observations were continued for five ovarian cycles after injections; treatments were then reversed. Mod-OB reduced food intake approximately 20% from injection day 1 to postinjection day 2. Body weight was reduced from injection day 3 to postinjection day 15 (maximum decrease, 25 +/- 4 g, postinjection days 3 and 4). Food intake was reduced due to decreases in nocturnal meal size, which appeared to be superimposed on the normal pattern of spontaneous feeding (i.e., reductions in meal size at estrus). Mod-OB did not significantly affect diurnal food intake or meal patterns, failed to alter wheel running, and did not disrupt the rats' ovarian cycles. We conclude that chronically administered Mod-OB reduces food intake in female rats by selectively affecting the mechanisms controlling meal size. Topics: Analysis of Variance; Animals; Body Weight; Circadian Rhythm; Drinking Behavior; Drug Administration Schedule; Energy Intake; Estrus; Feeding Behavior; Female; Humans; Injections, Subcutaneous; Leptin; Obesity; Proteins; Rats; Recombinant Proteins | 1998 |
Serum leptin is suppressed by growth hormone therapy in growth hormone-deficient children.
Leptin is a hormone which is exclusively synthesized and secreted by adipocytes. As of yet, little is known about the complex interplay of hormones in the modulation of circulating leptin levels. To investigate the effect of growth hormone (GH) therapy on leptin, leptin serum concentrations were measured by a specific radioimmunoassay in 29 children with GH deficiency (21 boys, 8 girls; age range 3-14 years) before and after 1, 3 and 6 months of treatment with recombinant human GH. At baseline, serum leptin levels were identical to those of healthy children. Serum leptin correlated with body mass index (BMI; r=0.60, p < 0.001) and weight (r=0.48, p=0.004), but not with height, age, insulinlike growth factor 1, or insulinlike growth factor-binding protein 3, and there was no sex difference (p > 0.05). After 1 month of treatment, the leptin levels had decreased to 73+/-(SEM) 13% of individual pretreatment levels (p=0.002) and remained constant thereafter. While the correlation between leptin, BMI, and weight persisted throughout the study period, the changes in leptin concentrations during treatment were not associated with changes in BMI, weight, height, insulinlike growth factor 1, and insulinlike growth factor binding protein 3. In conclusion, this preliminary study demonstrates that serum leptin decreases during GH treatment in children with GH deficiency. Topics: Adolescent; Body Mass Index; Body Weight; Child; Child, Preschool; Female; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Proteins | 1998 |
Cold exposure regulates the renin-angiotensin system.
The effect of cold exposure on the systemic renin-angiotensin system and on regulation of the angiotensin II (Ang II) receptor was examined in target organs for Ang II with cardiovascular relevance (left ventricle, kidney, lung) and metabolic relevance [interscapular brown adipose tissue (ISBAT), liver] to the functional consequences of cold exposure. In time course studies, the effects were examined of 4 hr or 1, 3 and 7 days of exposure to cold (4 degrees C) on plasma Ang II concentration and Ang II receptor binding characteristics in rat liver. Plasma Ang II concentration increased 10-fold after 4 hr of cold exposure, returned to control levels at days 1 and 3 of cold exposure, and was again increased (2-fold) at 7 days of cold exposure. The affinity of [125I]Sar1, Ile8-Ang II binding in membranes prepared from rat liver was not altered in cold-exposed rats. The density (Bmax) of binding sites in liver from cold-exposed rats was increased by day 1 and remained elevated over time-matched controls. Alterations in Ang II receptor density did not parallel plasma Ang II concentration in their time course, suggesting that cold-induced regulation of the Ang II receptor was not substrate mediated. In rats from the 7-day time point of cold exposure, Ang II receptor binding characteristics were examined in ISBAT and lung. Increases in Ang II receptor density were evident in ISBAT but not lung. To determine whether cold-induced increases in food intake contributed to elevations in plasma Ang II concentration and/or Ang II receptor density, a group of cold-exposed rats (7 days) were pair-fed to food intake levels of control rats. Pair-feeding of cold-exposed rats eliminated increases in plasma Ang II and norepinephrine concentration but did not prevent increases in Ang II receptor density in liver, ISBAT, kidney and left ventricle. Moreover, increases in Ang II receptor density were augmented in kidney and left ventricle from cold-exposed rats that were pair-fed. Results from these studies demonstrate that cold exposure resulted in an increase in plasma Ang II concentration through mechanisms related to increased food intake. Elevations in food intake in cold-exposed rats contributed to tissue-specific increases in Ang II receptor density. Moreover, cold-induced increases in Ang II receptor density were not related to plasma Ang II concentration. Topics: Adipose Tissue; Angiotensin I; Angiotensin II; Animals; Body Weight; Cold Temperature; Drinking; Eating; Iodine Radioisotopes; Leptin; Liver; Male; Norepinephrine; Proteins; Radioligand Assay; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Time Factors | 1998 |
Arcuate nucleus ablation prevents fasting-induced suppression of ProTRH mRNA in the hypothalamic paraventricular nucleus.
Fasting results in reduced thyroid hormone levels and inappropriately low or normal thyroid-stimulating hormone (TSH), partly attributed to central hypothyroidism due to suppression of pro TRH gene expression in the hypothalamic paraventricular nucleus. Recently, we demonstrated that the systemic administration of leptin to fasting animals restores plasma thyroxine (T4) and proTRH mRNA in the paraventricular nucleus to normal, suggesting that the fall in circulating leptin levels during fasting acts as a signal to hypophysiotropic neurons in the paraventricular nucleus to reset the set point for feedback regulation of pro TRH mRNA by thyroid hormone. To determine whether the effect of fasting on the hypothalamic-pituitary-thyroid axis is mediated through the hypothalamic arcuate nucleus where leptin receptors are highly concentrated, we studied the effect of fasting and exogenous leptin administration on plasma thyroid hormone levels and proTRH mRNA concentration in the paraventricular nucleus in adult animals with arcuate nucleus lesions induced pharmacologically by the neonatal administration of monosodium L-glutamate (MSG). In normal animals, fasting reduced plasma T4 and TSH levels and the concentration of proTRH mRNA in the hypothalamic paraventricular nucleus. In contrast, neither fasting nor leptin administration to fasting MSG-treated animals had any significant effects on plasma thyroid hormone and TSH levels and proTRH mRNA in the paraventricular nucleus. These studies suggest that during fasting, the arcuate nucleus is essential for the normal homeostatic response of the hypothalamic-pituitary-thyroid axis and may serve as a critical locus to mediate the central actions of leptin on proTRH gene expression in the paraventricular nucleus. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Weight; Corticosterone; Fasting; Gene Expression; Hypothalamo-Hypophyseal System; In Situ Hybridization; Leptin; Male; Paraventricular Hypothalamic Nucleus; Protein Precursors; Proteins; Pyrrolidonecarboxylic Acid; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroid Gland; Thyrotropin-Releasing Hormone | 1998 |
Resistance to adenovirally induced hyperleptinemia in rats. Comparison of ventromedial hypothalamic lesions and mutated leptin receptors.
Leptin regulates appetite and body weight via hypothalamic targets, but it can act directly on cultured pancreatic islets to regulate their fat metabolism. To obtain in vivo evidence that leptin may act peripherally as well as centrally, we compared the effect of adenovirally induced hyperleptinemia on food intake, body weight, and islet fat content in ventromedial hypothalamic-lesioned (VMHL) rats, sham-lesioned (SL) controls, and Zucker Diabetic Fatty (ZDF) rats in which the leptin receptor is mutated. Infusion with recombinant adenovirus containing the rat leptin cDNA increased plasma leptin by approximately 20 ng/ml in VMHL and ZDF rats but had no effect on their food intake, body weight, or fat tissue weight. Caloric matching of hyperphagic VMHL rats to SL controls did not reduce their resistance to hyperleptinemia. Whereas prediabetic ZDF rats had a fourfold elevation in islet fat, in VMHL rats islet fat was normal and none of them became diabetic. Isolated islets from ZDF rats were completely resistant to the lipopenic action of leptin, while VMHL islets exhibited 50% of the normal response; caloric matching of VMHL rats to SL controls increased leptin responsiveness of their islets to 92% of controls. We conclude that leptin regulation of adipocyte fat requires an intact VMH but that islet fat content is regulated independently of the VMH. Topics: Adenoviridae; Animals; Body Weight; Diet; Drug Resistance; Eating; Energy Intake; Gene Transfer Techniques; Hyperphagia; Insulin; Leptin; Lipids; Male; Muscle, Skeletal; Obesity; Proteins; Rats; Rats, Sprague-Dawley; Rats, Zucker; Recombinant Proteins; Ventromedial Hypothalamic Nucleus | 1998 |
Serum leptin in obese women with polycystic ovary syndrome is correlated with body weight and fat distribution but not with androgen and insulin levels.
Leptin is a hormone produced in the adipose tissue and its concentrations in peripheral blood are significantly correlated with the amount of body fat. Whether other factors, including the pattern of body fat distribution and several hormones (such as insulin, sex steroids, and glucocorticoids), may be involved in the regulation of circulating blood leptin levels is controversial. Women with the polycystic ovary syndrome (PCOS) are hyperandrogenic and most of them are characterized by hyperinsulinemia, insulin resistance, and obesity, particularly the visceral phenotype. To assess the potential contribution of anthropometric factors, androgens, and insulin in determining leptin levels, we examined their relationship with body-mass index (BMI), visceral (VAT) and subcutaneous (SAT) adipose tissue areas, basal androgen levels, and fasting and glucose-stimulated (AUC) insulin in different groups of obese women with PCOS (n = 23) and of age-matched obese (n = 16) and non-obese (n = 10) otherwise healthy controls. The VAT/SAT ratio was measured as a parameter of body fat distribution. Serum leptin levels were significantly higher in obese PCOS women than in obese and normal-weight healthy controls and, within the controls, in the obese than in the non-obese group. In all women considered together, and in each group separately, leptin concentrations were highly significantly correlated with BMI. In addition, after adjusting for BMI, both VAT and the VAT/SAT ratio were positively and significantly correlated with leptin. Partial correlations with the VAT/SAT ratio remained significant in both the obese PCOS group and in controls considered separately, whereas the correlation with the SAT value was significant only in the control group. After adjusting for BMI, no correlation between leptin, androgens and fasting or stimulated (like AUC) insulin was found. These findings indicate that leptin levels in obese women with PCOS are higher than those observed in obese and non-obese controls. Moreover, they suggest that, other than BMI, the pattern of body fat distribution may be an independent factor related to circulating leptin levels, which, on the contrary, do not appear to be related to either androgen or insulin concentrations. Topics: Adipose Tissue; Adult; Androgens; Blood Glucose; Body Constitution; Body Weight; Case-Control Studies; Female; Gonadal Steroid Hormones; Humans; Insulin; Leptin; Obesity; Polycystic Ovary Syndrome; Proteins | 1998 |
Failure of human and mouse leptin to affect insulin, glucagon and somatostatin secretion by the perfused rat pancreas at physiological glucose concentration.
In isolated perfused pancreas from normal rats, a rise in d-glucose concentration from 3.3 to 8.3 mM provoked a rapid phasic stimulation of both insulin and somatostatin secretion and rapid fall in glucagon output, these changes being reversed when the concentration of the hexose was brought back to its initial low level. In the presence of 8.3 mM d-glucose, the administration of either human or mouse leptin (10 nM in both cases) for 15 min failed to affect significantly the perfusion pressure and release of the three hormones. It is concluded that leptin does not exert any major immediate and direct effect upon pancreatic insulin, glucagon and somatostatin secretion, at least at the physiological concentration of d-glucose normally found in the plasma of fed rats. Topics: Animals; Blood Glucose; Body Weight; Female; Glucagon; Glucose; Humans; Insulin; Insulin Secretion; Leptin; Mice; Organ Size; Pancreas; Perfusion; Pressure; Proteins; Radioimmunoassay; Rats; Rats, Wistar; Somatostatin | 1998 |
Leptin is a potent stimulator of spontaneous pulsatile growth hormone (GH) secretion and the GH response to GH-releasing hormone.
Pulsatile GH secretion is exquisitely sensitive to perturbations in nutritional status, but the underlying mechanisms are largely unknown. Leptin, a recently discovered adipose cell hormone, is thought to be a sensor of energy stores and to regulate body mass, appetite, and metabolism at the level of the brain. Receptors for leptin are abundantly expressed in hypothalamic nuclei known to be involved in GH regulation, suggesting that leptin may serve as an important hormonal signal to the GH neuroendocrine axis in normal animals. To test this hypothesis, we examined the effects of intracerebroventricular infusion of recombinant murine leptin, at a dose of 1.2 microg/day for 7 days, on both spontaneous and GH-releasing hormone (GHRH)-stimulated GH secretion in free-moving adult male rats. Concomitant with suppressive effects on food intake, body weight, and basal plasma insulin-like growth factor I, insulin, and glucose concentrations, central infusion of leptin resulted in a 2- to 3-fold augmentation of GH pulse amplitude, 5-fold higher GH nadir levels, and a 2- to 3-fold increase in the integrated area under the 6-h GH response curve compared with those in vehicle-infused controls (P < 0.001). The intracerebroventricular infusion of leptin also produced a 3- to 4-fold increase in GHRH-induced GH release at GH trough times (P < 0.01). These studies demonstrate a potent stimulatory action of leptin on both spontaneous pulsatile GH secretion and the GH response to GHRH. The results suggest that the GH-releasing activity of leptin is mediated, at least in part, by an inhibition of hypothalamic somatostatin release. Thus, leptin may be a critical hormonal signal of nutritional status in the neuroendocrine regulation of pulsatile GH secretion. Topics: Animals; Body Weight; Eating; Growth Hormone; Growth Hormone-Releasing Hormone; Injections, Intraventricular; Leptin; Male; Proteins; Pulsatile Flow; Rats; Rats, Sprague-Dawley | 1998 |
Correlation between circulating leptin and luteinizing hormone during the menstrual cycle in normal-weight women.
Leptin is the hormonal product of the ob gene. It is expressed in adipocytes and participates in the regulation of food intake and metabolism. Since leptin also seems to signal metabolic information to the reproductive system, we studied the association between reproductive hormones and plasma leptin in normal-weight young women.. Eight young women with normal menstrual cycles (body mass index (BMI) 21.2 +/- 1.6 kg/m2) and eight young women using hormonal contraception (BMI 21.4 +/- 1.1 kg/m2) were studied. Furthermore, six women with normal menstrual cycles and no hormonal therapy (BMI 20.7 +/- 1.2 kg/m2) were studied around the time of the anticipated ovulation.. Serum leptin, estradiol, progesterone and luteinizing hormone (LH) concentrations were measured with radioimmunoassays.. Serum leptin concentrations were similar at the beginning of the cycle, at the time of the anticipated ovulation and at the end of the menstrual cycle (10.2 +/- 7.1, 10.7 +/- 7.0 and 11.8 +/- 6.9 microg/l respectively). There was an association between leptin and LH concentrations (r= 0.37, P< 0.01) when values recorded during different time points during the cycle were plotted with each other. There was no change in serum leptin in samples taken at different times of the cyclic treatment with an oral contraceptive. There was no significant difference in mean serum leptin concentrations between women using oral contraceptives and women with no hormonal therapy.. There is a link between serum leptin and LH concentrations during the menstrual cycle. Variations in circulating estrogen and/or progesterone concentrations have no major influence on circulating leptin in young female subjects. Topics: Adipose Tissue; Adult; Body Weight; Contraceptives, Oral; Estradiol; Female; Humans; Leptin; Luteal Phase; Luteinizing Hormone; Menstrual Cycle; Ovulation; Progesterone; Proteins | 1998 |
Reciprocal changes in hypothalamic receptor binding and circulating leptin in anorectic tumor-bearing rats.
Although reduced biological activity of the obese gene product, leptin, has been associated with obesity, little information is available concerning leptin alterations during anorexia. Therefore, we measured circulating leptin concentrations and hypothalamic leptin binding in anorectic tumor-bearing and pair-fed control rats. Plasma concentrations of leptin decreased in tumor-bearing rats early in the course of tumor growth, and fell to nearly non-detectable levels during severe anorexia. The pair-fed control rats that ate the same amount of food as did the anorectic tumor-bearing rats exhibited a 50% decrease in plasma leptin concentration. Concentrations of free fatty acids were elevated in both tumor-bearing and pair-fed groups, while circulating levels of triglycerides were increased only in anorectic tumor-bearing rats. Leptin receptor density was doubled in the hypothalamus of tumor bearing rats, while binding affinity was decreased by 50%. These results suggest that peripheral leptin production is down-regulated, perhaps due to increased lipolysis in tumor-bearing rats. It appears that hypothalamic leptin systems up-regulate receptor numbers in response to decreased blood leptin level, however, the decrease in binding affinity may compensate for these alterations. Therefore, the influence of leptin on hypothalamic neuropeptide Y feeding systems may be minimal in anorectic tumor-bearing rats. Topics: Animals; Anorexia; Body Weight; Carrier Proteins; Eating; Fasting; Fatty Acids, Nonesterified; Hypothalamus; Leptin; Male; Obesity; Protein Binding; Proteins; Rats; Rats, Inbred F344; Receptors, Cell Surface; Receptors, Leptin; Sarcoma, Experimental | 1998 |
Serum leptin concentrations in patients on hemodialysis.
Serum leptin concentrations in normal humans have been reported to correlate with the body mass index (BMI) as well as with the body fat mass. In this study, we measured serum leptin concentrations in 107 patients on hemodialysis, 30 of whom had diabetes mellitus as the cause, and examined the clinical significance. Furthermore, we evaluated the effects of high-flux dialysis membranes on serum leptin levels. Serum leptin concentrations had a linear correlation with BMI as well as with the percentage of body fat in patients on hemodialysis. The serum leptin concentrations showed a positive correlation with the serum concentrations of total cholesterol, low-density lipoprotein cholesterol, and triglyceride, the body weight, the BMI, and the percentage of body fat. The serum leptin levels were not different between the diabetic and the nondiabetic groups. The serum leptin levels in the nondiabetic group were nearly fourfold higher in women than in men. We investigated the differences in the rate of reduction in serum leptin after dialysis with polysulfone membrane dialyzers (PS-N and PS-UW) in comparison with a cellulose membrane dialyzer (AM-SD), and as a result, we found that the polysulfone membrane dialyzers removed serum leptin, while the cellulose membrane dialyzer did not. We conclude that in patients on hemodialysis, the serum leptin concentration is a valuable clinical marker of the body fat content and may also contribute to the evaluation of hyperlipidemia. Topics: Adipose Tissue; Aged; Body Mass Index; Body Weight; Diabetic Nephropathies; Female; Humans; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Proteins; Regression Analysis; Renal Dialysis; Sex Characteristics | 1998 |
Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: implications for gene therapy.
Replication-defective adenoviral (RDAd) vectors can be generated at high titers and infect both dividing and nondividing cells. Long term expression in the transduced tissue, however, has been a problem because of the cellular immune responses against the infected cells. We demonstrate that mice injected with RDAd vectors containing mouse leptin gene reduce food intake and lose weight for only 7 to 10 days. Splenocytes obtained from infected mice are able to lyse target cells infected with RDAd vectors. Surprisingly, target cells infected with psoralen-treated, UV-crosslinked, biologically inactive RDAd also were lysed efficiently by the effector cells. Furthermore, splenocytes obtained from mice injected with inactive RDAd vectors efficiently lysed target cells infected with RDAd vectors. Whether RDAd vectors were injected i.m. or i.v. or through an i.p. route, the extent of lysis was similar. We propose that cells infected with RDAd vectors present antigens for recognition by class 1 major histocompatibility complex-restricted cytotoxic T lymphocytes by a mechanism that does not require viral replication or de novo protein synthesis. These results should prompt reevaluation of the use of RDAd vectors for gene therapy when long-term expression is required. Topics: Adenoviridae; Animals; Body Weight; Cells, Cultured; Cross-Linking Reagents; Eating; Female; Ficusin; Gene Expression Regulation, Viral; Genetic Therapy; Genetic Vectors; Histocompatibility Antigens Class I; Immunity, Cellular; Leptin; Mice; Mice, Inbred Strains; Muscle, Skeletal; Proteins; Spleen; T-Lymphocytes, Cytotoxic; Ultraviolet Rays; Viral Proteins | 1998 |
Changes of maternal serum leptin levels during pregnancy.
Maternal leptin levels in serum and urine, their relations to maternal weight and body mass index, were examined in 9 healthy pregnant women from the 12th week of gestation until term. Serum leptin concentration was found to increase progressively during the first two trimesters followed by a slight decline thereafter. The peak value of 27.6 +/- 15.3 ng/ml (mean +/- SD) concentration was reached at the 28th week. Serum leptin levels during the first two trimesters correlated significantly with maternal weight (p = 0.002) and body mass index (p = 0.002) but such a relationship was absent during the third trimester. Leptin could be detected only in about half of urine samples; its concentrations proved to be independent of serum values. No correlation was found between maternal serum leptin levels and the birth weight of neonates. Maternal leptin levels appear to refer to alterations in maternal fat tissue mass that occur during pregnancy. Topics: Body Mass Index; Body Weight; Female; Gestational Age; Humans; Leptin; Pregnancy; Proteins; Reference Values | 1998 |
Serum leptin and IGF-I levels in cystic fibrosis.
The role of leptin in states of negative energy balance such as cystic fibrosis (CF) has not been explored. We hypothesized that leptin levels in patients with CF would be low due to correlation with body weight. Despite the importance of IGF-I in normal growth and anabolism, there are few data on IGF-I in CF. We studied 27 CF patients (25+/-5 yrs, 57+/-9 kg, 10M/17F) and 12 control subjects (25+/-4 yrs, 57+/-9 kg, 6M/6F). Each subject underwent analysis of lean body mass (LBM) and percent body fat by dual-energy x-ray absorptiometry (DEXA). Serum leptin and IGF-I levels were measured by radioimmunoassay. Serum leptin levels were similar both in CF and in controls (CF=5.3+/-4.1 ng/ml, C=4.4+/-3.6ng/ml; p=0.3), and there was no difference in percent body fat between the two groups (CF=26+/-13%, C=21+/-7%; p=0.3). Leptin levels were significantly lower in CF males than females corresponding to lower fat levels in males in both CF and controls. Leptin levels were positively correlated with percent body fat both in CF and controls (CF: r=0.8; p=0.01, CONTROL: r=0.8; p =0.2). Serum IGF-I levels were significantly lower in CF patients than in controls (CF=1.13+/-0.41 ng/ml, C=6.72+/-3.62 ng/ml; p=<0.01). We conclude that the physiological regulation of leptin is maintained in relation to body fat even in chronic illness and that the negative energy balance in CF is not caused by high leptin levels. Topics: Adult; Body Composition; Body Mass Index; Body Weight; Cystic Fibrosis; Fasting; Female; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Proteins; Radioimmunoassay | 1998 |
Measurement challenges and other practical concerns when studying massively obese individuals.
To describe the measurement challenges faced and to evaluate the measurement quality obtained with massively obese individuals.. A cross-sectional analysis of 107 individuals with body mass indices (kg/m2) > or = 50 was conducted. Individuals had their body fat measured via bioimpedance analysis (BIA), their serum leptin levels measured via radioimmunoassay (RIA), and height and weight measured via both laboratory scales and self-report.. Serum leptin appeared to be measured accurately, provided the serum was diluted prior to conducting the RIA. Difficulties remained, however, in evaluating what was an unusual or expected value of leptin among individuals this large. Measures of impedance appeared to provide reasonable ordinal indications of body fatness. However, currently available equations for converting measures of impedance to estimates of percent body fat were highly inaccurate. Self-reported height and weight were reasonably good proxies of measured height and weight among individuals who reported their height and weight. However, a substantial proportion were unable to provide estimates.. The above results suggest there are substantial challenges when trying to obtain meaningful measurements regarding obesity-related variables among massively obese individuals. Other logistic challenges also are discussed. It is hoped future research is directed at overcoming some of these challenges. Topics: Adipose Tissue; Adult; Body Height; Body Mass Index; Body Weight; Female; Humans; Leptin; Male; Obesity, Morbid; Proteins | 1998 |
Influence of age, hyperglycemia, leptin, and NPY on islet blood flow in obese-hyperglycemic mice.
This study aimed to elucidate possible age-related changes in islet blood perfusion in lean and obese C57BL/6 mice. Obese mice aged 1 mo were hyperglycemic and hyperinsulinemic and had an increased islet blood flow compared with age-matched lean mice. This augmented blood flow could be abolished by pretreatment with leptin. The islet blood perfusion was, in contrast to this, markedly decreased in obese 6- to 7-mo-old animals compared with age-matched lean mice. Reversal of hyperglycemia, but not hyperinsulinemia, in these obese mice with phlorizin normalized the islet blood flow. Spontaneous reversal of hyperglycemia, but not hyperinsulinemia, was seen in the 12-mo-old obese mice. Islet blood perfusion in obese mice at this age did not differ compared with lean mice. It is suggested that the initial increase in islet blood flow in obese mice is due to the leptin deficiency. The subsequent decrease in islet blood perfusion is probably caused by the chronic hyperglycemia. The described islet blood flow changes may be of importance for impairment of islet function in obese-hyperglycemic mice. Topics: Aging; Animals; Arginine; Blood Glucose; Body Weight; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Organ Size; Pancreas; Perfusion; Phlorhizin; Proteins; Receptors, Leptin; Receptors, Neuropeptide Y; Regional Blood Flow | 1998 |
Efficacy of exogenous recombinant murine leptin in lean and obese 10- to 12-mo-old female CD-1 mice.
Leptin efficacy was compared in obese and lean female CD-1 mice. Body weights in these 10- to 12-mo-old mice ranged from 29.7 to 62.0 g, and leptin levels correlated with body weight. Mice from the lean and obese ends of the weight distribution were treated with daily peripheral leptin injections (1-100 mg/kg) for a 33-day period. The half-maximal effective doses for weight loss and fat reduction were shifted 0.5-0.7 log to the right for obese mice. Leptin was less efficacious at low doses (1-3 mg/kg) in obese mice but equal to or more efficacious in obese than lean mice at high doses (30-100 mg/kg). Leptin's initial effects on weight loss could be explained by appetite suppression in both groups, but its effects on fat reduction were greater in leptin-treated than pair-fed mice, particularly in the lean group. Leptin also prevented the elevations in serum corticosterone and ketones found in pair-fed lean mice. These data allow a quantitative comparison of leptin sensitivity in obese vs. lean CD-1 mice and suggest that in mice where obesity is a function of outbreeding and age, leptin sensitivity is moderately reduced. Furthermore, although appetite suppression has a clear role in leptin's effects on body weight, leptin may also have specific effects on lipid metabolism and mobilization that are different from the metabolic compensations that normally occur with food deprivation. Topics: Adipose Tissue; Analysis of Variance; Animals; Body Composition; Body Weight; Dose-Response Relationship, Drug; Female; Leptin; Mice; Obesity; Proteins; Recombinant Proteins; Regression Analysis; Weight Loss | 1998 |
Gestational obesity accentuates obesity in obesity-prone progeny.
Maternal obesity and genetic background can affect the development of obesity and diabetes in offspring. Here we used selected strains of rats resistant (DR) vs. susceptible to development of diet-induced obesity (DIO) on high-energy (HE) diets to assess this issue. DR and DIO dams were fed either Chow or HE diet for 4 wk. DIO HE diet-fed dams and additional DR rats fed a palatable liquid diet (Ensure) became more obese and hyperinsulinemic than the other groups. During lactation, all dams were fed their respective diets, and offspring were fed Chow from weaning to 16 wk of age. All offspring of DIO dams gained more weight and had heavier retroperitoneal fat pads and higher leptin levels than DR progeny, but offspring of the more obese DIO HE dams had heavier fat pads and higher glucose levels than DIO Chow offspring. After 4 wk on HE diet, all DIO offspring gained more weight and had heavier total adipose depots and higher insulin and leptin levels than DR offspring. Offspring of DIO HE dams also gained more weight and had heavier fat depots and higher leptin levels than DIO Chow offspring. Therefore maternal obesity and hyperinsulinemia were associated with increased obesity in those offspring already genetically predisposed to become obese. Topics: Animal Feed; Animals; Blood Glucose; Body Weight; Diet; Dietary Sucrose; Disease Susceptibility; Female; Food, Formulated; Insulin; Leptin; Obesity; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Proteins; Rats; Taste; Weight Gain | 1998 |
Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene.
Brain serotonin and leptin signaling contribute substantially to the regulation of feeding and energy expenditure. Here we show that young adult mice with a targeted mutation of the serotonin 5-HT2C receptor gene consume more food despite normal responses to exogenous leptin administration. Chronic hyperphagia leads to a 'middle-aged'-onset obesity associated with a partial leptin resistance of late onset. In addition, older mice develop insulin resistance and impaired glucose tolerance. Mutant mice also responded more to high-fat feeding, leading to hyperglycemia without hyperlipidemia. These findings demonstrate a dissociation of serotonin and leptin signaling in the regulation of feeding and indicate that a perturbation of brain serotonin systems can predispose to type 2 diabetes. Topics: Animals; Blood Glucose; Body Weight; Causality; Diabetes Mellitus, Type 2; Dietary Fats; Eating; Homeostasis; Hyperphagia; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Mutant Strains; Mutation; Obesity; Proteins; Receptor, Serotonin, 5-HT2C; Receptors, Leptin; Receptors, Serotonin | 1998 |
Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women.
On the basis of observations in rodents, leptin is thought to play a key role in the regulation of energy expenditure and food intake, but less is known of its influence on ingestive behavior and energy balance in humans.. We examined the effect in women of a chronic energy deficit on plasma leptin concentrations and self-reported appetite and explored possible relations between leptin and appetite sensations.. Twelve healthy women (body mass index, in kg/m2: 23-37) participated in a metabolic ward study in which 3 wk of neutral energy balance was followed by 12 wk of energy deficit (energy intake reduced by 2 MJ/d and energy expenditure increased by 0.8 MJ/d). Body weight and composition were monitored, fasting leptin concentrations were measured 4 times, and feelings of hunger, fullness, desire to eat, and prospective consumption were monitored hourly throughout the day on 7 selected days.. Adiposity-adjusted leptin decreased by 54% after 1 wk of a moderate energy deficit and remained low after 6 and 12 wk. Leptin was associated with self-reported hunger, desire to eat, and prospective consumption (range of r: -0.6 to -0.7, P < 0.01). The greatest hunger increase coincided with the largest percentage drop in circulating leptin and the lowest final leptin concentration. The relation between leptin and hunger was not influenced by amount of weight or body fat loss.. These findings support the idea that leptin is a physiologic regulator of hunger during energy deficits in humans; the role of leptin in the long-term regulation of food intake warrants further study. Topics: Adipose Tissue; Adult; Appetite; Blood Glucose; Body Composition; Body Weight; Energy Intake; Energy Metabolism; Female; Humans; Insulin; Leptin; Proteins | 1998 |
The effects of a high fat diet on leptin mRNA, serum leptin and the response to leptin are not altered in a rat strain susceptible to high fat diet-induced obesity.
Osborne-Mendel (OM) and S5B/Pl rats differ in their sensitivity to develop obesity when fed a high fat (HF) diet; OM rats become obese, whereas S5B/Pl rats remain thin. We have investigated the possibilities that either an impaired leptin response or resistance to leptin action underlies the sensitivity to this form of obesity in OM rats. In Experiment 1, OM and S5B/Pl rats fed a nonpurified diet were killed at d 0 or were fed either a HF (56% fat energy) or a low fat (LF, 10% fat energy) diet for 2 or 7 d. The HF diet increased serum leptin significantly by d 2 to levels that were similar in both rat strains. At 7 d, leptin levels were lower than at d 2 but remained higher than levels in the d 0 control groups. The leptin mRNA:18S RNA ratio in epididymal adipose tissue increased to higher levels in HF-fed OM rats than in S5B/Pl rats fed that diet. However, although the LF diet had no effect in S5B/Pl rats, it increased leptin mRNA levels in epididymal adipose tissue of OM rats compared with the controls fed the nonpurified diet. In Experiment 2, OM and S5B/Pl rats were fed HF or LF diets for 5 wk. At that time, their feeding response to a range of leptin doses (0, 1, 5 or 10 microgram) given intracerebroventricularly was tested after overnight food deprivation. There was a similar dose-dependent reduction in energy intake in response to leptin in both OM and S5B/Pl rats. These responses were independent of the diet. The data suggest that the susceptibility of OM rats to HF diet-induced obesity is not related to either a loss of central sensitivity to leptin or a failure to enhance leptin production acutely, although the failure to maintain chronically increased levels of serum leptin could contribute to the obesity. Topics: Adipose Tissue; Animals; Body Weight; Dietary Fats; Leptin; Male; Obesity; Organ Size; Proteins; Rats; RNA, Messenger; Species Specificity | 1998 |
Intracerebroventricular administration of leptin markedly enhances insulin sensitivity and systemic glucose utilization in conscious rats.
This study examines the acute, subacute (overnight), and chronic (7-day) effects of intracerebroventricular (i.c.v.) administration of r-metMuLeptin on insulin sensitivity and systemic glucose turnover in conscious unrestrained rats (body weight, 250 to 300 g). Under postabsorptive conditions, acute i.c.v. leptin ([AL] 10 microg bolus) did not affect tracer (3-(3)H-glucose)-determined glucose production (GP) and utilization (GU) rates during the 2-hour hyperinsulinemic (2 mU x kg(-1) x min(-1)) euglycemic clamp. Chronic i.c.v. leptin ([CL] 10 microg/d for 7 days) administered by osmotic pumps markedly reduced the daily food consumption (P < .05), body weight (P < .05), and postabsorptive basal plasma glucose level (P < .01). During the glucose clamp, GP was markedly suppressed (55%) with CL (P < .001 v vehicle and pair-fed control groups). The insulin-induced increment in GU was significantly greater with CL (23.3 +/- 1.8 mg(-1) x kg(-1) x min(-1)) than with vehicle (16.9 +/- 0.2) and pair-feeding (17.1 +/- 0.6, both P < .001). Subacute i.c.v. leptin ([SL] 10 microg bolus) moderately but insignificantly decreased overnight food consumption (-18%) and body weight (-2.5 +/- 1.5 g). The glucose infusion rate during the final 60 minutes of the glucose clamp was 43% greater than for the vehicle group (P < .0001). SL also significantly increased GU (P < .005) and suppressed GP (P < .05) during the glucose clamp. Thus, we conclude that i.c.v. administered leptin has strong actions on the central nervous system that result in significant increases in insulin sensitivity and systemic GU, and these effects are achieved as early as overnight after leptin administration. Topics: Animals; Body Weight; Eating; Female; Glucose; Injections, Intraventricular; Insulin Resistance; Leptin; Proteins; Rats; Rats, Sprague-Dawley | 1998 |
Four-week ethanol intake decreases food intake and body weight but does not affect plasma leptin, corticosterone, and insulin levels in pubertal rats.
Long-term intake of ethanol decreases food intake and inhibits growth in experimental rats. The aim of this study was to determine the effect of 4-week oral ethanol ingestion on plasma leptin and adrenal function. Male 45-day-old Wistar rats were divided into three groups: absolute control (AC), ethanol (E) administered 10% (wt/vol) ethanol instead of tap water, and pair-fed (PF) given an amount of food corresponding to the food intake of E animals. E rats consumed less pelleted diet (74% cumulative total intake); however, this caloric deficit was compensated by ethanol ingestion. Net water intake in E animals was 76% of that in the control groups. The body growth of both E and PF rats was stunted compared with AC animals, but E rats were heavier than PF rats. The plasma leptin level was similar in E and AC and decreased in PF animals. There were no differences in plasma osmolality or glycemia among the three groups. Plasma insulin was decreased in PF compared with both AC and E rats. Plasma corticosterone was not affected by ethanol, but was increased in the food-restricted (PF) group. Although there were no differences in basal adrenal corticosterone production in vitro, there was a slightly higher response to corticotropin (ACTH) in E rats. We conclude that drinking 10% ethanol decreased the dietary intake and body growth. These changes were not mediated by plasma leptin changes. Although alcohol ingestion and its energy content theoretically normalized the total energy intake and prevented the decrease of plasma leptin, the growth of young rats was inhibited. Drinking 10% ethanol instead of tap water for 4 weeks did not stimulate basal adrenal activity. Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; Body Weight; Corticosterone; Drinking; Eating; Energy Intake; Ethanol; Insulin; Leptin; Male; Proteins; Rats; Rats, Wistar; Sexual Maturation | 1998 |
Leptin increases energy expenditure of a marsupial by inhibition of daily torpor.
Leptin plays an important role in regulating body fat stores of placental mammals, but the contribution of changes in energy expenditure to this adjustment remains controversial. We were interested in how recombinant murine leptin would affect metabolic rate (MR) and body temperature (Tb) of a marsupial mammal (Sminthopsis macroura, 25 g) known to display daily torpor but lacking thermogenetically active brown adipose tissue. In a group of eight animals deprived of food for 1 day at 18 degreesC, leptin treatment halved the duration of torpor bouts (time at Tb < 30 degreesC) and raised the average daily minimum Tb by 4.5 degreesC and minimum MR by 2.2-fold. Leptin treatment thus increased daily energy expenditure by 9%, although MR and Tb during the activity phase were not raised. Body mass was also not affected. These findings in a marsupial suggest that the adjustment of thermoregulatory energy expenditure during the rest phase in accordance with energy availability is a phylogenetically old function of leptin. Topics: Animals; Body Temperature; Body Weight; Energy Metabolism; Leptin; Male; Marsupialia; Proteins; Recombinant Proteins | 1998 |
Hyperphagia and weight gain after gold-thioglucose: relation to hypothalamic neuropeptide Y and proopiomelanocortin.
Genetic obesity is associated with increased neuropeptide Y (NPY) messenger RNA (mRNA) and decreased POMC mRNA in the hypothalamus of ob/ob and db/db mice, or impaired sensitivity to alphaMSH (derived from POMC) in the yellow agouti mouse. Acquired obesity can be produced by chemically lesioning the hypothalamus with either monosodium glutamate (MSG) in neonates or gold thioglucose (GTG) in adult mice. The present study examined whether elevated NPY mRNA and/or decreased POMC mRNA in the hypothalamus are associated with obesity due to hypothalamic lesions. GTG injection into adult mice produced a profound obese phenotype, including hyperphagia, increased body weight, and increased leptin mRNA and peptide, in association with reduced hypothalamic NPY mRNA and POMC mRNA. MSG treatment produced virtual elimination of NPY mRNA in the arcuate nucleus and a reduction of hypothalamic POMC mRNA, and led to elevated leptin. MSG pretreatment did not attenuate GTG-induced hyperphagia and obese phenotype. These results do not support a role for NPY-synthesizing neurons in the arcuate nucleus in mediating hypothalamic acquired obesity, but are consistent with the hypothesis that decreased activity of hypothalamic neurons synthesizing POMC play a role in mediating hypothalamic obesity. Topics: Animals; Aurothioglucose; Blotting, Northern; Body Weight; Hyperphagia; Hypothalamus; In Situ Hybridization; Leptin; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Protein Biosynthesis; RNA, Messenger; Sodium Glutamate; Weight Gain | 1998 |
Down-regulation of CCAAT/enhancer binding proteins alpha, beta and delta in adipose tissue by intracerebroventricular leptin in rats.
In our previous report, intracerebroventricular (i.c.v.) administration of leptin caused fat depletion by an induced adipocyte apoptosis in addition to influencing lipid metabolism. To uncover the biochemical mechanisms that mediate this response, the present study was designed to determine whether CCAAT/enhancer binding proteins (C/EBP)alpha, -beta and -delta play a role in the leptin-induced fat depletion. Expressions of C/EBPalpha, -beta and -delta in epididymal fat tissues were examined by Western immunoblot and in situ immunocytochemical analysis after 5 days of i.c.v. treatment. Young and old rats (3 and 8 months old) were treated with or without 5 micrograms/day leptin. The expression of C/EBPalpha, -beta and -delta was decreased by i.c.v. leptin treatment in young rats as compared with controls (P<0.05). However, leptin did not influence the expression of C/EBPalpha, -beta and -delta in adipose tissues of 8-month-old rats. The basal level of expression of C/EBPbeta was greater in 8-month-old rats than in 3-month-old rats, (P<0.05) whereas the basal expression of C/EBPalpha and -delta was not different between age groups. These results were confirmed by in situ immunocytochemical analysis. The present study suggests that leptin-induced down-regulation of C/EBPalpha, -beta and -delta might influence adipocyte differentiation and growth in a number of ways. Topics: Adipose Tissue; Aging; Animals; Body Weight; CCAAT-Enhancer-Binding Proteins; Cerebral Ventricles; DNA-Binding Proteins; Energy Intake; Enhancer Elements, Genetic; Epididymis; Escherichia coli; Gene Expression Regulation, Developmental; Immunohistochemistry; Injections, Intraventricular; Leptin; Male; Nuclear Proteins; Proteins; Rats; Rats, Sprague-Dawley; Recombinant Proteins | 1998 |
Circulating leptin did not associate with the development of the hyperglycemia accompanied by insulin insensitivity in spontaneous noninsulin dependent diabetes mellitus model Otsuka-Long-Evans-Tokushima-Fatty rats.
Leptin, the product of the ob gene, has been reported to regulate feeding behavior and energy metabolism. Plasma leptin concentration was strongly correlated with body fat content in humans. It is well known that increased body fat content is accompanied by insulin insensitivity. In order to study the relationship between serum leptin level and metabolic variables, we performed caloric restriction on Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of noninsulin dependent diabetes mellitus. The male OLETF rats were allocated at random to three groups: 100% group, and 85% and 70% groups (which consumed 85% and 70% of the amount of food consumed by the 100% group, respectively). A significant correlation between serum leptin level and the body fat content, body weight, triglyceride, and fasting plasma glucose was observed. Using a partial correlation analysis to control for body fat content, however, the correlation between serum leptin and these variables disappeared. No significant changes in serum leptin levels were observed before and after a 1 h hyperinsulinemic euglycemic clamp test. In conclusion, serum leptin was significantly correlated with body fat content rather than fasting plasma glucose, serum insulin and insulin sensitivity. This suggests that circulating leptin per se may not result in hyperinsulinemia and insulin insensitivity in the OLETF rat. Topics: Animals; Body Constitution; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Intake; Fats; Food; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Leptin; Male; Obesity; Proteins; Radioimmunoassay; Rats; Rats, Inbred Strains | 1998 |
Marked hyperleptinemia after high-fat diet associated with severe glucose intolerance in mice.
We asked whether the likelihood for mice of the C57BL/6J strain to develop glucose intolerance when fed a high-fat diet is related to the increase in circulating levels of leptin or free fatty acids (FFA). We therefore administered a high-fat diet (58% fat) or a control diet (11% fat) for 1.5 years. NMRI mice were used as a more glucose-tolerant control group. After a high-fat diet, the area under the glucose curve following an intraperitoneal glucose challenge (1 g/kg) increased more markedly in C57BL/6J mice (by 42+/-8%) than in NMRI mice (by 21+/-3%, P = 0.007). Plasma levels of insulin, leptin and FFA increased in both strains of mice, whereas plasma glucose levels were elevated after the high-fat diet only in C57BL/6J mice. The slope of the relationship between body weight and plasma leptin was higher in C57BL/6J mice than in NMRI mice. suggesting leptin insensitivity. Circulating leptin correlated to circulating insulin in both strains of mice, whereas plasma FFA correlated to plasma insulin in NMRI mice but not in C57BL/6J mice. These correlations remained significant after adjustment for body weight. The results show that elevated leptin and FFA levels evolve after high-fat feeding in mice, in conjunction with evolvement of glucose intolerance and hyperglycemia. Topics: Animals; Body Weight; Dietary Fats; Fatty Acids, Nonesterified; Glucose Intolerance; Hyperglycemia; Insulin; Insulin Resistance; Leptin; Mice; Mice, Inbred C57BL; Proteins | 1998 |
Association of leptin and hunger-satiety ratings in obese women.
To measure leptin, insulin and cholecystokinin (CCK) concentrations in obese women on calorie restriction and to determine their correlation with hunger-satiety ratings. Although it has been proposed to play a role in appetite regulation, the effects of physiological concentrations of these hormones on hunger-satiety in humans have not yet been well established.. Prospective metabolic study. A two week 'wash-in period' followed by a three-week observation period, during which each subject underwent six measurements of satiety, blood parameters and body weight.. Energy Metabolism Research Unit, Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.. 22 moderately to severely overweight women (mean age: 45 +/- 8 y; body mass index (BMI): 33 +/- 6 kg/m2).. Energy restriction, in the form of a 3.3 MJ (800 kcal) diet during five weeks.. Fasting blood levels of leptin, insulin, glucose and CCK, fasting hunger-satiety scores and body weight.. The mean (+/- s.d.) fasting serum leptin concentration at the beginning of the observation period was 26.1 +/- 15.9 ng/ml (range: 6.7-59.8 ng/ml). Leptin concentrations correlated positively with body weight (P < 0.0001). Furthermore, reductions in body weight were associated with decreases in fasting leptin levels (P = 0.002). Leptin concentrations correlated with serum levels of insulin (P = 0.0001) and CCK (P = 0.06), but in multivariate analysis including insulin, CCK and glucose, only leptin had a significant relationship with satiety (P = 0.04). This relationship was linear.. These results confirm the association between leptin levels, body weight and serum insulin. We also showed that higher serum leptin levels correlated with greater feelings of fullness, a relationship which was not blunted in the more obese subjects. These findings suggest that leptin is a satiety hormone that reduces appetite, even in obese individuals, and that weight gain must be due to other factors, overriding this feed-back regulation. Topics: Adult; Appetite; Black People; Body Weight; Cholecystokinin; Female; Humans; Hunger; Insulin; Leptin; Middle Aged; Obesity; Prospective Studies; Proteins; Satiety Response; White People | 1998 |
Elevated plasma leptin concentrations in early stages of experimental intestinal inflammation in rats.
Although leptin, an adipocyte derived hormone which regulates food intake and energy balance, is released after injections of tumour necrosis factor (TNF) and interleukin 1, plasma concentrations have not been characterised in chronic inflammation. Leptin may contribute to the anorexia and body weight loss associated particularly with the acute stages of inflammatory bowel disease.. To investigate plasma leptin concentrations during the time course of intestinal inflammation in different animal models.. Plasma leptin was measured at different time points in rats with trinitrobenzene sulphonic acid (TNBS) induced colitis, indomethacin induced ileitis, or endotoxic shock caused by lipopolysaccharide (LPS). Systemic TNF-alpha was also measured during acute inflammation.. Plasma leptin concentrations increased fourfold eight hours after induction of TNBS colitis (p<0.0001) and twofold after administration of ethanol alone (p<0.02). Plasma leptin responses throughout the first post-treatment day were correlated with myeloperoxidase activity and gross damage scores. Similar leptin overexpression was observed in indomethacin induced ileitis and in rats with endotoxic shock. Plasma concentrations were lower in TNBS treated rats than in controls on day 5 before reaching a similar concentration on day 14. Anorexia and body weight loss were observed during the first four days post-TNBS. A significant increase in systemic TNF-alpha was only detected in LPS treated rats.. Elevated plasma leptin concentrations, correlated with the degree of inflammation and associated with anorexia, were induced in rats during the early stages of experimental intestinal inflammation but proved transient; this might account for discrepancies in recent results concerning concentrations in patients with inflammatory bowel diseases. Topics: Animals; Body Weight; Colitis; Eating; Ileitis; Leptin; Male; Proteins; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha | 1998 |
Effects of intracerebroventricular leptin administration on food intake, body weight gain and diencephalic nitric oxide synthase activity in the mouse.
1. Intracranial administration of leptin reduces both food intake and body weight gain in the mouse. Inhibitors of nitric oxide (NO) synthase produce similar effects. 2. To investigate the role of the brain L-arginine/NO pathway in mediating this effect of leptin, we have evaluated food intake and body weight gain after daily (5 days) intracerebroventricular (i.c.v.) administration of leptin (0.5-2 microg) alone or in association with L-arginine (10 microg). Moreover, we measured diencephalic nitric oxide synthase (NOS) activity after a single i.c.v. leptin (0.25-2 microg) injection and after consecutive doses of leptin (0.25-2 microg) over 5 days. The time course of the effect of leptin on NOS activity was also evaluated. 3. I.c.v. injected leptin (1 and 2 microg) significantly and dose-dependently reduced food intake and body weight gain with respect to vehicle (food intake: 5.97+/-0.16 g 24 h(-1) and 4.27+/-0.18 g 24 h(-1), respectively, vs 8.05+/-0.34 g 24 h(-1), P<0.001, n=6 for each group; body weight gain: -10.7+/-0.46% and -15.7+/-0.65%, respectively, vs 5.14+/-0.38%, P<0.001, n=6 for each group). This effect was antagonized by L-arginine (food intake: 7.90+/-0.37 g 24 h; body weight gain: 5.11+/-0.31%, n=6). Diencephalic NOS activity was significantly reduced by the highest doses of leptin with respect to vehicle (vehicle: 0.90+/-0.04 nmol citrulline min(-1) g(-1) tissue; leptin 1 microg: 0.62+/-0.03 nmol citrulline min(-1) g(-1) tissue, P<0.001; leptin 2 microg: 0.44+/-0.03 nmol citrulline min(-1) g(-1) tissue, P<0.001, n=6 for each group). Similar results were obtained in animals treated with daily consecutive doses of leptin. The inhibitory effect appeared rapidly (within 30 min) and was long lasting (up to 12 h). 4. Our results suggest that the brain L-arginine/NO pathway may be involved in the central effect of leptin on feeding behaviour and body weight gain in mice. Topics: Animals; Arginine; Body Weight; Brain; Diencephalon; Drug Interactions; Eating; Injections, Intraventricular; Leptin; Male; Mice; Nitric Oxide Synthase; Obesity; Proteins; Time Factors | 1998 |
Genetic variants of the human obesity (OB) gene in subjects with and without Prader-Willi syndrome: comparison with body mass index and weight.
We investigated whether an association exists between genetic variants of the human obesity (OB or leptin) gene and body mass index (BMI) or weight in subjects with Prader Willi syndrome (PWS) and in age- and gender-matched lean and obese subjects without PWS. The study included 51 subjects with PWS (mean age = 17.7 +/- 9.5 years, BMI = 29.7 +/- 8.3 kg/m2); 50 non-PWS obese subjects (mean age = 18.2 +/- 10.8 years, BMI = 33.3 +/- 9.5 kg/m2); and 53 non-PWS lean subjects (mean age = 17.8 +/- 9.5 years, BMI = 19.5 +/- 2.9 kg/m2). Allele sizes were determined via standard polymerase chain reaction of the D7S1875 locus, a dinucleotide repeat polymorphism close to the OB gene and classified as trichotomous (homozygous < 208 bp, heterozygous < 208/ > or = 208 bp, homozygous > or = 208 bp) or dichotomous (homozygous < 208 bp or not). Non-PWS males showed a marked decrease in weight with larger alleles while females did not (interaction effect, p < 0.05). Comparable effects were not observed among the PWS subjects. Associations between BMI and genotype were statistically significant (r = 0.22, one-tailed p < 0.05) and comparable to previous research among the non-PWS subjects < 18 years, but not the adults (r = 0.05, one-tailed p = 0.38). Correlations were not statistically significant among either the adult or non-adult PWS subjects. Topics: Adult; Alleles; Body Mass Index; Body Weight; Chromosomes, Human, Pair 7; Female; Genetic Variation; Humans; Leptin; Male; Middle Aged; Obesity; Prader-Willi Syndrome; Proteins | 1998 |
Effect of repeated stress on body weight and body composition of rats fed low- and high-fat diets.
Exposure to the moderate stressor of 3-h restraint for 3 consecutive days causes a temporary drop in food intake but a permanent reduction in body weight in adult rats. Young rats did not show the same response. Food intake of adult rats exposed to repeated restraint was significantly lower than that of controls for 4 days after the end of stress, and there was no rebound hyperphagia. Body weight remained significantly lower for at least 40 days after stress. When the rats were fed a high-fat diet of 80% chow and 20% vegetable shortening (48% kcal fat, 16% protein), lean body mass accounted for all of the weight loss in stressed rats. When the experiment was repeated with a purified high-fat diet containing corn oil and coconut oil as the source of fat (41% kcal fat, 16% protein), weight loss consisted of both lean and fat tissue. There were no sustained changes in single time point measures of corticosterone, insulin, or leptin that could account for the reduced body weight in these rats. Topics: Aging; Animals; Body Composition; Body Weight; Corticosterone; Dietary Fats; Dietary Fats, Unsaturated; Eating; Insulin; Leptin; Male; Proteins; Rats; Rats, Sprague-Dawley; Recurrence; Restraint, Physical; Stress, Physiological | 1998 |
Serum leptin concentration and insulin sensitivity in men with abdominal obesity.
We have examined the association between generalized adiposity, abdominal adiposity, insulin sensitivity, and serum levels of leptin in a cross-sectional study of abdominally obese men.. Thirty men, 48 to 66 years of age with a body mass index (BMI) of between 25 kg/m2 and 35 kg/m2 and a waist hip ratio of >0.95, were included in the study. Serum leptin concentration was measured using radioimmunoassay. Total body fat percentage was determined from total body potassium, abdominal adiposity was measured by computed tomography, and the glucose disposal rate (GDR) was measured during an euglycemic, hyperinsulinemic glucose clamp.. Significant correlations were found between serum leptin concentration and BMI, percentage body fat, abdominal subcutaneous adipose tissue, serum insulin, GDR, and 24-hour urinary-free cortisol. In a multiple regression analysis, it was shown that abdominal subcutaneous adipose tissue, GDR, and BMI explained 72% of the variability of serum leptin concentration. GDR demonstrated an independent inverse correlation with serum leptin concentration.. In abdominally obese men with insulin resistance, it was demonstrated that most of the individual variability in serum leptin concentration was explained by the amount of subcutaneous abdominal adipose tissue, insulin sensitivity, and BMI. Topics: Abdomen; Adipose Tissue; Aged; Blood Glucose; Body Composition; Body Constitution; Body Mass Index; Body Weight; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Proteins | 1998 |
Evidence for involvement of the melanocortin MC4 receptor in the effects of leptin on food intake and body weight.
The hypothesis that the melanocortin MC4 receptor mediates the homeostatic effects of leptin was tested. Leptin (0.3 nmol, i.c.v.) lowered food intake at 4 and 24 h and body weight at 24 h. This effect was inhibited by pretreatment with an analogue of melanocyte stimulating hormone (MSH), the selective melanocortin MC4 receptor antagonist HS014 (cyclic [AcCys11,D-Nal14,Cys18,Asp-NH2(22)]-beta-MSH11-2 2, 0.3 nmol, i.c.v.). HS014 alone at this dose did not modify food intake or body weight. At a higher dose (1.0 nmol, i.c.v.) HS014 stimulated food intake and this orexigenic effect of HS014 was attenuated by leptin pretreatment (0.3 nmol, i.c.v.). These results confirm earlier findings that leptin inhibits food intake and lowers body weight via the melanocortin system and suggest that leptin affects signalling at the melanocortin MC4 receptor. Topics: Analysis of Variance; Animals; Body Weight; Eating; Leptin; Male; Peptides, Cyclic; Proteins; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Time Factors; Weight Loss | 1998 |
Relationships of serum leptin to body composition and resting energy expenditure.
Body weight (BW), body mass index (BMI), body fat, serum leptin concentration and resting energy expenditure (REE) were fitted in a multiple linear regression model in a group of individuals with stable body weight. While serum leptin concentration was well related to BW, to BMI and to body fat, no correlations with the REE values were found. This suggests that serum leptin concentration would represent an index of adiposity and poorly reflects energy metabolism. Topics: Adipose Tissue; Adult; Body Composition; Body Mass Index; Body Weight; Energy Metabolism; Female; Humans; Leptin; Linear Models; Male; Middle Aged; Proteins | 1998 |
Responses of lean and obese Zucker rats to centrally administered leptin.
Obese (Lepr(fa)/Lepr(fa)) Zucker rats have a missense mutation in the leptin receptor gene. One amino acid substitution in the extracellular domain common to all known leptin receptor proteins results from this mutation. Obese Zucker rats are unable to respond behaviorally to leptin which is peripherally administered. However, conflicting reports exist on whether obese Zucker rats can respond to centrally administered leptin. The purpose of this study was to determine whether obese Zucker rats responded behaviorally and metabolically to intracerebroventricularly (i.c.v.) administered leptin and to compare the responses of lean and obese Zucker rats. We found that both lean and obese Zucker rats had similar body weight and food intake responses when administered a single i.c.v. leptin injection in a range of doses (1.25, 2.5, 5, and 10 microg), as well as daily i.c.v. administered leptin for five consecutive days. Both single and daily leptin administration also decreased respiratory quotient (RQ) similarly in lean and obese Zucker rats, indicating mobilization of fat as an energy source for leptin-treated rats. After withdrawal of daily leptin treatment, lean and obese Zucker rats exhibited different recovery responses. It is concluded that obese Zucker rats can respond to exogenous leptin when leptin is delivered into the brain ventricles. Topics: Animals; Body Temperature Regulation; Body Weight; Calorimetry, Indirect; Dose-Response Relationship, Drug; Drinking; Eating; Female; Injections, Intraventricular; Leptin; Obesity; Proteins; Rats; Rats, Zucker; Recombinant Proteins | 1998 |
No evidence for involvement of the leptin gene in anorexia nervosa, bulimia nervosa, underweight or early onset extreme obesity: identification of two novel mutations in the coding sequence and a novel polymorphism in the leptin gene linked upstream regio
Mutations in the leptin gene can result in profound obesity in both rodents and humans. In humans, serum leptin levels correlate with body mass index (BMI: kg m(-2)). However, in patients with anorexia nervosa (AN) leptin levels are lower than in BMI-matched healthy controls. We had previously argued that genes involved in weight regulation should be considered as candidate genes for AN. To investigate this hypothesis we screened the coding region of the leptin gene and part of the leptin gene linked upstream region (LEGLUR) in 49 patients with AN and 315 children and adolescents with extreme obesity. Two novel mutations in the coding region (Ser-91-Ser; Glu-126-Gln), each found in a single proband, and a novel polymorphism in the LEGLUR (position -1387 G/A; frequency of both alleles approximately 0.50) were identified. Tests for association of LEGLUR polymorphism alleles were negative by comparing allele frequencies between 115 AN patients, 71 bulimia nervosa patients, 315 extremely obese children and adolescents, 141 healthy underweights and 50 controls that were not selected for body weight. Tests for transmission disequilibrium were also negative. Hence, an influence of variations in the leptin gene on eating disorders or extreme early onset obesity could not be detected. Topics: Adolescent; Age of Onset; Amino Acid Substitution; Anorexia Nervosa; Body Mass Index; Body Weight; Bulimia; Child; Gene Frequency; Genotype; Humans; Leptin; Linkage Disequilibrium; Nuclear Family; Obesity; Point Mutation; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Proteins; Reference Values; Regulatory Sequences, Nucleic Acid; Thinness | 1998 |
Hyperphagia induced by hypoglycemia in rats is independent of leptin and hypothalamic neuropeptide Y (NPY).
Hypoglycemia causes hyperphagia and weight gain, through unknown peripheral and central signals. We investigated the effect of hypoglycemia on NPY and leptin expression and the ability of leptin to inhibit hypoglycemia-induced hyperphagia. Acute hypoglycemia (60 U/kg SC insulin; n = 8) increased food intake (p < 0.01) compared with controls (n = 8). Insulin- and leptin-treated rats (300 microg/kg IP leptin; n = 8) had reduced hyperphagia (p < 0.05 vs. controls; p < 0.05 vs. insulin alone) and a 15% fall in NPY mRNA levels compared with controls (p < 0.01). Chronic hypoglycemia, (20-60 U/kg/day insulin; n = 8) increased food intake compared with vehicle-treated controls (p < 0.01). Leptin and insulin administration (300 microg/kg/day IP leptin; n = 8) reduced hyperphagia (p < 0.01 vs. controls, p < 0.05 vs. insulin alone), and NPY mRNA fell by 18% vs. controls (p < 0.01). We conclude that hypoglycemia-induced hyperphagia is not mediated by either a fall in leptin or an increase in hypothalamic NPY mRNA. Leptin can inhibit feeding in hyperphagic hypoglycemic rats, and this may partly be attributable to its inhibition of the NPY neurons. Topics: Acute Disease; Analysis of Variance; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Chronic Disease; Eating; Hyperphagia; Hypoglycemia; Insulin; Leptin; Male; Models, Biological; Neuropeptide Y; Protein Biosynthesis; Proteins; Rats; Rats, Wistar; RNA, Messenger | 1998 |
Longitudinal analysis of maternal serum leptin levels during pregnancy, at birth and up to six weeks after birth: relation to body mass index, skinfolds, sex steroids and umbilical cord blood leptin levels.
Leptin is an important regulator of body fat mass and energy expenditure during adult life. The mechanisms by which maternal and fetal weight are regulated during pregnancy are poorly understood. In order to gain more insight into a potential role of leptin during gestation, a prospective, longitudinal study was carried out to measure leptin concentrations in maternal serum of 29 healthy women during pregnancy up to 6 weeks after birth and also in umbilical cord blood of their newborns. Leptin concentrations were measured using a specific RIA. In addition, estradiol, testosterone, and sex hormone binding globulin were determined using commercially available RIAs. The mothers' skinfolds were determined at four sites using a Holtain caliper. Leptin levels increased continuously during pregnancy and reached 25.8 +/- 14.7 ng/ml at 38-40 weeks. At birth, leptin concentrations were 23.5 +/- 15.4 ng/ml. Three days after delivery a significant decrease of leptin levels to 10.6 +/- 6.0 ng/ml was observed. Six weeks after birth the leptin concentration in maternal serum was 13.8 +/- 8.6 ng/ml. At birth, maternal serum levels were significantly higher than levels in cord blood and did not correlate with leptin levels in cord blood or neonatal weight. Furthermore, leptin levels did not correlate with maternal sex steroids and sex hormone binding globulin levels. At 6-8 weeks of pregnancy, maternal leptin serum levels correlated significantly with BMI (r = 0.81). The correlation coefficients (leptin vs. BMI) dropped with increasing gestational age and at birth only a poor correlation persisted (r = 0.50). Six weeks after birth there was again a high correlation between leptin levels in maternal serum and BMI (r = 0.76). Subscapular skinfold thickness was correlated to leptin concentrations in maternal serum during the whole period of the investigation. In conclusion, maternal leptin levels continuously increased from 6-8 weeks up to 38-40 weeks of pregnancy. Maternal leptin levels decreased dramatically after birth. Six weeks after delivery, leptin levels were comparable to the values measured at the beginning of pregnancy. We hypothesize that leptin might play an important role during pregnancy and fetal development. Topics: Adipose Tissue; Adult; Body Composition; Body Mass Index; Body Weight; Estradiol; Female; Fetal Blood; Gonadal Steroid Hormones; Humans; Infant, Newborn; Leptin; Male; Pregnancy; Prospective Studies; Proteins; Radioimmunoassay; Sex Hormone-Binding Globulin; Skinfold Thickness; Testosterone | 1998 |
Fasting serum leptin levels in the analysis of body mass index cut-off values: are they useful for overweight screening in children and adolescents? A school population-based survey in three provinces of central Italy.
Body mass index (BMI) was determined in a population of school students from three provinces of central Italy. Fasting serum leptin concentrations were assayed in a large number of subjects from the same area, to determine their distribution as plotted against the standard deviation score (z-score) of BMI.. Height and weight were recorded from 31170 subjects (16175 male and 14995 female), aged 3-18 y, to construct BMI charts of children and adolescents from central Italy. Percentiles and z-score were calculated using the LMS method of Cole. Serum leptin concentrations were assayed in 1929 subjects (996 male and 933 female) after overnight fasting.. BMI percentiles of central Italy were higher than those from standards of other European and USA populations. When plotted against the z-score of BMI, serum leptin values were distributed according to an exponential curve, showing a steep pattern and a wide distribution, as BMI values increased. The hypothesis of the existence of two subgroups, based on a different relation between leptin and BMI, was verified and a separation point between the two subgroups was identified using cluster analysis, discriminant analysis and a novel method developed by our group, hereafter referred to as 'regression clustering'. This method allows identification of the value of the independent variable (z-score of BMI) which can be taken as a separation point. This analysis provided the best results and indicated the following separation points: central Italy standard, z-score = 0.72 (76.4th percentile) for males and z-score = 0.69 (75.5th percentile) for females; French standard (the one suggested for a European population by the European Childhood Obesity Group, ECOG), z-score = 1.46 (92.8th percentile) for males and z-score = 1.96 (97.5th percentile) for females. Similar but variable results were obtained when the same analysis was performed on serum leptin concentration, subdivided according to pubertal development (stage I, stage II-III, stage IV-V).. Children and adolescents from central Italy had greater BMI percentiles when compared to other European populations. Fasting serum leptin concentrations showed a distribution pattern related to z-score, thus allowing to identification of two different subgroups. The z-scores of BMI, identified as separation points, indicated a trend to leptin production by adipocytes that could be taken as indicators of significant increases of fat mass. This study proposes criteria and a statistical approach that could be useful in the identification of BMI cut-off values when screening children and adolescents for overweight. Topics: Adolescent; Body Mass Index; Body Weight; Child; Child, Preschool; Cluster Analysis; Discriminant Analysis; Europe; Fasting; Female; Humans; Italy; Leptin; Male; Proteins; Reference Values; Regression Analysis | 1998 |
Intracerebroventricular (i.c.v.) administration of mouse leptin in rats: behavioral specificity and effects on meal patterns.
Leptin is a protein that is produced primarily in fat tissue and is thought to be a lipostatic feedback signal for the regulation of body fat stores. The purpose of this study was to determine the behavioral specificity of i.c.v.-administered mouse leptin in rats and to assess the effects on meal patterns. Using a modified two-bottle paradigm we examined the putative aversive response to i.c.v. doses of 1, 5, 7, 10, and 30 microg of mouse leptin. Artificial CSF and intraperitoneal lithium chloride served as negative and positive controls, respectively. Saccharin consumption in all leptin treatments was not significantly different from the negative control. Following a recovery period, rats from the same group were used to assess the effects of a 30-microg i.c.v. dose on cumulative food intake and meal patterns using a computer-based system for acquisition of feeding data. Leptin (i.c.v.) significantly increased intermeal interval and decreased meal size. We, therefore, conclude that mouse leptin, at doses up to 30 microg i.c.v., is not aversive in the rat, and that leptin has a multiphasic effect on meal patterns. Topics: Animals; Avoidance Learning; Body Weight; Conditioning, Psychological; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Mice; Proteins; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Saccharin; Taste | 1998 |
Leptin activates hypothalamic CART neurons projecting to the spinal cord.
The adipocyte-derived hormone leptin decreases body weight in part by activating the sympathetic nervous system, resulting in increased thermogenesis and energy expenditure. We investigated hypothalamic pathways underlying leptin's effects on stimulating the sympathetic nervous system. We found that leptin activates neurons in the retrochiasmatic area (RCA) and lateral arcuate nucleus (Arc) that innervate the thoracic spinal cord and also contain cocaine- and amphetamine-regulated transcript (CART). We also found that most CART-containing neurons in the RCA and Arc of the hypothalamus also contain proopiomelanocortin (POMC) mRNA. The finding that leptin activates CART/POMC neurons innervating sympathetic preganglionic neurons in the thoracic spinal cord suggests that this pathway may contribute to the increased thermogenesis and energy expenditure and decreased body weight observed following leptin administration. Topics: Animals; Arcuate Nucleus of Hypothalamus; Body Temperature Regulation; Body Weight; Energy Metabolism; Hypothalamus; Leptin; Male; Microinjections; Nerve Tissue Proteins; Neural Pathways; Neurons; Organ Specificity; Pro-Opiomelanocortin; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Spinal Cord; Transcription, Genetic | 1998 |
Obesity due to high fat diet decreases the sympathetic nervous and cardiovascular responses to intracerebroventricular leptin in rats.
Obesity is associated with an increase in plasma leptin levels primarily derived from enhanced expression of the leptin gene in the adipose tissue. Leptin levels and expression are higher in females than males. The main functions of leptin are to decrease food intake and increase sympathetic nerve activity, especially in the brown adipose tissue. The high levels of leptin in obese, female rats suggest leptin resistance. In this article we describe experiments designed to investigate the effect of the intracerebroventricular (i.c.v.) administration of leptin on lumbar sympathetic nerve activity (LSNA) and cardiovascular parameters in female rats fed a low fat diet (control), a high fat diet (obese), or high fat diet followed by a period of food restrictions (reduced). The i.c.v. leptin administration increased LSNA in control rats, but decreased it in obese rats. In weight reduced animals the LSNA response to leptin returned to control levels. The i.c.v. leptin increased the mean arterial pressure in control and wt. reduced rats, but not in obese animals. The heart rate did not respond to leptin in any animal group. These results suggest that obesity decreases the central nervous system (CNS)-mediated lumbar sympathetic nervous and cardiovascular responses to leptin and that these responses recover following food restriction and wt. reduction. We conclude that obesity is associated with a decreased CNS response to leptin leading to a decrease in leptin effects to increase the activities of the autonomic nervous and cardiovascular systems. Topics: Animals; Blood Glucose; Body Weight; Cardiovascular Physiological Phenomena; Diet, Fat-Restricted; Dietary Fats; Female; Injections, Intraventricular; Insulin; Leptin; Obesity; Proteins; Rats; Rats, Wistar; Sympathetic Nervous System | 1998 |
Serum leptin levels do not rise during pregnancy in age-matched rats.
The serum leptin profile and its production in adipose tissue during pregnancy and lactation were investigated along with changes in appetite and factors reflecting nutritional status in 11-week-old rats. Serum leptin levels in pregnant rats were stable except on day 20 of pregnancy and significantly reduced during lactation compared to nonpregnant rats (P < 0.001). Circulating leptin levels corresponded with changes in appetite during pregnancy and postparturition. Leptin mRNA in parametrial adipose tissue reflected the circulating levels, also being significantly reduced during late pregnancy and during lactation (P < 0.05). Leptin mRNA expression was observed in placenta, but the amount suggested little influence on circulating leptin levels. These results indicate that reduction in leptin mRNA in parametrial adipose tissue and circulating leptin levels may increase appetite during late pregnancy and lactation and may play a role in regulating metabolic homeostasis around parturition in rats. Topics: Adipose Tissue; Age Factors; Animals; Appetite; Blood Glucose; Body Weight; Female; Insulin; Labor, Obstetric; Leptin; Male; Nutritional Status; Pregnancy; Pregnancy, Animal; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Triglycerides; Uterus | 1998 |
Concentrations of leptin in the serum of pregnant, lactating, and cycling rats and of leptin messenger ribonucleic acid in rat placental tissue.
Leptin concentrations were measured in the serum of cycling, pregnant, and lactating Sprague-Dawley rats. Serum leptin concentrations did not vary significantly during the estrous cycle. In contrast, as gestation advanced, serum leptin concentrations increased significantly, p < 0.0001. Following delivery, leptin concentrations declined and remained stable during lactation. Leptin messenger ribonucleic acid (mRNA) was identified in the visceral adipose tissue and placenta of rats sacrificed on days 14 and 21 of pregnancy. The relative abundance of placental leptin mRNA increased approximately 4 to 5 fold from day 14 to 21 of gestation. The pattern of elevated leptin concentrations in the serum of late pregnant rats is similar to that reported in pregnant women, therefore the rat may be a useful model for the study of leptin during pregnancy. The increase in leptin in the serum of late pregnant rats, as well as an increase in placental mRNA, raises the possibility that leptin may serve a physiological role for the late parturient rat and/or its young. Topics: Abdomen; Adipose Tissue; Animals; Blotting, Northern; Body Weight; Estrus; Female; Lactation; Leptin; Placenta; Pregnancy; Proteins; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Regression Analysis; RNA, Messenger; Time Factors | 1998 |
Leptin affects food intake via CRF-receptor-mediated pathways.
Topics: Animals; Body Weight; Corticotropin-Releasing Hormone; Dose-Response Relationship, Drug; Eating; Hormone Antagonists; Leptin; Male; Peptide Fragments; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone | 1998 |
Acute and chronic regulation of ob mRNA levels by beta3-adrenoceptor agonists in obese Yellow KK mice.
The inhibitory effect of beta3-adrenoceptor agonists on the ob gene in brown adipose tissue (BAT) and white adipose tissue (WAT) is now well documented both in vivo in lean animals and in vitro, but the reported effects of beta3-adrenoceptor agonists on ob gene expression in obese animals remain controversial. We investigated whether ob gene expression in BAT and WAT is reduced by acute and chronic administrations of a beta3-adrenoceptor agonist, CL316,243 (CL). The ob gene mRNA levels in BAT, perimetric and inguinal WAT of obese Yellow KK mice were about 4-fold higher than those of lean controls. Acute exposure (6 h) to CL decreased ob gene mRNA levels in three fat depots in both animals. Chronic exposure (10 days) to CL also decreased ob gene mRNA levels in BAT, perimetric, and inguinal WAT in both animals. We concluded that acute and chronic regulation by a beta3-adrenoceptor agonist suppressed ob gene expression in obese Yellow KK mice and lean controls. Topics: Adipose Tissue; Adrenergic beta-Agonists; Animals; Body Weight; Dioxoles; Down-Regulation; Eating; Gene Expression Regulation; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Organ Size; Proteins; RNA, Messenger | 1998 |
In search of factors regulating body weight.
Topics: Animals; Body Weight; Cachexia; Homeostasis; Humans; Hypothalamus; Leptin; Obesity | 1998 |
The effect of leptin is enhanced by microinjection into the ventromedial hypothalamus.
To determine whether changes in food intake produced by leptin involve targeting the hormone to distinct central nervous system regions, guide cannulas were positioned stereotaxically into three brain regions--the ventromedial hypothalamus (VMH) (bilaterally, n = 6), the dorsal raphe nucleus (n = 3), and the lateral ventricle (n = 3)--of nonobese male rats (400-500 g). Daily food intake and body weight changes were measured during twice-daily injections of saline (0.1 microl) followed by recombinant human leptin (0.05 microg) for 3 days via the brain cannulas. VMH-injected rats also were followed during a postleptin saline recovery interval. This small dose of leptin did not change food intake or body weight from that during the preceding saline injection period in ventricle-injected or dorsal raphe-injected rats. In sharp contrast, VMH-injected rats ate much less food (56 +/- 8% basal) and lost 9 +/- 3 g/day or 5% of their body weight during 3 days of leptin administration. VMH-injected animals fully recovered from leptin-induced effects within 3 days. We conclude that small doses of leptin that do not effect eating behavior when delivered to the ventricle or the dorsal raphe (another brain region believed to regulate feeding), suppress food intake when injected into the VMH. These data suggest that the VMH or a brain region in close proximity to it is a key target for the biological actions of leptin. Topics: Animals; Body Weight; Cerebral Ventricles; Feeding Behavior; Humans; Injections, Intraventricular; Leptin; Male; Microinjections; Obesity; Proteins; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Stereotaxic Techniques; Ventromedial Hypothalamic Nucleus | 1997 |
Early onset of reproductive function in normal female mice treated with leptin.
Numerous studies have revealed an association between nutritional status, adiposity, and reproductive maturity. The role of leptin, a hormone secreted from adipose tissue, in the onset of reproductive function was investigated. Normal prepubertal female mice injected with leptin grew at a slower rate than controls as a result of the hormone's thinning effects, but they reproduced up to 9 days earlier than controls and showed earlier maturation of the reproductive tract. These results suggest that leptin acts as a signal triggering puberty, thus supporting the hypothesis that fat accumulation enhances maturation of the reproductive tract. Topics: Animals; Body Weight; Eating; Estradiol; Estrus; Female; Genitalia, Female; Leptin; Luteinizing Hormone; Mice; Mice, Inbred C57BL; Organ Size; Proteins; Recombinant Proteins; Reproduction; Sexual Maturation | 1997 |
Racial differences in plasma leptin concentrations in obese postmenopausal women.
Leptin may play an important role in the regulation of body weight by influencing energy intake and expenditure. Differences in body composition, resting energy expenditure (REE), and physical activity between African-American and Caucasian women could be reflective of racial differences in plasma leptin concentrations. Thus, we examined racial differences in leptin levels and the relationships of leptin to body composition and resting metabolism in obese postmenopausal African-American (n = 28) and Caucasian (n = 29) women matched for level of body fat. African-American and Caucasian women were similar in age (64.1 +/- 1.3 vs. 63.2 +/- 1.0 yr), body weight (84.7 +/- 3.3 vs. 80.4 +/- 1.3 kg), adipose tissue mass (39.7 +/- 2.8 vs. 38.0 +/- 1.0 kg), waist to hip ratio (0.81 +/- 0.02 vs. 0.81 +/- 0.01), and maximal aerobic capacity (1.5 +/- 0.05 vs. 1.6 +/- 0.05 L/min). African-American women had greater lean tissue mass than Caucasian women (41.8 +/- 1.1 vs. 39.3 +/- 0.6 kg; P = 0.05). The leptin concentration was 20% lower in African-American than Caucasian women (36.0 +/- 4.8 vs. 45.8 +/- 3.5; P < 0.05), whereas REE values were similar. Leptin correlated strongly with percent body fat in African-American (r = 0.71; P < 0.0001) and Caucasian women (r = 0.61; P < 0.001) and with REE in African-American (r = 0.58; P < 0.001), but not Caucasian, women (r = 0.08). These findings suggest racial differences in plasma leptin levels and in leptin's role in the regulation of REE, which may play a role in the greater incidence of obesity in the African-American compared to the Caucasian population. Topics: Adipose Tissue; Aged; Black People; Body Composition; Body Constitution; Body Weight; Female; Humans; Leptin; Middle Aged; Obesity; Postmenopause; Proteins; White People | 1997 |
The alphabet of weight control.
Topics: Adipose Tissue; Animals; Body Weight; Hypothalamus; Leptin; Melanocyte-Stimulating Hormones; Mice; Neuropeptide Y; Obesity; Proteins; Receptor, Melanocortin, Type 4; Receptors, Peptide | 1997 |
Leptin accelerates the onset of puberty in normal female mice.
The fat-derived hormone, leptin, is proposed to serve as an adipostatic signal to the brain to reduce food intake and body weight. In addition to its effects on body weight, chronic leptin treatment restores puberty and fertility to ob/ob mice with total leptin deficiency, and acute treatment substantially corrects hypogonadism in mice starved for 2 d without affecting body weight. Leptin may therefore be a critical signal, linking adiposity and reproduction. Since body weight and adiposity appear to play a critical role in the timing of puberty in humans and rodents, and leptin levels rise with increasing adiposity, we studied the effects of once daily injections of recombinant leptin on the onset of puberty in female mice weaned on day 21 and fed ad libitum. There was a linear increase in body weight during the study period, which was not altered by the dose of leptin used. Mice injected with leptin had an earlier onset of three classic pubertal parameters (i.e., vaginal opening, estrus, and cycling) compared with saline-injected controls. Leptin is the first peripheral molecule demonstrated to accelerate the maturation of the reproductive axis in normal rodents. We propose that leptin is the signal that informs the brain that energy stores are sufficient to support the high energy demands of reproduction, and may be a major determinant of the timing of puberty. Topics: Animals; Blood Chemical Analysis; Body Weight; Estradiol; Estrus; Female; Growth; Leptin; Mice; Mice, Inbred C57BL; Proteins; Recombinant Proteins; Sexual Maturation; Signal Transduction; Time Factors; Vagina | 1997 |
Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels.
The factors responsible for the variability in plasma leptin levels observed among individuals with similar body compositions remain unclear. To examine the impact of dietary variables, we compared the changes in leptin levels induced by fasting and dietary fat restriction with the expected decrease following a significant loss in adipose mass. A 21.4 +/- 3.7% weight loss led to a 76.3 +/- 8.1% decrease in mean plasma leptin level (25.2 +/- 9.3 to 6.1 +/- 3.4 ng/mL, P = 0.0001) in a group of 9 obese males. Despite a weight loss of only 2.6 +/- 0.8%, mean plasma leptin levels fell by 61.9 +/- 25.2% (8.5 +/- 4.5 to 2.4 +/- 0.5 ng/mL, P < 0.01) in 7 nonobese females subjected to 3 days of fasting. Leptin levels in fasted subjects returned to baseline within 12 h of refeeding. Individual high- and low-fat meals given to 19 subjects after an overnight fast had no effect on plasma leptin levels. Reduction in dietary fat content from 37-10% of total calories for 7 weeks was also without effect on plasma leptin levels in these subjects. We conclude that plasma leptin levels primarily reflect total adipose mass, rather than meal consumption or dietary energy source, but that the reduction in leptin levels with ongoing fasting is disproportionate to the reduction in adipose mass. The ability of fasting to deactivate this presumed physiological satiety system may have been advantageous in environments characterized by rapid changes in food availability. Topics: Adult; Body Mass Index; Body Weight; Dietary Fats; Fasting; Food; Humans; Leptin; Male; Middle Aged; Obesity; Proteins | 1997 |
Leptin in human reproduction: serum leptin levels in pregnant and lactating women.
Experiments in ob/ob female mice demonstrated that leptin injections not only reduced weight and fat mass, but also restored fertility and partial lactation. To explore factors regulating ob gene expression in reproductive women, we measured serum leptin, body fat, energy expenditure, and milk production in 65 women at 36 weeks of gestation, and at 3 and 6 months postpartum. Serum leptin was measured by solid-phase sandwich enzyme immunoassay, and serum insulin and PRL by solid-phase 125I RIA. Total body water by deuterium dilution, body volume by hydrodensitometry, and bone density by dual-energy x-ray absorptiometry were used to estimate body fat. Serum leptin per unit fat mass was significantly higher at 36 weeks of pregnancy than at 3 and 6 months postpartum (1.25 vs. 0.75, 0.73 ng.mL-1.kg-1). Postpartum normalization of leptin was associated with changes not only in weight and fat mass, but also serum insulin. Leptin was not different between lactating and nonlactating women. Leptin may have affected milk production indirectly through its negative effect on serum PRL. Adjusted for fat-free mass and fat mass, rates of energy expenditure were not significantly correlated with leptin. Our results provide evidence that factors other than fat mass alone modulate serum leptin in reproductive women. Topics: Adult; Body Composition; Body Mass Index; Body Weight; Energy Metabolism; Fasting; Female; Humans; Insulin; Lactation; Leptin; Pregnancy; Prolactin; Proteins; Reproduction | 1997 |
Obesity sheds its secrets.
Topics: Agouti Signaling Protein; alpha-MSH; Animals; Body Weight; Carrier Proteins; Hormones; Humans; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Obese; Neuropeptide Y; Obesity; Proteins; Receptors, Cell Surface; Receptors, Corticotropin; Receptors, Leptin; Receptors, Melanocortin; Starvation | 1997 |
Leptin treatment rescues the sterility of genetically obese ob/ob males.
Leptin, a hormone secreted from white adipose tissue, has been shown to normalize the body weight of ob/ob but not db/db mice as postulated by Coleman in his classical parabiosis experiments. The major effect of leptin is therefore to decrease food intake, thus resulting in a breakdown of fat stores. Recently, we have suggested that leptin plays a role in reproductive physiology based on the observation that leptin treatment but not food restriction rescues the sterility of ob/ob females. In the present communication, we treated sterile ob/ob males with leptin and asked whether fertility could be induced, thus selecting their reproductive ability as the endpoint of the experiment. Our results show that all food-restricted ob/ob males are unable to impregnate normal C57BL/6J females. However, all leptin-treated ob/ob males fertilized normal females mice that carried out normal pregnancies and deliveries, demonstrating that the reproductive capacity of ob/ob males was corrected only with leptin treatment. Furthermore, reproductive indices such as testicular weight and histology are normalized in leptin-treated animals. Therefore, as in ob/ob females, leptin plays a significant role in the male mouse reproductive pathways. Topics: Animals; Body Weight; Eating; Female; Fertility; Infertility; Leptin; Male; Mice; Obesity; Organ Size; Proteins; Testis | 1997 |
The pharmacologic management of obesity.
Topics: Adult; Anti-Obesity Agents; Appetite Depressants; Body Mass Index; Body Weight; Chronic Disease; Fenfluramine; Forecasting; Humans; Leptin; Obesity; Phentermine; Proteins; United States; United States Food and Drug Administration | 1997 |
In vivo effects of leptin-related synthetic peptides on body weight and food intake in female ob/ob mice: localization of leptin activity to domains between amino acid residues 106-140.
In C57BL/6J ob/ob mice, a single base mutation of the ob gene in codon 105 results in the replacement of arginine by a premature stop codon and production of a truncated inactive form of leptin. These observations suggest that leptin activity may be localized, at least in part, to domains distal to amino acid residue 104. To investigate this possibility, we synthesized six overlapping peptide amides corresponding to residues 106-167 of leptin, and examined their effects on body weight and food intake in female C57BL/6J ob/ob mice. When compared with vehicle-injected control mice, weight gain by mice receiving 28 daily 1-mg i.p. injections of LEP-(106-120), LEP-(116-130), or LEP-(126-140) was significantly (P < 0.01) reduced with no apparent toxicity. Weight gain by mice receiving LEP-(136-150), LEP-(146-160), or LEP-(156-167) was not significantly different from that of vehicle-injected control mice. The effects of LEP-(106-120), LEP-(116-130), or LEP-(126-140) were most pronounced during the first week of peptide treatment. Within 7 days, mice receiving these peptides lost 12.3%, 13.8%, and 9.8%, respectively, of their initial body weights. After 28 days, mice given vehicle alone, LEP-(136-150), LEP-(146-160), or LEP-(156-167) were 14.7%, 20.3%, 25.0%, and 24.8% heavier, respectively, than they were at the beginning of the study. Mice given LEP-(106-120) or LEP-(126-140) were only 1.8% and 4.2% heavier, respectively, whereas mice given LEP-(116-130) were 3.4% lighter. Food intake by mice receiving LEP-(106-120), LEP-(116-130), or LEP-(126-140), but not by mice receiving LEP-(136-150), LEP-(146-160), or LEP-(156-167), was reduced by 15%. The results of this study indicate 1) that leptin activity is localized, at least in part, in domains between residues 106-140; 2) that leptin-related peptides have in vivo effects similar to those of native leptin; and 3) offer hope for development of peptide analogs of leptin having potential application in human or veterinary medicine. Topics: Amino Acid Sequence; Animals; Binding Sites; Body Weight; Eating; Female; Humans; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Sequence Data; Obesity; Peptide Fragments; Peptide Mapping; Peptides; Proteins | 1997 |
Glucocorticoids as counterregulatory hormones of leptin: toward an understanding of leptin resistance.
The product of the ob gene, leptin, is a hormone secreted by adipose tissue that acts in the hypothalamus to regulate the size of the body fat depot. Its central administration has been shown to decrease food intake and body weight, while favoring energy dissipation. As glucocorticoids are known to play a permissive role in the establishment and maintenance of obesity syndromes in rodents, it was hypothesized that they do so by restraining the effect of leptin. Leptin injected intracerebroventricularly as a bolus of 3 microg in normal rats induced modest reductions in body weight and food intake. In marked contrast, the same dose of leptin had very potent and long-lasting effects in decreasing both body weight and food intake when administered to adrenalectomized rats. Further, glucocorticoid supplementation of adrenalectomized rats dose-dependently inhibited these potent effects of leptin. These data suggest that glucocorticoids play a key inhibitory role in the action of leptin. Under normal conditions, this inhibitory influence of glucocorticoids may prevent lasting hypophagia. In obesity with degrees of hypercorticism, it may contribute to "leptin resistance," whose etiology is still little understood. Topics: Adrenalectomy; Animals; Body Weight; Eating; Female; Glucocorticoids; Injections, Intraventricular; Leptin; Proteins; Rats; Rats, Sprague-Dawley | 1997 |
Expression of leptin and beta 3-adrenergic receptors in rat adipose tissue in altered thyroid states.
The level of leptin [the obese (ob) gene product] mRNA is markedly elevated in hypothyroid male rats. The administration of tri-iodothyronine (T3) to hypothyroid rats resulted in a 40% decrease in leptin mRNA at 8 h. This decrease in leptin mRNA was associated with a parallel decline in circulating leptin levels of about 50% at 24 h. Conversely, beta 3-adrenergic receptor mRNA levels were markedly decreased in epididymal adipose tissue from hypothyroid rats. T3 administration resulted in a 147% increase at 12 h in beta 3-adrenergic receptor mRNA. There was a corresponding increase due to T3 in the lipolytic response to the specific beta 3-adrenergic agonist CL 316,243 that paralleled the increase in beta 3-adrenergic receptor mRNA. T3-mediated changes in leptin and beta 3-adrenergic receptor mRNAs were blocked by cycloheximide, suggesting the involvement of short-lived proteins in these effects. The present results indicate that T3 has opposite effects to those of insulin on the white adipose tissue of rats with respect to leptin mRNA expression. Topics: Adipocytes; Adipose Tissue; Animals; Blood Proteins; Body Weight; Hypothyroidism; Leptin; Lipolysis; Male; Obesity; Protein Biosynthesis; Proteins; Rats; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; RNA, Messenger | 1997 |
Effect of diet composition on leptin concentration in lean subjects.
The recently discovered leptin is thought to be a satiety signal regulating food intake. In mice, it has been shown that on a high-fat diet leptin concentration increases, but the increase was explained by increased fat mass. It is yet unknown whether leptin is influenced by other nutritional factors. Here, leptin levels were measured in human volunteers on a high-fat diet, while maintaining energy balance. Twelve healthy, non-obese males and females (age, 26 +/- 2 years; 21.4 +/- 0.5 body mass index, habitual fat intake, 29 +/- 1 energy % [en%]) consumed a high-fat diet (60 en% fat) for 7 days (days 1 to 7). Subjects were in energy balance (range, -0.15 to +0.23 MJ/d) as measured in a respiration chamber on days 1 to 3 and 7. Fasting baseline plasma leptin concentrations correlated with body fat percentage (R2 = .64, P < .005). On average, no changes in leptin concentration on the high-fat diet were observed. However, on an individual basis, changes in leptin concentrations in response to the high-fat diet correlated with changes in insulin concentrations. In conclusion, in the case of energy balance, short-term changes in diet composition have no effect on fasting leptin concentration in lean subjects. Topics: Blood Glucose; Body Composition; Body Weight; Diet; Fatty Acids, Nonesterified; Female; Humans; Leptin; Male; Proteins | 1997 |
Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats.
Leptin (ob protein) and glucagon-like peptide-1-(7-36) amide (GLP-1) are peptides recently proposed to be involved in the regulation of food intake. Although the ability of exogenous leptin and GLP-1 to modulate consummatory behavior is consistent with the suggestion that these peptides are endogenous regulatory agents, central administration of these peptides may have aversive side effects, which could explain the anorexia. In the present experiment, exposure to a saccharine taste was immediately followed by central administration of leptin or GLP-1 to determine if these drugs could produce a conditioned taste aversion (CTA) in rats. At doses equated for producing comparable reductions in short-term food intake, GLP-1, but not leptin, generated a robust CTA. Although leptin caused no aversion, this peptide was the only drug to cause relatively long-term reductions in food consumption (16 h) and body weight (24 h). Hence, the results indicate that central GLP-1 produces aversive side effects, and it is argued that these nonspecific effects may explain the anorectic actions of GLP-1. Topics: Animals; Avoidance Learning; Body Weight; Brain; Conditioning, Psychological; Eating; Glucagon-Like Peptide 1; Injections, Intraventricular; Leptin; Male; Peptides; Proteins; Rats; Rats, Inbred Strains; Saccharin; Solutions; Taste | 1997 |
Ill fitting genes: the biology of weight and shape control in relation to body composition and eating disorders.
Topics: Animals; Appetite Regulation; Body Composition; Body Constitution; Body Weight; Disease Models, Animal; Feeding and Eating Disorders; Humans; Leptin; Proteins | 1997 |
On raising energy expenditure in ob/ob mice.
Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Eating; Energy Intake; Energy Metabolism; Leptin; Mice; Mice, Obese; Neuropeptide Y; Obesity; Oxygen Consumption; Proteins | 1997 |
Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance.
Receptor subunits for the neurocytokine ciliary neurotrophic factor (CNTF) share sequence similarity with the receptor for leptin, an adipocyte-derived cytokine involved in body weight homeostasis. We report here that CNTF and leptin activate a similar pattern of STAT factors in neuronal cells, and that mRNAs for CNTF receptor subunits, similarly to the mRNA of leptin receptor, are localized in mouse hypothalamic nuclei involved in the regulation of energy balance. Systemic administration of CNTF or leptin led to rapid induction of the tis-11 primary response gene in the arcuate nucleus, suggesting that both cytokines can signal to hypothalamic satiety centers. Consistent with this idea, CNTF treatment of ob/ob mice, which lack functional leptin, was found to reduce the adiposity, hyperphagia, and hyperinsulinemia associated with leptin deficiency. Unlike leptin, CNTF also reduced obesity-related phenotypes in db/db mice, which lack functional leptin receptor, and in mice with diet-induced obesity, which are partially resistant to the actions of leptin. The identification of a cytokine-mediated anti-obesity mechanism that acts independently of the leptin system may help to develop strategies for the treatment of obesity associated with leptin resistance. Topics: Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Brain; Carrier Proteins; Cell Line; Ciliary Neurotrophic Factor; Diabetes Mellitus, Type 2; Dietary Fats; DNA-Binding Proteins; Grooming; Humans; Hybrid Cells; Insulin; Leptin; Male; Mice; Mice, Inbred AKR; Mice, Inbred C57BL; Mice, Obese; Motor Activity; Nerve Growth Factors; Nerve Tissue Proteins; Neuroblastoma; Neurons; Obesity; Point Mutation; Proteins; Receptor, Ciliary Neurotrophic Factor; Receptors, Cell Surface; Receptors, Leptin; Receptors, Nerve Growth Factor; Recombinant Proteins | 1997 |
[Leptin: a genetic solution to obesity?].
LEPTINE: Produced by adipose tissue, leptine is a regulatory hormone controlling body fat mass.. The human gene coding for leptine was first cloned in 1984. Its receptor, a member of the class 1 cytokine receptor family, has also been identified. VARIABLE SERUM LEVELS: Plasma levels of leptine in normal-weight subjects are in the 5ng/ml range and reach 50 ng/ml in obese subjects. Weight gain leads to higher blood levels and weight loss to lower levels. The effect of leptine is to approach a weight equilibrium. Leptine level is correlated with energy balance.. Leptine acts on hypothalamic centers controlling satiety. One of the essential mediators is neuropeptide Y. Resistance to leptine has been evidenced in human obesity. Resistance can occur as several levels and would be one of the explanations for massive obesity involving genetic factors. Leptine may also play a role in certain types of infertility. Topics: Animals; Body Weight; Energy Metabolism; Humans; Leptin; Mice; Mice, Obese; Obesity; Proteins | 1997 |
Invited editorial on "Acute and chronic effects of exercise on leptin levels in humans".
Topics: Adipose Tissue; Animals; Body Weight; Energy Metabolism; Exercise; Humans; Leptin; Mice; Mice, Inbred Strains; Obesity; Proteins | 1997 |
beta 3-Adrenergic-mediated suppression of leptin gene expression in rats.
To investigate the role of beta 3-adrenergic receptors in the suppression of leptin gene expression, we fasted F-344 rats to decrease leptin mRNA levels, refed the rats to stimulate leptin mRNA production, and examined the ability of the beta 3-adrenergic agonist CGP-12177 to prevent the rise in leptin mRNA levels. In the initial 2 h after CGP-12177 (0.75 mg/kg), there were significant reductions in both food consumption and leptin mRNA levels in epididymal, perirenal, and interscapular white adipose tissue. We were unable to detect leptin mRNA in interscapular brown adipose tissue (IBAT), whereas there was a significant increase in uncoupling protein mRNA levels in IBAT after CGP-12177. The suppression of leptin mRNA and food intake by CGP-12177 was confirmed in a second experiment using another rat strain, the F-344 x BN. Furthermore, refeeding after a period of fasting increased leptin mRNA, which was prevented by CGP-12177. These data indicate a role for beta 3-adrenergic-mediated regulation of leptin gene expression in nonmutant rodents and are consistent with other reports suggesting that beta 3-adrenergic agonists suppress food intake. Topics: Adipose Tissue; Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Body Weight; Carrier Proteins; Crosses, Genetic; Ion Channels; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Obesity; Propanolamines; Protein Biosynthesis; Rats; Rats, Inbred BN; Rats, Inbred F344; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; RNA, Messenger; Suppression, Genetic; Transcription, Genetic; Uncoupling Protein 1 | 1997 |
Loss of body fat in lean parabiotic partners of ob/ob mice.
The objective of this experiment was to confirm whether changes in serum leptin and leptin expression were consistent with it being the "lipostatic" factor implicated by earlier parabiosis studies. Lean (+/?) and obese (ob/ob) female C57B1/6J-ob mice were parabiosed (lean-ob/ob) at 7 wk of age. Controls were ob/ob-ob/ob and lean-lean pairs, and single lean and ob/ob mice. Pairs were maintained for 50 days. In ob/ob members of lean-ob/ob pairs serum insulin was normalized, food intake was suppressed, and body fat was reduced by 14%. Lean partners of ob/ob mice had a reduced rectal temperature and experienced a 37% reduction in body fat. Despite loss of fat, serum leptin and adipose leptin mRNA expression were unchanged in lean partners of ob/ob mice. These results suggest that, in lean-ob/ob parabiotic pairs, the ob/ob mouse responds to leptin originating in the lean parabiont, whereas the lean partner responds to a circulating signal, originating in the ob/ob mouse, that maintains leptin expression at inappropriate levels for the degree of adiposity of the lean animal. Topics: Adipose Tissue; Animals; Body Temperature; Body Weight; Eating; Female; Insulin; Leptin; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Parabiosis; Proteins; Rectum; Reference Values; RNA, Messenger | 1997 |
beta-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy.
Leptin was overexpressed in the liver of normal Wistar rats by infusing recombinant adenovirus containing the cDNA encoding leptin. Plasma leptin levels rose to 12-24 ng/ml (vs. <2 ng/ml in control rats), and food intake and body weight fell. Visible fat disappeared within 7 days. Plasma insulin fell to <50% of normal in association with hypoglycemia, suggesting enhanced insulin sensitivity. Although beta-cells appeared histologically normal, the pancreases were unresponsive to perfusion with stimulatory levels of glucose and arginine. Since islet triglyceride content was 0, compared with 14 ng/islet in pair-fed control rats, we coperfused a 2:1 oleate:palmitate mixture (0.5 mmol/l). This restored insulin responses to supranormal levels. When normal islets were cultured with 20 ng/ml of leptin, they too became triglyceride-depleted and failed to respond when perifused with glucose or arginine. Perifusion of fatty acids restored both responses. We conclude that in normal rats, hyperleptinemia for 2 weeks causes reversible beta-cell dysfunction by depleting tissue lipids, thereby depriving beta-cells of a lipid-derived signal required for the insulin response to other fuels. Topics: Adenoviridae; Animals; Arginine; beta-Galactosidase; Blood Glucose; Body Weight; Carrier Proteins; Disease Models, Animal; Eating; Genetic Therapy; Glucose; Immunoblotting; In Vitro Techniques; Infusions, Intra-Arterial; Insulin; Islets of Langerhans; Leptin; Male; Pancreas; Perfusion; Proteins; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Time Factors | 1997 |
Effects of leptin on insulin sensitivity in normal rats.
To determine whether leptin has insulin sensitizing effects in normal rodents, we measured plasma glucose and insulin concentrations in male Sprague-Dawley rats treated with leptin or vehicle by continuous s.c. infusion for 48 h. In additional experiments, we examined the acute effect of i.v. leptin upon insulin sensitivity under conditions of clamped glycemia. Subcutaneous leptin was administered at 10.0 and 1.0 microg/h. To avoid confounding effects of differences in food intake, both leptin- and vehicle-treated rats were fasted during the 48-h period of infusion. Infusion of leptin, 10 microg/h, significantly reduced both plasma glucose and insulin. Leptin, 1.0 microg/h, also decreased plasma glucose and insulin, although the effects on insulin did not achieve statistical significance. Leptin at either dose did not alter body weight or epididymal fat mass compared with vehicle treated controls. Leptin, 10 microg/h, decreased circulating insulin-like growth factor-1 levels. No differences in GLUT-4 content in either in brown or epididymal fat were observed as a result of leptin-treatment. Leptin, 10 microg/h, significantly decreased urine osmolality, increased water intake, and reduced renal potassium excretion compared with vehicle-infused rats. In additional rats, we measured the acute effect of i.v. leptin on insulin sensitivity determined as whole body glucose utilization during hyperinsulinemic glucose clamps performed at glucose targets of 60 and 90 mg/100 ml. Glucose utilization was increased by 29% during the last 135 min of glycemia clamped at 60 mg/100 ml (P < 0.05) and by 30% during the last 135 min of glycemia clamped at 90 mg/dl (P < 0.01) in rats infused with leptin compared with vehicle. In summary, leptin increased insulin sensitivity in normal rats both under fasting conditions and in the presence of hyperinsulinemia at clamped glucose. These effects did not appear dependent on altered body weight. Leptin also altered salt and water metabolism under fasting conditions resulting in increased water intake and more dilute urine. Topics: Adipose Tissue, Brown; Animals; Blood Glucose; Body Weight; Epididymis; Glucose; Glucose Transporter Type 4; Hyperinsulinism; Infusion Pumps, Implantable; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Male; Monosaccharide Transport Proteins; Muscle Proteins; Proteins; Rats; Rats, Sprague-Dawley; Time Factors; Water-Electrolyte Balance | 1997 |
Physiological response to long-term peripheral and central leptin infusion in lean and obese mice.
Recent data have identified leptin as an afferent signal in a negative-feedback loop regulating the mass of the adipose tissue. High leptin levels are observed in obese humans and rodents, suggesting that, in some cases, obesity is the result of leptin insensitivity. This hypothesis was tested by comparing the response to peripherally and centrally administered leptin among lean and three obese strains of mice: diet-induced obese AKR/J, New Zealand Obese (NZO), and Ay. Subcutaneous leptin infusion to lean mice resulted in a dose-dependent loss of body weight at physiologic plasma levels. Chronic infusions of leptin intracerebroventricularly (i.c.v.) at doses of 3 ng/hr or greater resulted in complete depletion of visible adipose tissue, which was maintained throughout 30 days of continuous i.c.v. infusion. Direct measurement of energy balance indicated that leptin treatment did not increase total energy expenditure but prevented the decrease that follows reduced food intake. Diet-induced obese mice lost weight in response to peripheral leptin but were less sensitive than lean mice. NZO mice were unresponsive to peripheral leptin but were responsive to i.c.v. leptin. Ay mice did not respond to subcutaneous leptin and were 1/100 as sensitive to i.c.v. leptin. The decreased response to leptin in diet-induced obese, NZO, and Ay mice suggests that obesity in these strains is the result of leptin resistance. In NZO mice, leptin resistance may be the result of decreased transport of leptin into the cerebrospinal fluid, whereas in Ay mice, leptin resistance probably results from defects downstream of the leptin receptor in the hypothalamus. Topics: Administration, Cutaneous; Animals; Body Weight; Diet; Dose-Response Relationship, Drug; Injections, Intraventricular; Leptin; Mice; Mice, Inbred C57BL; Obesity; Proteins | 1997 |
Regulation of plasma leptin in mice: influence of age, high-fat diet, and fasting.
Mechanisms regulating circulating leptin are incompletely understood. We developed a radioimmunoassay for mouse leptin to examine the influence of age, dietary fat content, and fasting on plasma concentrations of leptin in the background strain for the ob/ob mouse, the C57BL/6J mouse. Plasma leptin increased with age [5.3 +/- 0.6 ng/ml at 2 mo (n = 23) vs. 14.2 +/- 1.6 ng/ml at 11 mo (n = 15), P < 0.001]. Across all age groups (2-11 mo, n = 160), log plasma leptin correlated with body weight (r = 0.68, P < 0.0001), plasma insulin (r = 0.38, P < 0.001), and amount of intra-abdominal fat (r = 0.90, P < 0.001), as revealed by magnetic resonance imaging. Plasma leptin was increased by a high-fat diet (58% fat for 10 mo) and reduced by fasting for 48 h. The reduction of plasma leptin was correlated with the reduction of plasma insulin (r = 0.43, P = 0.012) but not with the initial body weight or the change in body weight. Moreover, the reduction in plasma leptin by fasting was impaired by high-fat diet. Thus plasma leptin in C57BL/6J mice 1) increases with age or a high-fat diet; 2) correlates with body weight, fat content, and plasma insulin; and 3) is reduced during fasting by an action inhibited by high-fat diet and related to changes of plasma insulin. Topics: Adipose Tissue; Aging; Animals; Body Weight; Dietary Fats; Fasting; Female; Insulin; Leptin; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Proteins; Radioimmunoassay; Reproducibility of Results | 1997 |
Postnatal development of the ob gene system: elevated leptin levels in suckling fa/fa rats.
The postnatal development of the ob gene system has been examined in Zucker fa/fa and +/fa plus +/+ (referred to as +/?) rats. White adipose tissue was taken from animals aged 1 to 28 days. Before weaning, white fat was predominantly subcutaneous, the amount increasing rapidly after birth. ob mRNA was detected by Northern blotting in samples of inguinal fat at 1 day of age and thereafter. Circulating leptin, measured by enzyme-linked immunosorbent assay, was also detectable from 1 day of age, the level rising to a peak by 10 days of age and then declining. The fa/fa genotype was determined from the size of the product after Msp I digestion of the Ob-receptor gene obtained by polymerase chain reaction amplification of genomic DNA. No statistically significant difference in ob mRNA level between fa/fa and +/? animals was obtained before 25 days of age. However, leptin levels were significantly higher in the fa/fa mutant by 10 days of age, despite the absence of any significant elevation in the weight of the major fat depots or in ob mRNA level. It is concluded that the ob gene is expressed and leptin produced early in postnatal life in rats; the elevation of circulating leptin in suckling fa/fa animals indicates that dysregulation of the leptin system occurs before the overt development of the obese phenotype. Topics: Adipose Tissue; Aging; Animals; Base Sequence; Body Weight; DNA Primers; Female; Gene Expression Regulation, Developmental; Genotype; Leptin; Male; Molecular Sequence Data; Obesity; Organ Size; Polymerase Chain Reaction; Protein Biosynthesis; Proteins; Rats; Rats, Zucker; RNA, Messenger; Transcription, Genetic | 1997 |
Attenuation of leptin-mediated effects by monosodium glutamate-induced arcuate nucleus damage.
Leptin is a protein secreted by adipocytes that is important in regulating appetite and adiposity. Recent studies have suggested the presence of leptin receptors in the arcuate nucleus of the hypothalamus (ANH). Neonatal administration of monosodium glutamate (MSG) damages the ANH, resulting in obesity and neuroendocrine dysfunction. Neonatal administration of MSG was utilized to test the hypothesis that the anatomic site for many of leptin's actions is the ANH. Female control (n = 6) and MSG-treated rats (n = 7) were implanted for 14 days with osmotic minipumps containing phosphate-buffered saline or leptin (1 mg.kg-1.day-1). Leptin suppressed (P < 0.05) body weight gain in controls but did not suppress weight gain in MSG-treated rats. Leptin decreased (P < 0.05) fat depots in controls but had no effect in MSG-treated rats. Night feeding was suppressed (P < 0.05) in leptin-treated control rats. MSG-treated rats showed a suppression in food intake that was of a smaller magnitude and appeared later in the course of leptin treatment. These findings suggest that leptin mediates some physiological actions related to fat mobilization via receptors located in the ANH. Topics: Adipose Tissue; Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Body Weight; Circadian Rhythm; Feeding Behavior; Female; Infusions, Parenteral; Leptin; Obesity; Pregnancy; Proteins; Rats; Rats, Sprague-Dawley; Reference Values; Sodium Glutamate; Time Factors; Weight Gain | 1997 |
[Advances in the pathogeny of obesity: the physiology of leptin].
Topics: Animals; Body Weight; Carrier Proteins; Gene Expression Regulation; Humans; Leptin; Mice; Neuropeptide Y; Obesity; Parabiosis; Proteins; Receptors, Cell Surface; Receptors, Leptin | 1997 |
Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage.
It is commonly accepted that at least in girls puberty starts when a minimum level of body mass or a certain amount of body fat are present. However the precise signal by which adipose stores inform the hypothalamus of the degree of energetic reserves is unknown. Leptin is a hormone produced by the adipocytes to regulate food intake and energy expenditure at the hypothalamic level. To understand whether leptin is the adipose tissue signal that allows puberty, 789 normal children of both sexes, age 5-15 yr, were transversally studied. Leptin levels, as well as gonadal and gonadotropins, levels, were analyzed in addition to the determination of auxological parameters. In an age-related analysis, leptin levels in girls rose from 5-15 yr (from 4.3 +/- 0.4 to 8.5 +/- 0.9 micrograms/L) in parallel with body weight. Boys always had lower leptin levels than girls (3.3 +/- 0.3 micrograms/L at 5 yr), but they rose in parallel with weight until 10 yr (5.3 +/- 0.7 micrograms/L), when a striking decrease was observed until 15 yr (3.0 +/- 0.3 micrograms/L). In girls, leptin was the first hormone to rise followed by FSH and later by LH and estradiol. A similar pattern occurred in boys, despite the fact that leptin dropped after 10 yr when testosterone rises. Divided into three pubertal stages, i.e. P1 = prepuberty, P2 = early puberty, and P3 = overt puberty, in girls the four hormones rose progressively from P1 to P3, but from P2 to P3 the present increment was greater for LH and estradiol. In boys, leptin decreased from P1 to P3, whereas FSH, LH, and testosterone rose. The age-related changes were not caused by adiposity variations, because data did not change when subtracting values of children over 97% of standard deviation score of body mass index.. 1) leptin appears to increase in both boys and girls before the appearance of other reproductive hormones related to puberty; 2) leptin levels in boys are always lower than in girls, although they increase with age until the age 10 yr; 3) leptin in boys declines about the time testosterone increases. Leptin may well be a permissive factor for the initiation of pubertal events. Topics: Adolescent; Aging; Body Mass Index; Body Weight; Child; Female; Gonadal Steroid Hormones; Hormones; Humans; Leptin; Male; Pituitary Hormones; Proteins; Puberty; Reference Values; Sex Characteristics | 1997 |
Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat.
Thiazolidinediones are potent antidiabetic compounds, in both animal and human models, which act by enhancing peripheral sensitivity to insulin. Thiazolidinediones are high-affinity ligands for peroxisome proliferator-activated receptor-gamma, a key factor for adipocyte differentiation, and they are efficient promoters of adipocyte differentiation in vitro. Thus, it could be questioned whether a thiazolidinedione therapy aimed at improving insulin sensitivity would promote the recruitment of new adipocytes in vivo. To address this problem, we have studied the in vivo effect of pioglitazone on glucose metabolism and gene expression in the adipose tissue of an animal model of obesity with insulin resistance, the obese Zucker (fa/fa) rat. Pioglitazone markedly improves insulin action in the obese Zucker (fa/fa) rat, but doubles its weight gain after 4 weeks of treatment. The drug induces a large increase of glucose utilization in adipose tissue, where it stimulates the expression of genes involved in lipid metabolism such as the insulin-responsive GLUT, fatty acid synthase, and phosphoenolpyruvate carboxykinase genes, but decreases the expression of the ob gene. These changes are related to both an enhanced adipocyte differentiation, as shown by the large increase in the number of small adipocytes in the retroperitoneal fat pad, and a direct effect of pioglitazone on specific gene expression (phosphoenolpyruvate carboxykinase and ob genes) in mature adipocytes. Topics: Adipocytes; Animals; Body Weight; Cell Differentiation; Fatty Acid Synthases; Female; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Glucose; Glucose Transporter Type 4; Insulin Resistance; Leptin; Lipid Metabolism; Lipid Mobilization; Monosaccharide Transport Proteins; Muscle Proteins; Obesity; Phosphoenolpyruvate Carboxykinase (GTP); Pioglitazone; Proteins; Rats; Rats, Mutant Strains; Thiazoles; Thiazolidinediones | 1997 |
Low plasma leptin in response to dietary fat in diabetes- and obesity-prone mice.
Despite the fact that mutations resulting in the absence of leptin or its receptor have been associated with severe obesity and diabetes, such mutations do not appear to be responsible for most human obesity. Indeed, diet-induced obesity in animals and humans has been characterized by hyperleptinemia. This has been interpreted as evidence for leptin resistance. However, no careful longitudinal studies evaluating the role of leptin in the development of obesity exist. We report a series of studies in A/J and C57BL/6J (B/6) mice that demonstrate a direct relationship between the ability to increase plasma leptin levels in response to a high-fat diet and resistance to the subsequent development of obesity and diabetes. While leptin levels are similar in lean, low-fat-fed A/J and B/6 mice, the effects of a high-fat diet on plasma leptin differ dramatically between the two strains. After 4 weeks of high-fat feeding, leptin levels in A/J mice increased 10-fold, and this elevated level was maintained independent of weight gain throughout a 14-week feeding period. However, in B/6 mice, leptin levels remained at least twofold lower and only rose very gradually along with a significant increase in adiposity, hyperglycemia, and hyperinsulinemia. These differences in the response of leptin to diet are independent of food intake and plasma insulin levels during the 1st month of feeding. Further, we demonstrated that leptin administration did not influence the expression of the novel uncoupling protein UCP2, which also responds to dietary fat. From these results, we suggest that the response of leptin to fat feeding may be an important predictor of the development of subsequent obesity. Topics: Animals; Body Temperature; Body Weight; Diabetes Mellitus, Experimental; Dietary Fats; Ion Channels; Leptin; Membrane Transport Proteins; Mice; Mice, Inbred A; Mice, Inbred C57BL; Mice, Inbred Strains; Mitochondrial Proteins; Obesity; Proteins; Time Factors; Uncoupling Protein 2 | 1997 |
Effects of leptin administration on long-term selected fat mice.
To assess the role of genetic changes in sensitivity to leptin hormone in contributing to responses to long-term selection for fatness, leptin was administered to a long-term fat selected (F) and a control line (C) of mice. These lines differ almost three fold in their percentage of fat (fat%) at about 15 weeks of age. Treated (T) animals received twice-daily intraperitoneal injections of 5mg/kg leptin from 91 to 105 days of age; untreated (U) animals received equivolume injections of phosphate-buffered saline. Treated compared with untreated animals in both lines had significantly (P < 0.05) lower mean body weight, food intake and fatness at the end of test (fat%: CT 3%, CU 7.4%, FT 14.9%, FU 21.1%). The differences in response between the lines [(CT-CU)-(FT-FU)] were all non-significant (P > 0.05), however. There was a very wide range of fatness (estimated from dry matter content) among FT animals (3-29%), much higher than in FU (15-31%), CT (0.7-6.4%) and CU (2-15%) animals. While sensitivity to leptin remains in the fat line, response appears to vary among animals at the dose level used. Topics: Adipose Tissue; Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Leptin; Male; Mice; Mice, Inbred Strains; Obesity; Proteins; Selection, Genetic | 1997 |
Morphologic and molecular changes induced by recombinant human leptin in the white and brown adipose tissues of C57BL/6 mice.
Leptin is a 16-kd protein synthesized and secreted by adipose tissue, which regulates adiposity and body weight. To investigate the peripheral effects of recombinant human leptin, lean C57BL/6 mice were treated with subcutaneous injections of vehicle or 20 mg/kg/day leptin for 1 to 14 days. Groups of animals were killed on Days 1, 2, 3, 4, 7, or 8 and 15 to evaluate the time course of clinical chemistry, morphologic, and molecular changes in white (WAT) and brown adipose tissue (BAT) depots. There was a progressive daily reduction in the body weight of mice receiving leptin. By Day 15, the body weight of leptin-treated groups decreased by 6% to 8% relative to base-line weight. Clinical chemistry changes in treated mice included decreased cholesterol and triglyceride levels. At necropsy, the mice had rapidly progressive atrophy of subcutaneous, intra-abdominal, and retroperitoneal WAT and interscapular BAT depots, with complete depletion of fat stores by Days 3 to 4 in most females and by Days 7 to 14 in male mice. Histologically, white and brown adipocytes underwent marked atrophy with loss of lipid droplets and activation of BAT cells in WAT depots. Ultrastructurally, white and brown adipocytes contained numerous, enlarged mitochondria. Molecular analysis of key adipose tissue genes in brown and white fat depots revealed a rapid, selective increase in the mRNA expression of thermogenic proteins and lipolytic enzymes, including uncoupling proteins 1 and 2, lipoprotein lipase, and hormone-sensitive lipase, with decreases in the lipogenic enzyme fatty acid synthase, endogenous leptin, and cytochrome c oxidase. These data suggest that the peripheral effects of leptin include increased thermogenesis and lipid oxidation in brown fat coupled with increased lipolysis and decreased fat synthesis in white and brown fat, which lead to a rapid reduction in the body weight and adiposity of mice. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Atrophy; Blood; Body Weight; Female; Humans; In Situ Hybridization; Leptin; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron; Molecular Sequence Data; Nucleic Acid Hybridization; Proteins; Recombinant Proteins; Ribonucleases | 1997 |
Hyperleptinemia, leptin resistance, and polymorphic leptin receptor in the New Zealand obese mouse.
New Zealand Obese (NZO) mice exhibit a polygenic syndrome of hyperphagia, obesity, hyperinsulinemia, and hyperglycemia similar to that observed in young diabetes mutant mice on the C57BLKS/J background (C57BLKS/J-Lepr(db)/Lepr(db)). Here we show that in NZO this syndrome is accompanied by a marked elevation of the leptin protein in adipose tissue and serum. The promoter region and the complementary DNA of the ob gene of NZO mice, including its 5'-untranslated region, are identical with the wild-type sequence (C57BL, BALB/c), except that the transcription start is located 5 bp upstream of the reported site. In contrast to C57BLKS/J+/+ and C57BL/6J-Lep(ob)/Lep(ob) mice, NZO mice failed to respond to recombinant leptin (7.2 microg/g) with a reduction of food intake. Leptin receptor messenger RNA as detected by PCR appears as abundant in hypothalamic tissue of NZO mice as in tissue from lean mice. Ten nucleotide polymorphisms are found in the complementary DNA of the leptin receptor, resulting in two conservative substitutions (V541I and V651I) in the extracellular part of the receptor and one nonconservative substitution (T1044I) in the intracellular domain between the presumed Jak and STAT binding boxes. However, these mutations are also present in the related lean New Zealand Black strain (body fat at 9 weeks: New Zealand Black, 6.2 +/- 1.3%; NZO, 17.0 +/- 1.7%). Thus, the polymorphic leptin receptor seems to play only a minor, if any, role in the obesity and hyperleptinemia of the NZO mouse. It is suggested that the main defect in NZO is located distal from the leptin receptor or at the level of leptin transport into the central nervous system. Topics: Adipose Tissue; Animals; Base Sequence; Blotting, Northern; Body Weight; Carrier Proteins; Disease Models, Animal; DNA, Complementary; Eating; Hyperglycemia; Hyperinsulinism; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Sequence Data; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; Precipitin Tests; Promoter Regions, Genetic; Proteins; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; RNA, Messenger | 1997 |
Thyroid hormones influence serum leptin concentrations in the rat.
Leptin, the product of the ob gene, is secreted by adipocytes and has been shown to decrease appetite and increase energy expenditure. Leptin mRNA in adipocytes correlates with body wt, and serum leptin levels correlate with body fat. Alterations in thyroid status are frequently associated with changes in body wt. To evaluate the possible influence of thyroid status on the leptin system, we have measured serum leptin concentrations in thyroidectomized rats infused either with placebo, or with different doses of T4 (0.8 to 8.0 microg/100 g body wt per day) or T3 (0.25 to 2.0 microg/100 g body wt per day), covering a wide range of thyroid hormone concentrations, from overt hypothyroidism to hyperthyroidism. Intact animals infused with placebo were used as euthyroid controls. Infusion of T4 or T3 into thyroidectomized rats resulted in a decrease in serum leptin levels with respect to the thyroidectomized animals infused with placebo. When compared to the control group, serum leptin levels were decreased in the groups infused with the higher T4 and T3 doses, and tended to be elevated in the thyroidectomized animals infused with placebo. The leptin/body wt ratio was markedly increased in thyroidectomized rats infused with placebo, and decreased in the animals infused with the higher thyroid hormone doses. In conclusion, thyroid hormones exert a negative influence on serum leptin concentrations, which is greater than expected by the changes in body wt The precise mechanism of this influence remains to be elucidated. Topics: Analysis of Variance; Animals; Body Weight; Dose-Response Relationship, Drug; Female; Hyperthyroidism; Hypothyroidism; Leptin; Proteins; Rats; Rats, Wistar; Thyroid Gland; Thyroid Hormones; Thyroidectomy; Thyrotropin; Thyroxine; Triiodothyronine | 1997 |
Reversal of the sex difference in serum leptin levels upon cross-sex hormone administration in transsexuals.
Women have higher circulating leptin levels than men. This sex difference is not simply explained by differences in the amount of body fat and is possibly influenced by their different sex steroid milieus. This prompted us to study prospectively the effects of cross-sex steroid hormones on serum leptin levels in 17 male to female transsexuals and 15 female to male transsexuals. Male to female transsexuals were treated with 100 micrograms ethinyl estradiol and 100 mg cyproterone acetate (antiandrogen) daily, and female to male transsexuals received testosterone esters (250 mg/2 weeks, im). Before and after 4 and 12 months of cross-sex hormone treatment, serum leptin levels and measures of body fatness were assessed. Before treatment, female subjects had higher serum leptin levels than male subjects independently of the amount of body fat (P < 0.01). Cross-sex hormone administration induced a reversal of the sex difference in serum leptin levels. Estrogen treatment in combination with antiandrogens in male subjects increased median serum leptin levels from 1.9 ng/mL before treatment to 4.8 ng/mL after 4 months and 5.5 ng/mL after 12 months of treatment (P < 0.0001). Testosterone administration in female subjects decreased median serum leptin levels from 5.6 to 2.6 ng/mL after 4 months and to 2.5 ng/mL after 12 months (P < 0.0001). Analysis of covariance revealed that the changes in serum leptin levels were independent of changes in body fatness in both groups (P < 0.01). In conclusion, these results indicate that sex steroid hormones, in particular testosterone, play an important role in the regulation of serum leptin levels. The prevailing sex steroid milieu, not genetic sex, is a significant determinant of the sex difference in serum leptin levels. Topics: Adipose Tissue; Adolescent; Adult; Androgen Antagonists; Body Weight; Estrogens; Female; Gonadal Steroid Hormones; Humans; Leptin; Male; Prospective Studies; Proteins; Sex Characteristics; Testosterone; Transsexualism | 1997 |
The adipose tissue/central nervous system axis.
Topics: Adipose Tissue; Animals; Body Weight; Central Nervous System; Gene Expression Regulation; Humans; Leptin; Mice; Neuropeptide Y; Obesity; Proteins | 1997 |
Leptin interacts with glucagon-like peptide-1 neurons to reduce food intake and body weight in rodents.
The adipose tissue hormone, leptin, and the neuropeptide glucagon-like peptide-1 (7-36) amide (GLP-1) both reduce food intake and body weight in rodents. Using dual in situ hybridization, long isoform leptin receptor (OB-Rb) was localized to GLP-1 neurons originating in the nucleus of the solitary tract. ICV injection of the specific GLP-1 receptor antagonist, exendin(9-39), at the onset of dark phase, did not affect feeding in saline pre-treated controls, but blocked the reduction in food intake and body weight of leptin pre-treated rats. These findings suggest that GLP-1 neurons are a potential target for leptin in its control of feeding. Topics: Animals; Body Weight; Carrier Proteins; DNA Probes; Eating; Gene Expression; Glucagon; Glucagon-Like Peptide 1; In Situ Hybridization; Leptin; Light; Male; Mice; Mice, Inbred Strains; Neurons; Peptide Fragments; Proglucagon; Protein Precursors; Proteins; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Solitary Nucleus | 1997 |
Inhibition of food response to intracerebroventricular injection of leptin is attenuated in rats with diet-induced obesity.
The fat-derived hormone, leptin, is thought to regulate adipose tissue mass by acting on the brain to reduce food intake and increase thermogenesis. We have produced obesity in rats more than 8 weeks old by feeding a high-calorie diet and have then examined the inhibitory effect of intracerebroventricularly injected recombinant murine leptin on their food intake versus control rats. In control rats, randomized injections of leptin (0.5, 2.0, or 10.0 microg) or sterile saline vehicle into the lateral ventricle produced a dose-dependent reduction in normal laboratory diet consumed 1, 4, and 24 h after the lights were turned off. However, in diet-induced obesity, the dose-dependent inhibition of food intake was observed at 1 h only, and the effect was attenuated. Switching the diet-induced obese rats to a normal laboratory diet 1 week before injections of leptin were commenced resulted in a reduction in the daily food consumption. These data suggest that rats made obese by feeding a high-calorie diet override the normal satiety effects of leptin since when they are returned to a normal laboratory diet, they reduce their calorie intake, possibly as a result of a restoration of the satiety effects of endogenous leptin. However, the fact that the hypophagic response to exogenous leptin is impaired in these rats at this time suggests some residual impairment of the satiety signal, perhaps caused by reduced receptor sensitivity and/or near total occupation of receptors by endogenous leptin molecules, levels of which are raised in plasma. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cerebral Ventricles; Corticosterone; Diet; Energy Intake; Fatty Acids, Nonesterified; Feeding Behavior; Injections, Intraventricular; Insulin; Leptin; Male; Obesity; Organ Size; Proteins; Rats; Rats, Wistar; Triglycerides | 1997 |
Tissue triglycerides, insulin resistance, and insulin production: implications for hyperinsulinemia of obesity.
Obesity is associated with both insulin resistance and hyperinsulinemia. Initially hyperinsulinemia compensates for the insulin resistance and thereby maintains normal glucose homeostasis. Obesity is also associated with increased tissue triglyceride (TG) content. To determine whether both insulin resistance and hyperinsulinemia might be secondary to increased tissue TG, we studied correlations between TG content of skeletal muscle, liver, and pancreas and plasma insulin, plasma [insulin] x [glucose], and beta-cell function in four rat models with widely varying fat content: obese Zucker diabetic fatty rats, free-feeding lean Wistar rats, hyperleptinemic Wistar rats with profound tissue lipopenia, and rats pair fed to hyperleptinemics. Correlation coefficients >0.9 (P < 0.05) were obtained among TG of skeletal muscle, liver, and pancreas and among plasma insulin, [insulin] x [glucose] product, and beta-cell function as gauged by basal, glucose-stimulated, and arginine-stimulated insulin secretion by the isolated perfused pancreas. Although these correlations cannot prove cause and effect, they are consistent with the hypothesis that the TG content of tissues sets the level of both insulin resistance and insulin production. Topics: Animals; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hyperinsulinism; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Liver; Male; Muscle, Skeletal; Obesity; Pancreas; Protein Biosynthesis; Proteins; Rats; Rats, Wistar; Rats, Zucker; Regression Analysis; Transcription, Genetic; Triglycerides | 1997 |
Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity.
Mammalian bombesin-like peptides are widely distributed in the central nervous system as well as in the gastrointestinal tract, where they modulate smooth-muscle contraction, exocrine and endocrine processes, metabolism and behaviour. They bind to G-protein-coupled receptors on the cell surface to elicit their effects. Bombesin-like peptide receptors cloned so far include, gastrin-releasing peptide receptor (GRP-R), neuromedin B receptor (NMB-R), and bombesin receptor subtype-3 (BRS-3). However, despite the molecular characterization of BRS-3, determination of its function has been difficult as a result of its low affinity for bombesin and its lack of an identified natural ligand. We have generated BRS-3-deficient mice in an attempt to determine the in vivo function of the receptor. Mice lacking functional BRS-3 developed a mild obesity, associated with hypertension and impairment of glucose metabolism. They also exhibited reduced metabolic rate, increased feeding efficiency and subsequent hyperphagia. Our data suggest that BRS-3 is required for the regulation of endocrine processes and metabolism responsible for energy balance and adiposity. BRS-3-deficient mice provide a useful new model for the investigation of human obesity and associated diseases. Topics: Adipose Tissue, Brown; Animals; Blood Pressure; Body Weight; Energy Metabolism; Female; Gene Deletion; Gene Targeting; Glucose; Glucose Tolerance Test; Heart Rate; Hormones; Leptin; Male; Metabolic Diseases; Mice; Mice, Inbred ICR; Motor Activity; Obesity; Proteins; Receptors, Bombesin | 1997 |
Serum leptin in short children born small for gestational age: relationship with the growth response to growth hormone treatment. The Swedish Study Group for Growth Hormone Treatment.
The product of the obese (ob) gene, leptin, is an adipocyte-derived hormone that is involved in the regulation of appetite and body weight. This study was undertaken in order to describe the basal serum levels of leptin in prepubertal short children born small for gestational age (SGA) and their relationship with growth parameters, before and during growth hormone (GH) treatment. Eighty-nine prepubertal short children (66 boys, 23 girls; height standard deviation score (SDS), -5.4 to -2.0; age, 2.0 to 12.8 years) born SGA, 12 of whom (9 boys, 3 girls) had signs of Silver-Russell syndrome, were included in the study. Serum leptin concentrations were measured by radioimmunoassay. Leptin levels in the children born SGA were compared with those in a reference group of 109 prepubertal healthy children born at an appropriate size for gestational age (AGA). The mean (S.D.) change in height SDS was 0.11 (0.22) during the year before the start of GH therapy (0.1 IU/kg/day) and increased to 0.82 (0.44) during the first year (P < 0.001) and to 1.28 (0.59) during the 2-year period of GH therapy (P < 0.001). The children born SGA were significantly leaner than the reference group. An inverse correlation was found between leptin and chronological age in the SGA group (r = -0.31, P < 0.01). The mean serum level of leptin in the children born SGA who were older than 5.5 years of age was 2.8 micrograms/l which was significantly lower than the mean value of 3.7 micrograms/l found in the children born AGA of the same age range. The difference remained after adjustment of leptin levels for sex, age, body mass index (BMI) and weight-for-height SDS (WHSDSSDS). Leptin correlated with WHSDSSDS (r = 0.32, P < 0.001) and BMI (r = 0.36, P < 0.01) in the reference population, but not in the SGA group. No correlation was found between leptin and spontaneous 24-h GH secretion, insulin-like growth factor (IGF)-I or IGF-binding protein-3 levels, or with fasting insulin or cortisol levels. Leptin levels at the start of GH treatment were correlated with the growth response over both 1 year (r = 0.46, P < 0.001) and 2 years (r = 0.51, P < 0.001) of GH therapy. Using multiple regression analysis, models including leptin levels at the start of GH therapy could explain 51% of the variance in the growth response after 1 year and 44% after 2 years of GH treatment. In conclusion, serum leptin levels are reduced in short children born SGA and are inversely correlated with chronological age. Lepti Topics: Aging; Body Height; Body Mass Index; Body Weight; Child; Child Development; Child, Preschool; Cohort Studies; Female; Growth Hormone; Hormones; Human Growth Hormone; Humans; Infant, Small for Gestational Age; Leptin; Male; Osmolar Concentration; Proteins; Reference Values; Sex Characteristics | 1997 |
Site-specific regulation of gene expression by n-3 polyunsaturated fatty acids in rat white adipose tissues.
Dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) limit abdominal fat depot hypertrophy. This could be due to regulation of the expression of proteins involved in adipose tissue metabolism. We investigated in vivo whether fatty acid synthase (FAS), hormone-sensitive lipase (HSL), lipoprotein lipase (LPL), phosphoenolpyruvate carboxykinase (PEPCK), CCAAT/enhancer binding protein alpha (C/EBP alpha), and leptin mRNA levels are affected in retroperitoneal (RP) and subcutaneous adipose tissues (SC) of rats fed n-3 PUFAs. For 4 weeks rats were fed high fat diets (20% fat) containing n-3 PUFAs given as eicosapentaenoic acid (EPA group), docosahexaenoic acid (DHA group), a mixture of these two fatty acids (MIX group), or native fish oil (FO group). A control group was fed with lard plus olive oil (LOO group). Final mean fat cell weight in RP ranged according to: LOO > or = EPA > or = DHA = FO = MIX. There was no difference in fat cell size of SC when comparing the LOO and MIX groups. The fatty acid compositions of RP and SC were similar and resemble that of dietary fat within each experimental group. In RP and compared to the LOO group, FAS, HSL, PEPCK, LPL, C/EBP alpha, and leptin mRNA levels decreased although not significantly in the EPA group, and were 40-75% lower in the DHA and MIX groups. mRNA levels were positively correlated to fat cell size in RP. In contrast, n-3 PUFAs had no effect on gene expression in SC. We conclude that n-3 PUFAs and mainly 22:6n-3 affect gene expression in a site-dependent manner in white adipose tissues via possible antiadipogenic effects. Topics: Adipose Tissue; Animals; Blotting, Northern; Body Weight; Carboxy-Lyases; DNA-Binding Proteins; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acid Synthases; Fatty Acids; Fatty Acids, Omega-3; Gene Expression Regulation; Insulin; Leptin; Lipoprotein Lipase; Male; Nuclear Proteins; Proteins; Rats; Rats, Wistar; Regression Analysis; RNA, Messenger; Sterol Esterase; Triglycerides | 1997 |
Effect of restraint stress on food intake and body weight is determined by time of day.
Three experiments were conducted to investigate the effect of restraint stress applied at different times of the light-dark cycle on feeding behavior and body weight of rats. Sprague-Dawley rats were restrained for 3 h in restraining tubes either at the start or the end of the light cycle. There was a significant reduction in food intake on the day of restraint and no change in food intake during a 10-day recovery period in either experiment. Reductions of food intake on the day of restraint were about the same for both restrained groups compared with their controls. When stress was applied in the evening, eating was inhibited during the first 2 h after restraint, whereas in rats restrained in the morning, feeding was suppressed twice: during the 4 h after restraint and during the first 2 h of the dark cycle. Restraint induced a significant weight loss that was greater in the rats stressed in the morning. Neuropeptide Y (NPY) levels determined at the time of food suppression for both experiments (beginning of the dark cycle) revealed an elevation of NPY in the paraventricular nucleus of rats stressed in the morning compared with other groups, but no difference in hypothalamic NPY mRNA expression. Expression of uncoupling protein mRNA in brown adipose tissue and leptin mRNA in epididymal fat, measured at the start of the dark period, was not altered by stress. There was an elevation of dopamine turnover in the hypothalami of rats restrained at the end of light cycle, but not those restrained in the morning. These results show that restraint stress has a greater effect on metabolism and energy balance when it is applied in the morning. Additional studies are needed to elucidate mechanisms involved in the suppression of food intake 9 h after restraint. Topics: 3,4-Dihydroxyphenylacetic Acid; Adipose Tissue; Animals; Biogenic Monoamines; Body Weight; Brain Stem; Circadian Rhythm; Darkness; Dopamine; Energy Metabolism; Epididymis; Feeding Behavior; Hypothalamus; Leptin; Light; Male; Methoxyhydroxyphenylglycol; Neuropeptide Y; Norepinephrine; Paraventricular Hypothalamic Nucleus; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Reference Values; Restraint, Physical; RNA, Messenger; Serotonin; Stress, Psychological; Transcription, Genetic | 1997 |
Production and refolding of recombinant leptin.
Topics: Adipose Tissue; Animals; Base Sequence; Body Weight; Chromatography, Affinity; Cloning, Molecular; DNA, Complementary; Escherichia coli; Female; Gene Expression; Leptin; Mice; Mice, Obese; Plasmids; Polymerase Chain Reaction; Protein Biosynthesis; Protein Folding; Proteins; Recombinant Proteins; RNA; RNA-Directed DNA Polymerase | 1997 |
Effects of intracerebroventricular infusion of leptin in obese Zucker rats.
The obese Zucker rat (OZR) exhibits a missense mutation in the cDNA for the leptin receptor, producing a single amino acid substitution in the extracellular domain of the receptor. A mutation in the leptin receptor gene of the db/db mouse prevents the synthesis of the long splice variant of the receptor. The possibility that the OZR, like the db/db mouse, is refractory to the actions of murine leptin was tested by infusing the protein intracerebroventricularly via a minipump for 7 days. Lean Zucker rats (LZR) infused with leptin acted as positive controls, and other groups of OZR and LZR were infused with vehicle. In LZR, leptin reduced bodyweight and food intake and increased brown adipose tissue (BAT) temperature. Plasma corticosterone increased (61%) in these rats, and plasma triglycerides fell (78%). Leptin treatment improved tolerance to an oral glucose load (16% reduction in the area under the blood glucose curve) while lowering plasma insulin. In OZR, the actions of leptin were blunted. Food intake was slightly, but not significantly, reduced. Although there was a reduction in the rate of increase in body mass, the effect of leptin was about half that seen in LZR. BAT temperature and glucose tolerance were unchanged. In contrast to the elevated plasma corticosterone seen in LZR, leptin reduced the level of this hormone (27%) in OZR. In OZR and LZR treated with leptin, the plasma leptin levels were increased 24-fold and 47-fold, respectively. The results suggest that leptin retains some efficacy in OZR, although these rats are less responsive than LZR. Topics: Adipose Tissue, Brown; Animals; Blood Glucose; Body Temperature; Body Weight; Brain; Corticosterone; Eating; Energy Metabolism; Infusion Pumps, Implantable; Insulin; Leptin; Male; Mice; Obesity; Proteins; Rats; Rats, Zucker; Recombinant Proteins; Triglycerides | 1997 |
Leptin and the development of obesity and diabetes in Psammomys obesus.
The recently discovered ob gene and its circulating product, leptin, may be critical factors in the control of energy balance. Recent studies in ob/ob mice, which lack circulating leptin, have shown dramatic reductions in food intake and bodyweight after leptin treatment. In addition, studies in both humans with obesity and animal models of obesity have demonstrated hyperleptinemia. Here, we report a longitudinal study examining changes in circulating leptin during the development of obesity and diabetes in Psammomys obesus. Over the 8 weeks of the study, lean animals increased their bodyweight by 154% and leptin levels remained essentially unchanged. In contrast, animals that developed obesity (223% increase in bodyweight), hyperglycemia, and hyperinsulinemia also developed hyperleptinemia between 4 weeks and 8 weeks of age. These results demonstrate that the development of hyperleptinemia is associated with the development of obesity and subsequent metabolic abnormalities. Topics: Adipose Tissue; Aging; Animals; Blood Glucose; Body Composition; Body Weight; Diabetes Mellitus; Disease Models, Animal; Drug Resistance; Eating; Gerbillinae; Insulin; Leptin; Obesity; Proteins; Weight Gain | 1997 |
The leptin receptor mediates apparent autocrine regulation of leptin gene expression.
The possibility that the leptin receptor (LEPR) mediates autocrine regulation of leptin expression in adipose tissue was examined in 10-day-old Zucker rat pups with different copy numbers of the leptin receptor mutation (Lepr(fa)). Plasma leptin concentrations and adipose tissue mRNA levels for leptin were related to copy number of the mutation (fa/fa > fa/+ > +/+). These relationships were independent of plasma insulin concentration. Reduced copy number for the functional leptin receptor apparently results in a diminished negative feedback signal to the leptin gene in adipose tissue. Thus, leptin appears to close a short regulatory loop controlling its own synthesis in adipose tissue. Topics: Adipose Tissue; Analysis of Variance; Animals; Body Weight; Carrier Proteins; Gene Expression Regulation; Genotype; Leptin; Mutation; Protein Biosynthesis; Proteins; Rats; Rats, Inbred BN; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Regression Analysis | 1997 |
Melanocortin receptors in leptin effects.
Topics: Animals; Anorexia; Body Weight; Eating; Glucagon-Like Peptides; Leptin; Male; Melanocyte-Stimulating Hormones; Paraventricular Hypothalamic Nucleus; Peptides; Proteins; Proto-Oncogene Proteins c-fos; Rats; Receptors, Corticotropin; Receptors, Melanocortin; Signal Transduction | 1997 |
Troglitazone action is independent of adipose tissue.
We have investigated the antidiabetic action of troglitazone in aP2/DTA mice, whose white and brown fat was virtually eliminated by fat-specific expression of diphtheria toxin A chain. aP2/DTA mice had markedly suppressed serum leptin levels and were hyperphagic, but did not gain excess weight. aP2/DTA mice fed a control diet were hyperlipidemic, hyperglycemic, and had hyperinsulinemia indicative of insulin-resistant diabetes. Treatment with troglitazone alleviated the hyperglycemia, normalized the tolerance to intraperitoneally injected glucose, and significantly decreased elevated insulin levels. Troglitazone also markedly decreased the serum levels of cholesterol, triglycerides, and free fatty acids both in wild-type and aP2/DTA mice. The decrease in serum triglycerides in aP2/DTA mice was due to a marked reduction in VLDL- and LDL-associated triglyceride. In skeletal muscle, triglyceride levels were decreased in aP2/DTA mice compared with controls, but glycogen levels were increased. Troglitazone treatment decreased skeletal muscle, but not hepatic triglyceride and increased hepatic and muscle glycogen content in wild-type mice. Troglitazone decreased muscle glycogen content in aP2/DTA mice without affecting muscle triglyceride levels. The levels of peroxisomal proliferator-activated receptor gamma mRNA in liver increased slightly in aP2/DTA mice and were not changed by troglitazone treatment. The results demonstrate that insulin resistance and diabetes can occur in animals without significant adipose deposits. Furthermore, troglitazone can alter glucose and lipid metabolism independent of its effects on adipose tissue. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cholesterol; Chromans; Diabetes Mellitus, Type 2; Eating; Fatty Acids; Glycogen; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Lipoproteins, LDL; Lipoproteins, VLDL; Mice; Mice, Transgenic; Organ Size; Proteins; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors; Triglycerides; Troglitazone | 1997 |
Leptin is present in human milk and is related to maternal plasma leptin concentration and adiposity.
Leptin is elevated during pregnancy and may be involved in the regulation of milk production in women. Immunoreactive leptin was quantified in human milk by modified radioimmunoassay. Leptin concentration was higher in whole vs. skim milk fractions; however, leptin concentration was not correlated with percentage milk fat. Leptin concentrations in whole and skim milk were correlated with maternal plasma leptin concentrations, maternal body weight, body mass index, and tricep skinfold thickness, but not with plasma insulin concentration. These data provide the first evidence for the presence of leptin in human milk in the range of concentrations found in human plasma and indicate that the concentration of leptin in milk reflects maternal adiposity. Determining the biological role(s) of milk-borne leptin could add to our understanding of neonatal metabolism and the mechanisms underlying the development of body fat and obesity in humans. Topics: Adipose Tissue; Body Weight; Female; Humans; Leptin; Lipids; Milk Proteins; Milk, Human; Obesity; Pregnancy; Proteins; Radioimmunoassay; Skinfold Thickness | 1997 |
Leptin selectively decreases visceral adiposity and enhances insulin action.
Intraabdominal adiposity and insulin resistance are risk factors for diabetes mellitus, dyslipidemia, arteriosclerosis, and mortality. Leptin, a fat-derived protein encoded by the ob gene, has been postulated to be a sensor of energy storage in adipose tissue capable of mediating a feedback signal to sites involved in the regulation of energy homeostasis. Here, we provide evidence for specific effects of leptin on fat distribution and in vivo insulin action. Leptin (LEP) or vehicle (CON) was administered by osmotic minipumps for 8 d to pair-fed adult rats. During the 8 d of the study, body weight and total fat mass decreased similarly in LEP and in CON. However, while moderate calorie restriction (CON) resulted in similar decreases in whole body (by 20%) and visceral (by 21%) fat, leptin administration led to a specific and marked decrease (by 62%) in visceral adiposity. During physiologic hyperinsulinemia (insulin clamp), leptin markedly enhanced insulin action on both inhibition of hepatic glucose production and stimulation of glucose uptake. Finally, leptin exerted complex effects on the hepatic gene expression of key metabolic enzymes and on the intrahepatic partitioning of metabolic fluxes, which are likely to represent a defense against excessive storage of energy in adipose depots. These studies demonstrate novel actions of circulating leptin in the regulation of fat distribution, insulin action, and hepatic gene expression and suggest that it may play a role in the pathophysiology of abdominal obesity and insulin resistance. Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Eating; Gene Expression; Glucose; Insulin; Leptin; Liver; Male; Mice; Proteins; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Viscera | 1997 |
Increased feeding in fatty Zucker rats by the thiazolidinedione BRL 49653 (rosiglitazone) and the possible involvement of leptin and hypothalamic neuropeptide Y.
1. The thiazolidinedione BRL 49653 (rosiglitazone) induces hyperphagia and weight gain in obese, insulin-resistant fatty Zucker rats but not in lean insulin-sensitive rats. We investigated whether these responses might involve neuropeptide Y (NPY), leptin and insulin. 2. BRL 49653 (1 mg kg(-1) day(-1), orally) was given for 7 or 20 days to fatty and lean Zucker and Wistar rats. 3. In lean rats of either strain, BRL 49653 had no effect on food intake, body weight, plasma insulin and corticosterone, NPY or NPY mRNA levels. 4. Fatty rats given BRL 49653 showed a 30% increase in food intake and accelerated body weight gain (both P<0.01) after 7 and 20 days, but without significant changes in regional hypothalamic NPY or NPY mRNA levels. 5. Plasma leptin levels were twice as high in untreated fatty Zucker rats as in lean rats (P<0.01), but were unaffected by BRL 49653 given for 20 days. However, BRL 49653 reduced insulin levels by 42% and increased corticosterone levels by 124% in fatty rats (both P<0.01). 6. Hyperphagia induced in fatty Zucker rats by BRL 49653 does not appear to be mediated by either a fall in circulating leptin levels or increased activity of hypothalamic NPYergic neurones. The fall in plasma insulin and/or rise in corticosterone levels during BRL 49653 treatment may be involved, consistent with the postulated role of these hormones in the control of food intake. Topics: Animals; Appetite Stimulants; Body Weight; Eating; Hyperphagia; Hypoglycemic Agents; Hypothalamus; Leptin; Male; Neuropeptide Y; Proteins; Rats; Rats, Wistar; Rats, Zucker; Rosiglitazone; Thiazoles; Thiazolidinediones | 1997 |
Increased serum GHBP levels in obese pubertal children and adolescents: relationship to body composition, leptin and indicators of metabolic disturbances.
The serum concentration of the high-affinity growth hormone-binding protein (GHBP) is increased in obesity but the mechanisms are poorly understood. This study assessed the physiological mechanisms involved in the regulation of GHBP in adiposity.. We tested a number of obesity specific parameters for their association with GHBP. In this study, 199 normal or overweight children and adolescents (101 boys, 98 girls, aged (mean +/- s.d.): 13.7 +/- 2.3 y) underwent an anthropometric evaluation (circumference measurements and bioimpedance analysis) combined with blood withdrawal for the measurement of insulin-like growth factor-I (IGF-I), insulin, leptin and GHBP (by specific RIA), uric acid, triglycerides and cholesterol.. By linear regression analysis GHBP correlated significantly (P < 0.001) with percent body fat mass (r = 0.71), waist (r = 0.73) and hip (r = 0.69) circumference, weight (r = 0.61) waist hip ratio (WHR) (r = 0.54), as well as with the serum concentrations of leptin (r = 0.64), uric acid (r = 0.54), insulin (r = 0.45), LDL-cholesterol (r = 0.43), cholesterol (r =0.33), LDL/HDL ratio (r = 0.47), triglycerides (r = 0.30) and with height standard deviations scores (SDS) (r = 0.23). Age, gender and pubertal stage had no impact on GHBP. In a multiple regression analysis containing age and gender, as well as the anthropometric variables, percent fat mass and waist circumference, as independent variables, associations between GHBP and leptin (P < 0.001), cholesterol (P < 0.01), LDL-cholesterol (P = 0.01), LDL/HDL ratio (P = 0.02), triglycerides (P = 0.01) remained significant. In a final model using the stepwise analysis involving age, gender and all the independent predictors of GHBP, waist circumference (P < 0.001), accounted for 49.5% of the 60.0% total variability in GHBP, while the implication of leptin (P < 0.001), age (P < 0.01) and cholesterol (P < 0.05) increased the predicted variability for 7.5%, 1.9%, and 1.0%, respectively. Serum GHBP was significantly reduced in a subgroup of 104 overweight or obese patients during a diet-induced weight loss programme, the coefficient of correlation between GHBP and leptin after (r = 0.45, P < 0.001) and before weight reduction (r = 0.41, P < 0.001) were comparable.. Waist circumference, an indicator of abdominal body fat mass, is a major determinant of GHBP levels during childhood, while leptin may be one candidate for a signal linking adipocytes to the growth hormone receptor related GHBP release. Additionally, elevated serum levels of GHBP may reflect metabolic disturbances of adiposity. Topics: Adolescent; Aging; Body Composition; Body Constitution; Body Mass Index; Body Weight; Carrier Proteins; Child; Cholesterol; Female; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Linear Models; Male; Obesity; Proteins; Puberty; Triglycerides; Weight Loss | 1997 |
Leptin is a physiologically important regulator of food intake.
These studies were designed to test the hypothesis that endogenous leptin, acting within the brain plays a physiologically important role in the control of food intake in lean rats.. Antibodies directed against mouse leptin were raised in rabbits. The purified IgG fractions prepared from pre-immune and immune sera were injected into the right lateral ventricle of lean Sprague-Dawley rats and obese Zucker fatty fa/fa rats. Changes in food intake were measured over the following 20 h period.. The anti-leptin antibodies recognized a major epitope in the C-terminal region of the leptin molecule. The antibodies bound both mouse and rat leptin with high affinity, but did not bind human leptin, or a selected range of other hormones and neurotransmitters known to affect food intake. In competition studies, the binding of mouse, but not human leptin to the human Ob-Rb receptor was prevented by the antibodies. This indicates that the antibodies can block the action of leptin by preventing its binding to the ob-Rb receptor. Injection of the anti-leptin antibodies into the brain of lean rats led to an increase in food intake during the first hour after injection which was not compensated during the following 19 h period. Injection of the anti-leptin antibodies did not affect food intake in Zucker fatty fa/fa rats which express an abnormal ob-Rb receptor.. Endogenous leptin acting within the brain plays a physiologically important role in the control of food intake in lean rats. Topics: Amino Acid Sequence; Animals; Antibodies; Body Weight; Circadian Rhythm; Eating; Energy Metabolism; Epitopes; Humans; Immunoglobulin G; Leptin; Male; Mice; Molecular Sequence Data; Obesity; Proteins; Rabbits; Rats; Rats, Sprague-Dawley; Rats, Zucker; Time Factors | 1997 |
Influence of endogenous leptin tone on the estrous cycle and luteinizing hormone pulsatility in female rats.
Recent data indicate that leptin may well play an important regulatory role in the hypothalamo-pituitary-gonadal axis. In order to further unravel the mechanisms by which leptin acts, we have studied the effect of treatment (8 days) of leptin antiserum (5 microl daily; i.c.v.) on LH pulsatility and estrous cycle in adult female rats. The administration of leptin antiserum led to a marked decrease in LH pulsatility as assessed by the area under the curve (13.5 +/- 4.7 ng/ml) in comparison to rats treated with normal rabbit serum (114 f 53 ng/ml; p < 0.01). Furthermore, rats treated with leptin antiserum showed an impairment of reproductive function as shown by the fact that all rats remained in anestrus. In conclusion, these data show that leptin markedly influences LH secretion and the estrous cycle in the female rat. Topics: Animals; Body Weight; Estrus; Female; Leptin; Luteinizing Hormone; Proteins; Rats; Rats, Sprague-Dawley; Secretory Rate | 1997 |
Effect of diabetes mellitus on the permeability of the blood-brain barrier to insulin.
Insulin derived from the peripheral circulation has been shown to exert various effects on the brain due to its ability to cross the blood-brain barrier (BBB). The relation between diabetes mellitus and insulin has been extensively studied for peripheral tissues but not for central nervous system tissues. We examined the effects that streptozotocin- or alloxan-induced diabetes have on the transport of insulin across the murine BBB. We used multiple-time regression analysis to measure the unidirectional influx rate constant (Ki) and vascular association (Vi) of intravenously injected, radioactively labeled human insulin (I-Ins). Treatment with streptozotocin induced an enhancement of both the Ki and Vi of I-Ins that correlated with the onset of diabetes. Brain perfusion showed that the enhanced uptake was not due to altered vascular space or levels of insulin in the serum. Alloxan enhanced Ki and Vi after 5 days but the early phase of diabetes was associated with a decreased Ki. Hyperglycemia induced by the intraperitoneal injection of glucose elevated the Vi but abolished the Ki. Furthermore, altered I-Ins uptake by brain was not associated with changes in brain or body weight. These results show that there is an increased uptake of I-Ins by the brain in the diabetic state that is not due to acute changes in the serum levels of glucose or insulin, altered vascular space, or catabolic events. Chronic changes in levels of glucose, insulin or other hormone or neuroendocrine agents are likely to underlie the altered rate of transport of insulin across the BBB of diabetic mice. Topics: Alloxan; Animals; Biological Transport; Blood Glucose; Blood-Brain Barrier; Body Weight; Brain; Cell Membrane Permeability; Diabetes Mellitus, Experimental; Fasting; Glucose; Insulin; Leptin; Male; Mice; Organ Size; Perfusion; Proteins; Regression Analysis; Streptozocin | 1997 |
Neuropeptide Y, galanin, and leptin release in obese women and in women with anorexia nervosa.
The study objective was to determine circulating levels of the appetite-controlling neuropeptides, neuropeptide Y (NPY), galanin, and leptin, in subjects with eating disorders. The study group consisted of 48 obese women aged 19 to 45 years, 15 women with anorexia nervosa aged 18 to 23 years, and 19 lean healthy women aged 18 to 42 years (control group). The obese women were divided into four groups: (A) body mass index (BMI) = 25 to 30 kg/m2, n = 9 (overweight); (B) BMI = 31 to 40 kg/m2, n = 23 (moderate obesity); (C) BMI greater than 40 kg/m2, n = 9 (severe obesity); and (D) BMI = 31 to 40 kg/m2, n = 7 (moderate obesity + non-insulin-dependent diabetes mellitus [NIDDM]). Plasma NPY, galanin, and leptin concentrations were measured in peripheral blood samples with radioimmunoassay methods. Plasma NPY levels in obese women (groups A, B, C, and D) were significantly higher as compared with the control group (P < .01, P < .001, P < .001, and P < .001, respectively). The highest plasma NPY concentrations were observed in obese women with NIDDM. Plasma galanin levels were significantly higher in groups B, C, and D (P < .001, P < .001, and P < .001, respectively). Plasma leptin concentrations were significantly higher in groups C and D as compared with the control group (P < .001 and P < .001, respectively). Plasma NPY and galanin concentrations in women with anorexia nervosa did not differ from the levels in the control group. However, plasma leptin concentrations were significantly lower in anorectic women than in the control group (P < .01). Our results indicate that inappropriate plasma concentrations of NPY, galanin, and leptin in obese women may be a consequence of their weight status, or could be one of many factors involved in the pathogenesis of obesity. Topics: Adolescent; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Female; Galanin; Humans; Leptin; Neuropeptide Y; Obesity; Proteins; Radioimmunoassay | 1997 |
The decrease of serum leptin levels in oestrogen-treated male mice.
Adipocyte hormone leptin (OB protein) is considered to be an "adiposity signal" regulating body weight homeostasis and energy balance. We have previously reported that oestrogens (oestradiol-benzoate) significantly decrease the body weight in male rats, increase anterior pituitary and serum levels of the intracellular messenger cAMP, which activates cAMP-dependent protein kinase A, their targets include hormone-sensitive lipase and they influence the brain sympathetic system. The present study tested our hypothesis that oestrogens could influence serum leptin levels in male mice. We found that chronic administration of oestradiol-benzoate significantly attenuated serum levels of leptin, in the dependence on the duration of its administration, and simultaneously decreased body weight. We suppose that oestrogens affect leptin levels interacting with the signal transmission system of cAMP, possibly at the genome level. Our observations that the food consumption of mice with simultaneously decreased body weight and levels of serum leptin support the idea that there exists a satiety factor that counters the effect of low leptin. Topics: Adipocytes; Animals; Body Weight; Estradiol; Leptin; Male; Mice; Proteins | 1997 |
Augmented expression of obese (ob) gene during the process of obesity in genetically obese-hyperglycemic Wistar fatty (fa/fa) rats.
Expression of the obese (ob) gene is up-regulated in the adipose tissue in several obese rodent models. To study the regulation of the ob gene expression during the development of obesity, we examined the ob gene expression in genetically obese-hyperglycemic Wistar fatty (fa/fa) rats at several stages of obesity. The ob mRNA levels in the adipose tissue from Wistar fatty rats was unequivocally augmented and continued to rise in the process of obesity. Furthermore, the ob gene expression in this obese model was much more rapidly enhanced in the mesenteric fat than in the subcutaneous fat. Moreover, the ob gene expression was more greatly augmented in the mesenteric fat than the lipoprotein lipase gene expression. These results suggest the presence of obesity-linked and region-specific regulation of the ob gene expression. Topics: Adipose Tissue; Age Factors; Animals; Body Weight; Disease Models, Animal; Gene Expression; Hyperglycemia; Leptin; Lipoprotein Lipase; Male; Obesity; Proteins; Rats; Rats, Wistar; RNA, Messenger; Tissue Distribution | 1996 |
Role of leptin in fat regulation.
Topics: Adipose Tissue; Adipose Tissue, Brown; alpha-Methyltyrosine; Animals; Body Temperature Regulation; Body Weight; Catecholamines; Eating; Enzyme Inhibitors; Female; Leptin; Methyltyrosines; Mice; Mice, Inbred C57BL; Norepinephrine; Obesity; Proteins; Sympathetic Nervous System; Tyrosine 3-Monooxygenase | 1996 |
Serum leptin in normal-weight and obese humans.
Topics: Body Weight; Carrier Proteins; Humans; Leptin; Obesity; Proteins; Receptors, Cell Surface; Receptors, Leptin | 1996 |
Fat regulation. Life without neuropeptide Y.
Topics: Amino Acid Sequence; Animals; Body Weight; Feeding Behavior; Leptin; Mice; Mice, Knockout; Molecular Sequence Data; Neuropeptide Y; Proteins | 1996 |
Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y.
Neuropeptide Y (NPY), a 36-amino-acid transmitter distributed throughout the nervous system, is thought to function as a central stimulator of feeding behaviour. NPY has also been implicated in the modulation of mood, cerebrocortical excitability, hypothalamic-pituitary signalling, cardiovascular physiology and sympathetic function. However, the biological significance of NPY has been difficult to establish owing to a lack of pharmacological antagonists. We report here that mice deficient for NPY have normal food intake and body weight, and become hyperphagic following food deprivation. Mutant mice decrease their food intake and lose weight, initially to a greater extent than controls, when treated with recombinant leptin. Occasional, mild seizures occur in NPY-deficient mice and mutants are more susceptible to seizures induced by a GABA (gamma-aminobutyric acid) antagonist. These results indicate that NPY is not essential for certain feeding responses or leptin actions but is an important modulator of excitability in the central nervous system. Topics: Animals; Body Weight; Eating; Feeding Behavior; Female; Food Deprivation; GABA Antagonists; Gene Targeting; Humans; Hyperphagia; Leptin; Male; Mice; Neuropeptide Y; Pentylenetetrazole; Proteins; Seizures | 1996 |
Gaining on fat.
Topics: Adipose Tissue; Animals; Body Composition; Body Constitution; Body Mass Index; Body Weight; Chromosome Mapping; Dietary Fats, Unsaturated; Environment; Fatty Acids; Female; Humans; Indians, North American; Leptin; Male; Obesity; Proteins; Risk Factors; Sucrose | 1996 |
Fat regulation. Prime time for neuropeptide Y.
Topics: Animals; Body Weight; Feeding Behavior; Leptin; Neuropeptide Y; Obesity; Proteins; Receptors, Neuropeptide Y | 1996 |
Role of leptin in the neuroendocrine response to fasting.
A total deficiency in or resistance to the protein leptin causes severe obesity. As leptin levels rise with increasing adiposity in rodents and man, it is proposed to act as a negative feedback 'adipostatic signal' to brain centres controlling energy homeostasis, limiting obesity in times of nutritional abundance. Starvation is also a threat to homeostasis that triggers adaptive responses, but whether leptin plays a role in the physiology of starvation is unknown. Leptin concentration falls during starvation and totally leptin-deficient ob/ob mice have neuroendocrine abnormalities similar to those of starvation, suggesting that this may be the case. Here we show that preventing the starvation-induced fall in leptin with exogenous leptin substantially blunts the changes in gonadal, adrenal and thyroid axes in male mice, and prevents the starvation-induced delay in ovulation in female mice. In contrast, leptin repletion during this period of starvation has little or no effect on body weight, blood glucose or ketones. We propose that regulation of the neuroendocrine system during starvation could be the main physiological role of leptin. Topics: Adrenal Glands; Animals; Blood Glucose; Body Weight; Eating; Estrus; Fasting; Female; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Neurosecretory Systems; Proteins; Recombinant Proteins; Thyroid Gland | 1996 |
Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A.
Cyclic AMP is an important second messenger in the coordinated regulation of cellular metabolism. Its effects are mediated by cAMP-dependent protein kinase (PKA), which is assembled from two regulatory (R) and two catalytic (C) subunits. In mice there are four R genes (encoding RI alpha, RI beta, RII alpha, and RII beta) and two C gene (encoding C alpha and C beta), expressed in tissue-specific patterns. The RII beta isoform is abundant in brown and white adipose tissue and brain, with limited expression elsewhere. To elucidate its functions, we generated RII beta knockout mice. Here we report that mutants appear healthy but have markedly diminished white adipose tissue despite normal food intake. They are protected against developing diet-induced obesity and fatty livers. Mutant brown adipose tissue exhibits a compensatory increase in RI alpha, which almost entirely replaces lost RII beta, generating an isoform switch. The holoenzyme from mutant adipose tissue binds cAMP more avidly and is more easily activated than wild-type enzyme. This causes induction of uncoupling protein and elevations of metabolic rate and body temperature, contributing to the lean phenotype. Our results demonstrate a role for the RII beta holoenzyme in regulating energy balance and adiposity. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Carrier Proteins; Cyclic AMP; Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; Cyclic AMP-Dependent Protein Kinases; Dietary Fats; Eating; Energy Metabolism; Female; Ion Channels; Isoenzymes; Leptin; Male; Membrane Proteins; Mice; Mice, Knockout; Mitochondrial Proteins; Protein Binding; Proteins; Thinness; Triglycerides; Uncoupling Protein 1 | 1996 |
Reduced ob mRNA in hypophysectomised rats is not restored by growth hormone (GH), but further suppressed by exogenously administered insulin-like growth factor (IGF) I.
To examine whether GH and IGF-I participate in the regulation of obese (ob) mRNA expression we determined ob mRNA levels in epididydimal fat pads of hypophysectomised (hypox) rats, hypox rats treated with recombinant human (rh) GH or rhIGF-I and normal, weight-matched controls. We found that 1. ob mRNA was markedly suppressed after hypophysectomy (37 +/- 25% of controls), 2. GH infusion had no effect on ob mRNA, but stimulated IGF-I mRNA in fat pads, 3. IGF-I treatment further suppressed ob mRNA (3.5% +/- 0.6% of controls) and 4. serum insulin levels were decreased in all hypox groups (11.2 to 15.9% of controls). In conclusion, exogenous and GH-induced IGF-I differ in their effects on ob mRNA expression and GH is unable to restore ob mRNA towards normal at low insulin levels. Topics: Adipose Tissue; Animals; Base Sequence; Body Weight; DNA Primers; DNA Probes; Growth Hormone; Humans; Hypophysectomy; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Molecular Sequence Data; Polymerase Chain Reaction; Protein Biosynthesis; Proteins; Rats; Rats, Inbred Strains; Recombinant Proteins; Reference Values; RNA, Messenger; Transcription, Genetic | 1996 |
Regulation of obese (ob) mRNA and plasma leptin levels in rhesus monkeys. Effects of insulin, body weight, and non-insulin-dependent diabetes mellitus.
We have cloned the rhesus monkey obese cDNA and have analyzed its expression in monkeys with a wide range of body weights (lean to very obese) and with or without non-insulin-dependent diabetes mellitus to examine the relationship of ob gene expression to obesity and non-insulin-dependent diabetes mellitus. The sequence of monkey ob protein, excluding the signal peptide, showed 91% identity with the human protein. We observed a significant correlation between the level of ob mRNA and body weight. We also found a significant relationship between ob mRNA and fasting plasma insulin concentration; however, insulin stimulation during a 100-140-min euglycemic/hyperinsulinemic clamp did not result in any changes in ob mRNA levels. Circulating levels of the ob gene product leptin were also significantly correlated with body weight. These results show that ob gene expression is related to body weight and is not acutely regulated by insulin. Topics: Amino Acid Sequence; Animals; Base Sequence; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; DNA, Complementary; Gene Expression Regulation; Humans; Hyperinsulinism; Leptin; Macaca mulatta; Mice; Molecular Sequence Data; Obesity; Organ Specificity; Primate Diseases; Protein Biosynthesis; Protein Sorting Signals; Proteins; Rats; Regression Analysis; RNA, Messenger; Sequence Homology, Amino Acid; Transcription, Genetic | 1996 |
Long-term and rapid regulation of ob mRNA levels in adipose tissue from normal (Sprague Dawley rats) and obese (db/db mice, fa/fa rats) rodents.
Increased levels of mRNA transcribed from the ob gene in adipose tissue of obese/hyperinsulinaemic Zucker (fa/fa) rats were detectable as early as 3 weeks after birth and continued to rise there after in parallel with body weight and serum insulin. mRNA levels of two other fat-specific genes (ARL4, FST44) were unaltered. In C57BL/KsJ db/db mice, ob mRNA levels also increased in parallel with body weight and serum insulin, and remained elevated in older animals when insulin levels decreased. In heterozygous control animals (db/+; fa/Fa), mRNA levels were comparable with those in the homozygous controls. In normal Sprague Dawley rats, the ob mRNA increased continuously, but more slowly than in Zucker rats, in parallel with body weight and insulin levels, and reached 15 times higher levels in the heaviest rats (400 g) studied. In Sprague Dawley rats made diabetic by an injection of streptozotocin, ob mRNA levels were reduced by approximately 50% after 24 h. A 24-h fasting period reduced the ob mRNA by 50% in lean Sprague Dawley and Fa/Fa, but not in obese Zucker fa/fa rats, although insulin levels were reduced in both groups. These data indicate that ob mRNA levels increase in both normal and obese rodents in parallel with age, body weight and serum insulin, reflecting an early (Zucker rats, db-mice) or slowly developing (Sprague Dawley rats) resistance to leptin and insulin. This increase does not appear to be mediated by the recently described rapid regulation of ob mRNA by insulin, but seems to be due to a different, long-term control mechanism which signals the size of the fat depots. Topics: Adipose Tissue; Age Factors; Animals; Blotting, Northern; Body Weight; Diabetes Mellitus, Experimental; Fasting; Gene Expression Regulation; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Protein Biosynthesis; Proteins; Rats; Rats, Sprague-Dawley; Rats, Zucker; RNA, Messenger; Time Factors | 1996 |
The weight-reducing effect of an intracerebroventricular bolus injection of leptin in genetically obese fa/fa rats. Reduced sensitivity compared with lean animals.
The effect of different doses of leptin, given as an intracerebroventricular (ICV) bolus, on body weight gain and food intake was investigated during refeeding, following a 24-h fast in lean (FA/fa) rats. It was observed that ICV leptin resulted in a dose-dependent decrease in body weight gain, compared with vehicle injection, a difference that persisted for at least 6 days. This was associated with a transient reduction in food intake over the first 2 days after leptin injection. More importantly, the effect of leptin was also observed in genetically obese fa/fa rats but at the expense of two to ten times higher leptin concentrations, indicating the presence of decreased leptin sensitivity. Furthermore, ICV leptin injections were able to decrease neuropeptide Y (NPY) levels in the arcuate and paraventricular hypothalamic nuclei in both lean and genetically obese fa/fa rats, although a higher leptin dose was again needed in the obese group. These observations provide further evidence for the implication of NPY and leptin in a regulatory loop controlling body homeostasis. This loop is functional in lean and genetically obese fa/fa rats, provided that leptin levels in the central nervous system are high enough in the obese group, in particular. Since human obesity is frequently associated with elevated circulating leptin levels, a state of decreased leptin sensitivity (i.e., leptin resistance), similar to that described here in fa/fa rats, could possibly occur in human syndromes as well. Topics: Animals; Appetite; Body Weight; Cerebral Ventricles; Dose-Response Relationship, Drug; Eating; Fasting; Humans; Hypothalamus; Injections, Intraventricular; Leptin; Male; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Mutant Strains; Thinness; Time Factors | 1996 |
Role of fragment peptides from ob protein on body weight and thermogenesis control: a screening.
Topics: Animals; Body Temperature Regulation; Body Weight; Leptin; Peptide Fragments; Proteins; Rats | 1996 |
Reduction of food intake and weight gain by the ob protein requires a specific secondary structure and is reversible.
Obesity, the condition of excessive accumulation of fat is a poorly understood disorder and is a risk factor for type II diabetes, hypertension, and hyperlipidaemia. Recently, a putative mouse obese gene was cloned and its product, termed ob protein, was shown to be involved in the regulation of body weight.. Bacterial and insect cells were used for expression of recombinant mouse ob protein. Amino-terminal sequence analysis and site-directed mutagenesis were used to identify and characterize the mature form of ob protein. Genetically obese mice and wild-type rats were used to determine the biological activity of ob protein.. Mouse ob protein is synthesized as a precursor molecule, the mature form of which was found in mouse serum. Biochemical analysis identified the processing site in the ob precursor molecule and an intramolecular disulfide bond in the mature form that is necessary for activity. Reduction of food intake and weight gain after administration of ob protein to genetically obese mice and wild-type rats is reversible.. This study demonstrates that ob protein is a secreted satiety factor which regulates body weight and reduces food intake even in animals with no genetic body weight abnormalities. The failure of ob protein to effect these parameters in db/db mice supports the hypothesis that these mice are deficient in a signaling molecule that normally responds to the ob protein. Topics: Amino Acid Sequence; Animals; Base Sequence; Body Weight; Cloning, Molecular; Diet; Disulfides; Dithiothreitol; DNA Primers; Electrophoresis, Polyacrylamide Gel; Immunoblotting; Leptin; Mice; Mice, Obese; Molecular Sequence Data; Obesity; Protein Processing, Post-Translational; Protein Structure, Secondary; Proteins; Rats; Recombinant Proteins; Sequence Analysis | 1996 |
Gender differences in serum leptin levels in humans.
Leptin, the product of the ob gene, is an adipose tissue-derived hormone that appears to regulate both satiety and thermogenesis. In the present report, we have reexamined the relationship between circulating leptin concentration and body fat in humans using a more valid measure of adiposity (hydrodensitometry) and have extended these observations to examine the influence of regional body fat distribution and cardiorespiratory fitness. Fasting serum leptin concentration was 6.9 +/- 0.3 ng.ml-1 in males (N = 333) and 15.2 +/- 1.3 ng.ml-1 in females (N = 63). Interestingly, total fat mass did not differ between groups (males 20.5 +/- 0.5 kg; females 20.4 +/- 1.5 kg), suggesting that females have higher leptin levels per unit fat mass. In a multiple regression model, fat mass was the best predictor of serum leptin concentration in males, accounting for 51% of the variance in leptin concentration. In females, percentage body fat was the best predictor of leptin, accounting for 49% of the variance. In both groups, the relationship between leptin and adiposity remained significant after adjusting for age, maximal treadmill time, waist circumference, and fasting insulin concentration. These observations support previous conclusions that circulating leptin is primarily a function of adiposity and demonstrate for the first time that this relationship is independent of fat distribution or cardiorespiratory fitness. The data also suggest that there is a gender dichotomy in the relationship between leptin and body fat mass in humans. Topics: Adult; Aged; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Fasting; Female; Humans; Insulin; Leptin; Male; Middle Aged; Proteins; Sex Characteristics | 1996 |
Serum leptin levels in women with anorexia nervosa.
Leptin is a protein encoded by the ob gene that is expressed in adipocytes and regulates eating behavior via central neuroendocrine mechanisms. Serum leptin levels have been shown to correlate with weight and percent body fat in normal and obese individuals; however, it is not known whether the regulation of leptin is normal below a critical threshold of body fat in chronic undernutrition. We investigated serum leptin levels in 22 women, aged 23 +/- 4 yr, with anorexia nervosa. Duration of disease, weight, BMI, percent body fat, and serum leptin levels were determined for each patient. Nutritional status was assessed further by caloric intake and measurement of insulin and insulin-like growth factor I (IGF-I) levels. Twenty-three healthy women, aged 23 +/- 4 yr, taking no medications, with normal menstrual function and body mass index (BMI) between 20-26 kg/m2 (mean, 23.7 +/- 1.7 kg/m2), served as a control population for comparison of leptin levels. Subjects with anorexia nervosa were low weight (BMI, 16.3 +/- 1.6 kg/m2; normal, 20-26 kg/m2) and exhibited a striking reduction in percent body fat (7 +/- 2%; normal, 20-30%). The mean serum leptin level was significantly decreased in subjects with anorexia nervosa compared with that in age- and sex-matched controls of normal body weight (5.6 +/- 3.7 vs. 19.1 +/- 8.1 ng/mL; P < 0.0001). Serum leptin levels were correlated highly with weight, as expressed either BMI (r = 0.66; P = 0.002) or percent ideal body weight (r = 0.68; P = 0.0005), body fat (r = 0.70; P = 0.0003), and IGF-I (r = 0.64; P = 0.001), but not with caloric intake or serum levels of estradiol or insulin in subjects with anorexia nervosa. The correlation between leptin and body fat was linear, with progressively lower, but detectable, leptin levels measured even in patients with less than 5% body fat, but was not significant when the effects of weight were taken into account. In contrast, the correlation between leptin and IGF-I remained significant when the effects of weight, body fat, and caloric intake were taken into account. In normal controls, leptin correlated with BMI (r = 0.55; P = 0.007) and IGF-I (r = 0.44; P < 0.05), but not with fat mass. These data demonstrate that serum leptin levels are reduced in association with low weight and percent body fat in subjects with anorexia nervosa compared to normal controls. Leptin levels correlate highly with weight, percent body fat, and IGF-I in subjects with anorexia nervosa, suggesting tha Topics: Adipose Tissue; Adolescent; Adult; Anorexia Nervosa; Body Mass Index; Body Weight; Case-Control Studies; Energy Intake; Female; Humans; Insulin-Like Growth Factor I; Leptin; Proteins | 1996 |
Serum leptin levels are reduced in response to exercise training, but not hormone replacement therapy, in older women.
The aim of this study was to evaluate the effects of exercise training and hormone replacement therapy (HRT) on serum leptin levels in older women. Previously sedentary, healthy women, aged 60-72 yr, were assigned to control (n = 16), exercise (n = 17), HRT (n = 15), or exercise + HRT (n = 13) groups. Exercise training consisted of a 2-month flexibility-exercise program followed by a 9-month exercise program that included walking, jogging, and stair climbing. HRT consisted of 11 months of continuous conjugated estrogens (0.625 mg/day) and medroxyprogesterone acetate (5 mg/day) for 13 days every third month. Body composition was assessed by dual-energy x-ray absorptiometry, and serum insulin levels were measured in the fasted state and in response to a glucose challenge. Leptin levels were reduced by 23 +/- 25% and 22 +/- 27% (both P < 0.01) in response to exercise and exercise + HRT, respectively. There was no effect of HRT on leptin. Fat mass was the strongest predictor of serum leptin concentration, both before (r = 0.81; P < 0.001) and after (r = 0.85; P < 0.001) the study period, and the change in fat mass in the exercisers was significantly correlated with the change in leptin (r = 0.55; P < 0.01). There did not seem to be an effect of exercise, independent of the reduction in fat mass, on leptin. Insulin levels were significantly correlated with leptin levels, but this was not independent of the association with adiposity. The curvilinear relationship between leptin level and fat mass and the finding that the ratio of leptin mass to fat mass decreased after weight loss suggest that fat cell size is an important determinant of circulating leptin levels. Topics: Adipose Tissue; Aged; Body Weight; Cell Size; Estrogen Replacement Therapy; Exercise; Female; Humans; Insulin; Leptin; Middle Aged; Obesity; Physical Education and Training; Proteins | 1996 |
Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y.
The obesity syndrome of ob/ob mice results from lack of leptin, a hormone released by fat cells that acts in the brain to suppress feeding and stimulate metabolism. Neuropeptide Y (NPY) is a neuromodulator implicated in the control of energy balance and is overproduced in the hypothalamus of ob/ob mice. To determine the role of NPY in the response to leptin deficiency, ob/ob mice deficient for NPY were generated. In the absence of NPY, ob/ob mice are less obese because of reduced food intake and increased energy expenditure, and are less severely affected by diabetes, sterility, and somatotropic defects. These results suggest that NPY is a central effector of leptin deficiency. Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Body Height; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Eating; Energy Metabolism; Female; Fertility; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Mutant Strains; Mice, Obese; Neuropeptide Y; Obesity; Oxygen Consumption; Proteins; RNA, Messenger | 1996 |
Leptin inhibits prehibernation hyperphagia and reduces body weight in arctic ground squirrels.
The ob gene product leptin is thought to play a physiological role in the fine tuning of a homeostatic mechanism regulating satiety and adiposity. Mouse recombinant leptin was administered to seasonally hyperphagic arctic ground squirrels as a first step in demonstrating the evolutionary conservation of leptin function and the potential involvement of leptin in the seasonal regulation of adiposity in hibernators. Continuous infusion of leptin for 3 wk via miniosmotic pumps resulted in a reduction in food intake and body weight in a manner consistent with its proposed role as a satiety hormone. During the recovery period after leptin administration, squirrels that had received leptin became hyperphagic relative to controls. Percent body fat was estimated at weekly intervals by measuring total body electrical conductivity and decreased after 3 wk of leptin administration. Our observations support the role of leptin as a regulatory hormone involved in the control of satiety, adiposity, and possibly energy expenditure in hibernating mammals. Topics: Adipose Tissue; Animals; Arctic Regions; Body Composition; Body Weight; Hibernation; Hyperphagia; Leptin; Mice; Proteins; Recombinant Proteins; Sciuridae | 1996 |
Intraventricular leptin reduces food intake and body weight of lean rats but not obese Zucker rats.
The protein encoded by the obese (ob) gene, leptin, is secreted from adipose tissue and is proposed to act in the brain as an important regulator of food intake and body weight. To investigate the direct effects of leptin within the CNS, we injected 3.5 microg of either mouse or human leptin into the third ventricle (ICV) of lean Long-Evans rats or obese (fa/fa) Zucker rats, in which obesity results from a mutation in the leptin receptor gene. ICV administration of leptin reduced 4-h food intake in both deprived and non-deprived lean rats. In addition, repeated ICV administration produced a long-lasting reduction in body weight while peripheral administration of the same dose had no effect. ICV administration of the same dose of leptin into the third ventricle of obese Zucker rats did not reduce food intake. These results are consistent with the hypothesis that leptin has direct actions in the CNS as an afferent signal related to the state of energy stores in adipose tissue. Furthermore, insensitivity to these central effects of leptin may be an important determinant of obesity. Topics: Animals; Body Weight; Eating; Humans; Injections, Intraventricular; Leptin; Male; Mice; Obesity; Proteins; Rats; Rats, Zucker | 1996 |
Plasma leptin in depressed patients and healthy controls.
Leptin is known to regulate food intake and energy expenditure. Since loss of appetite and bodyweight are important signs and symptoms of major depression we studied leptin plasma concentrations in both depressed patients (n = 24) suffering from loss of appetite and a healthy control group (n = 33). To rule out the possibility of inferences with other endocrine parameters known to be changed in depression or suspected to be related to leptin, we also studied cortisol, insulin, growth hormone (GH) and GH-binding protein (GHBP). We found that leptin plasma concentrations did not differ between depressed patients and healthy controls. However, leptin was positively associated with female gender, body mass index (BMI) and morning insulin. 24-hour mean cortisol was not related to leptin. Also, GH and GHBP were not related to leptin when controlled for BMI in an ANCOVA model. We conclude that leptin plasma concentrations are unchanged in depression and that there is no evidence for leptin playing a major role in loss of appetite and body weight in depressed patients. Topics: Adult; Aged; Appetite; Body Mass Index; Body Weight; Depression; Energy Metabolism; Female; Humans; Hydrocortisone; Insulin; Leptin; Male; Middle Aged; Proteins; Reference Values; Sex Characteristics | 1996 |
Circulating TNF-alpha and leptin levels in offspring of NIDDM patients do not correlate to individual insulin sensitivity.
Obesity plays a central role in the development of skeletal muscle insulin resistance. The molecular mechanism causing skeletal muscle insulin resistance in obese people is still poorly understood. It has been speculated that circulating factors derived from adipose tissue impair insulin signalling in the skeletal muscle cell. TNF-alpha and leptin, which are overproduced in fat tissue of obese insulin resistant animal models and in obese humans, might mediate such an inhibitory effect on insulin signalling in skeletal muscle. The aim of the present study was to evaluate whether circulating TNF-alpha and leptin correlates to the individual skeletal muscle insulin sensitivity in individuals with different degrees of obesity and insulin resistance. We measured circulating TNF-alpha and leptin values in non diabetic offsprings of NIDDM patients. 36 German and 47 Finnish subjects participated in the study. The GDR of each participant was determined by the euglycemic hyperinsulinemic clamp technique, a range between 1.37 to 14.01 mg/kg LBM x min was observed. Percent of desirable body weight (PDW) covered also a wide range (87.58% to 197.06%). Although linear regression analysis suggested a dependence between TNF-alpha and GDR (Germany group: r = -0.37, p < 0.05, Finnish group: r = -0.32, p < 0.05) and a dependence between TNF and PDW (German group: r = 0.46, p < 0.05, Finnish group: r = 0.38, p < 0.05), in multiple linear regression analysis only the correlation with PDW was significant. Leptin levels were measured from 29 German and 36 Finnish subjects and a strong association was found between leptin and PDW (German group: r = 0.55, p < 0.05, Finnish group: r = 0.73, p < 0.05). In contrast, leptin levels did not correlate with GDR and TNF-alpha. In summary, even though, in a few insulin resistant subjects, higher circulating TNF-alpha or leptin levels with the individual insulin sensitivity can be demonstrated, the data suggest that the circulating pool of TNF-alpha and leptin in blood is unlikely to be a major contributing factor for obesity induced insulin resistance in the vast majority of individuals at high risk to develop NIDDM. Topics: Adult; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Family; Female; Finland; Germany; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Proteins; Regression Analysis; Tumor Necrosis Factor-alpha | 1996 |
Augmented expression of the obese gene in the adipose tissue from rats fed high-fat diet.
Expression of the obese (ob) gene is augmented in the adipose tissue in several rodent models of genetic obesity. In the present study, we examined the ob gene expression in a rodent model of acquired obesity obtained by pure overfeeding of normal rats. Male Sprague-Dawley rats at 8 weeks of age were fed standard diet or high-fat diet. Rats fed high-fat diet developed moderate degree of obesity, hyperglycemia, and hyperlipidemia as compared with rats fed standard diet. Northern blot analysis revealed that the ob gene is expressed abundantly in the adipose tissue obtained from the epididymal, mesenteric, subcutaneous, retroperitoneal, and interscapular fat pads in rats fed standard diet. Expression of the ob gene was augmented in all the adipose tissue examined in rats fed high-fat diet. The present study demonstrates that the ob gene expression is augmented in the adipose tissue in diet-induced obesity, thereby suggesting the pathophysiologic roles of the ob gene in acquired obesity. Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Dietary Fats; Gene Expression; Hyperglycemia; Hyperlipidemias; Leptin; Male; Obesity; Organ Size; Protein Biosynthesis; Proteins; Rats; Rats, Sprague-Dawley | 1995 |
Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action.
The regulation of body weight and composition involves input from genes and the environment, demonstrated, for example, by the variable susceptibility of inbred strains of mice to obesity when offered a high-fat diet. The identification of the gene responsible for obesity in the ob/ob mouse provides a new approach to defining links between diet and genetics in the regulation of body weight. The ob gene protein product, leptin, is an adipocyte-derived circulating protein. Administration of recombinant leptin reduces food intake and increases energy expenditure in ob/ob mice, suggesting that it signals to the brain the magnitude of fat stores. Information on the regulation of this protein is limited. In several rodent models of obesity including db/db, fa/fa, yellow (Ay/a) VMH-lesioned, and those induced by gold thioglucose, monosodium glutamate, and transgenic ablation of brown adipose tissue, leptin mRNA expression and the level of circulating leptin are increased, suggesting resistance to one or more of its actions. We have assessed the impact of increased dietary fat on circulating leptin levels in normal FVB mice and FVB mice with transgene-induced ablation of brown adipose tissue. We find that high-fat diet evokes a sustained increase in circulating leptin in both normal and transgenic mice, with leptin levels accurately reflecting the amount of body lipid across a broad range of body fat. However, despite increased leptin levels, animals fed a high-fat diet became obese without decreasing their caloric intake, suggesting that a high content of dietary fat changes the 'set point' for body weight, at least in part by limiting the action of leptin. Topics: Amino Acid Sequence; Animals; Body Weight; Dietary Fats; Female; Leptin; Lipid Metabolism; Male; Mice; Mice, Transgenic; Molecular Sequence Data; Obesity; Proteins | 1995 |
Diet- and diabetes-induced changes of ob gene expression in rat adipose tissue.
ob gene regulation is as yet unknown. We first examined whether the ob gene is under physiological control by the nutritional state. Fasting produced a sharp (95%) decrease of ob mRNA in epididymal and inguinal fat pads from 24 h onward. Refeeding rapidly (3-6 h) re-induced ob gene expression and corrected it within 24 h. Similar changes in fatty acid synthase (FAS) and GLUT4 mRNAs were observed, whereas phosphoenolpyruvate carboxykinase (PEPCK) mRNA showed an opposite evolution. We next examined the potential role of insulin. In adipose tissue of streptozotocin-diabetic rats, ob mRNA levels were decreased by 80%. Insulin treatment (4 days) only marginally increased ob mRNA, but restored euglycemia and overcorrected FAS, GLUT4 and PEPCK expression. In conclusion, we provide evidence for a physiological regulation of ob gene by variations in the nutritional state. We also show that ob expression is impaired in streptozotocin-diabetic rats and only slightly restored by insulin treatment, which suggests that ob gene is not or only minimally regulated by the hormone. Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus, Experimental; Fasting; Food; Gene Expression Regulation; Glucose Transporter Type 4; Insulin; Leptin; Male; Monosaccharide Transport Proteins; Muscle Proteins; Proteins; Rats; Rats, Wistar; RNA, Messenger | 1995 |
Recombinant ob protein reduces feeding and body weight in the ob/ob mouse.
To determine whether the product of the recently cloned ob gene functions as an adipose-related satiety factor, recombinant murine ob protein was administered intraperitoneally to ob/ob mice. Monomeric ob protein given as single morning injections to groups of three animals at seven doses ranging from 5 to 100 micrograms reduced 24-h chow consumption in a dose-dependent manner from values of 81 +/- 6.8% of control (10-micrograms dose, P = 0.04) to 29 +/- 7.7% of control (100-micrograms dose, P < 0.0001). Daily injections of 80 micrograms of ob protein into six ob/ob mice for 2 wk led to an 11 +/- 1.6% decrease in body weight (P = 0.0009) and suppressed feeding to 26 +/- 4.9% of baseline (P < 0.0001), with significant reduction of serum insulin and glucose levels. The effect of recombinant ob protein on feeding was not augmented by cofactors secreted by adipose tissue, nor did exposure of adipose tissue to ob protein affect intracellular ob mRNA levels. Posttranslational modification of ob protein was not required for activity; however, addition of a hexahistidine tag to the amino terminus of the mature ob protein resulted in prolonged suppression of feeding after injection into ob/ob mice. These results demonstrate a direct effect of the ob protein to suppress feeding in the ob/ob mouse and suggest that this molecule plays a critical role in regulating total body fat content. Topics: Adipose Tissue; Animals; Body Weight; Cells, Cultured; Cricetinae; Eating; Leptin; Male; Mice; Mice, Obese; Obesity; Proteins; Rabbits; Rats; Recombinant Proteins | 1995 |
The role of neuropeptide Y in the antiobesity action of the obese gene product.
Recently Zhang et al. cloned a gene that is expressed only in adipose tissue of the mouse. The obese phenotype of the ob/ob mouse is linked to a mutation in the obese gene that results in expression of a truncated inactive protein. Human and rat homologues for this gene are known. Previous experiments predict such a hormone to have a hypothalamic target. Hypothalamic neuropeptide Y stimulates food intake, decreases thermogenesis, and increases plasma insulin and corticosterone levels making it a potential target. Here we express the obese protein in Escherichia coli and find that it suppresses food intake and decreases body weight dramatically when administered to normal and ob/ob mice but not db/db (diabetic) mice, which are thought to lack the appropriate receptor. High-affinity binding was detected in the rat hypothalamus. One mechanism by which this protein regulated food intake and metabolism was inhibition of neuropeptide-Y synthesis and release. Topics: Animals; Body Weight; Cell Membrane; Diabetes Mellitus, Experimental; Eating; Escherichia coli; Humans; Hypothalamus; In Vitro Techniques; Leptin; Mice; Neuropeptide Y; Obesity; Proteins; Rats; Recombinant Proteins | 1995 |
Advances in the understanding of the molecular basis of obesity.
Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Insulin Resistance; Leptin; Mice; Mice, Obese; Mutation; Obesity; Polymorphism, Genetic; Proteins; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Satiation | 1995 |
[Reducing weight with leptin].
Topics: Animals; Appetite Regulation; Body Weight; Cloning, Molecular; Leptin; Mice; Mice, Obese; Mutation; Proteins; Species Specificity | 1995 |